Retrospective Drug Use Criteria Handbook

Last Updated

C-1. Introduction

The Texas Drug Utilization Review (DUR) Board evaluates criteria used in retrospective and prospective drug utilization reviews each quarter for Medicaid. HHSC bases the criteria evaluations on drug use information available on the compendia and peer-reviewed medical literature. Criteria and standards are periodically revised to ensure they reflect the current compendia and prescribing recommendations.

HHSC may revise the criteria for individual medications or drug classes determined by the DUR Board and VDP staff based on safety issues or appropriate use. All criteria contain the following categories:

  • Dosage/Maximum Dosage
  • Duration of Therapy
  • Duplicative Therapy
  • Drug-Drug Interactions (significant)

Staff develops new retrospective criteria when the DUR Board deems it necessary, based on therapeutic and clinical materials presented at the DUR board. The information is for the convenience of the public, and HHSC is not responsible for any errors in transmission or any errors or omissions in the content. Staff with the Drug Information Service, UT Health San Antonio, and the College of Pharmacy at the University of Texas at Austin review and update the criteria on behalf of HHSC.

C-2. Drug Use Compendia

Last Updated

The resources identified in the compendia provide comprehensive, organized data concerning FDA-approved medications and biologicals. The list includes pharmacology, dosages, recommended use in specific disease states, adverse reactions, and drug interactions.

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: June 8, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at:  http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed June 8, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; Accessed June 8, 2021.
  4. AHFS Drug Information 2021. Jackson, WY: Teton Data Systems, 2021. Electronic Medical Library. Available at:  http://online.statref.com.libproxy.uthscsa.edu/. Accessed June 8, 2021.
  5. Lexi-Drugs. Lexicomp Online [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021. Available at:  https://online-lexi-com.ezproxy.lib.utexas.edu/lco/action/home. Accessed June 8, 2021.
  6. DiPiro JT, Yee GC, Posey LM, et al.  Pharmacotherapy: a pathophysiologic approach. 11th ed. New York, McGraw-Hill, 2020. Access Pharmacy Web site. Available at:  http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/content.aspx?bookid=1861&sectionid=146065193. Accessed June 8, 2021.
  7. Alldredge BK, Corelli RL, Ernst ME, et al., eds. Koda-Kimble and Young’s applied therapeutics: the clinical use of drugs. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2013.
  8. Chisholm-Burns MA, Schwinghammer TL, Malone PM, et al., eds. Pharmacotherapy: principles and practice. 5th ed. New York, McGraw-Hill, 2019. Access Pharmacy Web site. Available at: https://ppp-mhmedical-com.ezproxy.lib.utexas.edu/book.aspx?bookid=2440. Accessed June 10, 2021.
  9. Post TW, ed. UpToDate. Waltham, MA: pToDate Inc. https://www.uptodate.com. Accessed June 8, 2021.  
  10. Hughes HK, Kahl LK, eds. The Harriet Lane handbook. 22nd ed. Philadelphia, PA: Elsevier; 2021.  Available at: https://www-clinicalkey-com.ezproxy.lib.utexas.edu. Accessed June 10, 2021.
  11. Pediatric and Neonatal Lexi-Drugs. Lexicomp Online [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021. Available at: https://online-lexi-com.ezproxy.lib.utexas.edu/lco/action/home. Accessed June 8, 2021.
  12. National Institutes of Health. National Library of Medicine. DailyMed Drug Database. Accessed June 25, 2021.
  13. StatPearls [Internet]. StatPearls Publishing: 2021. Accessed June 25, 2021.
  14. Manufacturer websites and package inserts.
  15. Various practice guidelines.

Acetylcholinesterase Inhibitors

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • July 23, 2021; May 24, 2019; May 2017; June 2015; October 2013; December 2011; January 2010
  • Initially developed
    • April 2006

1.1. Adults

Alzheimer’s disease is associated with significant losses in cholinergic neurons and decreased concentrations of acetylcholine, a neurotransmitter significantly involved in learning and memory processes. Acetylcholinesterase inhibitors (ACIs) exert pharmacologic effects by increasing availability of intrasynaptic acetylcholine in the presence of intact cholinergic neurons. All available ACIs are FDA-approved in adults for the management of mild to moderate Alzheimer’s dementia, while donepezil is also FDA-approved for management of severe Alzheimer’s disease. Additionally, rivastigmine (Exelon®) is FDA-approved for use in mild-to-moderate dementia associated with Parkinson’s disease.

A combination product containing donepezil and memantine extended-release (Namzaric®) is also FDA-approved for use in patients with moderate to severe Alzheimer’s dementia stabilized on donepezil and memantine. Memantine, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist, exerts pharmacologic effects by blocking glutamate activity, the key excitatory neurotransmitter in the central nervous system. Glutamate is released into synapses when certain neurons die and activates NMDA receptors, causing over excitation, an influx of calcium ions and, ultimately, death of downstream neurons. NMDA receptor activation is thought to be one of the main causes of neurodegeneration in various types of dementia, including Alzheimer’s-associated dementia. ACI monotherapy and combination therapy recommended dosages are summarized in Table 1 and Table 2, respectively. Dosages exceeding these recommendations will be reviewed.

Table 1. Recommended Adult Dosages for ACIs: Monotherapy

Treatment Indication Drug Name Dosage Form and Strength Maximum Recommended Dosage
mild to moderate Alzheimer’s  donepezil (Aricept®, generics) tablets (5 mg, 10 mg, 23 mg) 10 mg/day, as a single dose
    orally disintegrating tablets (5 mg, 10 mg) 10 mg/day, as a single dose
moderate to severe Alzheimer’s     23 mg/day, as a single dose
mild to moderate Alzheimer’s galantamine (Razadyne®, Razadyne® ER, generics)

immediate-release tablets (4 mg, 8 mg, 12 mg)

oral solution (4 mg/ml)

24 mg/day, in 2 divided doses
mild to moderate Alzheimer’s   extended-release capsules (8 mg, 16 mg, 24 mg) 24 mg/day once daily
mild/moderate Alzheimer’s rivastigmine (Exelon®, generics) immediate-release capsules (1.5 mg, 3 mg, 4.5 mg, 6 mg) 12 mg/day, in 2 divided doses
Parkinson’s disease dementia     12 mg/day, in 2 divided doses
mild/moderate Alzheimer’s   transdermal (extended-release) patch (4.6 mg/24 h, 9.5 mg/24 h, 13.3 mg/24 h) 13.3 mg/24 h
Parkinson’s disease dementia      13.3 mg/24 h

Table 2: Recommended Adult Dosages for ACIs: Combination Therapy

Treatment Indication Drug Name Dosage Form and Strength Maximum Recommended Dosage
moderate to severe Alzheimer’s dementia in patients stabilized on donepezil alone or memantine and donepezil memantine extended-release/donepezil (Namzaric®) capsules (7 mg/10 mg, 14 mg/10 mg, 21 mg/10 mg, 28 mg/10 mg) 28 mg/10 mg once daily

Although not FDA-approved, ACIs have also been evaluated for use in vascular dementia, dementia with Lewy bodies, post stroke aphasia, and memory improvement in multiple sclerosis patients.

1.1.1. Renal Impairment

Patients prescribed galantamine with moderate renal impairment [creatinine clearance (CrCl) 9-59 ml/min] should have doses titrated cautiously; dosages should not exceed 16 mg daily. Galantamine is not recommended for use in patients with severe renal impairment (CrCl less than 9 ml/min).

Patients with severe renal impairment (CrCl 5-29 ml/min) stabilized on memantine.

5 mg twice daily immediate-release or 14 mg daily extended-release and donepezil.

10 mg daily or donepezil 10 mg once daily without memantine may utilize memantine/donepezil combination therapy in doses not exceeding 14 mg/10 mg daily.

1.2. Pediatrics

ACIs and memantine/donepezil combination therapy are not recommended for use in children, as adequate, well-controlled clinical trials have not documented safety and efficacy of these agents for any disease state in the pediatric population.

2. Duration of Therapy

ACIs do not alter the long-term progressive decline of Alzheimer’s disease, but have been shown to delay time to institutionalization, which may be cost-effective. ACIs may be prescribed to stabilize dementia in Alzheimer’s patients, as determined by periodic assessment of functional and cognitive ability. ACIs should be discontinued when dementia becomes unresponsive to therapy and progressively severe, as the efficacy of these agents diminishes due to loss of intact cholinergic neurons.

3. Duplicative Therapy

Combined use of two or more ACIs does not provide enhanced therapeutic benefit and may result in additive adverse effects. Concurrent administration of two or more ACIs is not recommended and will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for ACIs are summarized in Table 3. Only those drug-drug interactions classified as clinical significance level 1 or those considered life threatening which have not yet been classified will be reviewed.

Table 3: Drug-Drug Interactions for ACIs

Target Drug Interacting Drug Interaction Recommendations Clinical Significance
ACIs anticholinergics potential for reduced cholinergic activity with centrally acting anticholinergics; may manifest as reduced activities of daily living but not cognitive function; peripherally acting anticholinergics less likely to attenuate ACI therapeutic effects

monitor for diminished cholinergic effects; choose agents with less centrally acting anticholinergic activity

moderate (DrugReax) 3 - moderate (CP)
ACIs cholinergic agents and other cholinesterase inhibitors enhanced cholinergic/ adverse effects avoid combination, if possible; if combination needed, monitor for enhanced cholinergic effects; may adjust doses to achieve tolerable clinical effects moderate (DrugReax) 2 - major (CP)
ACIs drugs that lower seizure threshold (e.g., bupropion) concurrent use may increase seizure risk as seizures observed with ACIs use cautiously together; begin with low ACI doses and titrate slowly major (DrugReax)
ACIs NSAIDs potential for additive gastrointestinal effects monitor for gastrointestinal intolerance and/or bleeding 3 - moderate (CP)
ACIs beta blockers increased risk of bradycardia when prescribed concurrently; ACIs may increase vagal tone, resulting in bradycardia, hypotension, and syncope monitor blood pressure, heart rate during therapy 3 - moderate (CP)
donepezil QT interval-prolonging medications adjunctive use may increase risk of QT interval prolongation and torsades de pointes as donepezil has increased risk of QT interval prolongation and torsades de pointes avoid combined use; if used together, monitor patients for efficacy and cardiovascular adverse outcomes contraindicated (DrugReax) 1 - severe (CP)
donepezil, galantamine CYP3A4 and CYP2D6 inducers potential for reduced donepezil serum concentrations and decreased efficacy monitor for reduced donepezil efficacy 3 - moderate (CP)
donepezil, galantamine CYP3A4 and CYP2D6 inhibitors potential for increased donepezil and galantamine serum concentrations monitor for increased cholinergic effects

major, moderate (DrugReax) galantamine: 2 - major; donepezil, galantamine: 3 - moderate (CP)

donepezil/ memantine alkalinizing agents (e.g., select carbonic anhydrase inhibitors, sodium bicarbonate) memantine clearance reduced by about 80% in alkaline conditions (pH > 8); adjunctive administration with alkalinizing agents may decrease memantine elimination and increase memantine serum levels and potential for increased pharmacologic/ adverse effects administer drug combination cautiously together; monitor patients for increased pharmacologic/ adverse effects moderate (DrugReax) 3 - moderate (CP)
donepezil/ memantine other drugs excreted by renal tubular secretion (e.g., amiloride, cimetidine, dofetilide, nicotine, quinidine, ranitidine) memantine eliminated by renal tubular cationic transport; combined administration may result in altered serum levels of both memantine and other drugs excreted by renal tubular secretion due to competition for transport system; elevated dofetilide levels may increase potential for arrhythmias, including torsades de pointes monitor patient responses, observe for adverse effects or loss of efficacy, and adjust doses as necessary moderate (DrugReax) dofetilide, procainamide, quinidine: 2-major; all other drugs: 3-moderate (CP)
rivastigmine metoclopramide combined use may increase risk of extrapyramidal effects as both agents associated with extrapyramidal signs/ symptoms avoid concurrent use; monitor closely for extrapyramidal effects if combined therapy necessary     contraindicated (DrugReax) 2 - major (CP)

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: June 8, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed June 8, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; June 8, 2021.
  4. AHFS Drug Information 2021. Jackson, WY: Teton Data Systems. Stat!Ref Electronic Medical Library. Available at: http://online-statref-com.libproxy.uthscsa.edu/. Accessed June 8, 2021. 
  5. Rivastigmine transdermal system (Exelon® Patch) package insert.  Novartis, December 2020.
  6. Galantamine extended-release capsules, tablets and oral solution (Razadyne® ER, Razadyne®) package insert. Janssen Pharmaceuticals, September 2020.
  7. Donepezil tablets, orally disintegrating tablets (Aricept®, Aricept® ODT) Package Insert. Eisai Inc., December 2018.
  8. Memantine extended-release/donepezil capsules (Namzaric®) package insert. Allergan USA, Inc., January 2019.
  9. Farlow MR, Cummings JL.  Effective pharmacologic management of Alzheimer’s disease. Am J Med. 2007;120:388-97.
  10. Blennow K, deLeon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006;368:387-403.
  11. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006, Issue 1. Art. No.: CD005593. DOI: 10.1002/14651858.CD005593.
  12. Press D, Alexander M. Cholinesterase inhibitors in the treatment of dementia. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on June 8, 2021.)
  13. Mayeux R. Clinical practice. Early Alzheimer's disease. N Engl J Med.  2010;362(23):2194-201.
  14. Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148(5):379-97.
  15. Deardorff WJ, Grossberg GT. A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer's disease. Drug Des Devel Ther. 2016;10:3267-79.
  16. Szeto JY, Lewis SJ. Current treatment options for Alzheimer's disease and Parkinson's disease dementia. Curr Neuropharmacol. 2016;14(4):326-38.
  17. Ehret MJ, Chamberlin KW. Current practices in the treatment of Alzheimer disease: where is the evidence after the phase III trials? Clin Ther. 2015;37(8):1604-16.
  18. Kumar A, Singh A, Ekavali. A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep. 2015;67(2):195-203.
  19. Howard E, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med. 2012;366(10):893-903.
  20. Epperly T, Dunay MA, Boice JL.  Alzheimer disease: pharmacologic and nonpharmacologic therapies for cognitive and functional symptoms. Am Fam Physician. 2017;95(12):771-8. 
  21. Grossberg GT, Tong G, Burke AD, Tariot PN. Present Algorithms and Future Treatments for Alzheimer's Disease. J Alzheimers Dis. 2019;67(4):1157-1171.
     

Aerosolized Agents - metered-dose inhalers: anti-cholinergic drugs

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • Revised April 23, 2021; March 2019; March 2017; November 2015; March 2014; August 2012; June 2012; October 2010; January 2008; January 2003; January 2002; January 2001; March 2000; January 2000; February 1999; February 1998; February 1997; August 1995.  
  • Initially developed
    • January 1995

1.1. Adults

Ipratropium (Atrovent®), a short-acting, inhalational anticholinergic agent, is FDA-approved to manage bronchospasm associated with chronic bronchitis and emphysema, collectively known as chronic obstructive pulmonary disease (COPD). Ipratropium is considered a second-line agent in the treatment of asthma as the bronchodilatory effects seen with ipratropium are less than those seen with beta-adrenergic drugs. While not FDA approved, the Expert Panel 3 guidelines from the National Heart Lung and Blood Institute document benefit when multiple ipratropium doses are administered adjunctively with beta2-agonists in the emergency department to manage more severe acute asthma exacerbations, and the Global Initiative for Asthma (GINA) guidelines state that ipratropium may be considered an alternative bronchodilator in patients who experience adverse effects to short-acting beta2-agonists (e.g., tachycardia, arrhythmia, tremor). Additionally, ipratropium may be administered in conjunction with short-acting beta agonists, corticosteroids, or oxygen in patients with acute, life-threatening asthma exacerbations awaiting transfer to an acute care center. The “2020 Focused Updates to the Asthma Management Guidelines” do not address the use of short acting muscarinic antagonist agents. Ipratropium is available as a metered-dose, inhalation aerosol solution and is FDA-approved for use in adult COPD patients receiving an aerosol bronchodilator who continue to have bronchospasm and require a second bronchodilator.

Tiotropium (Spiriva®) is a long-acting, inhalational anticholinergic agent FDA-approved for long-term use in managing bronchospasm associated with COPD and reducing COPD exacerbations, as well as maintenance therapy for asthma. GINA guidelines state that tiotropium is recommended as Step 4 and 5 add-on therapy in adults, adolescents, and children 6 years of age or older with asthma and a history of exacerbations. Tiotropium is available as a dry inhalation powder in capsule form or aerosol solution for oral inhalation. Due to the compound’s extended duration of action, tiotropium is approved for only once daily administration.

Aclidinium (Tudorza Pressair®), is FDA-approved as long-term maintenance therapy for bronchospasm associated with COPD, is available as a breath-actuated dry powder inhaler and is dosed twice daily. Umeclidinium (Incruse Ellipta®), another breath-actuated inhalation powder, is also approved for long-term COPD maintenance treatment.

Ipratropium is also available in combination with albuterol as Combivent Respimat®, which is FDA- approved for use in adult COPD patients receiving an aerosol bronchodilator who continue to have bronchospasm and require a second bronchodilator. This propellant-free product provides a slow-moving mist to supply the active ingredients and has replaced the metered-dose inhaler which used chlorofluorocarbons to deliver medication (i.e., Combivent®). Combivent Respimat® requires only one actuation per dose compared to the older Combivent® product, which required two actuations per dose.

Combination therapy including umeclidinium (inhaled anticholinergic) plus the long-acting beta-2 agonist (LABA), vilanterol, marketed as Anoro Ellipta®, is FDA-approved for use in adults with COPD as maintenance therapy. This product is the first dual therapy bronchodilator available for once daily use. Three additional anticholinergic/LABA combination products, tiotropium/olodaterol (Stiolto Respimat®), glycopyrrolate/formoterol (Bevespi Aerosphere®), and aclidinium bromide/ formoterol (Duaklir Pressair®) are also FDA approved for COPD maintenance therapy.

Triple therapy with fluticasone (inhaled corticosteroid), umeclidinium (inhaled anticholinergic), and vilanterol (inhaled LABA), marketed as Trelegy Ellipta®, is the most recent inhaled anticholinergic combination therapy FDA-approved for use to manage COPD in adults who continue to have bronchospasm while treated with a bronchodilator and require a second bronchodilator. In September of 2020 it was approved for the maintenance treatment of asthma in patients 18 years of age and older.

In March of 2020 Sunovion Pharmaceuticals announced the discontinuation of Utibron Neohaler® (indacaterol/glycopyrrolate) and Seebri Neohaler® (glycopyrrolate). These products are no longer available in the United States as of April 1, 2020.

Recommended doses for anticholinergic MDI monotherapy and combination products are summarized in Tables 1 and 2, respectively. Dosages exceeding the approved recommendations will be reviewed.

Table 1: Maximum Recommended Adult Anticholinergic Metered-Dose Inhaler Daily Dose - Monotherapy

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
chronic obstructive pulmonary disease (COPD) aclidinium (Tudorza Pressair®) dry powder inhaler (400 mcg/actuation) 2 actuations/day (total dose = 800 mcg)
COPD ipratropium bromide HFA (Atrovent HFA®) aerosol (17 mcg/actuation) 12 actuations/day in divided doses (total dose = 204 mcg)
COPD tiotropium (Spiriva HandiHaler®) inhalation capsule (18 mcg/capsule) 2 inhalations of one capsule powder contents once daily (total dose = 18 mcg)
asthma tiotropium (Spiriva Respimat®) inhalation cartridge (1.25 mcg/ actuation) 2 inhalations of 1.25 mcg/actuation once daily (total dose = 2.5 mcg)
COPD   inhalation cartridge (2.5 mcg/ actuation) 2 inhalations of 2.5 mcg/actuation once daily (total dose = 5 mcg)
COPD umeclidinium (Incruse Ellipta®) dry powder inhaler (62.5 mcg/actuation) 1 actuation/day (total dose = 62.5 mcg)

 

Table 2: Maximum Recommended Adult Anticholinergic Metered-Dose Inhaler Daily Dose – Combination Therapy

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
COPD aclidinium bromide/ formoterol fumarate (Duaklir Pressair®) inhalation powder: 400 mcg/ 12 mcg/ inhalation 2 actuations/day (1 actuation twice daily); total dose = 800 mcg/24 mcg/day
asthma fluticasone/ umeclidinium/ vilanterol (Trelegy Ellipta®) inhalation powder: 100 mcg/ 62.5 mcg/ 25 mcg/ inhalation 1 inhalation/day (total dose = 100 mcg/62.5 mcg/ 25 mcg)
COPD     1 inhalation/day (total dose = 100 mcg/62.5 mcg/ 25 mcg)
asthma   inhalation powder: 200 mcg/ 62.5 mcg/ 25 mcg/ inhalation 1 actuation/day; total dose = 200 mcg/62.5 mcg/ 25 mcg/day
COPD glycopyrrolate/ formoterol (Bevespi Aerosphere®) aerosol (9 mcg/4.8 mcg/actuation) 4 actuations/day in two divided doses  (total dose = 36 mcg/19.2 mcg)
COPD ipratropium/ albuterol (Combivent Respimat®) aerosol solution (20 mcg ipratropium/100 mcg albuterol base/actuation) 6 actuations/day in divided doses (no more than 6 inhalations/day) (total dose = 120 mcg ipratropium/600 mcg albuterol base)
COPD tiotropium/ olodaterol (Stiolto Respimat®) aerosol solution (2.5 mcg/2.5 mcg/ actuation) 2 inhalations once daily (total dose = 5 mcg/5 mcg)
COPD umeclidinium/ vilanterol (Anoro Ellipta®) inhalation powder (62.5 mcg/25 mcg/actuation) 1 actuation/day (total dose = 62.5 mcg/25  mcg)

 

1.2. Pediatrics

Tiotropium is FDA-approved for asthma maintenance therapy in pediatric patients 6-17 years of age. Safety and efficacy of inhaled aclidinium, ipratropium, umeclidinium, and glycopyrrolate in children have not been established, as COPD does not usually develop in the pediatric population. Maximum recommended inhaled anticholinergic pediatric dosages are summarized in Table 3. Dosages exceeding these recommendations will be reviewed.

2. Duration of Therapy

Inhalational anticholinergic agents are suitable for chronic administration as side effects are minimal and drug effectiveness is maintained over years of regular, continuous use. Since inhalation anticholinergics are indicated in the management of chronic, lifelong diseases, there is no basis for limiting the duration of therapy. However, days’ supply for each MDI anticholinergic canister is limited based on the number of inhalations per canister as well as the maximum recommended dose per day. Days’ supply for inhalational anticholinergic therapy is summarized in Tables 4 and 5, based on the maximum recommended dose and the number of actuations per canister or number of capsules per blister card listed in Tables 1-3. Excessive use may be identified based on refill frequency. Inappropriate supply of inhaled anticholinergic agents will be monitored by reviewing excessive refills.

Table 4: Days’ Supply for Anticholinergic Metered-Dose Inhaler Products - Monotherapy

Drug Number of Actuations Per Canister Days’ Supply (based on maximum dose per day)+
aclidinium
400 mcg/ actuation
30
60
15
30
ipratropium bromide HFA (12.9 g inhaler) 200 ~16-17
tiotropium inhalation capsules (5 capsules, 30 capsules, 90 capsules)     5 to 90 (based on capsule number prescribed) 5 to 90 (based on number of capsules prescribed)
tiotropium inhalation spray 1.25 mg/actuation 60 30
tiotropium inhalation spray 2.5 mcg/actuation 28
60
14
30
umeclidinium inhalation powder
box of 7 foil blister powder strips
box of 30 foil blister powder strips
7
30
7
30

Legend:

  • + calculated based on canister size/blister package size and maximum dose allowed per day

Table 5: Days’ Supply for Anticholinergic Metered-Dose Inhaler Products – Combination Therapy

Drug Number of Actuations Per Canister Days’ Supply (based on maximum dose per day)+
aclidinium bromide/ formoterol fumarate inhalation
400 mcg/12 mcg/inhalation
60 30
fluticasone furoate/ umeclidinium/ vilanterol inhalation powder~
100 mcg/62.5 mcg/25 mcg/actuation
28 blisters
(one strip contains fluticasone, one strip contains umeclidinium and vilanterol)
60 blisters
(one strip contains fluticasone, one strip contains umeclidinium and vilanterol)

14

30

14

30

fluticasone furoate/ umeclidinium/ vilanterol inhalation powder~
200 mcg/62.5 mcg/25 mcg/actuation
28 blisters
(one strip contains fluticasone, one strip contains umeclidinium and vilanterol)
60 blisters
(one strip contains fluticasone, one strip contains umeclidinium and vilanterol)

14

30

14

30

glycopyrrolate/formoterol aerosol inhalation (10.7 g inhaler)

28

120

7

30

ipratropium/albuterol spray (4 g cartridge) 120 20
tiotropium/olodaterol spray (4 g cartridge) 60 30
umeclidinium/vilanterol inhalation powder~
14 blisters
(one strip contains umeclidinium, one strip contains vilanterol)
60 blisters
(one strip contains umeclidinium, one strip contains vilanterol)

70

30

70

30

Legend:

  • + calculated based on canister size/blister package size and maximum dose allowed per day 
  • ~ not indicated for use in children

3. Duplicative Therapy

Concurrent administration of inhaled anticholinergics has not been evaluated in controlled studies and may not offer additional clinical benefit but may increase anticholinergic adverse effects. Combined administration of multiple inhaled anticholinergics is not recommended and will be reviewed.

Although inhaled anticholinergic systemic absorption is minimal, adjunctive administration with other anticholinergic medications has the potential to amplify anticholinergic pharmacologic and adverse effects. Combined therapy with inhaled anticholinergics and other anticholinergic dosage forms should be considered cautiously.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug interactions considered clinically relevant for inhaled anticholinergics with beta agonists are summarized in Table 6. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 6: Drug-Drug Interactions with Inhaled Combination Anticholinergics

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level
fluticasone/umeclidinium/vilanterol strong CYP3A4 inhibitors (e.g., azole antifungals, erythromycin, clarithromycin, protease inhibitors) potential for increased steroid concentrations with risk for excessive adrenal suppression and Cushing syndrome development concurrent administration not advised; if combined administration necessary, give cautiously; monitor patients for signs/ symptoms of corticosteroid excess fluticasone: major (DrugReax) - 2-major (CP)
ipratropium/albuterol glycopyrrolate/formoterol, tiotropium/olodaterol, umeclidinium/vilanterol QT interval-prolonging medications (e.g., dofetilide, ziprasidone) combined administration of beta2-agonists with drugs known to prolong the QT interval may increase arrhythmia risk administer combination cautiously or avoid combination; monitor closely contraindicated (DrugReax) - 1-severe (CP)
ipratropium/albuterol, umeclidinium/vilanterol, glycopyrrolate/formoterol, tiotropium/olodaterol MAOIs* (including linezolid) concurrent administration of MAOIs with beta2-agonists may increase risk of development of tachycardia, hypomania, or agitation due to potentiation of effects on vascular system administer combination cautiously or within 2 weeks of MAOI discontinuation; observe patients for adverse effects major (DrugReax) - 1-severe (CP)
ipratropium/albuterol, umeclidinium/vilanterol, glycopyrrolate/formoterol, tiotropium/olodaterol     beta blockers concurrent administration may decrease effectiveness of beta-adrenergic blocker or beta2- agonists like albuterol combination not recommended in asthma/COPD patients; if adjunctive therapy necessary, utilize cardioselective beta blocker (e.g., atenolol, bisoprolol) major (DrugReax) - 2-major (CP)
ipratropium/albuterol, umeclidinium/vilanterol, glycopyrrolate/formoterol, tiotropium/olodaterol diuretics potential for worsening of diuretic associated hypokalemia and/or ECG changes with beta-agonist concurrent administration, especially with high beta-agonist doses administer combination cautiously; monitoring potassium levels may be necessary 3-moderate (CP)
steroids quinolones increased potential for serious tendonitis, tendon rupture with concurrent therapy closely monitor patients requiring combination therapy; discontinue quinolone if tendon pain develops 3-moderate (CP)
systemic steroids bupropion potential increased seizure risk due to systemic steroid-induced lowering of seizure threshold utilize only recommended bupropion dosages; initiate bupropion therapy with low doses and titrate slowly when combination therapy warranted; closely monitor patients for seizure development major (DrugReax)
umeclidinium/vilanterol strong CYP3A4 inhibitors (e.g., fluconazole, ketoconazole, ritonavir, nefazodone) adjunctive administration may result in elevated vilanterol serum levels and enhanced pharmacologic and adverse effects, including QT interval prolongation, as vilanterol is a CYP3A4 substrate administer combination cautiously, and closely monitor patients for adverse cardiovascular/QT interval outcomes contraindicated (DrugReax) - 2-major (CP)

Legend:

  • + CP = Clinical Pharmacology
  • *MAOIs = monoamine oxidase inhibitors
  • ^TCAs = tricyclic antidepressant 

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www- micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: March 31, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology- ip.com.ezproxy.lib.utexas.edu/. Accessed March 31, 2021.
  3. American Society of Health-System Pharmacists. 2021. AHFS Drug Information® - 2021st Ed. Bethesda, MD. American Society of Health-System Pharmacists®. ISBN-10: 1-58528-654-0, ISBN-13: 978-1-58528-654-6. ISSN: 8756-6028. STAT!Ref Online Electronic Medical Library. https://online.statref.com/document/cQfe8yqMRNqgSGqm4Qo8Qj. March 31, 2021.
  4. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Full Report 2007. (NIH Publication No. 07-4051). Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed March 31, 2021.
  5. National Heart, Lung, and Blood Institute. 2020 focused updates to the asthma management guidelines: a report from the national asthma education and prevention program coordinating committee expert panel working group. National Institutes of Health. December 2020. Accessed March 24, 2021.
  6. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease. 2021 report. Available at: https://goldcopd.org/2021-gold-reports/. Accessed March 31, 2021.
  7. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2020. Available from: https://ginasthma.org/gina-reports/. Accessed March 24, 2021.
  8. Aclidinium/ formoterol fumarate powder (Duaklir Pressair®) metered dose inhaler package insert. Circassia Pharmaceuticals, Inc., July 2020.
  9. Ipratropium bromide HFA inhalation aerosol (Atrovent® HFA) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., January 2021.
  10. Ipratropium/albuterol inhalation spray (Combivent® Respimat®) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., October 2020.
  11. Tiotropium inhalation powder (Spiriva® HandiHaler®) package insert.
  12. Boehringer Ingelheim Pharmaceuticals, Inc., October 2019.
  13. Tiotropium inhalation spray (Spiriva® Respimat®) package insert.
  14. Boehringer Ingelheim Pharmaceuticals, Inc., August 2020.
  15. Aclidinium inhalation powder (Tudorza® Pressair®) package insert.
  16. AstraZeneca, February 2021.
  17. Umeclidinium/vilanterol inhalation powder (Anoro® Ellipta®) package insert.
  18. GlaxoSmithKline, August 2020.
  19. Umeclidinium inhalation powder (Incruse® Ellipta®) package insert.
  20. GlaxoSmithKline, August 2020.
  21. Tiotropium/olodaterol inhalation spray (Stiolto® Respimat®) package insert.
  22. Boehringer Ingelheim Pharmaceuticals, Inc., October 2020.
  23. Glycopyrrolate/formoterol inhalation aerosol (Bevespi Aerosphere®) package insert. AstraZeneca, November 2020.
  24. Fluticasone/umeclidinium/vilanterol inhalation powder (Trelegy® Ellipta®) package insert. GlaxoSmithKline, September 2020.
  25. Blake KV, Lang JE. Chapter 43. Asthma. (Chapter) In: DiPiro JT, Talbert RL, Yee GC, et al. (eds): Pharmacotherapy: a pathophysiologic approach. 11th edition. New York, McGraw-Hill, 2020. Access Pharmacy Web site. Available at: https://accesspharmacy-mhmedical- com.ezproxy.lib.utexas.edu/content.aspx?bookid=2577&sectionid=228901475. Accessed March 31, 2021.
  26. Bourdet SV, Williams DM. Chapter 44. Chronic obstructive pulmonary disease (Chapter) In: DiPiro JT, Talbert RL, Yee GC, et al. (eds): Pharmacotherapy: a pathophysiologic approach. 11th edition. New York, McGraw-Hill, 2020. Access Pharmacy Website. Available at: https://accesspharmacy-mhmedical- com.ezproxy.lib.utexas.edu/index.aspx. Accessed March 31, 2021.
  27. Barnes PJ. The role of anticholinergics in chronic obstructive pulmonary disease. Am J Med. 2004;117(Suppl12A):24S-32S.
  28. Appleton S, Jones T, Poole P, et al. Ipratropium bromide versus short acting beta-2 agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006;(2):CD001387.
  29. Barr RG, Bourbeau J, Camargo CA, Ram FS. Tiotropium for stable chronic obstructive pulmonary disease: a meta-analysis. Thorax. 2006;61:854-62.
  30. Currie GP, Rossiter C, Miles SA, Lee DK, Dempsey OJ. Effects of tiotropium and other long acting bronchodilators in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2006;19:112-9.
  31. Somand H, Remington TL. Tiotropium: a bronchodilator for chronic obstructive pulmonary disease. Ann Pharmacother. 2005;39:1467-75.
  32. Wilt TJ. Niewoehner D. MacDonald R. Kane RL. Management of stable chronic obstructive pulmonary disease: a systematic review for a clinical practice guideline. Ann Intern Med. 2007;147:639-53.
  33. Barr RG, Bourbeau J, Camargo CA. Tiotropium for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005;(2):CD002876.
  34. Woods JA, Nealy KL, Barrons RW. Aclidinium bromide: an alternative long- acting inhaled anticholinergic in the management of chronic obstructive pulmonary disease. Ann Pharmacother. 2013;47(7-8):1017-28.
  35. Carter NJ. Inhaled glycopyrronium bromide: a review of its use in patients with moderate to severe chronic obstructive pulmonary disease. Drugs. 2013;73(7):741-53.
  36. FDA Drug Shortages. Indacaterol maleate and glycopyrrolate (Utibron Neohaler®) Inhalation Powder. Current and resolved drug shortages and discontinuations reported to FDA. March 10, 2020. Available at: https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredient Details.cfm?AI=Indacterol+Maleate+and+Glycopyrrolate+%28Utibron+Neoha ler%29+Inhalation+Powder&st=d&tab=tabs-2. Accessed March 25, 2021.
  37. FDA Drug Shortages. Glycopyrrolate (Seebri Neohaler®) Inhalation Powder. Current and resolved drug shortages and discontinuations reported to FDA. March 10, 2020. Available at: https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredient Details.cfm?AI=Glycopyrrolate+%28Seebri+Neohaler%29+Inhalation+Powde r&st=d&tab=tabs-2. Accessed March 25, 2021.

Aerosolized Agents - metered-dose inhalers: anti-inflammatory drugs

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • April 23, 2021; March 2019; March 2017; November 2015; March 2014; August 2012; June 2012; August 2010; July 2010; July 2007; February 2003; January 2002; January 2001; March 2000; January 2000; February 1999; March 1998; August 1997; February 1997
  • Initially developed
    • January 1995

1. Dosage

Because asthma is comprised of both inflammatory and bronchoconstrictive components, asthma treatment plans include routine use of inhaled corticosteroids (ICS) to manage inflammatory processes in asthma patients requiring chronic treatment. Higher ICS doses may contribute to a decrease in linear growth velocity in children, but adult height does not appear to be significantly inhibited following ICS use in childhood. All ICS doses may contribute to decreased bone formation in children and bone mineral density in adults. Close monitoring of growth and bone formation markers in children and fracture risk in adults is warranted with long-term ICS use. The lowest effective ICS dose should be utilized for the shortest required time period.

1.1. Adults

Maximum recommended adult orally inhaled doses for available aerosolized corticosteroids as individual agents are summarized in Table 1. Prescribed dosages exceeding these recommendations will be reviewed.

ICS combined with LABAs are FDA-approved for use in adults and children as asthma maintenance therapy: fluticasone propionate/salmeterol metered aerosol (Advair HFA®) is approved for patients 12 years of age and older, mometasone/formoterol inhalation aerosol (Dulera®) is FDA-approved for use as maintenance therapy for asthma in patients 5 years of age and older, and fluticasone propionate/salmeterol inhalation powder (Advair Diskus®) is FDA-approved for use in asthma maintenance in patients 4 years of age and older. A newer fluticasone/salmeterol inhalation powder (AirDuo RespiClick®) that provides additional dosage strengths has been approved for use in asthma patients 12 years and older. Budesonide/formoterol inhalation aerosol (Symbicort®) and Advair Diskus® are FDA-approved for use in adults as COPD maintenance therapy. The newer combination agent, fluticasone/vilanterol (Breo Ellipta®), is indicated for use in adults as maintenance therapy for COPD and maintenance therapy for asthma. Additionally, a triple therapy inhaler containing fluticasone, umeclidinium and vilanterol (Trelegy Ellipta®) has now been approved for COPD and asthma management. Advair Diskus® 250 mcg/50 mcg is the only fluticasone/salmeterol dose approved for use in adult patients with COPD, while budesonide/formoterol (Symbicort®) 160 mcg/4.5 mcg is the only recommended strength for COPD.

The maximum recommended orally inhaled doses for available aerosolized corticosteroids as combination therapy is summarized in Table 2. Prescribed dosages exceeding these recommendations will be reviewed.

Table 1: Maximum Daily Recommended Adult Doses for ICS as Monotherapy in Asthma

Drug Name Dosage Form/Strength Maximum Recommended Dosage
beclomethasone dipropionate HFA (QVAR Redihaler®) inhalation aerosol: 40 mcg/actuation 16 actuations/day in divided doses (8 actuations twice daily); total dose = 640 mcg/day
  inhalation aerosol: 80 mcg/actuation 8 actuations/day in divided doses (4 actuations twice daily); total dose = 640 mcg/day
budesonide (Pulmicort Flexhaler®) inhalation powder: 90 mcg/actuation 16 actuations/day in divided doses (8 actuations twice daily); total dose = 1440 mcg/day
  inhalation powder: 180 mcg/actuation 8 actuations/day in divided doses (4 actuations twice daily); total dose = 1440 mcg/day
ciclesonide (Alvesco®) inhalation aerosol: 80 mcg/actuation prior therapy with bronchodilators alone: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 320 mcg/day
    prior therapy with ICS, oral corticosteroids: 8 (4 actuations twice daily); total dose = 640 mcg/day
  inhalation aerosol: 160 mcg/actuation prior therapy with bronchodilators alone: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 320 mcg/day
    prior therapy with ICS, oral corticosteroids: 160 mcg/actuation: 4 (2 actuations twice daily); total dose = 640 mcg/day
fluticasone furoate (Arnuity Ellipta®) dry powder inhaler: 100 mcg/actuation 1 actuation once daily; total dose = 100 mcg/day*
  dry powder inhaler: 200 mcg/actuation 1 actuation once daily; total dose = 200 mcg/day*
fluticasone propionate HFA (Flovent HFA®) inhalation aerosol: 44 mcg/actuation no previous ICS: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 176 mcg/day
  inhalation aerosol: 110 mcg/actuation

prior therapy with bronchodilators alone, ICS: 16 actuations/day in divided doses (8 actuations twice daily); total dose = 1760 mcg/day

  inhalation aerosol: 220 mcg/actuation prior therapy with bronchodilators alone, ICS: 8 actuations/day in divided doses (4 actuations twice daily); total dose = 1760 mcg/day
    prior therapy with oral corticosteroids: 8 (4 actuations twice daily); total dose = 1760 mcg/day
fluticasone propionate (Flovent Diskus®) inhalation powder: 100 mcg/actuation total dose = 2000 mcg/day
  inhalation powder: 250 mcg/actuation 8 actuations/day in divided doses (4 actuations twice daily); total dose = 2000 mcg/day
fluticasone propionate (ArmonAir Digihaler®) inhalation powder: 55 mcg/actuation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 110 mcg
  inhalation powder: 113 mcg/actuation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 226 mcg
  inhalation powder: 232 mcg/actuation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 464 mcg
mometasone HFA (Asmanex HFA®) inhalation aerosol: 100 mcg/actuation prior therapy with medium-dose ICS: 4 actuations/day (2 actuations twice daily); total dose = 400 mcg/day
  inhalation aerosol: 200 mcg/actuation

prior therapy high-dose ICS, oral corticosteroids: 4 actuations/day (2 actuations twice daily); total dose = 800 mcg/day ^

mometasone (Asmanex Twisthaler®) inhalation powder: 110 mcg/actuation prior therapy with bronchodilators alone, ICS: 4 actuations/day (4 actuations once daily in evening or 2 actuations twice daily); total dose = 440 mcg/day
    prior therapy with oral corticosteroids: 8 actuations/day in divided doses (4 actuations twice daily); total dose = 880 mcg/day
  inhalation powder: 220 mcg/actuation prior therapy with bronchodilators alone, ICS: 2 actuations/day (2 actuations once daily in evening or 1 actuation twice daily); total dose = 440 mcg/day
    prior therapy with oral corticosteroids: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 880 mcg/day

Legend:

  • * initial fluticasone furoate dose in patients not on ICS is 100 mcg once/day; if 100 mcg not effective, dose should be increased to 200 mcg once/day
  • ^ prednisone should be tapered slowly, beginning at least one week after mometasone use

Table 2: Maximum Adult Daily Recommended Doses for ICS as Combination Therapy for Asthma and COPD

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
asthma budesonide/ formoterol (Symbicort®) inhalation aerosol:  80 mcg/4.5 mcg/ actuation 4 actuations/day (2 actuations twice daily); total dose = 320 mcg/18 mcg/day
asthma   inhalation aerosol: 160 mcg/4.5 mcg/ actuation 4 actuations/day (2 actuations twice daily); total dose = 640 mcg/18 mcg/day
chronic obstructive pulmonary disease (COPD)     4 actuations/day (2 actuations twice daily); total dose = 640 mcg/18 mcg/day
asthma fluticasone propionate/salmeterol xinafoate (Advair HFA®) inhalation aerosol: 45 mcg fluticasone/21 mcg salmeterol/actuation 4 actuations/day (2 actuations twice daily); total dose = 180 mcg/84 mcg/day
    inhalation aerosol: 115 mcg fluticasone/21 mcg salmeterol/actuation 4 actuations/day (2 actuations twice daily); total dose = 460 mcg/84 mcg/day
    inhalation aerosol: 230 mcg fluticasone/21 mcg salmeterol/actuation 4 actuations/day (2 actuations twice daily); total dose = 920 mcg/84 mcg/day
asthma fluticasone propionate/salmeterol (Advair Diskus®, Wixela Inhub®) inhalation powder: 100 mcg fluticasone/50 mcg salmeterol/actuation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 200 mcg/100 mcg/day
asthma   inhalation powder: 250 mcg fluticasone/50 mcg salmeterol/ actuation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 500 mcg/100 mcg/day
COPD     2 actuations/day in divided doses (1 actuation twice daily); total dose =500 mcg/100 mcg/day
asthma   inhalation powder: 500 mcg fluticasone/50 mcg salmeterol/ actuation 2 actuations/day in divided doses (1 actuation twice daily);  total dose = 1000 mcg/100 mcg/day
asthma fluticasone propionate/salmeterol (AirDuo RespiClick®) inhalation powder: 55 mcg fluticasone/14 mcg salmeterol/ actuation 2 actuations/day in divided doses (1 actuation twice daily);  total dose = 110 mcg/28 mcg/day
    inhalation powder: 113 mcg fluticasone/14 mcg salmeterol/ actuation 2 actuations/day in divided doses (1 actuation twice daily);  total dose = 226 mcg/28 mcg/day
    inhalation powder: 232 mcg fluticasone/14 mcg salmeterol/ actuation 2 actuations/day in divided doses (1 actuation twice daily);  total dose = 464 mcg/28 mcg/day
asthma fluticasone propionate/salmeterol (AirDuo Digihaler®) inhalation powder: 55 mcg fluticasone/ 14 mcg salmeterol/ inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 110 mcg/28 mcg/day
    inhalation powder: 113 mcg fluticasone/ 14 mcg salmeterol/ inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 226 mcg/28 mcg/day
    inhalation powder: 232 mcg fluticasone/ 14 mcg salmeterol/ inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 464 mcg/28 mcg/day
asthma fluticasone furoate/umeclidinium/vilanterol (Trelegy Ellipta®) inhalation powder: 100 mcg/ 62.5 mcg/ 25 mcg/inhalation 1 actuation/day; total dose = 100 mcg/62.5 mcg/ 25 mcg/day
COPD     1 actuation/day; total dose = 100 mcg/62.5 mcg/ 25 mcg/day
asthma   inhalation powder: 200 mcg/ 62.5 mcg/ 25 mcg/inhalation 1 actuation/day; total dose = 200 mcg/62.5 mcg/ 25 mcg/day 
asthma fluticasone furoate/vilanterol (Breo Ellipta®) inhalation powder: 100 mcg fluticasone/25 mcg vilanterol/actuation 1 actuation/day; total dose = 100 mcg/25 mcg/day
    200 mcg fluticasone/25 mcg vilanterol/actuation 1 actuation/day; total dose = 200 mcg/25 mcg/day
COPD   inhalation powder: 100 mcg fluticasone/25 mcg vilanterol/ actuation 1 actuation/day; total dose = 100 mcg/25 mcg/day
asthma mometasone/formoterol (Dulera®) inhalation aerosol: 100 mcg mometasone/5 mcg formoterol/actuation patients on medium-dose inhaled corticosteroids: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 400 mcg/20 mcg/day
    inhalation aerosol: 200 mcg mometasone/5 mcg formoterol/actuation patients on high-dose inhaled corticosteroids: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 800 mcg/20 mcg/day

Legend:

  • Number of maximum actuations per day based on dose of salmeterol and formoterol, and independent of inhaled corticosteroid dose

1.2. Pediatrics

ICS as individual agents are FDA-approved for use in pediatric asthma management in children as young as 4 years of age. Pediatric therapy initiation differs by age for individual agents and is summarized in Table 3. Prescribed dosages exceeding these recommendations will be reviewed.

Combined therapy with inhaled ICS and long-acting beta2-agonists is only FDA-approved for use in asthma treatment in children greater than or equal to 5 years of age; combined ICS/ long-acting beta2-agonist therapy as inhalation powder is FDA-approved for use in asthma management in children 4 years of age and older. Maximum recommended orally inhaled doses for available aerosolized corticosteroids as combination therapy are summarized in Table 4. Prescribed dosages exceeding these recommendations will be reviewed.

Table 3: Maximum Recommended Pediatric Doses for ICS as Monotherapy in Asthma

Drug Name Dosage Form/Strength Patient Age/Maximum Recommended Dosage
beclomethasone dipropionate HFA (QVAR Redihaler®) inhalation aerosol: 40 mcg/actuation
  • children 4-11 years: 
    • 4 actuations/day in divided doses (2 actuations twice daily); total dose = 160 mcg/day
  • adolescents 12-17 years: 
    • 16 actuations/day in divided doses (8 actuations twice daily); total dose = 640 mcg/day
  inhalation aerosol: 80 mcg/actuation
  • children 4-11 years: 
    • 2 actuations/day in divided doses (1 actuation twice daily); total dose = 160 mcg/day 
  • adolescents 12-17 years: 
    • 8 actuations/day in divided doses (4 actuations twice daily); total dose = 640 mcg/day
budesonide (Pulmicort Flexhaler®) inhalation powder: 90 mcg/actuation
  • children, adolescents 6-17 years: 
    • 8 actuations/day in divided doses (4 actuations twice daily); total dose = 720 mcg/day
  inhalation powder: 180 mcg/actuation
  • children, adolescents 6-17 years: 
    • 4 actuations/day in divided doses (2 actuations twice daily); total dose = 720 mcg/day
ciclesonide (Alvesco®) inhalation aerosol:  80 mcg/actuation
  • adolescents 12-17 years:
    • prior therapy with bronchodilators alone: 
      • 4 actuations/day in divided doses(2 actuations twice daily); total dose = 320 mcg/day
    • prior therapy with ICS, oral corticosteroids: 
      • 8 actuations/day in divided doses(4 actuations twice daily); total dose = 640 mcg/day
  inhalation aerosol: 160 mcg/actuation
  • adolescents 12-17 years:
    • prior therapy with bronchodilators alone: 
      • 2 actuations/day in divided doses(1 actuation twice daily); total dose = 320 mcg/day
    • prior therapy with ICS, oral corticosteroids: 
      • 4 actuations/day in divided doses(2 actuations twice daily); total dose = 640 mcg/day
fluticasone furoate (Arnuity Ellipta®) dry powder inhaler: 50 mcg/actuation
  • children 5-11 years: 
    • 1 actuation once daily; total dose = 50 mcg/day
  dry powder inhaler: 100 mcg/actuation
  • adolescents 12-17 years:
    • 1 actuation once daily; total dose = 100 mcg/day*
  dry powder inhaler: 200 mcg/actuation
  • adolescents 12-17 years: 
    • 1 actuation once daily; total dose = 200 mcg/day*
fluticasone propionate HFA (Flovent HFA®) inhalation aerosol: 44 mcg/actuation
  • children 4-11 years:
    • regardless of prior therapy:
      • 4 actuations/day in divided doses (2 actuations twice daily); total dose = 176 mcg/day
  inhalation aerosol: 110 mcg/actuation
  • adolescents 12-17 years:
    • prior therapy with bronchodilators alone, ICS:
      • 16 actuations/day in divided doses (8 actuations twice daily); total dose = 1760 mcg/day
  inhalation aerosol: 220 mcg/actuation
  • adolescents 12-17 years:
    • prior therapy with bronchodilators alone, ICS:
      • 8 actuations/day in divided doses (4 actuations twice daily); total dose = 1760 mcg/day
fluticasone propionate (Flovent Diskus®) dry powder inhaler: 50 mcg/actuation
  • children 4-11 years: 
    • regardless of prior therapy:
      • 4 actuations/day in divided doses (2 actuations twice daily); total dose = 200 mcg/day 
  dry powder inhaler: 100 mcg/actuation
  • children 4-11 years: 
    • regardless of prior therapy:
      • 2 actuations/day in divided doses (1 actuation twice daily); total dose = 200 mcg/day 
  • adolescents 12-17 years:
    • total dose = 2000 mcg/day
  dry powder inhaler: 250 mcg/actuation
  • adolescents 12-17 years:
    • 8 actuations/day in divided doses (4 actuations twice daily); total dose = 2000 mcg/day
fluticasone propionate (ArmonAir Digihaler®) dry powder inhaler:  55 mcg/actuation
  • adolescents 12-17 years: 
    • no current corticosteroid therapy:
    • 2 actuations/day in divided doses (1 actuation twice daily); total dose = 110 mcg
  dry powder inhaler: 113 mcg/actuation
  • adolescents 12-17 years: 
    • prior treatment with ICS:
      • 2 actuations/day in divided doses (1 actuation twice daily); total dose = 226 mcg
  dry powder inhaler: 232 mcg/actuation
  • adolescents 12-17 years: 
    • prior treatment with ICS:
      • 2 actuations/day in divided doses (1 actuation twice daily); total dose = 464 mcg
mometasone HFA (Asmanex HFA®) inhalation aerosol: 50 mcg/actuation
  • children 5-11 years: 
    • regardless of prior therapy:
      • 4 actuations/day (2 actuations twice daily); total dose = 200 mcg/day
  inhalation aerosol: 100 mcg/actuation
  • adolescents 12-17 years: 
    • prior therapy with medium-dose ICS:
    • 4 actuations/day (2 actuations twice daily); total dose = 400 mcg/day
  inhalation aerosol: 200 mcg/actuation
  • adolescents 12-17 years:
    • prior therapy with high-dose ICS, oral corticosteroids:
      • 4 actuations/day (2 actuations twice daily); total dose = 800 mcg/day^
mometasone (Asmanex Twisthaler®) inhalation powder: 110 mcg/actuation
  • children 4-11 years:
    • 1 actuation/day once daily in evening; total dose = 110 mcg/day
  inhalation powder: 220 mcg/actuation
  • adolescents 12-17 years:
    • prior therapy with bronchodilators alone, ICS:
      • 1 actuation twice daily or 2 actuations once daily; total dose = 440 mcg/day
    • prior therapy with oral corticosteroids:
      • 4 actuations/day (2 actuations twice daily); total dose = 880 mcg/day

Legend:

  • * initial fluticasone furoate dose in patients not on ICS is 100 mcg once/day; if 100 mcg not effective, dose should be increased to 200 mcg once daily
  • ^ prednisone should be tapered slowly, beginning at least one week after mometasone use

Table 4: Maximum Pediatric Recommended Doses for ICS as Combination Therapy for Asthma

Drug Name Dosage Form/Strength Patient Age/Maximum Recommended Dosage
budesonide/ formoterol (Symbicort®) inhalation aerosol: 80 mcg/4.5 mcg/ actuation 6 to 11 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 320 mcg/18 mcg/day
    12-17 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 320 mcg/18 mcg/day
  inhalation aerosol: 160 mcg/4.5 mcg/actuation 12-17 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 640 mcg/18 mcg /day
fluticasone propionate/ salmeterol xinafoate (Advair HFA®) inhalation aerosol: 45 mcg/21 mcg/ actuation 12-17 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 180 mcg/84 mcg/day
  inhalation aerosol: 115 mcg/21 mcg/ actuation 12-17 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 460 mcg/84 mcg/day
  inhalation aerosol: 230 mcg/21 mcg/ actuation 12-17 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 920 mcg /84 mcg/day
fluticasone propionate/salmeterol (Advair Diskus®) inhalation powder: 100 mcg/50 mcg/ actuation 4-11 years of age: 2 actuations/day (1 actuation twice daily); total dose = 200 mcg/100 mcg/day
  inhalation powder: 100 mcg/50 mcg/actuation 12-17 years of age: 2 actuations/day (1 actuation twice daily); total dose = 200 mcg/100 mcg/day
  inhalation powder: 250 mcg/50 mcg/actuation 12-17 years of age: 2 actuations/day (1 actuation twice daily); total dose = 500 mcg/100 mcg/day
  inhalation powder: 500 mcg/50 mcg/actuation 12-17 years of age: 2 actuations/day (1 actuation twice daily); total dose = 1000 mcg/100 mcg/day
fluticasone propionate/salmeterol (AirDuo RespiClick®) inhalation powder: 55 mcg fluticasone/14 mcg salmeterol/ actuation 12-17 years of age: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 110 mcg/28 mcg/day
  113 mcg fluticasone/14 mcg salmeterol/actuation 12-17 years of age: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 226 mcg/28 mcg/day
  232 mcg fluticasone/14 mcg salmeterol/actuation 12-17 years of age: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 464 mcg/28 mcg/day
fluticasone propionate/salmeterol (AirDuo Digihaler®) 55 mcg fluticasone/ 14 mcg salmeterol/inhalation Greater than or equal to 12 years of age: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 110 mcg/28 mcg/day
  inhalation powder: 113 mcg fluticasone/14 mcg salmeterol/inhalation Greater than or equal to 12 years of age: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 226 mcg/28 mcg/day
  inhalation powder: 232 mcg fluticasone/14 mcg salmeterol/inhalation Greater than or equal to 12 years of age: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 464 mcg/28 mcg/day
mometasone/formoterol (Dulera®) inhalation aerosol: 50 mcg/5 mcg/ actuation 5-11 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 200 mcg/ 20 mcg/ day 
  inhalation aerosol: 100 mcg/5 mcg/ actuation 12-17 years of age: patients on medium-dose inhaled corticosteroids: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 400 mcg/20 mcg/day
  200 mcg/5 mcg/actuation 12-17 years of age: patients on high-dose inhaled corticosteroids: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 800 mcg/20 mcg/day

Number of maximum actuations per day based on dose of salmeterol and formoterol, and independent of inhaled corticosteroid dose.

2. Duration of Therapy

ICS, both as individual agents and as combination therapy, are FDA-approved for managing chronic asthma and COPD and may be continued indefinitely, as both COPD and asthma are chronic, lifelong processes. However, days’ supply per canister is limited based on the number of actuations per canister combined with the maximum recommended dose per day. Recommended days’ supply for available ICS as monotherapy or combined with long-acting beta2-agonists are summarized in Tables 5 and 6. Fluticasone is available as both the furoate and propionate salts; fluticasone propionate is available as four different formulations in three dosage strengths per formulation. Each dosage strength is associated with a maximum recommended dose (cited in Tables 1 and 3) which is used in combination with the number of actuations per drug canister to calculate days’ supply. New fluticasone/salmeterol inhalation powder formulations have also been approved for asthma management (AirDuo RespiClick® and AirDuo Digihaler®) with three different dosage formulations available; days’ supply can be calculated using dosages provided in Tables 2 and 4. Combined therapy with fluticasone furoate and vilanterol is available as two blister strips, with fluticasone in one strip and vilanterol in the second strip; similarly, triple therapy with fluticasone furoate, umeclidinium, and vilanterol is available as two blister strips, with fluticasone in one strip and umeclidinium and vilanterol in the second strip. Excessive use of ICS may be identified based on refill frequency. Inappropriate supply of ICS will be reviewed by monitoring refill requests. 

Table 5: Days’ Supply+ for Available ICS as Monotherapy When Maximum Doses are Utilized (Adults and Children)

Drug Name # of Actuations Per Canister Days’ Supply (based on maximum dose per day) +
beclomethasone dipropionate HFA aerosol 40 mcg/actuation (10.6 g canister) 120
  • 7.5 days (adult, adolescent)
  • 30 days (child)
80 mcg/actuation (10.6 g canister) 120
  • 15 days (adult, adolescent)
  • 60 days (child)
budesonide inhalation powder 90 mcg/actuation 60
  • -- (adult)
  • ~ 7.5 days (child)
180 mcg/actuation 120
  • 15 days (adult)
  • 30 days (child)
ciclesonide inhalation aerosol 80 mcg/actuation     60
  • BD alone: 15 days (adult, adolescents)
  • ICS, OCS: 7.5 days (adults, adolescents)
160 mcg/actuation 60
  • BD alone: 30 days (adult, adolescents)
  • ICS, OCS: 15 days (adults, adolescents)
fluticasone furoate dry powder inhaler 50 mcg/actuation 30 blisters 30 30
100 mcg/actuation
14 blisters
30 blisters
  • 14
  • 30
  • 14
  • 30
200 mcg/actuation
14 blisters
30 blisters
  • 14
  • 30
  • 14
  • 30
fluticasone propionate HFA aerosol 44 mcg/actuation (10.6 g canister) 120 30 days (child)
110 mcg/actuation (12 g canister) 120 7.5 days (adults, adolescents)
220 mcg/actuation (12 g canister) 120 15 days (adults, adolescents)
fluticasone propionate dry powder inhaler 50 mcg/actuation
60 blisters
60 15 days (child)
100 mcg/actuation
60 blisters
60 30 days (child)
250 mcg/actuation
28 blisters
60 blisters
  • 28
  • 60
  • 3.5 days (adults, adolescents)
  • 7.5 days (adults, adolescents)
fluticasone propionate dry powder inhaler (Digihaler®)
55 mcg/actuation
60 30 days (adults, adolescents)
113 mcg/actuation 60 30 days (adults, adolescents)
232 mcg/actuation 60 30 days (adults, adolescents)
mometasone inhalation aerosol 50 mcg/actuation 120 30 days (child)
100 mcg/actuation 120 30 days (adults, adolescents)
200 mcg/actuation 120 30 days (adults, adolescents)
200 mcg/actuation 120 30 days (adults, adolescents)
mometasone inhalation powder 110 mcg/actuation 30
  • 30 (child)
  • BD alone, ICS: 7.5 days (adults, adolescents)
  • OCS: 3.75 days (adults, adolescents)
mometasone inhalation powder
220 mcg/actuation
14 doses
14 BD alone, ICS: 7 days (adult, adolescents)
OCS: 3.5 days (adults, adolescents)
mometasone inhalation powder
220 mcg/actuation
30 doses
30 BD alone, ICS: 15 days (adult, adolescents)
OCS: 7.5 days (adults, adolescents)
mometasone inhalation powder
220 mcg/actuation
60 doses
60 BD alone, ICS: 30 days (adults, adolescents)
OCS: 15 days (adults, adolescents)
mometasone inhalation powder
220 mcg/actuation
120 doses
120 BD alone, ICS: 60 days (adults, adolescents)
OCS: 30 days (adults, adolescents)

Legend:

  • + calculated based on canister size and maximum dose allowed per day (summarized in Tables 1 and 3)
  • * for more than 2 inhalations daily
  • BD = bronchodilator
  • ICS = inhaled corticosteroids
  • OCS = oral corticosteroids

Table 6: Days’ Supply+ for Available ICS as Monotherapy When Maximum Doses are Utilized (Adults and Children)

Drug # of Actuations Per Canister Days’ Supply (based on maximum dose per day)+
budesonide/formoterol inhalation aerosol#
80 mcg/4.5 mcg/actuation
60
120
15
30
160 mcg/4.5 mcg/actuation 60
120
15
30
fluticasone propionate/ salmeterol xinafoate inhalation aerosol^
45 mcg fluticasone/21 mcg salmeterol / actuation
120
60
30
15
115mcg fluticasone/21 mcg salmeterol/ actuation 120
60
30
15
230 mcg fluticasone/21 mcg salmeterol/ actuation 120
60
30
15
fluticasone propionate/salmeterol inhalation powder*
100 mcg fluticasone/50 mcg salmeterol/ actuation
14 blisters
60 blisters
14
60
7
30
250 mcg fluticasone/50 mcg salmeterol/ actuation
14 blisters
60 blisters
14
60
7
30
500 mcg fluticasone/50 mcg salmeterol/ actuation
14 blisters
60 blisters
14
60
7
30
fluticasone/salmeterol inhalation powder
55 mcg/14 mcg/actuation    
60 30
113 mcg/14 mcg/actuation 60 30
232 mcg/14 mcg/actuation 60 30
fluticasone furoate/ umeclidinium/ vilanterol inhalation powder~
100 mcg/62.5 mcg/25 mcg/actuation
  • 28 blisters (one strip contains fluticasone, one strip contains umeclidinium and vilanterol)
  • 60 blisters (one strip contains fluticasone, one strip contains umeclidinium and vilanterol)

14

30

14

30

200 mcg/62.5 mcg/25 mcg/actuation
  • 28 blisters (one strip contains fluticasone, one strip contains umeclidinium and vilanterol)
  • 60 blisters (one strip contains fluticasone, one strip contains umeclidinium and vilanterol)

14

30

14

30

fluticasone furoate/vilanterol inhalation powder $
100 mcg/25/mcg/actuation
  • 28 blisters (one strip contains fluticasone, one strip contains vilanterol)
  • 60 blisters (one strip contains fluticasone, one strip contains vilanterol)

14

30

14

30

200 mcg/25 mcg/actuation
  • 28 blisters (one strip contains fluticasone, one strip contains vilanterol)
  • 60 blisters (one strip contains fluticasone, one strip contains vilanterol)

14

30

14

30

mometasone furoate/formoterol inhalation aerosol#
50 mcg/5 mcg/actuation
120 30
100 mcg/5 mcg/actuation

60

120

15

30

200 mcg/5 mcg/actuation

60

120

15

30

Legend:

  • + calculated based on canister size and maximum allowed dose per day (summarized in Tables 2 & 4)
  • * Salmeterol inhalation powder, alone or in combination with fluticasone as Advair Diskus®, may be used in children greater than 4 years of age
  • # Budesonide/formoterol indicated in children 6 years of age and older and mometasone/formoterol inhalation aerosols is indicated for children 5 years of age and older
  • ^ Fluticasone/salmeterol inhalation aerosol only indicated for children greater than or equal to 12 years of age
  • $ Fluticasone/vilanterol powder not indicated for use in children

3. Duplicative Therapy

Concurrent use of inhaled corticosteroids with systemic corticosteroids may result in augmented adverse effects, especially when high doses of inhaled corticosteroids are utilized.

When using single maintenance and reliever therapy (SMART), the “2020 Focused Updates to the Asthma Management Guidelines” recommends using a single inhaled corticosteroid (ICS)/long acting beta2-agonist combination inhaler as the preferred therapy as opposed to using a separate ICS inhaler. Additionally, the guidelines recommend intermittent use of a single ICS inhaler for patients 12 years of age and older with mild persistent asthma in certain situations when the patient is not already using ICS controller therapy.

The concomitant use of two or more inhaled corticosteroids for the treatment of asthma is not recommended and will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug interactions considered clinically relevant for inhaled corticosteroids with or without beta agonists are summarized in Table 7. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 7: ICS Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level+
budesonide, budesonide/salmeterol, fluticasone, fluticasone/salmeterol,fluticasone/vilanterol, mometasone, mometasone/ formoterol strong CYP3A4 inhibitors (e.g., azole antifungals, erythromycin, clarithromycin, protease inhibitors) potential for increased steroid concentrations with risk for excessive adrenal suppression and Cushing syndrome development concurrent administration not recommended by Advair HFA®/Advair Diskus®, Flovent® Diskus by manufacturers; Flovent® HFA not recommended with ritonavir; for all others, adjunctively administer combination cautiously; monitor patients for signs/symptoms of corticosteroid excess budesonide, mometasone: 3-moderate; fluticasone: 2-major (CP) budesonide: major, moderate; fluticasone: major (DrugReax)
steroids quinolones increased potential for serious tendonitis, tendon rupture with concurrent therapy closely monitor patients requiring combination therapy; discontinue quinolone if tendon pain develops 3-moderate (CP)
systemic steroids bupropion potential increased seizure risk due to systemic steroid-induced lowering of seizure threshold utilize only recommended bupropion dosages; initiate bupropion therapy with low doses and titrate slowly when combination therapy warranted; closely monitor patients for seizure development major (DrugReax)
budesonide/ formoterol, fluticasone/salmeterol, fluticasone/vilanterol,  mometasone/formoterol MAOIs* (including linezolid) concurrent administration of MAOIs with beta agonists may increase risk of tachycardia, hypomania, or agitation due to potentiation of effects on vascular system administer combination cautiously or within 2 weeks of MAOI discontinuation; observe patients for adverse effects major (DrugReax) 1-severe (CP)
budesonide/ formoterol, fluticasone/salmeterol, fluticasone/vilanterol, mometasone/formoterol TCAs^ concurrent administration of TCAs with beta agonists may potentiate effects on cardiovascular system and increase risk of adverse events cautiously administer TCAs and beta agonists together, including within 2 weeks of TCA discontinuation; monitor patients and observe for changes in blood pressure, heart rate and ECG moderate (DrugReax) moderate (CP)
budesonide/formoterol, fluticasone/salmeterol, fluticasone/vilanterol, mometasone/formoterol beta blockers concurrent administration may decrease effectiveness of beta-adrenergic blocker or beta-2 agonists like formoterol, salmeterol combination not recommended in asthma/COPD patients; if adjunctive therapy necessary, utilize cardioselective beta blocker (e.g., atenolol, bisoprolol) major (DrugReax) 2-major (CP)
budesonide/formoterol, fluticasone/salmeterol, fluticasone/vilanterol, mometasone/formoterol diuretics potential for worsening of diuretic-associated hypokalemia and/or ECG changes with beta-agonist concurrent administration, especially with high beta-agonist doses administer combination cautiously; monitoring potassium levels may be necessary 3-moderate (CP)

Legend:

  • +CP = Clinical Pharmacology
  • COPD = chronic obstructive pulmonary disease
  • ECG = electrocardiogram
  • MAOIs = monoamine oxidase inhibitors
  • TCAs = tricyclic antidepressants

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: March 30, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed March 30, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; March 30, 2021.
  4. American Society of Health-System Pharmacists. 2021. AHFS Drug Information® - 2021st Ed. Bethesda, MD. American Society of Health-System Pharmacists®. ISBN-10: 1-58528-654-0, ISBN-13: 978-1-58528-654-6. ISSN: 8756-6028. STAT!Ref Online Electronic Medical Library.  https://online.statref.com/document/cQfe8yqMRNqgSGqm4Qo8Qj.  March 30, 2021. 
  5. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Full Report 2007. (NIH Publication No. 07-4051).  Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.  Accessed March 30, 2021.
  6. National Heart, Lung, and Blood Institute. 2020 focused updates to the asthma management guidelines: a report from the national asthma education and prevention program coordinating committee expert panel working group. National Institutes of Health. December 2020. Accessed March 30, 2021.
  7. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease.  2021 report. Available at: https://goldcopd.org/2021-gold-reports/ Accessed March 30, 2021.
  8. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2020. Available from: https://ginasthma.org/gina-reports/. Accessed March 30, 2021.
  9. Beclomethasone dipropionate HFA inhalation aerosol (QVAR® Redihaler) package insert. Teva Respiratory, January 2021.
  10. Budesonide inhalation powder (Pulmicort Flexhaler®) package insert.  AstraZeneca, October 2019.
  11. Ciclesonide inhalation aerosol (Alvesco®) package insert. Covis Pharma, October 2020.
  12. Fluticasone propionate inhalation aerosol (Flovent® HFA) package insert.  GlaxoSmithKline, February 2021.
  13. Fluticasone propionate inhalation powder (Flovent® Diskus®) package insert.  GlaxoSmithKline, February 2020.
  14. Fluticasone furoate inhalation powder (Arnuity® Ellipta®) package insert.  GlaxoSmithKline, February 2020.
  15. Mometasone furoate inhalation powder (Asmanex® Twisthaler®) package insert. Merck & Co., February 2021.
  16. Mometasone furoate HFA inhalation aerosol (Asmanex® HFA) package insert.  Merck & Co., December 2020.
  17. Fluticasone inhalation powder (ArmonAir™ RespiClick®) package insert. Teva Respiratory, June 2020.
  18. Fluticasone/salmeterol inhalation powder (AirDuo RespiClick®) package insert. Teva Pharmaceuticals, February 2020.
  19. Fluticasone/salmeterol inhalation powder (AirDuo Digihaler®) package insert. Teva Pharmaceuticals, June 2020.
  20. Fluticasone/salmeterol inhalation aerosol (Advair® HFA) package insert.  GlaxoSmithKline, February 2021.
  21. Fluticasone/salmeterol inhalation powder (Advair Diskus®) package insert.  GlaxoSmithKline, October 2020.
  22. Fluticasone/vilanterol inhalation powder (Breo® Ellipta™) package insert. GlaxoSmithKline, January 2019.
  23. Fluticasone/umeclidinium/vilanterol inhalation powder (Trelegy® Ellipta®) package insert. GlaxoSmithKline, September 2020.
  24. Budesonide/formoterol fumarate inhalation aerosol (Symbicort®) package insert. AstraZeneca, July 2019.
  25. Mometasone furoate/formoterol inhalation aerosol (Dulera®) package insert.  Merck & Co., December 2020.
  26. Kelly HW. Comparison of inhaled corticosteroids: an update.  Ann Pharmacother. 2009;43(3):519-27.
  27. Self TH, Chrisman CR, Finch CK.  Asthma. In: Alldredge BK, Corelli RL, Ernst ME, et al, eds. Koda-Kimble and Young’s applied therapeutics: the clinical use of drugs. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2013:565-600.
  28. Diaz PT, Knoell DL.  Chronic obstructive pulmonary disease. In: Alldredge BK, Corelli RL, Ernst ME, et al, eds.  Koda-Kimble and Young’s applied therapeutics: the clinical use of drugs. 10th ed.  Philadelphia:  Lippincott Williams & Wilkins; 2013:601-18.
  29. Frois C, Wu EQ, Ray S, Colice GL.  Inhaled corticosteroids or long-acting beta-agonists alone or in fixed-dose combinations in asthma treatment: a systematic review of fluticasone/budesonide and formoterol/salmeterol. Clin Ther. 2009;31(12):2779-803.
  30. Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst Rev. 2010;4:CD005533.
  31. Cates CJ, Lasserson TJ. Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events. Cochrane Database Syst Rev. 2010;1:CD007694.
  32. Lemanske RF Jr, Mauger DT, Sorkness CA, et al for the Childhood Asthma Research and Education (CARE) Network of the National Heart, Lung, and Blood Institute. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. New Engl J Med. 2010;362(11):975-85.
  33. Pohunek P, Kuna P, Jorup C, De Boeck K. Budesonide/formoterol improves lung function compared with budesonide alone in children with asthma.  Pediatr Allergy Immunol. 2006;17:458-65.
  34. Ni Chroinin M, Greenstone IR, Danish A, et al. Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma. Cochrane Database Syst Rev. 2005(4):CD005535.
  35. Greenstone IR, Ni Chroinin MN, Masse V, et al. Combination of inhaled long-acting beta2-agonists and inhaled steroids versus higher dose of inhaled steroids in children and adults with persistent asthma. Cochrane Database Syst Rev. 2005(4):CD005533.
  36. Kiri VA, Bettoncelli G, Testi R, Viegi G. Inhaled corticosteroids are more effective in COPD patients when used with LABA than with SABA. Respir Med. 2005;99:1115-24. 
  37. Redding GJ, Stoloff SW. Changes in recommended treatments for mild and moderate asthma. J  Fam Pract. 2004;53:692-700.
  38. Ernst P, McIvor A, Ducharme FM, et al. Canadian Asthma Guideline Group. Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids. Ann Intern Med. 2006;145:692-4.
  39. Saag KG, Furst DE, Barnes PJ. Major side effects of inhaled glucocorticoids. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. (Accessed on March 31, 2021.)

Aerosolized Agents - metered-dose inhalers: beta2 adrenergic drugs (long-acting)

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • Revised April 23, 2021; March 2019; March 2017; Oct. 2014; Feb. 2013; Oct. 2012; Jan. 2011; July 2007; March 2003; April 2002; March 2001; March 2000; Feb. 1999; March 1998; March 1997; Aug. 1995.
  • Initially developed
    • Jan. 1995

1. Dosage

Long-acting, selective beta2-agonists (LABAs) are FDA-approved for use as adjunctive therapy with long-term asthma control medications, such as inhaled corticosteroids (ICS), in managing reversible obstructive airways disease, including asthma and nocturnal asthma, in patients inadequately controlled with long-term asthma control medications. LABAs are contraindicated for use as monotherapy in asthma management due to an increased risk of asthma-related death as well as increased risks in asthma-related hospitalizations in pediatric and adolescent patients. Serevent Diskus® (salmeterol) is FDA-approved for asthma in adults and children four years of age and older, and it is also FDA-approved for use to acutely prevent exercise-induced bronchospasm (EIB) on an as-needed basis. LABAs are FDA-approved for use in adults as maintenance therapy for bronchoconstriction associated with chronic obstructive pulmonary disease (COPD), including emphysema and chronic bronchitis. Striverdi Respimat® (olodaterol) is another LABA available without an ICS, and it is FDA-approved for the management of COPD. It does not have an FDA-approval for asthma.

LABAs combined with ICS are FDA-approved for use in adults and children as asthma maintenance therapy: Advair® HFA metered aerosol (fluticasone propionate/salmeterol) is FDA-approved for use in patients 12 years of age and older, and Dulera® (mometasone/formoterol) inhalation aerosol is FDA-approved for use in patients 5 years of age and older.  Advair Diskus® (fluticasone propionate/salmeterol) inhalation powder is FDA-approved for use in asthma maintenance in patients 4 years of age and older. AirDuo RespiClick® and AirDuo Digihaler® (fluticasone/salmeterol) inhalation powders provide additional dosage strengths, and they have been approved for use in patients with asthma who are 12 years and older. Symbicort® (budesonide/formoterol) inhalation aerosol and Advair Diskus® (fluticasone propionate/salmeterol) are FDA-approved for use in adults as COPD maintenance therapy. Symbicort® is also FDA-approved for the management of asthma in adults and children 6 years of age and older. The combination Breo Ellipta® (fluticasone/ vilanterol) is FDA approved for the management of COPD and asthma in patients 18 years of age and older.

Anoro Ellipta® (umeclidinium/vilanterol), Bevespi Aerosphere® (glycopyrrolate/formoterol), Utibron® Neohaler® (indacaterol/glycopyrrolate), and Stiolto Respimat® (tiotropium/olodaterol) are indicated for use in adults as maintenance therapy for COPD but are not FDA-approved for use in asthma.

Additionally, a triple therapy inhaler containing fluticasone, umeclidinium and vilanterol, Trelegy Ellipta®, is approved for COPD management to treat airway obstruction and reduce exacerbations, and in September of 2020 it was approved for the maintenance treatment of asthma in patients 18 years of age and older.

Duaklir Pressair® (aclidinium bromide/ formoterol) is a long-acting beta agonist and long-acting muscarinic antagonist combination product that was FDA approved in 2019 for the management of COPD in adults.

In March of 2020 Sunovion Pharmaceuticals announced the discontinuation of Utibron Neohaler® (indacaterol/glycopyrrolate), Seebri Neohaler® (glycopyrrolate), and Arcapta Neohaler® (indacaterol), and these products are no longer available in the United States as of April 1, 2020.

1.1. Adults

To manage EIB in adults, one salmeterol 50 mcg inhalation is administered at least 30 minutes before exercise on an as needed basis and should not be repeated for at least 12 hours after administration of the previous dose.  Patients receiving twice daily LABA doses chronically should not administer additional LABA doses for EIB management.

Maximum recommended adult daily doses for LABA use as monotherapy in asthma and COPD are summarized in Table 1. Prescribed dosages exceeding these guidelines will be reviewed.

LABA/ICS combinations are FDA-approved for use in asthma and COPD maintenance therapy. Advair Diskus® 250 mcg/50 mcg is the only fluticasone/salmeterol dose approved for use in adult patients with COPD.  Symbicort® 80 mcg/4.5 mcg and 160 mcg/4.5 mcg are FDA-approved for use in asthma, while 160 mcg/4.5 mcg is the recommended strength for budesonide/formoterol in COPD. Advair HFA®, AirDuo RespiClick®, AirDuo Digihaler®, and Dulera® are FDA-approved for asthma management only.

Maximum adult daily dosages for LABA combination therapy are summarized in Table 2. Dosages exceeding these recommendations will be reviewed.

Table 1: LABA Maximum Daily Dosage Recommendations in Adults with Asthma and COPD - Monotherapy

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
COPD olodaterol hydrochloride (Striverdi Respimat®) inhalation aerosol: 2.5 mcg/actuation 2 actuations once daily; total dose = 5 mcg/day
asthma salmeterol (Serevent Diskus®) inhalation powder: 50 mcg/inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 100 mcg/day
COPD     2 actuations/day in divided doses (1 actuation twice daily); total dose = 100 mcg/day

 

Table 2: LABA Maximum Daily Dosage Recommendations in Adults with Asthma and COPD - Combination Therapy

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
COPD aclidinium bromide/formoterol fumarate (Duaklir Pressair®) inhalation powder: 400 mcg/ 12 mcg/ inhalation 2 actuations/day (1 actuation twice daily); total dose = 800 mcg/24 mcg/day
asthma budesonide/ formoterol (Symbicort®) inhalation aerosol: 80 mcg/4.5 mcg/ inhalation 4 actuations/day (2 actuations twice daily); total dose = 320 mcg/18 mcg/day
asthma   inhalation aerosol: 160 mcg/4.5 mcg/inhalation 4 actuations/day (2 actuations twice daily); total dose = 640 mcg/18 mcg/day
chronic obstructive pulmonary disease (COPD)     4 actuations/day (2 actuations twice daily); total dose = 640 mcg/18 mcg/day
asthma fluticasone propionate/salmeterol xinafoate (Advair HFA®) inhalation aerosol: 45 mcg fluticasone/21 mcg salmeterol/inhalation 4 actuations/day (2 actuations twice daily); total dose = 180 mcg/84 mcg/day
    inhalation aerosol: 115 mcg fluticasone/21 mcg salmeterol/inhalation 4 actuations/day (2 actuations twice daily); total dose = 460 mcg/84 mcg/day
    inhalation aerosol: 230 mcg fluticasone/21 mcg salmeterol/inhalation 4 actuations/day (2 actuations twice daily); total dose = 920 mcg/84 mcg/day
asthma fluticasone propionate/ salmeterol (Advair Diskus®, Wixela Inhub®) inhalation powder: 100 mcg fluticasone/50 mcg salmeterol/ inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 200 mcg/100 mcg/day
asthma   inhalation powder: 250 mcg fluticasone/50 mcg salmeterol/inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose =500 mcg/100 mcg/day
COPD     2 actuations/day in divided doses (1 actuation twice daily); total dose =500 mcg/100 mcg/day
asthma   inhalation powder: 500 mcg fluticasone/50 mcg salmeterol/inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 1000 mcg/100 mcg/day
asthma fluticasone propionate/salmeterol (AirDuo RespiClick®) inhalation powder: 55 mcg fluticasone/14 mcg salmeterol/inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 110 mcg/28 mcg/day
    inhalation powder: 113 mcg fluticasone/14 mcg salmeterol/inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 226 mcg/28 mcg/day
    inhalation powder: 232 mcg fluticasone/14 mcg salmeterol/inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 464 mcg/28 mcg/day
asthma fluticasone propionate/salmeterol (AirDuo Digihaler®) inhalation powder: 55 mcg fluticasone/ 14 mcg salmeterol/inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 110 mcg/28 mcg/day
    inhalation powder: 113 mcg fluticasone/14 mcg salmeterol/inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 226 mcg/28 mcg/day
    inhalation powder: 232 mcg fluticasone/14 mcg salmeterol/inhalation 2 actuations/day in divided doses (1 actuation twice daily); total dose = 464 mcg/28 mcg/day
asthma fluticasone furoate/umeclidinium/vilanterol (Trelegy® Ellipta®) inhalation powder: 100 mcg/ 62.5 mcg/ 25 mcg/inhalation 1 actuation/day; total dose = 100 mcg/62.5 mcg/ 25 mcg/day
COPD     1 actuation/day; total dose = 100 mcg/62.5 mcg/ 25 mcg/day
asthma   inhalation powder: 200 mcg/ 62.5 mcg/ 25 mcg/inhalation 1 actuation/day; total dose = 200 mcg/62.5 mcg/ 25 mcg/day
asthma fluticasone furoate/vilanterol (Breo® Ellipta®) inhalation powder: 100 mcg fluticasone/25 mcg vilanterol/inhalation 1 actuation/day; total dose = 100 mcg/25 mcg/day
    inhalation powder: 200 mcg fluticasone/25 mcg vilanterol/inhalation 1 actuation/day; total dose = 200 mcg/25 mcg/day
COPD   inhalation powder: 100 mcg fluticasone/25 mcg vilanterol/inhalation 1 actuation/day; total dose = 100 mcg/25 mcg/day
COPD glycopyrrolate/ formoterol (Bevespi Aerosphere®) inhalation aerosol: 9 mcg glycopyrrolate/ 4.8 mcg formoterol/ actuation 4 actuations/day in two divided doses (2 actuations twice daily); total dose = 36 mcg/19.2 mcg/day
asthma mometasone/ formoterol (Dulera®) inhalation aerosol: 100 mcg mometasone/5 mcg formoterol/inhalation for patients on medium-dose inhaled corticosteroids: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 400 mcg/20 mcg/day
    inhalation aerosol: 200 mcg mometasone/5 mcg formoterol/inhalation patients on high-dose inhaled corticosteroids: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 800 mcg/20 mcg/day
COPD tiotropium/olodaterol (Stiolto® Respimat®) inhalation aerosol: 2.5 mcg tiotropium/2.5 mcg olodaterol/inhalation 2 actuations once daily (total dose = 5 mcg/5 mcg/day
COPD umeclidinium/vilanterol (Anoro® Ellipta®) inhalation powder: 62.5 mcg umeclidinium/25 mcg vilanterol/inhalation 1 actuation/day; total dose = 62.5 mcg/25 mcg/day

Legend:

  • Number of maximum actuations per day based on dose of salmeterol and formoterol, and independent of inhaled corticosteroid dose.
     

1.2. Pediatrics

The safety and efficacy of inhalational salmeterol in children < 4 years of age have not been established. Indacaterol and olodaterol are not approved for use in children as safety and efficacy of these agents have not been established in the pediatric population. Similarly, the glycopyrrolate/formoterol, aclidinium/formoterol, fluticasone/vilanterol, and the umeclidinium/vilanterol combination products are not FDA-approved for pediatric use as safety and efficacy have not been determined in this patient population for these inhalation combinations.

To prevent EIB in pediatric patients 4 years of age and older, one salmeterol 50 mcg inhalation is administered at least 30 minutes before exercise on an as-needed basis; doses should not be repeated for at least 12 hours after administration of the previous dose. Patients receiving twice daily LABA doses chronically should not administer additional LABA doses for EIB management.

Pediatric dosages for LABAs used as maintenance asthma therapy are summarized in Tables 3 and 4.

Table 4: Pediatric LABA Maximum Daily Dosage Recommendations for Asthma - Combination Therapy

Drug Name Dosage Form/Strength Patient Age/Maximum Recommended Dosage
budesonide/formoterol (Symbicort®) inhalation aerosol: 80 mcg/4.5 mcg/ inhalation 6 to 11 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 320 mcg/18 mcg/day
    Greater than or equal to 12 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 320 mcg/18 mcg/day
  inhalation aerosol: 160 mcg/4.5 mcg/inhalation Greater than or equal to 12 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 640 mcg/18 mcg /day
fluticasone propionate/ salmeterol xinafoate (Advair HFA®) inhalation aerosol: 45 mcg/21 mcg/ inhalation Greater than or equal to 12 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 180 mcg/84 mcg/day
  inhalation aerosol: 115 mcg/21 mcg/ inhalation Greater than or equal to 12 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 460 mcg/84 mcg/day
  inhalation aerosol: 230 mcg/21 mcg/inhalation Greater than or equal to 12 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 920 mcg /84 mcg/day
fluticasone propionate/ salmeterol (Advair Diskus®) inhalation powder: 100 mcg/50 mcg/ inhalation 4-11 years of age: 2 actuations/day (1 actuation twice daily); total dose = 200 mcg/100 mcg/day
  inhalation powder: 100 mcg/50 mcg/inhalation Greater than or equal to 12 years of age: 2 actuations/day (1 actuation twice daily); total dose = 200 mcg/100 mcg/day
  inhalation powder: 250 mcg/50 mcg/inhalation Greater than or equal to 12 years of age: 2 actuations/day (1 actuation twice daily); total dose = 500 mcg/100 mcg/day
  inhalation powder: 500 mcg/50 mcg/ inhalation Greater than or equal to 12 years of age: 2 actuations/day (1 actuation twice daily); total dose = 1000 mcg/100 mcg/day
fluticasone propionate/salmeterol (AirDuo RespiClick®) inhalation powder: 55 mcg fluticasone/14 mcg salmeterol/inhalation Greater than or equal to 12 years of age: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 110 mcg/28 mcg/day
  113 mcg fluticasone/14 mcg salmeterol/inhalation Greater than or equal to 12 years of age: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 226 mcg/28 mcg/day
  232 mcg fluticasone/14 mcg salmeterol/inhalation Greater than or equal to 12 years of age: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 464 mcg/28 mcg/day
fluticasone propionate/salmeterol (AirDuo Digihaler®) 55 mcg fluticasone/14 mcg salmeterol/inhalation Greater than or equal to 12 years of age: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 110 mcg/28 mcg/day
  inhalation powder: 113 mcg fluticasone/14 mcg salmeterol/inhalation Greater than or equal to 12 years of age: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 226 mcg/28 mcg/day
  inhalation powder: 232 mcg fluticasone/14 mcg salmeterol/inhalation Greater than or equal to 12 years of age: 2 actuations/day in divided doses (1 actuation twice daily); total dose = 464 mcg/28 mcg/day
mometasone/ formoterol (Dulera®) inhalation aerosol: 50 mcg/5 mcg/ inhalation 5-11 years of age: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 200 mcg/ 20 mcg/ day
  100 mcg/5 mcg/inhalation Greater than or equal to 12 years of age: patients on medium-dose inhaled corticosteroids: 4 actuations/day in divided doses (2 actuations twice daily); total dose = 400 mcg/20 mcg/day
  200 mcg/5 mcg/inhalation  

Legend:

  • Number of maximum actuations per day based on dose of salmeterol and formoterol, and independent of inhaled corticosteroid dose.

2. Duration of Therapy

Unlike other available short-acting selective beta2-agonists, salmeterol possesses a longer duration of bronchodilation of at least 12 hours which allows for twice daily dosing. Salmeterol does not exhibit immediate pharmacologic activity due to its delayed onset of action. The onset of effective bronchodilation is approximately 10-20 minutes, with the time to maximum effect approaching one hour. This delayed onset has been attributed to slower receptor binding by salmeterol. Therefore, salmeterol administered either alone or in combination with fluticasone propionate is not effective in the treatment of acute asthmatic attacks but is reserved for use as preventive asthma therapy. Patients should never receive salmeterol as treatment for acute bronchospasm due to the delayed onset of action (10-20 minutes) attributed to this agent. Deaths have been reported when patients mistakenly used salmeterol to combat acute bronchospasm. Similarly, indacaterol, olodaterol, and vilanterol possess longer durations of bronchodilation allowing for once daily dosing and should also never be used to manage acute bronchospasm. Olodaterol is indicated for use as maintenance therapy in COPD while vilanterol is approved for the maintenance treatment of asthma and COPD.

For maintenance therapy, daily administration of LABAs alone or in combination with ICS is warranted in asthma and COPD. Formoterol combination products, olodaterol monotherapy and combination products, salmeterol monotherapy and combination products, and vilanterol combination products are metered-dose inhalers designed to deliver a set number of inhalations based on the canister size as well as the medication prescribed. Tables 5 and 6 summarize the number of inhalations available LABA and LABA combination products provide, respectively, and the days’ supply per inhaler or blister package based on the maximum dose allowed per day (see Tables 1 through 4). Excessive use may be identified based on refill frequency. Inappropriate supply of salmeterol metered-dose inhalers, salmeterol/fluticasone blister packages, formoterol blister packages, budesonide/formoterol metered-dose inhalers, or mometasone/formoterol metered-dose inhalers will be monitored by reviewing excessive refills.

Table 5: Days’ Supply for Available Long-Acting Beta2-Adrenergic Metered Dose Inhalers (Adult and Pediatric Patients) - Monotherapy

Drug # of Actuations Per Canister Days’ Supply (based on maximum dose per day) +
salmeterol dry powder inhaler *
60 blisters
60 30
olodaterol inhalation aerosol ~ 60 30

Legend:

  • + calculated based on canister size/blister package size and maximum dose allowed per day
  • * Salmeterol inhalation powder, alone or in combination with fluticasone, may be used in children less than 4 years of age

Table 6: Days’ Supply for Available Long-Acting Beta2-Adrenergic Metered Dose Inhalers (Adult and Pediatric Patients) – Combination Therapy

Drug # of Actuations Per Canister Days’ Supply (based on maximum dose per day) +
aclidinium bromide/ formoterol fumarate inhalation
400 mcg/12 mcg/inhalation
60 30
budesonide/formoterol inhalation aerosol #
80 mcg/4.5 mcg/inhalation
60
120
15
30
160 mcg/4.5 mcg/inhalation 60
120
15
30
fluticasone propionate/salmeterol xinafoate inhalation aerosol ^
45 mcg fluticasone/21 mcg salmeterol/ inhalation
60
120
15
30
115 mcg fluticasone/21 mcg salmeterol/inhalation 60
120
15
30
230 mcg fluticasone/21 mcg salmeterol/inhalation 60
120
15
30
fluticasone propionate/salmeterol inhalation powder *
100 mcg fluticasone/50 mcg salmeterol/ inhalation:
14 blisters
60 blisters
14
60
7
30
250 mcg fluticasone/50 mcg salmeterol/inhalation:
14 blisters
60 blisters
14
60
7
30
500 mcg fluticasone/50 mcg salmeterol/inhalation:
14 blisters
60 blisters
14
60
7
30
fluticasone/salmeterol inhalation powder ^
55 mcg/14 mcg/actuation (0.45 g canister)
60 30
113 mcg/14 mcg/actuation (0.45 g canister) 60 30
232 mcg/14 mcg/actuation (0.45 g canister) 60 30
fluticasone furoate/ umeclidinium/vilanterol inhalation powder ~
100 mcg/62.5 mcg/25 mcg/actuation
28 blisters
(one strip contains fluticasone, one strip contains umeclidinium and vilanterol)
60 blisters
(one strip contains fluticasone, one strip contains umeclidinium and vilanterol)
14
30

14
30

200 mcg/62.5 mcg/25 mcg/actuation
28 blisters
(one strip contains fluticasone, one strip contains umeclidinium and vilanterol)
60 blisters
(one strip contains fluticasone, one strip contains umeclidinium and vilanterol)
14
30
14
30
fluticasone furoate/vilanterol inhalation powder ~
100 mcg/25 mcg/actuation
28 blisters
(one strip contains fluticasone, one strip contains vilanterol)
60 blisters
(one strip contains fluticasone, one strip contains vilanterol)
14
30
14
30
200 mcg/25 mcg/actuation
28 blisters
(one strip contains fluticasone, one strip contains vilanterol)
60 blisters
(one strip contains fluticasone, one strip contains vilanterol)
14
30
14
30
glycopyrrolate/formoterol inhalation aerosol ~
9 mcg/4.8 mcg/actuation
28
120
7
30
mometasone furoate/formoterol inhalation aerosol ^
50 mcg/5 mcg/inhalation!
120 30
100 mcg/5 mcg/inhalation 60
120
15
30
200 mcg/5 mcg/inhalation 60
120
15
30
tiotropium/ olodaterol inhalation aerosol ~
2.5 mcg/ 2.5 mcg/inhalation
60
10
30
5
umeclidinium/vilanterol inhalation powder ~
14 blisters
(one strip contains umeclidinium, one strip contains vilanterol)
60 blisters
(one strip contains umeclidinium, one strip contains vilanterol)
7
30
7
30

Legend:

  • + calculated based on canister size/blister package size and maximum dose allowed per day
  • ~ not indicated for use in children
  • * Salmeterol inhalation powder, alone or in combination with fluticasone, may be used in children > 4 years of age
  • # Budesonide/formoterol indicated for children > 6 years of age
  • ^ Fluticasone/salmeterol inhalation aerosol and fluticasone/salmeterol inhalation powder as AirDuo® RespiClick and AirDuo Digihaler® as well as  mometasone/formoterol inhalation aerosols only indicated for children > 12 years of age
  • ! Mometasone furoate/ formoterol 50 mcg/ 5mcg/ inhalation is approved for children 5 years of age and older

3. Duplicative Therapy

Acute asthma exacerbations require treatment with short-acting beta2-adrenergic agents even though maintenance therapy with LABAs may be prescribed concomitantly. Patients may receive a long- and short-acting beta2-adrenergic drug concurrently for short time periods to manage acute attacks. LABAs used in conjunction with frequently administered short-acting beta2-adrenergic drugs (i.e., frequent refill of a short-acting beta2-adrenergic agonist within a 30-day time period) will be reviewed.

Current literature does not support the adjunctive use of multiple LABAs for prevention and control of asthma symptoms. Concomitant LABA use will be reviewed as clinical evidence does not validate improved outcome with conjunctive therapy.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for LABAs and combination products are summarized in Table 7. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 7: Key Drug-Drug Interactions for Inhaled LABAs and Combination Products

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level +
beta2-agonists atomoxetine concurrent administration may increase risk of cardiovascular adverse effects (e.g., tachycardia, hypertension); interaction may be less likely with inhaled beta2-agonists monitor patients for increased cardiovascular adverse effects major (DrugReax) 3-moderate (CP)
beta2-agonists beta blockers concurrent administration may decrease effectiveness of beta-adrenergic blocker or beta-2 agonists combination not recommended in asthma/COPD patients; if adjunctive therapy necessary, utilize cardioselective beta blocker (e.g., atenolol, bisoprolol) major (DrugReax) 2-major (CP)
beta2-agonists diuretics, xanthine derivatives (e.g., theophylline), corticosteroids potential for worsening of hypokalemia and/or ECG changes with beta2-agonist concurrent administration, especially with high beta2-agonist doses administer combination cautiously, although common for xanthines and steroids to be administered adjunctively with beta2-agonists; monitor potassium levels as necessary 3-moderate (CP)
beta2-agonists MAOIs (including linezolid) concurrent administration may increase risk of tachycardia, hypomania, or agitation due to potentiation of effects on vascular system administer combination cautiously or within 2 weeks of MAOI discontinuation; observe patients for adverse effects major (DrugReax) 2-major (CP)
beta2-agonists QTc interval-prolonging medications (e.g., class I, III anti-arrhythmic, ziprasidone, dolasetron) concurrent administration may increase risk of cardiotoxicity (e.g., life-threatening arrhythmias, cardiac arrest) due to potential for additive QTc interval prolongation and, rarely, torsades de pointes administer combination cautiously contraindicated (vilanterol) DrugReax) 1-severe, 2-major, 3-moderate (CP)
beta2-agonists TCAs concurrent administration may potentiate effects on cardiovascular system and increase risk of adverse events cautiously administer together, including within 2 weeks of TCA discontinuation; monitor patients and  observe for changes in blood pressure, heart rate and ECG moderate (DrugReax) 3-moderate (CP)
salmeterol, ICS strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) salmeterol, ICS extensively CYP3A4 metabolized; conjunctive administration may increase salmeterol, ICS serum levels and potential for increased adverse cardiovascular effects (salmeterol), steroid adverse effects (ICS) avoid combination, if possible; if combination necessary, monitor for salmeterol, ICS adverse effects and adjust therapy as necessary major (DrugReax) 2-major (CP)
steroids quinolones increased potential for serious tendonitis, tendon rupture with concurrent therapy closely monitor patients requiring combination therapy; discontinue quinolone if tendon pain develops 3-moderate (CP)
systemic steroids bupropion potential increased seizure risk due to systemic steroid-induced lowering of seizure threshold utilize only recommended bupropion dosages; initiate bupropion therapy with low doses and titrate slowly when combination therapy warranted; closely monitor patients for seizure development major (DrugReax)

Legend:

  • +CP = Clinical Pharmacology
  • COPD = chronic obstructive pulmonary disease
  • ECG = electrocardiogram
  • MAOIs = monoamine oxidase inhibitors
  • TCAs = tricyclic antidepressants

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: March 24, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed March 24, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; March 24, 2021.
  4. American Society of Health-System Pharmacists. 2021. AHFS Drug Information® - 2021st Ed. Bethesda, MD. American Society of Health-System Pharmacists®. ISBN-10: 1-58528-654-0, ISBN-13: 978-1-58528-654-6. ISSN: 8756-6028. STAT!Ref Online Electronic Medical Library.  https://online.statref.com/document/cQfe8yqMRNqgSGqm4Qo8Qj.  March 24, 2021. 
  5. National Heart, Lung, and Blood Institute. 2020 focused updates to the asthma management guidelines: a report from the national asthma education and prevention program coordinating committee expert panel working group. National Institutes of Health. December 2020. Accessed March 24, 2021.
  6. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Full Report 2007. (NIH Publication No. 07-4051).  Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.  Accessed March 24, 2021.
  7. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease.  2021 report. Available at: https://goldcopd.org/2021-gold-reports/ Accessed March 24, 2021.
  8. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2020. Available from: https://ginasthma.org/gina-reports/. Accessed March 24, 2021.
  9. Aclidinium/ formoterol fumarate powder (Duaklir Pressair®) metered dose inhaler package insert. Circassia Pharmaceuticals, Inc., July 2020.
  10. Olodaterol inhalation spray (Striverdi® Respimat®) package insert.  Boehringer Ingelheim Pharmaceutical, Inc., September 2020.
  11. Salmeterol xinafoate inhalation powder (Serevent® Diskus®) package insert.  GlaxoSmithKline, January 2020.
  12. Budesonide/formoterol fumarate inhalation aerosol (Symbicort®) package insert. AstraZeneca, July 2019.
  13. Fluticasone/salmeterol inhalation powder (AirDuo RespiClick®) package insert. Teva Pharmaceuticals, February 2020.
  14. Fluticasone/salmeterol inhalation powder (AirDuo Digihaler®) package insert. Teva Pharmaceuticals, June 2020.
  15. Fluticasone/salmeterol inhalation aerosol (Advair® HFA) package insert.  GlaxoSmithKline, February 2021.
  16. Fluticasone/salmeterol inhalation powder (Advair Diskus®) package insert.  GlaxoSmithKline, October 2020.
  17. Fluticasone/vilanterol inhalation powder (Breo® Ellipta™) package insert. GlaxoSmithKline, January 2019.
  18. Fluticasone/umeclidinium/vilanterol inhalation powder (Trelegy® Ellipta®) package insert. GlaxoSmithKline, September 2020.
  19. Glycopyrrolate/formoterol inhalation aerosol (Bevespi Aerosphere®) package insert. AstraZeneca, November 2020.
  20. Mometasone furoate/formoterol inhalation aerosol (Dulera®) package insert.  Merck & Co., December 2020.
  21. Tiotropium/olodaterol (Stiolto® Respimat®) package insert. Boehringer-Ingelheim Pharmaceuticals, Inc., October 2020.
  22. Umeclidinium/vilanterol inhalation powder (Anoro® Ellipta®) package insert.  GlaxoSmithKline, August 2020.
  23. Blake KV, Lang JE. Chapter 43. Chronic obstructive pulmonary disease (Chapter) In: DiPiro JT, Talbert RL, Yee GC, et al. (eds): Pharmacotherapy: a pathophysiologic approach. 11th edition. New York, McGraw-Hill, 2020. Access Pharmacy Web site. Available at: https://accesspharmacy-mhmedical-com.ezproxy.lib.utexas.edu/index.aspx. Accessed March 25, 2021.
  24. Bourdet SV, Williams DM. Chapter 44. Chronic obstructive pulmonary disease (Chapter) In: DiPiro JT, Talbert RL, Yee GC, et al. (eds): Pharmacotherapy: a pathophysiologic approach. 11th edition. New York, McGraw-Hill, 2020. Access Pharmacy Web site. Available at: https://accesspharmacy-mhmedical-com.ezproxy.lib.utexas.edu/index.aspx. Accessed March 25, 2021.
  25. Ducharme FM, Ni CM, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst Rev. 2010, Issue 4. Art. No.: CD005533. DOI: 10.1002/14651858.CD005533.pub2.
  26. Ohar JA, Donohue JF.  Mono- and combination therapy of long-acting bronchodilators and inhaled corticosteroids in advanced COPD.  Semin Respir Crit Care Med. 2010;31(3):321-33.
  27. Gordon E, Lazarus SC. Management of chronic obstructive pulmonary disease: moving beyond the asthma algorithm. J Allergy Clin Immunol 2009;124:873-80.
  28. Chapman KR, Barnes NC, Greening AP, et al. Single maintenance and reliever therapy (SMART) of asthma: a critical appraisal. Thorax. 2010;65:747-52.
  29. Rodrigo GJ, Moral VP, Marcos LG, Castro-Rodriguez JA. Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review. Pulm Pharmacol Ther. 2009;22(1):9-19.
  30. FDA Drug Shortages. Indacaterol maleate and glycopyrrolate (Utibron Neohaler®) Inhalation Powder. Current and resolved drug shortages and discontinuations reported to FDA. March 10, 2020. Available at:  https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Indacterol+Maleate+and+Glycopyrrolate+%28Utibron+Neohaler%29+Inhalation+Powder&st=d&tab=tabs-2. Accessed March 25, 2021.
  31. FDA Drug Shortages. Glycopyrrolate (Seebri Neohaler®) Inhalation Powder. Current and resolved drug shortages and discontinuations reported to FDA. March 10, 2020. Available at: https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Glycopyrrolate+%28Seebri+Neohaler%29+Inhalation+Powder&st=d&tab=tabs-2. Accessed March 25, 2021.
  32. FDA Drug Shortages. Indacaterol maleate (Arcapta Neohaler®) Inhalation Powder. Current and resolved drug shortages and discontinuations reported to FDA. March 10, 2020. Available at: https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Indacterol+Maleate+%28Arcapta+Neohaler%29+Inhalation+Powder&st=d&tab=tabs-2. Accessed March 25, 2021.

Aerosolized Agents - metered-dose inhalers: beta2 adrenergic drugs (short-acting)

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • April 23, 2021; March 2019; March 2017; May 2016; Feb. 2016; July 2014; Oct. 2012; Oct. 2010; Jan. 2008; March 2003; March 2002; March 2001; March 2000; May 1999; Feb. 1999; Feb. 1998; March 1997; Aug. 1995
  • Initially developed
    • Jan. 1995

1.1. Adults

Beta2-adrenergic drugs, used routinely in asthma management, can be identified as long-acting or short-acting agents. Both short- and long-acting compounds can be used to prevent bronchospasm. However, short-acting compounds are the drugs of choice for acute bronchospasm as these agents act within minutes to cause bronchodilation. Drugs in this category include albuterol and levalbuterol. For acute bronchospasm, treatment is initiated with a short-acting beta2-adrenergic agent either as a metered-dose inhaler or a nebulizer solution. Treatment of acute attacks is usually for a finite time period based on the intensity of the attack and/or the need for medical attention either through emergency department management or hospitalization. Usage is individualized based on patient characteristics..

Although not FDA-approved, beta2-selective adrenergic agents such as albuterol are effective in chronic obstructive pulmonary disease (COPD) maintenance therapy to improve lung function and mucociliary clearance. Albuterol has become one of the mainstays of therapy for acute exacerbations of chronic obstructive pulmonary disease COPD due to rapid onset of action as well as efficacy in producing bronchodilation.

For preventive/ maintenance therapy, albuterol is FDA-approved as preventive therapy for exercise-induced asthma. To manage exercise-induced bronchospasm (EIB) in adults, two 90 mcg albuterol inhalations are administered at least 15 to 30 minutes before exercise on an as-needed basis.

Ipratropium/albuterol combination therapy is FDA-approved for use as second-line therapy in adult COPD patients who continue to experience bronchospasm with an aerosol bronchodilator and require a second bronchodilator.

Maximum recommended daily doses for available inhalational beta2-adrenergic agents as monotherapy and combination therapy are summarized in Tables 1 and 2. Prescribed dosages exceeding these criteria will be reviewed.

C-3.5. Table 1: Maximum Adult Daily Dose for Inhalational Beta2-Adrenergic Agents (Short-Acting) - Monotherapy

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
asthma albuterol aerosol solution (Proventil HFA®, Ventolin HFA®, ProAir HFA®, generic) aerosol (90 mcg albuterol base/actuation) 12 actuations/day (total dose = 1080 mcg albuterol base)
asthma albuterol inhalation powder (ProAir RespiClick®, ProAir Digihaler®) (90 mcg albuterol base/actuation) 12 actuations/day (total dose = 1080 mcg albuterol base)
asthma levalbuterol (Xopenex HFA®, generic) aerosol (45 mcg levalbuterol free base/actuation) 12 actuations/day (total dose = 540 mcg levalbuterol free base)

 

1.2. Pediatrics

Proventil® HFA, Ventolin® HFA, ProAir® HFA, and ProAir RespiClick® are FDA-approved for use in children 4 years of age and older for prevention/treatment of bronchospasm and prevention of exercise-induced bronchospasm. Recently, ProAir Digihaler® was also FDA-approved for use in pediatric patients 4 years of age and older to treat or prevent bronchospasm as well as prevent exercise-induced bronchospasm. Levalbuterol is FDA-approved for use in children 4 years of age and older for prevention or treatment of bronchospasm.

To prevent EIB in pediatric patients 4 years of age and older, two albuterol 90 mcg inhalations are administered at least 15 to 30 minutes before exercise on an as-needed basis.

Combination therapy with ipratropium and albuterol is not FDA-approved for use in pediatric patients as safety and efficacy in this patient population have not been established.

Pediatric dosages for short-acting beta2-agonists used to manage acute asthma exacerbations are summarized in Table 3. Dosages exceeding these recommendations will be reviewed.

Table 3: Maximum Recommended Pediatric Daily Dose for Inhalational Beta2-Adrenergic Agents (Short-Acting) - Monotherapy

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
asthma albuterol (Proventil HFA®, Ventolin HFA®, ProAir HFA®) aerosol solution (90 mcg albuterol base/actuation) Greater than or equal to 4 years of age: 12 actuations/day (total dose = 1080 mcg albuterol base)
asthma albuterol (ProAir RespiClick®, ProAir Digihaler®) inhalation powder (90 mcg albuterol base/actuation) Greater than or equal to 4 years of age: 12 actuations/day (total dose = 1080 mcg albuterol base)
asthma levalbuterol (Xopenex HFA®) aerosol (45 mcg levalbuterol free base/actuation) Greater than or equal to 4 years of age: 12 actuations/day (total dose = 540 mcg levalbuterol free base)

 

2. Duration of Therapy

Metered-dose inhalers are designed to deliver a set number of inhalations based on the canister size as well as the medication prescribed. Days’ supply for inhalational beta2-adrenergic agents is summarized in Table 4 and 5, based on the maximum recommended doses listed in Tables 1-3, and the number of actuations per canister or number of capsules per blister card listed in Tables 4 and 5. Excessive use may be identified based on refill frequency. Inappropriate supply of short-acting beta2-adrenergic agents will be monitored by reviewing excessive refills.

Table 4: Days’ Supply for Available Short-Acting Beta2-Adrenergic Agent Metered-Dose Inhalers (Adult and Pediatric Patients) - Monotherapy

Drug # of Actuations Per Canister Days’ Supply (based on maximum dose per day) +
Albuterol (ProAir HFA®)
  • 8.5 g canister
200 ~ 16 days
Albuterol (ProAir RespiClick®)
  • 0.65 g inhaler
200 ~16 days
Albuterol (ProAir Digihaler®)
  • 0.65 g inhaler
200 ~16 days
Albuterol (Proventil HFA®)
  • 6.7 g canister
200 ~16 days
Albuterol (Ventolin HFA®) 
  • 8 g canister
  • 18 g canister
60
200
5 days
~16 days
Levalbuterol (Xopenex HFA®)
  • 8.4 g canister 
  • 15 g canister
80
200
~6 days
~ 16 days

Legend:

  • + calculated based on canister size and maximum dose allowed per day (summarized in Tables 1 and 2)

3. Duplicative Therapy

The use of two or more metered-dose inhaler short-acting beta2-adrenergic compounds concurrently for prevention and control of asthma symptoms is not justified and will be reviewed. Nebulized short-acting beta2-adrenergic therapy is available for pediatric patients who are too ill or too young to obtain medication from an aerosolized metered-dose device.  However, adjunctive administration of a short-acting beta2-adrenergic agonist metered-dose inhaler with a short-acting beta2-agonist nebulized bronchodilator is also not recommended and will be reviewed.

Acute asthma exacerbations require treatment with short-acting beta2-adrenergic agents even though maintenance therapy with a long-acting beta2-agonist like salmeterol may be prescribed concomitantly. Patients may receive a long- and short-acting beta2-adrenergic drug concurrently for short time periods to manage acute attacks. Patient profiles containing excessive prescriptions for a short-acting beta2-adrenergic drug (i.e., frequent refill of short-acting beta2-adrenergic agonist within a 30-day time period) in conjunction with long-acting beta2-agonists will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug interactions considered clinically relevant for short-acting beta2-adrenergic bronchodilators are summarized in Table 6. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 6: Inhaled Short-Acting Beta2-Adrenergic Agents Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level +
beta2-agonists MAOIs (including linezolid) concurrent administration of MAOIs with beta2-agonists may increase risk of tachycardia, hypomania, or agitation due to potentiation of effects on vascular system administer combination cautiously or within 2 weeks of MAOI discontinuation; observe patients for adverse effects major (DrugReax) 2-major (CP)
beta2-agonists TCAs concurrent administration of TCAs with beta2-agonists may potentiate effects on cardiovascular system and increase risk of adverse events cautiously administer TCAs and beta2-agonists together, including within 2 weeks of TCA discontinuation; monitor patients and observe for changes in blood pressure, heart rate and ECG moderate (DrugReax) 3-moderate (CP)
beta2-agonists beta blockers concurrent administration may decrease effectiveness of beta-adrenergic blocker or beta-2 agonists combination not recommended in asthma/ COPD patients; if adjunctive therapy necessary, utilize cardioselective beta blocker (e.g., atenolol, bisoprolol) major (DrugReax) 2-major (CP)
beta2-agonists diuretics potential for worsening of diuretic- associated hypokalemia and/or ECG changes with beta2-agonist concurrent administration, especially with high beta2-agonist doses administer combination cautiously; monitor potassium levels as necessary moderate (DrugReax) 3-moderate (CP)
beta2-agonists atomoxetine concurrent administration may increase risk of cardiovascular adverse effects (e.g., tachycardia, hypertension); interaction may be less likely with inhaled beta2-agonists monitor patients for increased cardiovascular adverse effects major (DrugReax) 3-moderate (CP)
beta2-agonists QTc interval-prolonging medications (e.g., class I, III anti-arrhythmic, tricyclic antidepressants, dolasetron) concurrent administration may increase risk of cardiotoxicity (e.g., life-threatening arrhythmias, cardiac arrest) as arformoterol and formoterol may cause QTc interval prolongation and, rarely, torsades de pointes administer combination cautiously 2-major, 3-moderate (CP)
ipratropium/albuterol antimuscarinics co-administration may produce additive anticholinergic effects and potential for increased adverse effects cautiously administer ipratropium with other antimuscarinics; monitor for increased adverse effects minor (DrugReax) 3-moderate (CP)

Legend:

  • +CP = Clinical Pharmacology
  • COPD = chronic obstructive pulmonary disease
  • ECG = electrocardiogram
  • MAOIs = monoamine oxidase inhibitors
  • TCAs = tricyclic antidepressants

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: February 25, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021.  Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed February 25, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; February 25, 2021.
  4. American Society of Health-System Pharmacists. 2021. AHFS Drug Information® - 2021st Ed. Bethesda, MD. American Society of Health-System Pharmacists®. ISBN-10: 1-58528-654-0, ISBN-13: 978-1-58528-654-6. ISSN: 8756-6028. STAT!Ref Online Electronic Medical Library. https://online.statref.com/document/cQfe8yqMRNqgSGqm4Qo8Qj. Accessed February 25, 2021. 
  5. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Full Report 2007. (NIH Publication No. 07-4051). Available at:  http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed February 26, 2021.
  6. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease. 2021 report. Available at: https://goldcopd.org/2021-gold-reports/. Accessed February 26, 2021.
  7. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2020. Available from: https://ginasthma.org/reports/. Accessed February 26, 2021.
  8. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC). 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. 
  9. Diaz PT, Knoell DL. Chapter 24. Chronic obstructive pulmonary disease. In: Alldredge BK, Corelli RL, Ernst ME, et al, eds. Koda-Kimble and Young’s applied therapeutics: the clinical use of drugs. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2013:601-18.
  10. Self TH, Chrisman CR, Finch CK. Chapter 23. Asthma. In: Alldredge BK, Corelli RL, Ernst ME, et al, eds. Koda-Kimble and Young’s applied therapeutics: the clinical use of drugs.  10th ed. Philadelphia: Lippincott Williams & Wilkins; 2013:565-600.
  11. Bourdet SV, Williams DM. Chapter 44. Chronic obstructive pulmonary disease (Chapter) In: DiPiro JT, Talbert RL, Yee GC, et al. (eds): Pharmacotherapy: a pathophysiologic approach. 11th edition. New York, McGraw-Hill, 2020. Access Pharmacy Website. Available at: https://accesspharmacy-mhmedical-com.ezproxy.lib.utexas.edu/index.aspx. Accessed February 26, 2021.
  12. Albuterol inhalation aerosol (ProAir® HFA) package insert. Teva Respiratory, August 2020.
  13. Albuterol inhalation aerosol (Proventil® HFA) package insert. Merck & Co., Inc., October 2019.
  14. Albuterol inhalation aerosol (Ventolin® HFA) package insert. GlaxoSmithKline, February 2021.
  15. Levalbuterol inhalation aerosol (Xopenex HFA®) package insert. Sunovion Pharmaceuticals Inc., June 2020.
  16. Albuterol inhalation powder (ProAir RespiClick®) package insert. Teva Respiratory, October 2020.
  17. Albuterol inhalation powder (ProAir Digihaler®) package insert. Teva Respiratory, October 2020.
  18. Ipratropium/albuterol (Combivent® Respimat® Inhalation Spray) package insert.  Boehringer Ingelheim Pharmaceuticals, Inc., October 2020.
  19. Ferguson GT, Make B. Management of stable chronic obstructive pulmonary disease. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA. February 2021. (Accessed March 3, 2021.)
  20. Stoller JK. Management of exacerbations of chronic obstructive pulmonary disease. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA. February 2021. (Accessed March 3, 2021.)
  21. Blake K. Review of guidelines and the literature in the treatment of acute bronchospasm in asthma. Pharmacotherapy. 2006;26(9 Pt 2):148S-55S.
  22. Schreck DM. Asthma pathophysiology and evidence-based treatment of severe exacerbations. Am J Health-Syst Pharm. 2006;63(10 Suppl 3):S5-13.
  23. Kelly WH. Risk versus benefit considerations for the β2-agonists. Pharmacotherapy. 2006;26(9Pt2):164S-74S.
  24. Bel EH. Clinical practice. Mild asthma. N Engl J Med. 2013;369(6):549-57.
  25. McCracken JL, Veeranki SP, Ameredes BT, Calhoun WJ. Diagnosis and management of asthma in adults: a review. JAMA. 2017;318(3):279-90.

Angiotensin II Receptor Blockers

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • January 22, 2021; December 2018; December 2016; October 2014; December 2012; March 2011; April 2008; July 2003; July 2002; September 2001; September 2000; July 1999; June 1998; July 1997; December 1996
  • Initially developed
    • April 1996

1.1. Adults

Angiotensin II receptor blockers (ARBs) as monotherapy are FDA-approved for use in hypertension (all available ARBs), diabetic nephropathy (irbesartan, losartan), heart failure (candesartan, valsartan), stroke prophylaxis (losartan), cardiovascular risk reduction in patients unable to take angiotensin-converting enzyme (ACE) inhibitors (telmisartan), and post-myocardial infarction (valsartan). ARB combination therapy is FDA-approved for use in hypertension and stroke risk reduction in hypertensive patients as well as patients with left ventricular hypertrophy (Hyzaar®). Sacubitril/valsartan (Entresto®) combination therapy is FDA-approved to reduce the risk of cardiovascular death and hospitalization in chronic heart failure with reduced ejection fraction. The maximum recommended daily doses assigned to ARBs as monotherapy and combination therapy for adult patients are summarized in Tables 1 and 2. Patient profiles containing ARB dosage regimens exceeding these recommendations will be reviewed. 

Table 1: Maximum Daily Adult Dosages for Angiotensin II Receptor Blockers - Monotherapy

Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
azilsartan (Edarbi®) hypertension 40 mg, 80 mg tablets 80 mg/day
candesartan (Atacand®, generics) heart failure 4 mg, 8 mg, 16 mg, 32 mg tablets 32 mg/day
  hypertension   32 mg/day
eprosartan (generics) hypertension 600 mg tablets 900 mg/day
irbesartan (Avapro®, generics) diabetic nephropathy 75 mg, 150 mg, 300 mg tablets 300 mg/day
  hypertension   300 mg/day
losartan (Cozaar®, generics) diabetic nephropathy 25 mg, 50 mg, 100 mg tablets 100 mg/day
  hypertension   100 mg/day
  hypertension with left ventricular hypertrophy/ stroke prevention   100 mg/day
olmesartan (Benicar®, generics) hypertension 5 mg, 20 mg, 40 mg tablets 40 mg/day
telmisartan (Micardis®, generics) cardiovascular risk reduction/ stroke prevention/ myocardial infarction prevention 20 mg, 40 mg, 80 mg tablets 80 mg/day
  hypertension   80 mg/day
valsartan (Diovan®, generics) heart failure 40 mg, 80 mg, 160 mg, 320 mg tablets 320 mg/day in divided doses
  hypertension   320 mg/day
  left ventricular dysfunction/failure after myocardial infarction   320 mg/day in divided doses

Table 2: Maximum Daily Adult Dosages for Angiotensin II Receptor Blockers - Combination Therapy

Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
amlodipine/ olmesartan (Azor®, generics) hypertension 5 mg/20 mg, 10 mg/20 mg, 5 mg/40 mg, 10 mg/40 mg tablets 10 mg/40 mg/day
amlodipine/ valsartan (Exforge®, generics) hypertension 5 mg/160 mg, 5 mg/320 mg, 10 mg/160 mg, 10 mg/320 mg tablets 10 mg/320 mg/day
amlodipine/ valsartan/ hydrochlorothiazide (Exforge® HCT, generics) hypertension 5 mg/160 mg/12.5 mg, 10 mg/160 mg/12.5 mg, 5 mg/160 mg/25 mg, 10 mg/160 mg/25 mg, 10 mg/320 mg/25 mg tablets 10 mg/320 mg/25 mg/day
azilsartan/ chlorthalidone (Edarbyclor®) hypertension 40 mg/12.5 mg, 40 mg/25 mg tablets 40 mg/25 mg/day
candesartan/ hydrochlorothiazide (Atacand HCT®, generic) hypertension 16 mg/12.5 mg, 32 mg/12.5 mg, 32 mg/25 mg tablets 32 mg/25 mg/day
eprosartan/ hydrochlorothiazide (Teveten HCT®) hypertension 600 mg/ 25 mg 900 mg/ 25 mg
irbesartan/ hydrochlorothiazide (Avalide®, generic) hypertension 150 mg/12.5 mg, 300 mg/12.5 mg tablets 300 mg/25 mg/day
losartan/hydrochlorothiazide (Hyzaar®, generic) hypertension 50 mg/12.5 mg, 100 mg/12.5 mg, 100 mg/25 mg tablets 100 mg/25 mg/day
  stroke prevention in hypertension with left ventricular hypertrophy   100 mg/25 mg/day
olmesartan/ amlodipine/ hydrochlorothiazide (Tribenzor®, generics) hypertension 20 mg/5 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg, 40 mg/10 mg/25 mg tablets 40 mg/10 mg/25 mg/day
olmesartan/ hydrochlorothiazide (Benicar HCT®, generics) hypertension 20 mg/12.5 mg, 40 mg/12.5 mg, 40 mg/25 mg tablets 40 mg/25 mg/day
sacubitril/valsartan (Entresto®) heart failure 24 mg/26 mg, 49 mg/51 mg, 97 mg/103 mg tablets 194 mg/206 mg/day in two divided doses
telmisartan/ amlodipine (Twynsta®, generics) hypertension 40 mg/5 mg, 40 mg/10 mg, 80 mg/5mg, 80 mg/10 mg tablets 80 mg/10 mg/day
telmisartan/ hydrochlorothiazide (Micardis HCT®, generics) hypertension 40 mg/12.5 mg, 80 mg/12.5 mg, 80 mg/25 mg tablets 160 mg/25 mg/day
valsartan/ hydrochlorothiazide (Diovan HCT®, generic) hypertension 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg, 320 mg/ 25 mg tablets 320 mg/25 mg/day

1.2. Pediatrics

Candesartan is FDA-approved to manage hypertension in children 1 to less than 17 years of age. Losartan, olmesartan, and valsartan are FDA-approved to manage hypertension in pediatric patients 6 years of age and older. Irbesartan is not FDA-approved for use in pediatric patients and has not demonstrated sustained efficacy in managing elevated blood pressure in patients 6 years of age and older. Recommended dosages are summarized in Table 3. Dosages exceeding these recommendations will be reviewed.

The safety and efficacy of azilsartan, eprosartan, and telmisartan in pediatric patients have not been established. The safety and efficacy of ARBs in combination with hydrochlorothiazide, aliskiren, or amlodipine in pediatric patients have not been established. Nebivolol/ valsartan and sacubitril/valsartan combination therapy is not recommended for use in pediatric patients as safety and efficacy have not been established in this patient population.

Table 3: Pediatric Maximum Daily Angiotensin II Receptor Blocker Dosages for Hypertension – Monotherapy

Drug Patient Characteristics Maximum Daily Dosage
candesartan 1 to less than 6 years of age:     
6 to less than 17 years of age:  
Less than 50 kg:
Greater than 50 kg:
0.4 mg/kg/day
16 mg/day
32 mg/day
losartan 6 to 17 years of age: 1.4 mg/kg/day to a maximum of 100 mg/day
olmesartan 6 to 16 years of age:     
Less than 35 kg:  
Greater than or equal to 35 kg:  
17 years of age:
20 mg/day
40 mg/day
40 mg/day
valsartan 6 to 16 years of age:
17 years of age:
2.7 mg/kg/day to a maximum of 160 mg/day
320 mg/day

2. Duration of Therapy

There is no basis for limiting therapy duration for ARBs as reduction of cardiovascular mortality post-myocardial infarction, stroke risk reduction, managing hypertension, treating diabetic nephropathy, and managing heart failure requires chronic treatment.

3. Duplicative Therapy

Administration of two or more ARBs concurrently is not justified. Additional therapeutic benefit is not appreciated when multiple ARBs are utilized concomitantly. Patient profiles containing regimens comprised of two or more ARBs administered concurrently will be reviewed.

Recent studies have documented concurrent administration of ARBs and ACE inhibitors may result in an increased incidence of adverse effects (e.g., hypotension, hyperkalemia, syncope, renal failure) in patients with heart failure due to myocardial infarction or left ventricular dysfunction, as well as other patients at high risk for vascular events (e.g., diabetic patients) without added benefit. Additional studies have not documented significant benefit with ACE inhibitor-ARB combination therapy in managing hypertension or diabetic nephropathy. The American College of Cardiology/American Heart Association guidelines state that ARB-ACE inhibitor combination therapy may be considered in heart failure patients, not recently post myocardial infarction, who have not responded to target doses of an ACE inhibitor and beta blocker. The guidelines warn that routine combined use of an ACE inhibitor, an ARB, and an aldosterone antagonist is potentially harmful to patients with heart failure with a reduced ejection fraction. The 2017 focused update recommends an ACE inhibitor OR an ARB, but they do not explicitly address the use of both agents at the same time. Adjunctive administration of ARBs and ACE inhibitors should be considered cautiously, if at all, in these patient populations.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for ARBs are summarized in Table 4. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 4: ARB Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
ARBs, nebivolol/ valsartan, sacubitril/valsartan aliskiren increased risk for renal impairment, hyperkalemia, and hypotension with adjunctive administration most likely due to additive effects; documented in ALTITUDE trial (type 2 diabetics with renal impairment had increased stroke, renal complications, hypotension when given ARBs and aliskiren concurrently) combined administration in diabetics contraindicated by manufacturer; avoid combination in patients with CrCl less than 60 ml/min; use cautiously together in other patients and closely monitor renal function, serum potassium levels contraindicated (DrugReax) - 2-major (CP)
ARBs, nebivolol/ valsartan, sacubitril/valsartan lithium potential for enhanced lithium pharmacologic/adverse effects with combined administration; speculated that ARBs augment lithium reabsorption by decreasing lithium renal excretion monitor patients for increased signs/symptoms of lithium toxicity and adjust lithium doses as necessary; may select alternate cardiovascular therapy that does not interact with lithium major (DrugReax) - 3-moderate (CP)
ARBs, nebivolol/valsartan, sacubitril/valsartan nonsteroidal anti-inflammatory drugs combined administration may increase risk for renal function deterioration and alter response to antihypertensives, especially in volume-depleted, elderly, or renally compromised patients, due to vasodilatory prostaglandin inhibition monitor renal function, antihypertensive efficacy when combined administration required

moderate (DrugReax) - 3-moderate (CP)

ARBs, nebivolol/ valsartan, sacubitril/valsartan potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements combined therapy may increase risk for hyperkalemia as ARBs reduce circulating aldosterone concentrations, resulting in potassium retention; elderly as well as patients with impaired renal function, diabetes,  or high potassium diets may be at greater risk measure serum potassium concentrations, monitor for signs and symptoms of hyperkalemia when administered concurrently, especially in patients with predisposing factors moderate (DrugReax) - 2-major (CP)
nebivolol/valsartan CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) adjunctive administration may result in enhanced nebivolol pharmacologic effects (e.g., reduced heart rate, hypotension) due to increased nebivolol serum levels as nebivolol is metabolized by CYP2D6 combined use should be avoided; if concurrent administration necessary, monitor patients for unwanted pharmacologic/ adverse effects; adjust dosages as needed major (DrugReax) - 2-major (CP)
nebivolol/valsartan hypotensive agents concurrent administration may result in large reductions in sympathetic activity due to added beta-blocking activity; patients may have increased orthostasis and bradycardia avoid nebivolol use with other beta blockers; withdraw nebivolol slowly over several days in patients prescribed clonidine concurrently 2-major, 3-moderate (CP)
nebivolol/valsartan digitalis glycosides co-administration may increase bradycardia risk as both nebivolol and digitalis glycosides reduce atrioventricular conduction and decrease heart rate administer nebivolol with digitalis glycosides cautiously and monitor heart rate moderate (DrugReax) - 3-moderate (CP)
nebivolol/valsartan calcium channel blockers combined use of beta blockers like nebivolol with calcium channel blockers can be useful in some circumstances; however, combined administration may result in additive negative inotropic and/or chronotropic effects if combined therapy needed, monitor heart rate and cardiac conduction; adjust doses as necessary moderate (DrugReax) - 3-moderate (CP)

Legend:

  • * Clinical Pharmacology

5. References

  1. Azilsartan tablets (Edarbi™) package insert. Arbor Pharmaceuticals, Inc./ Takeda, June 2020.
  2. Candesartan tablets (Atacand®) package insert. ANI Pharmaceuticals, Inc., June 2020.
  3. Eprosartan tablets package insert. Mylan Pharmaceuticals, Inc., December 2014.
  4. Irbesartan tablets (Avapro®) package insert.  Sanofi-Aventis, November 2020.
  5. Losartan/hydrochlorothiazide tablets (Hyzaar®) package insert. Merck & Co., Inc., August 2020.
  6. Losartan tablets (Cozaar®) package insert. Merck & Co., November 2019.
  7. Olmesartan tablets (Benicar®) package insert. Daiichi Sankyo, Inc., July 2020.
  8. Olmesartan/amlodipine/hydrochlorothiazide tablets (Tribenzor®) package insert. Daiichi Sankyo, Inc., October 2020.
  9. Telmisartan tablets (Micardis®) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., September 2020.
  10. Telmisartan/hydrochlorothiazide tablets (Micardis® HCT) package insert.  Boehringer Ingelheim Pharmaceuticals, Inc., August 2020.
  11. Telmisartan/amlodipine tablets (Twynsta®) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., January 2020.
  12. Valsartan tablets (Diovan®) package insert. Novartis, November 2020.
  13. Valsartan/hydrochlorothiazide tablets (Diovan HCT®) package insert.  Novartis, November 2020.
  14. Amlodipine/valsartan tablets (Exforge®) package insert. Novartis, November 2020.
  15. Amlodipine/valsartan/hydrochlorothiazide tablets (Exforge® HCT) package insert. Novartis, November 2020.
  16. Azilsartan/chlorthalidone (Edarbyclor®) package insert. Arbor Pharmaceuticals, Inc./Takeda, June 2020.
  17. U.S. Food and Drug Administration. Current and Resolved Drug Shortages and Discontinuations Reported to FDA: nebivolol hydrochloride and valsartan (Byvalsan®) discontinuation. Available at: https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Nebivolol%20Hydrochloride%20and%20Valsartan%20(BYVALSAN)%20Tablets&st=d. Accessed November 30, 2020.
  18. Sacubitril/valsartan (Entresto®) package insert. Novartis, November 2020.
  19. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2020. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed November 29, 2020.
  20. IMB Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu. Accessed November 29, 2020.
  21. Facts & Comparisons eAnswers [database online].  Hudson, Ohio:  Wolters Kluwer Clinical Drug Information, Inc.; 2020. Available at:  http://online.factsandcomparisons.com.ezproxy.lib.utexas.edu/index.aspx. Accessed November 29, 2020.
  22. AHFS Drug Information 2020.  Bethesda, MD: American Society of Health-System Pharmacists. 2020. Available at: https://online-statref-com.libproxy.uthscsa.edu. Accessed November 29, 2020.
  23. Litwin M, Grenda R, Sladowska J, Antoniewicz J. Add-on therapy with angiotensin II receptor 1 blocker in children with chronic kidney disease already treated with angiotensin-converting enzyme inhibitors. Pediatr Nephrol. 2006;21:1716-22.
  24. Majani G, Giardini A, Opasich C, et al. Effect of valsartan on quality of life when added to usual therapy for heart failure: results from the Valsartan Heart Failure Trial. J Cardiac Fail. 2005;11:253-9.
  25. Fujisawa T, Ikegami H, Ono M, et al. Combination of half doses of angiotensin type 1 receptor antagonist and angiotensin-converting enzyme inhibitor in diabetic nephropathy. Am J Hypertens. 2005;18:13-7.
  26. Cocco G, Kohn S, Jerie P. Effects of combined treatment with enalapril and losartan on myocardial function in heart failure. Heart. 2002;88:185-6.
  27. Bohm M. Angiotensin receptor blockers versus angiotensin-converting enzyme inhibitors: where do we stand now? Am J Cardiol. 2007;100(suppl):38J-44J.
  28. Matchar DB, McCrory DC, Orlando LA, et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med. 2008;148:16-29.
  29. McCall KL, Craddock D, Edwards K. Effect of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers on the rate of new-onset diabetes mellitus: a review and pooled analysis. Pharmacotherapy. 2006;26:1297-306.
  30. Finnegan PM, Gleason BL. Combination ACE inhibitors and angiotensin II receptor blockers for hypertension. Ann Pharmacother. 2003;37:886-9.
  31. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-59.
  32. Phillips CO, Kashani A, Ko DK, et al. Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction. A quantitative review of data from randomized clinical trials. Arch Intern Med. 2007;167:1930-6.
  33. Baker WL, Coleman CI, Kluger J, et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers for ischemic heart disease. Ann Intern Med. 2009;151(12):861-71.
  34. Catanzaro DF, Frishman WH. Angiotensin receptor blockers for management of hypertension. South Med J. 2010;103(7):669-73.
  35. Holdiness A, Monahan K, Minor D, de Shazo RD. Renin angiotensin aldosterone system blockade: little to no rationale for ACE inhibitor and ARB combinations. Am J Med. 2011;124(1):15-9.
  36. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547-59.
  37. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;128:e240-e327.
  38. Yancy Clyde W., Jessup Mariell, Bozkurt Biykem, et al. 2017 acc/aha/hfsa focused update of the 2013 accf/aha guideline for the management of heart failure. Journal of the American College of Cardiology. 2017;70(6):776-803.
  39. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-20.
  40. U.S. Food and Drug Administration. FDA Drug Safety Communication: new warning and contraindication for blood pressure medicines containing aliskiren (Tekturna). (April 20, 2012)  Available at:  http://www.fda.gov/Drugs/DrugSafety/ucm300889.htm . Accessed November 29, 2020.
  41. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;71:e127-e248.
  42. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64:e139-e228.

Angiotensin-Converting Enzyme Inhibitors

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Initially developed
    • June 1996
  • Revision history
    • January 22, 2021; December 2018; December 2016; December 2014; March 2013; April 2011; March 2011; April 2008; June 2003; July 2002; September 2001; June 2001; June 2000; July 1999; June 1998; June 1997

1.1. Adults

Angiotensin-converting enzyme (ACE) inhibitors are FDA-approved for use in adults for diabetic nephropathy (captopril only), heart failure, hypertension, and improved survival/reduction of complications post-myocardial infarction. Combination therapy is FDA-approved for the management of hypertension. ACE inhibitors are available as monotherapy as well as combination products with a calcium channel blocker or hydrochlorothiazide. Adult maximum daily doses for ACE inhibitors are summarized in Tables 1 and 2 for mono- and combination therapy, respectively. Dosages exceeding these recommendations will be reviewed.

Table 1: ACE Inhibitors as Monotherapy - Maximum Daily Adult Dose

Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
benazepril (Lotensin®, generics) hypertension 5 mg, 10 mg, 20 mg, 40 mg tablets 80 mg/day*
captopril (generics) diabetic nephropathy/ proteinuria 12.5 mg, 25 mg, 50 mg, 100 mg tablets 150 mg/day
  heart failure   450 mg/day
  hypertension   450 mg/day
  post-myocardial infarction   150 mg/day
enalapril (Vasotec®, generics; Epaned®) asymptomatic left ventricular dysfunction 2.5 mg, 5 mg, 10 mg, 20 mg tablets; 1 mg/ml oral solution 20 mg/day
  heart failure   40 mg/day
  hypertension   40 mg/day
fosinopril (generics) heart failure 10 mg, 20 mg (generic only), 40 mg tablets 40 mg/day
  hypertension   80 mg/day
lisinopril (Prinivil®, Zestril®, generics; Qbrelis®) acute myocardial infarction
 
2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg tablets; 1 mg/ml oral solution 10 mg/day
  heart failure   40 mg/day
  hypertension   80 mg/day
moexipril (generics) hypertension 7.5 mg, 15 mg tablets 30 mg/day
perindopril (Aceon®, generics) hypertension 2 mg, 4 mg, 8 mg tablets

16 mg/day

elderly, renal function impairment:  8 mg/day

  myocardial infarction prophylaxis   8 mg/day
quinapril (Accupril®, generics) heart failure 5 mg, 10 mg, 20 mg, 40 mg tablets 40 mg/day
  hypertension   80 mg/day
ramipril (Altace®, generics) heart failure (post myocardial infarction) 1.25 mg, 2.5 mg, 5 mg, 10 mg capsules 10 mg/day
  hypertension   20 mg/day
  myocardial infarction/ stroke prophylaxis in patients 55 years of age or older   10 mg/day
trandolapril (generics) hypertension 1 mg, 2 mg, 4 mg tablets 8 mg/day
  post myocardial infarction (heart failure, left ventricular dysfunction)   4 mg/day

Legend:

  • *Doses as high as 80 mg have provided increased response; however, experience with these higher dosages is limited.

Table 2: Adult Maximum Dosage Recommendations for ACE Inhibitor Combination Therapy in Hypertension Management

Drug Name Dosage Form/Strength Maximum Recommended Dosage
amlodipine/benazepril (Lotrel®, generics) 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg, 10 mg/40 mg capsules 10 mg/40 mg/day
benazepril/hydrochlorothiazide (Lotensin HCT®, generics) 5 mg/6.25 mg (generic only), 10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg tablets 20 mg/25 mg/day
captopril/hydrochlorothiazide (generics) 25 mg/15 mg, 25 mg/25 mg, 50 mg/15 mg, 50 mg/25 mg tablets150 mg/50 mg/day 150 mg/50 mg/day
enalapril/hydrochlorothiazide (Vaseretic®, generics) 5 mg/12.5 mg (generic only), 10 mg/25 mg tablets 20 mg/50 mg/day
fosinopril/hydrochlorothiazide (generics) 10 mg/12.5 mg, 20 mg/12.5 mg tablets 80 mg/50 mg/day
lisinopril/hydrochlorothiazide (Zestoretic®, generics) 10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg tablets 80 mg/50 mg/day
moexipril/hydrochlorothiazide (generics) 7.5 mg/12.5 mg, 15 mg/12.5 mg, 15 mg/25 mg tablets 30 mg/50 mg/day
perindopril/amlodipine (Prestalia®) 3.5 mg/2.5 mg, 7 mg/5 mg, 14 mg/10 mg tablets 14 mg/10 mg/day
quinapril/hydrochlorothiazide (Accuretic®, generics) 10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg tablets 40 mg/25 mg/day
trandolapril/verapamil (Tarka®, generics) 1 mg/240 mg, 2 mg/180 mg, 2 mg/240 mg, 4 mg/240 mg extended-release tablets 4 mg/240 mg/day

1.2. Pediatrics

Select ACE inhibitors are FDA-approved for use to manage hypertension in pediatric patients. Maximum recommended ACE inhibitor doses for pediatric patients are summarized in Table 3. Dosages exceeding these recommendations will be reviewed.

2. Duration of Therapy

There is no basis for limiting ACE inhibitor therapy duration when utilized to manage hypertension, heart failure, and proteinuria associated with diabetic nephropathy, as these conditions require chronic treatment. The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) focused update supports that ACE inhibitor use reduces cardiovascular morbidity and mortality in heart failure patients with reduced ejection fraction. Additionally, the ACC/AHA 2013 guidelines for ST-elevation myocardial infarction (STEMI) recommend immediate ACE inhibitor therapy within the first 24 hours) in patients with an anterior infarction, heart failure, or ejection fraction less than 0.40 who have no contraindications for ACE inhibitor use as well, as indefinite therapy with ACE inhibitors post-myocardial infarction for these patients. The ACC/AHA 2014 guidelines for unstable angina/non-STEMI patients recommend immediate ACE inhibitor therapy (within first 24 hours) in those with pulmonary congestion or left ventricular ejection fraction less than 0.40, and no hypotension or contraindications to ACE inhibitor therapy. These guidelines also recommend prolonged use of ACE inhibitors in patients with heart failure, left ventricular ejection fraction less than 0.40, hypertension, or diabetes mellitus without contraindications to ACE inhibitor therapy to reduce cardiovascular mortality.

3. Duplicative Therapy

The use of two or more ACE inhibitors concurrently is not justified. Additional therapeutic benefit is not realized when ACE inhibitors are used in combination.  Patient profiles documenting the receipt of multiple ACE inhibitors will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for ARBs are summarized in Table 4. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 4: ACE Inhibitor Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
ACE inhibitors aliskiren potential for additive hypotensive effects; increased hyperkalemia risk with this drug combination as both decrease serum aldosterone levels  administer drug combination cautiously; monitor serum potassium levels closely moderate (DrugReax) 3-moderate (CP)
ACE inhibitors angiotensin II receptor blockers potential for enhanced pharmacologic/ adverse effects (e.g., hypotension, hyperkalemia, changes in renal function) as both agents block renin-angiotensin-aldosterone system avoid combination; if concurrent therapy necessary, monitor blood pressure, potassium and renal function and observe for adverse events major (DrugReax) 2-major (CP)
ACE inhibitors antidiabetic agents potential for enhanced hypoglycemic effects due to improved insulin sensitivity by ACE inhibitors closely monitor blood glucose levels; reduced antidiabetic doses may be necessary moderate (DrugReax) 3-moderate (CP)
ACE inhibitors azathioprine increased risk of anemia, leukopenia with drug combination; mechanism unknown avoid combination, if possible; if combined therapy necessary, monitor for myelosuppression major (DrugReax) 2-major (CP)
lisinopril clozapine potential for increased serum clozapine levels and enhanced pharmacologic, adverse effects; lisinopril may decrease clozapine renal elimination through unknown mechanism assess clinical response, monitor serum clozapine levels if drug combination utilized 3-moderate (CP)
ACE inhibitors cyclosporine increased risk of acute renal failure, hyperkalemia with drug combination due to ACE inhibition, which causes decreased angiotensin II and aldosterone closely monitor renal function and serum potassium levels  moderate (DrugReax) 3-moderate (CP)
ACE inhibitors entecavir potential for increased entecavir serum levels and enhanced pharmacologic/
adverse effects due to ACE inhibitor effects on renal function
monitor for increased adverse events if drug combination is administered 3-moderate (CP)
ACE inhibitors eplerenone increased risk of hyperkalemia as both agents decrease aldosterone levels  closely monitor serum potassium levels 2-major (CP)
ACE inhibitors lithium potential for increased serum lithium levels and enhanced pharmacologic, toxic effects, possibly due to decreased lithium clearance avoid combination, if possible; if drug combination necessary, monitor serum lithium levels and observe for signs of lithium toxicity moderate (DrugReax) 3-moderate (CP)
ACE inhibitors monoamine oxidase inhibitors potential for additive hypotensive effects monitor blood pressure closely, if drug combination utilized 3-moderate (CP)
ACE inhibitors NSAIDs, salicylates, COX-2 inhibitors potential for decreased antihypertensive effects, increased renal impairment risk (especially in patents dependent on renal prostaglandins for perfusion), with combined therapy due to inhibition of prostaglandin synthesis monitor blood pressure, renal function, and clinical status if drug combination utilized; low-dose aspirin less likely to reduce ACE inhibitor antihypertensive, cardioprotective effects moderate (DrugReax) 3-moderate (CP)
ACE inhibitors potassium-sparing diuretics, potassium salts ACE inhibitors reduce aldosterone concentrations, resulting in increased potassium concentrations; increased hyperkalemia risk with drug combination due to additive pharmacologic effects monitor serum potassium levels and signs/symptoms of hyperkalemia if drug combination administered; patients with renal failure, diabetes, advanced age may be at increased risk; use combination cautiously in heart failure patients major (DrugReax) 2-major (CP)
ACE inhibitors pregabalin combined therapy may increase risk of developing life-threatening angioedema with respiratory compromise observe patients closely if drug combination utilized 2-major (CP)
ACE inhibitors sacubitril/ valsartan (Entresto®) concurrent administration may result in angioedema due to inhibition of bradykinin degradation  avoid drug combination; monitor blood pressure, renal function, and electrolytes if combined therapy is utilized contraindicated (DrugReax) 1-contraindicated (CP)
ACE inhibitors trimethoprim co-administration may increase risk of additive hyperkalemia due to decreased aldosterone synthesis by ACE inhibitor and potassium-sparing effect on distal nephron by trimethoprim monitor serum potassium levels and monitor patients for signs/symptoms of hyperkalemia if drug combination administered moderate (DrugReax) 2-major (CP)
trandolapril/verapamil flibanserin (Addyi®) verapamil (CYP3A4 inhibitor) and flibanserin (CYP3A4 substrate) administered concurrently may result in increased serum flibanserin levels with resultant severe hypotension, syncope, sedation  avoid combined use; if adjunctive use necessary, discontinue CYP3A4 inhibitor for at least 2 weeks before initiating/reinitiating flibanserin therapy, or discontinue flibanserin at least 2 days before starting/restarting CYP3A4 inhibitor therapy contraindicated (DrugReax) 1-severe (CP)
trandolapril/verapamil colchicine colchicine is p-glycoprotein (P-gp) and CYP3A4 substrate; adjunctive use may result in increased colchicine serum concentrations and enhanced pharmacologic/ adverse effects due to P-gp and CYP3A4 inhibition by verapamil avoid concurrent use; if combined use necessary, observe for serious colchicine adverse effects, including neuromuscular toxicity, and adjust colchicine dosages contraindicated (DrugReax) 2-major (CP)
trandolapril/verapamil dofetilide (Tikosyn®) concomitant administration may result in increased cardiotoxicity risk (e.g., torsades de pointes, QT interval prolongation, cardiac arrest) due to increased dofetilide absorption/serum levels combined use is contraindicated contraindicated (DrugReax) 1-severe (CP)

Legend:

  • *Clinical Pharmacology

5. References

  1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2020. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed November 23, 2020.
  2. IMB Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu. Accessed November 23, 2020.
  3. Facts & Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2020. Available at:  http://online.factsandcomparisons.com.ezproxy.lib.utexas.edu/index.aspx. Accessed November 23, 2020.
  4. AHFS Drug Information 2020. Bethesda, MD: American Society of Health-System Pharmacists. 2020. Available at: https://online-statref-com.libproxy.uthscsa.edu. Accessed November 23, 2020.
  5. Benazepril/hydrochlorothiazide (Lotensin HCT®) package insert. Validus Pharmaceuticals, October 2020.
  6. Quinapril/hydrochlorothiazide (Accuretic®) package insert. Pfizer, May 2020.
  7. Enalapril oral solution (Epaned®) package insert. Azurity Pharmaceuticals, Inc., March 2020.
  8. Lisinopril oral solution (Qbrelis®) package insert. Azurity Pharmaceuticals, Inc., March 2020.
  9. Perindopril/amlodipine tablets (Prestalia®) package insert. Adhera Therapeutics, Inc., October 2019.
  10. Trandolapril/verapamil tablets (Tarka®) package insert. AbbVie Inc., November 2020.
  11. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;71:e127-e248.
  12. Unger Thomas, Borghi Claudio, Charchar Fadi, et al. 2020 international society of hypertension global hypertension practice guidelines. Hypertension. 2020;75(6):1334-1357.
  13. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017;70:776-803.
  14. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64:e139-e228.
  15. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:e78-e140.
  16. Reeder GS. Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: recommendations for use. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on November 24, 2020.)
  17. Hoogwerf BJ. Renin–angiotensin system blockade and cardiovascular and renal protection. Am J Cardiol. 2010;105[suppl]:30A–35A.
  18. Pregabalin (Lyrica®) package insert. Pfizer, June 2020.
  19. Bangalore S, Fakheri R, Wandel S, et al. Renin angiotensin system inhibitors for patients with stable coronary artery disease without heart failure: systematic review and meta-analysis of randomized trials. BMJ. 2017;356:j4.
  20. Potier L, Roussel R, Elbez Y, et al . Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in high vascular risk. Heart 2017;103:1339-46.
  21. Bavishi C, Bangalore S, Messerli FH. Renin angiotensin aldosterone system inhibitors in hypertension: is there evidence for benefit independent of blood pressure reduction? Prog Cardiovasc Dis. 2016;59(3):253-61.

Anti-depressants, oral (other)

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • April 23, 2021; March 2019; March 2017; April 2015; March 2015; June 2013; July 2011; September 2009; August 2009; March 2009; December 2003; November 2002; October 2002; November 2001; September 2001; October 2000; January 2000; October 1999; October 1998; September 1997; December 1996
  • Initially developed
    • January 1995

1.1. Adults

The FDA requires that all antidepressant drugs display a black box warning describing the potential for increased suicidal thinking and behavior when prescribed to young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders. In short-term clinical trials, the suicide risk was increased in young adults managed with antidepressants compared to those receiving placebo in the first few months of treatment. Suicide risk was not shown to increase in adults over 24 years of age, and patients 65 years of age and older manifested a decreased suicide risk. Young adult patients prescribed antidepressant drugs should be closely monitored for changes in behavior.

Nonselective serotonin reuptake inhibitor monotherapy antidepressant drugs are FDA-approved for use in MDD, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder (PD). Additionally, bupropion is FDA-approved for seasonal affective disorder (AD) and smoking cessation (SC), milnacipran is FDA-approved for fibromyalgia (F) management, and duloxetine is FDA-approved for neuropathic pain (NP), F, and chronic musculoskeletal pain in adults (CMP). Recently, doxepin has received FDA approval for insomnia in adults (I). Vilazodone, a selective serotonin reuptake inhibitor (SSRI) as well as a partial agonist at the 5-HT1A receptor, is FDA-approved for MDD. Levomilnacipran (Fetzima®), a serotonin and norepinephrine reuptake inhibitor (SNRI) and an enantiomer of milnacipran, has also been FDA-approved for use in treating MDD. The antidepressant agent, vortioxetine, an SSRI that also acts as an agonist at 5-HT1A receptors and an antagonist at 5-HT3 receptors, has gained FDA approval to manage MDD. Combination therapy is FDA-approved for severe depression, treatment-resistant depression (TRD), and moderate anxiety/agitation/depression.

Maximum recommended daily doses for antidepressant drugs in adults, including the elderly population, are summarized in Tables 1-6. Maximum recommended dosages for antidepressant combination therapy are summarized in Table 7.  However, in all patients, the lowest effective antidepressant dose should be utilized to minimize unwanted adverse effects. Patient profiles with antidepressant dosages exceeding these recommendations will be reviewed.

Table 1: Adult and Elderly Maximum Recommended Antidepressant Dosages (Monotherapy) - Tricyclic Antidepressants

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage 
MDD amitriptyline (Elavil®, generics) generics: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg tablets
  • Less than or equal to 65 years:
    • 150 mg/day
  • Greater than 65 years:
    • 150 mg/day
MDD amoxapine (generics) 25 mg, 50 mg, 100 mg, 150 mg tablets
  • Less than or equal to 65 years:
    • 300 mg/day *
  • Greater than 65 years:
    • 300 mg/day *
OCD clomipramine (Anafranil®, generics) 25 mg, 50 mg 75 mg capsules
  • Less than or equal to 65 years:
    • 250 mg/day
  • Greater than 65 years:
    • 250 mg/day
MDD desipramine (Norpramin®, generics) generics: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg tablets
Norpramin®: 10 mg, 25 mg tablets
  • Less than or equal to 65 years:
    • 300 mg/day
  • Greater than 65 years:
    • 150 mg/day
MDD doxepin (generics) 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg capsules; 10 mg/mL oral concentrate
  • Less than or equal to 65 years:
    • mild to moderate illness:
      • 150 mg/day
  • Greater than 65 years:
    • mild to moderate illness:
      • 150 mg/day
     
  • Less than or equal to 65 years:
    • severe illness:
      • 300 mg/day
  • Greater than 65 years:
    • severe illness:
      • 300 mg/day
Anxiety#    
  • Less than or equal to 65 years:
    • mild to moderate illness:
      • 150 mg/day
  • Greater than 65 years:
    • mild to moderate illness:
      • 150 mg/day
     
  • Less than or equal to 65 years:
    • severe illness:
      • 300 mg/day
  • Greater than 65 years:
    • severe illness:
      • 300 mg/day
I doxepin (Silenor®) 3 mg, 6 mg tablets
  • Less than or equal to 65 years:
    • 6 mg/day
  • Greater than 65 years:
    • 6 mg/day
MDD imipramine (Tofranil®, generics) generics:10 mg, 25 mg, 50 mg tablets; 75 mg 100 mg, 125 mg, 150 mg capsules
Tofranil®: 10 mg, 25 mg tablets
  • Less than or equal to 65 years:
    • 200 mg/day
  • Greater than 65 years:
    • 100 mg/day ^
MDD nortriptyline (Pamelor®, generics) 10 mg, 25 mg, 50 mg, 75 mg capsules; 10 mg/5 mL oral solution (generic only)
  • Less than or equal to 65 years:
    • 150 mg/day
  • Greater than 65 years:
    • 50 mg/day
MDD protriptyline (generics) 5 mg, 10 mg tablets
  • Less than or equal to 65 years:
    • 60 mg/day
  • Greater than 65 years:
    • 30 mg/day+
MDD trimipramine (generics) 25 mg, 50 mg 100 mg capsules
  • Less than or equal to 65 years:
    • 200 mg/day
  • Greater than 65 years:
    • 100 mg/day

Legend:

  • I = insomnia
  • MDD = major depressive disorder
  • OCD = obsessive-compulsive disorder 
  • * The maximum amoxapine dose in elderly patients and in most adults is 300 mg/day. Those patients Less than or equal to 65 years of age who have not responded adequately to a two-week trial utilizing 300 mg/day may receive a trial of 400 mg amoxapine per day.  
  • + Elderly patients should usually be given lower than average protriptyline doses. Elderly patients receiving protriptyline doses greater than 20 mg daily should receive close cardiac monitoring. 
  • # Doxepin is also recommended for depression and anxiety associated with psychoneurosis, alcoholism, and organic disease.
  • ^ may increase to 150 mg/day if needed; doses usually do not exceed 100 mg/day in geriatric patients

Table 2: Adult and Elderly Maximum Recommended Antidepressant Dosages (Monotherapy) - Tetracyclic Antidepressants

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage
MDD maprotiline (generics) 25 mg, 50 mg, 75 mg tablets
  • Less than or equal to 65 years:
    • 150 mg/day **
    • Greater than 65 years:
      • 150 mg/day **
MDD mirtazapine (Remeron®, generics) 7.5 mg, 15 mg, 30 mg, 45 mg tablets; 15 mg, 30 mg, 45 mg orally disintegrating tablets
  • Less than or equal to 65 years:
    • 45 mg/day
  • Greater than 65 years:
    • 45 mg/day

Legend:

  • MDD = major depressive disorder 
  • **Maximum maprotiline doses listed are for outpatient use; maprotiline is also FDA approved for anxiety associated with depression, dysthymic disorder, and the depressive component of bipolar disorder
     

Table 3: Adult and Elderly Maximum Recommended Antidepressant Dosages (Monotherapy) - Monoamine Oxidase Inhibitors

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage 
MDD isocarboxazid (Marplan®) 10 mg tablets
  • Less than or equal to 65 years:
    • 60 mg/day
  • Greater than 65 years:
    • 60 mg/day *
MDD phenelzine (Nardil®, generics) 15 mg tablets
  • Less than or equal to 65 years:
    • 90 mg/day
  • Greater than 65 years:
    • 90 mg/day *
MDD selegiline (EMSAM®) transdermal patch  6 mg/ 24 hours, 9 mg/ 24 hours, 12 mg/ 24 hours transdermal patch
  • Less than or equal to 65 years:
    • 12 mg/ 24 hours
  • Greater than 65 years:
    • 12 mg/ 24 hours
MDD tranylcypromine (Parnate®, generics) 10 mg tablets
  • Less than or equal to 65 years:
    • 60 mg/day
  • Greater than 65 years:
    • 60 mg/day*

Legend:

  • MDD = major depressive disorder 
  • * Use MAOIs cautiously in elderly patients due to a greater risk of morbidity if hypertensive crisis develops

Table 4: Adult and Elderly Maximum Recommended Antidepressant Dosages (Monotherapy) – Serotonin and Norepinephrine Reuptake Inhibitors

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage
MDD desvenlafaxine (Pristiq®, generics, Khedezla®) 25 mg, 50 mg 100 mg 24-hour ER tablets
  • Less than or equal to 65 years:
    • 400 mg/day^
  • Greater than 65 years:
    • 400 mg/day^
CMP, F, NP duloxetine (Cymbalta®, Drizalma Sprinkle®, generics) 20 mg, 30 mg, 40 mg 60 mg delayed-release capsules
  • Less than or equal to 65 years:
    • 60 mg/day
  • Greater than 65 years:
    • 60 mg/day
GAD, MDD    
  • Less than or equal to 65 years:
    • 120 mg/day #
  • Greater than 65 years:    
    • 120 mg/day #
MDD levomilnacipran (Fetzima®) 20 mg, 40 mg 80 mg, 120 mg 24-hour ER capsules
  • Less than or equal to 65 years:
    • 120 mg/day
  • Greater than 65 years:
    • 120 mg/day
F milnacipran (Savella®)12.5 mg, 25 mg, 50 mg 100 mg tablets 12.5 mg, 25 mg, 50 mg 100 mg tablets
  • Less than or equal to 65 years:
    • 200 mg/day
  • Greater than 65 years:
    • 200 mg/day
MDD venlafaxine (generics) 25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg IR tablets
  • Less than or equal to 65 years:
    • 375 mg/day ~
  • Greater than 65 years:
    • 375 mg/day ~
GAD, MDD, PD venlafaxine (Effexor XR®, generics) 37.5 mg, 75 mg, 150 mg 24-hour ER capsules
  • Less than or equal to 65 years:
    • 225 mg/day
  • Greater than 65 years:
    • 225 mg/day
SAD    
  • Less than or equal to 65 years:
    • 75 mg/day
  • Greater than 65 years:
    • 75 mg/day
MDD venlafaxine (generics) 37.5 mg, 75 mg, 150 mg, 225 mg 24-hour ER tablets
  • Less than or equal to 65 years:
    • 225 mg/day
  • Greater than 65 years:
    • 225 mg/day
SAD    
  • Less than or equal to 65 years:
    • 75 mg/day
  • Greater than 65 years:
    • 75 mg/day

Legend:

  • CMP = chronic musculoskeletal pain
  • F = fibromyalgia
  • GAD = generalized anxiety disorder
  • MDD = major depressive disorder
  • NP = neuropathic pain
  • PD = panic disorder
  • SAD = social anxiety disorder
  • ^ In studies, desvenlafaxine doses up to 400 mg per day were no more effective than 50 mg daily doses and were associated with increased adverse events. 
  • # Duloxetine doses of 120 mg, while effective, are no more effective than 60 mg daily doses.
  • ~ The maximum recommended venlafaxine dose is 225 mg/day for moderately depressed outpatients.  Dosages Greater than 225 mg/day in moderately depressed outpatients do not demonstrate additional efficacy.  However, more severely depressed inpatients may respond to venlafaxine dosages up to 375 mg/day.

Table 5: Adult and Elderly Maximum Recommended Antidepressant Dosages (Monotherapy) – Selective Serotonin Reuptake Inhibitors (SSRIs)/5-HT1A Receptor Agonists and SSRIs/5-HT1A Receptor Agonists/5-HT3 Receptor Antagonists

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage
MDD vilazodone (Viibryd®) 10 mg, 20 mg, 40 mg tablets
  • Less than or equal to 65 years:
    • 40 mg/day
  • Greater than  65 years:
    • 40 mg/day
MDD vortioxetine (Trintellix®) 5 mg, 10 mg, 20 mg tablets
  • Less than or equal to 65 years:
    • 20 mg/day
  • Greater than  65 years:    
    • 20 mg/day

Legend:

  • MDD = major depressive disorder 

Table 6: Adult and Elderly Maximum Recommended Antidepressant Dosages (Monotherapy) – Miscellaneous Agents

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage
MDD bupropion (generics)  75 mg, 100 mg IR tablets
  • Less than or equal to 65 years:
    • 450 mg/day
  • Greater than 65 years:
    • 450 mg/day
MDD bupropion (Forfivo XL®, Wellbutrin XL®, generics) Wellbutrin XL®, generics: 150 mg, 300 mg 24-hour ER tablets
Forfivo XL®, generics:
450 mg 24-hour-ER tablets
  • Less than or equal to 65 years:
    • 450 mg/day
  • Greater than 65 years:
    • 450 mg/day
MDD bupropion (Wellbutrin SR®, generics) 100 mg, 150 mg, 200 mg 12-hour ER tablets
  • Less than or equal to 65 years:
    • 400 mg/day
  • Greater than 65 years:
    • 400 mg/day
MDD bupropion (Aplenzin®) 174 mg, 348 mg, 522 mg 24-hour ER tablets
  • Less than or equal to 65 years:
    • 522 mg/day
  • Greater than 65 years:
    • 522 mg/day
AD    
  • Less than or equal to 65 years:
    • 348 mg/day
  • Greater than 65 years:
    • 348 mg/day
AD bupropion (Wellbutrin XL®, generics) Wellbutrin XL®, generics: 150 mg, 300 mg 24-hour ER tablets
  • Less than or equal to 65 years:
    • 300 mg/day
  • Greater than 65 years:
    • 300 mg/day
SC bupropion (generics) 150 mg 12-hour ER tablets
  • Less than or equal to 65 years:
    • 300 mg/day
  • Greater than 65 years:
    • 300 mg/day
MDD nefazodone (generics) 50 mg, 100 mg, 150 mg, 200 mg, 250 mg tablets
  • Less than or equal to 65 years:
    • 600 mg/day
  • Greater than 65 years:
    • 600 mg/day
MDD trazodone (generics) 50 mg, 100 mg, 150 mg, 300 mg IR tablets
  • Less than or equal to 65 years:
    • outpatients:
      • 400 mg/day
  • Greater than 65 years:
    • outpatients:
      • 400 mg/day
MDD trazodone (Oleptro®) 150 mg, 300 mg 24-hour ER tablets
  • Less than or equal to 65 years:
    • 375 mg/day
  • Greater than 65 years:
    • 375 mg/day

Legend:

  • AD = seasonal affective disorder
  • MDD = major depressive disorder
  • SC = smoking cessation

Table 7: Adult Maximum Recommended Antidepressant Dosages (Combination Therapy)

Treatment Indication Drug Name  Available Dosage Strengths Maximum Recommended Dosage
severe depression chlordiazepoxide/ amitriptyline (generics) 5 mg/ 12.5 mg, 10 mg/25 mg tablets 60 mg/150 mg/day * 
anxiety/agitation/depression perphenazine/ amitriptyline (generics) 2 mg/10 mg, 4 mg/10 mg, 2 mg/25 mg, 4 mg/25 mg, 4 mg/50 mg tablets 16 mg/200 mg/day

Legend:

  • * Lower chlordiazepoxide/amitriptyline dosages and close monitoring are recommended in elderly patients due to greater risks for impaired cognitive/motor function.

1.2. Pediatrics

The FDA requires that all antidepressant drugs display a black box warning describing the potential for increased suicidal thinking and behavior when prescribed to children and adolescents with MDD and other psychiatric disorders. In short-term clinical trials, the suicide risk occurred twice as frequently with antidepressant-treated children/adolescents compared to those receiving placebo (4% vs. 2%, respectively) in the first few months of treatment. Pediatric patients prescribed antidepressant drugs should be closely monitored for changes in behavior.

Maximum recommended doses for non-SSRI antidepressants approved for use as monotherapy in pediatric patients are summarized in Tables 8-10. An additional column reflecting literature-based dosing included in the Texas Health and Human Services Psychotropic Medication Utilization Parameters for Children and Youth in Texas Public Behavioral Health (6th Version) is included in Tables 8-11. Dosages exceeding these recommendations will be reviewed.

Table 8: Pediatric Maximum Recommended Antidepressant Drug Dosages (Monotherapy) - Tricyclic Antidepressants

Treatment Indication Drug Name Available Dosage Strengths Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
MDD amitriptyline (generics) generics: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg tablets Reviewed but not included/ recommended
  • Greater than or equal to 12 years of age:
    • 10 mg three times daily and 20 mg at bedtime
OCD clomipramine (Anafranil®, generics) 25 mg, 50 mg 75 mg capsules Age 10-17 years: 3 mg/kg/day or 200 mg/ day, whichever is less
  • Greater than or equal to 10 years of age:  
    • 3 mg/kg/day or 200 mg/day, whichever is less
aa desipramine (Norpramin®, generics) generics: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg tablets
Norpramin®: 10 mg, 25 mg tablets
Reviewed but not included/ recommended
  • adolescents:  
    • 150 mg/day
MDD imipramine (Tofranil®, generics) generics:10 mg, 25 mg, 50 mg tablets; 75 mg 100 mg, 125 mg, 150 mg capsules
Tofranil®: 10 mg, 25 mg, 50 mg tablets
Reviewed but not included/ recommended
  • adolescents:
    • 100 mg/day
nocturnal enuresis      
  • 6-11 years of age:
    • 2.5 mg/kg/day up to 50 mg/day
  • Greater than or equal to 12 years of age:
    • 2.5 mg/kg/day up to 75 mg/day
MDD nortriptyline (Pamelor®, generics) 10 mg, 25 mg, 50 mg, 75 mg capsules; 10 mg/5 mL oral solution (generic only) Reviewed but not included/ recommended
  • adolescents:
    • 50 mg/day
MDD protriptyline 5 mg, 10 mg tablets Reviewed but not included/ recommended
  • adolescents:  
    • 30 mg/day*
MDD trimipramine (generics) 25 mg, 50 mg 100 mg capsules Reviewed but not included/recommended
  • adolescents:  
    • 100 mg/day

Legend:

  • MDD = major depressive disorder
  • OCD = obsessive-compulsive disorder 
  • *Adolescents should usually be given lower than average protriptyline doses

Table 9: Pediatric Maximum Recommended Antidepressant Drug Dosages (Monotherapy)– Monoamine Oxidase Inhibitors

Treatment Indication Drug Name Available Dosage Strengths Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
MDD isocarboxazid (Marplan®) 10 mg tablets Not reviewed
  • Greater than or equal to 16 years of age:  
    • 60 mg/day
MDD selegiline (EMSAM®) transdermal patch 6 mg/ 24 hours, 9 mg/ 24 hours, 12 mg/ 24 hours transdermal patch Age ≥ 12 years: 12 mg per 24 hours Not approved for pediatric use

Legend:

  • MDD = major depressive disorder

Table 10: Pediatric Maximum Recommended Antidepressant Drug Dosages (Monotherapy) – Serotonin and Norepinephrine Reuptake Inhibitors

Treatment Indication Drug Name Available Dosage Strengths Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
Major depressive disorder desvenlafaxine (Pristiq®, generics, Khedezla®) 25 mg, 50 mg 100 mg 24-hour ER tablets Age 7-17 years: 50 mg/day Not approved for pediatric use
General anxiety disorder duloxetine (Cymbalta®, generics) 20 mg, 30 mg, 40 mg 60 mg delayed-release capsules Age 7-17 years: 120 mg/day
  • 7-17 years of age:  
    • 120 mg/day
Fibromyalgia      
  • 13 years of age:
    • 60 mg/ day

1.3. Renal Impairment

Many antidepressants do not require significant dosage modifications in renal impairment. However, dosage guidelines for select non-SSRI antidepressants in renal impairment are available. Tables 12-15 summarizes dosage modifications and/or restrictions for specific non-SSRI antidepressant medications.

Table 14: Select non-SSRI Antidepressant Dosage Modifications in Renal Impairment – Serotonin and Norepinephrine Reuptake Inhibitors

Drug Name Dosage in Renal Impairment 
Desvenlafaxine
  • Moderate renal impairment (CrCl 30-50 ml/min):
    • 50 mg/day
  • Severe renal impairment (CrCl less than 30 ml/min), ESRD:
    • 25 mg once daily or 50 mg every other day
Duloxetine
  • Mild to moderate renal impairment:
    • start with lower dose, titrate gradually
  • Severe renal impairment, ESRD:
    • not recommended
Levomilnacipran
  • Moderate renal impairment (CrCl 30-59 ml/min):
    • 80 mg/day
  • Severe renal impairment (CrCl 15-29 ml/min):
    • 40 mg/day
  • ESRD:
    • not recommended
Milnacipran
  • Moderate renal impairment (CrCl 30-49 ml/min):
    • use cautiously
  • Severe renal impairment (CrCl 5-29 ml/min):
    • reduce dose by 50% to 25-50 mg twice daily (based on response and tolerability)
  • ESRD:
    • not recommended
Venlafaxine
  • Mild to moderate renal impairment (CrCl 30-89 ml/min):
    • IR:  reduce total daily dose by 25%
    • ER:  reduce total daily dose by 25% to 50%
  • Severe renal impairment (CrCl less than 30 ml/min) and hemodialysis:
    • reduce total daily dose by 50%
  • Adjust doses based on response and tolerability due to variability in renal clearance

Legend:

  • CrCl = creatinine clearance
  • ESRD = end-stage renal disease
  • ER = extended-release
  • IR = immediate-release 

Table 15: Select non-SSRI Antidepressant Dosage Modifications in Renal Impairment – Other Miscellaneous Agents

Drug Name Dosage in Renal Impairment
Bupropion Administer cautiously in renal impairment due to potential for accumulation and risk for adverse events (e.g., seizures); consider reduced dosage/dosage frequency Forfivo™ XL: not recommended in renal impairment as no lower dose available
Trazodone Use cautiously in patients with CrCl less than 50 ml/min

Legend:

  • CrCl = creatinine clearance

2. Duration of Therapy

There is no basis for limiting antidepressant therapy duration when used to manage MDD, OCD, GAD, PTSD, or PD as these disorders can all be characterized as chronic conditions.

While clinical trials have not evaluated vilazodone use in MDD beyond 8 weeks, it is accepted that vilazodone therapy may exceed 8 weeks, as acute episodes of MDD require extended (several months or longer) drug therapy. Patients should be periodically assessed for the continued need for vilazodone treatment.

Duloxetine treatment duration in diabetic NP lasting greater than 6 months has not been evaluated in clinical trials. Additionally, duloxetine efficacy in CMP beyond 13 weeks has not been established in clinical trials.

Duloxetine use lasting greater than 12 months as F therapy has not been evaluated in clinical trials. Recent clinical trials have evaluated milnacipran use for up to one year in F with sustained results in pain management. F patients should be routinely evaluated for treatment effectiveness, with milnacipran therapy tapered and discontinued if positive treatment outcomes are no longer present.

3. Duplicative Therapy

The concurrent use of two antidepressant medications with the same spectrum of activity may not be justified. The concomitant use of two cyclic antidepressants, two MAOIs or two SNRIs will be reviewed.

The concurrent use of three or more antidepressants is not justified. Therefore, the adjunctive use of three or more antidepressants, including MAOIs, SNRIs, SSRIs, cyclic antidepressants, trazodone, bupropion, and nefazodone, will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. The following drug-drug interactions summarized in Table 16 are considered clinically relevant for antidepressants.  Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 16: Major Drug-Drug Interactions for Non-SSRI Antidepressant Drugs

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
bupropion systemic corticosteroids concurrent administration may increase seizure risk as both agents lower seizure threshold reduce initial doses and titrate doses upward slowly; monitor closely for seizure activity major (DrugReax) - 2-major (CP)
cyclic antidepressants, SNRIs, bupropion, levomilnacipran, milnacipran, nefazodone, trazodone, vilazodone, vortioxetine monoamine oxidase inhibitors (MAOIs) increased risk of serotonin syndrome (e.g., mental status changes, hyperpyrexia, restless, shivering, hypertonia, tremor) due to serotonin metabolism inhibition by monoamine oxidase allow 14 days after MAOI discontinuation before initiating other antidepressant therapy; wait 5 weeks after discontinuing fluoxetine before initiating MAOIs contraindicated (DrugReax) - 1-severe (CP)
fluoxetine ergot derivatives increased risk of ergotism due to fluoxetine inhibition of CYP3A4-mediated ergot metabolism avoid concurrent use contraindicated (DrugReax) - major (CP)
MAOIs select CNS stimulants (amphetamines, atomoxetine, methylphenidate, and derivatives) increased risk of hypertensive crisis due to additive effects on catecholamine neurotransmitters     avoid concurrent use; allow two weeks between discontinuing MAOIs and initiating CNS stimulant  therapy    contraindicated (DrugReax) - 1-severe (CP)
MAOIs cyclobenzaprine increased risk of hyperpyretic crisis, seizures, and death potentially due to additive adrenergic activity avoid concurrent use; allow two weeks between discontinuing MAOIs and initiating cyclobenzaprine therapy contraindicated (DrugReax) - 1-severe (CP)
MAOIs morphine increased risk of hypotension and enhanced CNS/respiratory depression as MAOIs amplify morphine pharmacologic effects avoid concurrent use; allow two weeks between discontinuing morphine and initiating MAOI therapy

contraindicated (DrugReax) - 1-severe (CP)

MAOIs sympathomimetics increased risk of hypertensive crisis as MAOIs increase norepinephrine availability at neuronal storage sites as well as enhance adrenergic effects avoid concurrent use; allow two weeks between discontinuing sympathomimetics and initiating MAOI therapy contraindicated (DrugReax) - 1-severe (CP)
MAOIs sympathomimetics increased risk of hypertensive crisis as MAOIs increase norepinephrine availability at neuronal storage sites as well as enhance adrenergic effects avoid concurrent use; allow two weeks between discontinuing sympathomimetics and initiating MAOI therapy contraindicated (DrugReax) - 1-severe (CP)
nefazodone (NZD) carbamazepine reduced NZD serum levels/antidepressant effects and increased carbamazepine (CBZ) serum levels and potential for toxicity due to induced CYP3A4-mediated NZD metabolism and inhibited CYP3A4-mediated CBZ metabolism avoid concurrent use contraindicated (DrugReax) - 1-severe (CP)
NZD pimozide enhanced pimozide pharmacologic effects and potential for cardiovascular toxicity due to NZD-mediated CYP3A4 inhibition avoid concurrent use contraindicated (DrugReax) - 1-severe (CP)
SNRIs, vilazodone, vortioxetine anticoagulants co-administration may increase bleeding risk due to impaired platelet aggregation most likely resulting from platelet serotonin depletion patients should be monitored for signs/symptoms of bleeding (including INR) if combined therapy necessary major (DrugReax) - 3-moderate (CP)
SNRIs, vortioxetine antiplatelet agents adjunctive administration may increase bleeding risk due to impaired platelet aggregation most likely resulting from platelet serotonin depletion patients should be monitored for signs/symptoms of bleeding if combined therapy necessary major (DrugReax) - 3-moderate (CP)
SNRIs, vilazodone, vortioxetine drugs with serotonergic properties (e.g., antipsychotics, dextromethorphan, tramadol, triptans) or dopamine antagonist properties (e.g., phenothiazines, metoclopramide) combined use may increase risk of serotonin syndrome or neuroleptic malignant syndrome (NMS) cautiously administer concurrently and closely observe for signs/symptoms of serotonin syndrome or NMS, especially with treatment initiation or dosage increases major (DrugReax) - 2-major (CP)
SNRIs, vortioxetine tramadol increased risk of serotonin syndrome and seizures due to increased nervous system serotonin concentrations (additive effects on serotonin, SSRI inhibition of CYP2D6-mediated tramadol metabolism) as well as potential reduced seizure threshold with SNRIs, SSRIs avoid concurrent use major (DrugReax) - 2-major (CP)
TCAs pimozide increased risk of pimozide toxicity including cardiotoxicity (QT prolongation) due to elevated plasma concentrations or additive effects on QT interval avoid concurrent use contraindicated (DrugReax) - 1-severe (CP)
TCAs, duloxetine select phenothiazines (mesoridazine, thioridazine) increased risk of somnolence, bradycardia and serious cardiotoxicity (QT prolongation, torsades de pointes) due to potential additive effects on QT interval prolongation; increased thioridazine serum concentrations/decreased thioridazine elimination and potential for serious cardiac arrhythmias due to CYP2D6 inhibition by duloxetine, fluoxetine, or paroxetine avoid concurrent use; if adjunctive use necessary, monitor for increased pharmacologic/toxic effects; adjust dose as necessary contraindicated (DrugReax) - 1-severe (CP)
vilazodone CYP3A4 inducers combined administration may result in reduced vilazodone serum levels and decreased pharmacologic effects, as vilazodone is primarily metabolized by CYP3A4 monitor for decreased pharmacologic effects and adjust doses as necessary 3-moderate (CP)
vilazodone CYP3A4 inhibitors adjunctive administration may result in increased vilazodone serum levels and enhanced pharmacologic/adverse effects, as vilazodone is primarily metabolized by CYP3A4 monitor for increased pharmacologic/adverse effects; reduce vilazodone dose to 20 mg daily when prescribed concurrently with strong (e.g., ketoconazole) CYP3A4 inhibitors; reduce vilazodone dose to 20 mg daily when co-administered with moderate (e.g., erythromycin) CYP3A4 inhibitors and intolerable adverse effects are present moderate (DrugReax) - 2-major (CP)
vortioxetine strong CYP2D6 inducers combined administration may result in reduced vortioxetine serum levels and decreased pharmacologic effects, as vortioxetine is primarily metabolized by CYP2D6 monitor for decreased pharmacologic effects; increase the vortioxetine dose (by no more than 3x the recommended dose) if strong CYP2D6 inducer administered concurrently for more than 14 days; reduce vortioxetine dose to original dose within 14 days of CYP2D6 inducer discontinuation Major (DrugReax) - 2-major (CP)
vortioxetine strong CYP2D6 inhibitors adjunctive administration may result in increased vortioxetine serum levels and enhanced pharmacologic/adverse effects, as vortioxetine is primarily metabolized by CYP2D6 Reduce vortioxetine dose by 50% when administered concurrently with strong CYP2D6 inhibitor; reduce vortioxetine dose to original dose when CYP2D6 inhibitor discontinued major (DrugReax) - 2-major (CP)

Legend:

  • #CP = Clinical Pharmacology
  • CNS = central nervous system
  • SNRIs = serotonin and norepinephrine reuptake inhibitors
  • TCAs = tricyclic antidepressants

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: February 22, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed February 22, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; February 22, 2021.
  4. American Society of Health-System Pharmacists. 2021. AHFS Drug Information® - 2021st Ed. Bethesda, MD. American Society of Health-System Pharmacists®. ISBN-10: 1-58528-654-0, ISBN-13: 978-1-58528-654-6. ISSN: 8756-6028. STAT!Ref Online Electronic Medical Library.  https://online.statref.com/document/cQfe8yqMRNqgSGqm4Qo8Qj. Accessed February 22, 2021.
  5. Bupropion extended-release tablets (Forfivo XL®) package insert. Almatica Pharmaceuticals, December 2019.
  6. Clomipramine capsules (Anafranil) package insert. Mallinckrodt, February 2020.
  7. Amoxapine tablets package insert. Actavis Pharma, Inc., February 2015.
  8. Doxepin capsules package insert. Par Pharmaceutical, December 2019.
  9. Bupropion extended-release tablets (Aplenzin®) package insert. Bausch Health US LLC, June 2020.
  10. Protriptyline package insert. Epic Pharma, LLC, June 2020.
  11. Phenelzine package insert. Greenstone LLC, December 2020.
  12. Tranylcypromine (Parnate®) package insert. Actavis Pharma, Inc., January 2021.
  13. Desvenlafaxine extended-release tablets package insert. Wyeth Pharmaceuticals LLC, November 2019.
  14. Venlafaxine extended-release capsules (Effexor XR®) package insert. Wyeth Pharmaceuticals LLC, November 2019.
  15. Milnacipran tablets (Savella®) package insert. Allergan USA, Inc., December 2017.
  16. Levomilnacipran extended-release capsules (Fetzima®) package insert. Allergan USA, Inc., October 2019.
  17. Vortioxetine (Trintellix®) package insert. Takeda Pharmaceuticals America, Inc., February 2021.
  18.  
  19. Selegiline (EMSAM®) transdermal patch package insert. Mylan Specialty LP, May 2020.
  20. Duloxetine (DRIZALMA SPRINKLE®) delayed release capsule package insert. Sun Pharmaceutical industries, Inc., July 2020.
  21. American Psychiatric Association. Work Group on Major Depressive Disorder.  Practice guideline for the treatment of patients with major depressive disorder, 3rd edition; 2010.  Available at:  http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Accessed February 22, 2021.
  22. Zuckerbrot RA, Cheung A, Jensen PS, et al. Guidelines for adolescent depression in primary care (GLAD-PC): Part I. Practice preparation, identification, assessment, and initial management. Pediatrics. 2018;141(3):e20174081. 
  23. Cheung AH, Zuckerbrot RA, Jensen PS, et al. Guidelines for adolescent depression in primary care (GLAD- PC): Part II. Treatment and ongoing management. Pediatrics. 2018;141(3):e20174082. 
  24. Mease PJ, Russell IJ, Kajdasz DK, et al. Long-term safety, tolerability, and efficacy of duloxetine in the treatment of fibromyalgia.  Semin Arthritis Rheum. 2010;39(6):454-64.
  25. Goldenberg DL, Clauw DJ, Palmer RH, et al. Durability of therapeutic response to milnacipran treatment for fibromyalgia. Results of a randomized, double-blind, monotherapy 6-month extension study. Pain Med. 2010; 11: 180–94.
  26. Clauw DJ, Mease P, Palmer RH, et al. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clin Ther. 2008;30(11):1988-2004.
  27. Milnacipran (Savella®) for fibromyalgia. Med Lett Drugs Ther. 2009;51:45-6.
  28. Mease PJ, Clauw DJ, Gendreau RM, et al. The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial. J Rheumatol. 2009;36(2):398-409.
  29. Uceyler N, Hauser W, Sommer C. A systematic review on the effectiveness of treatment with antidepressants in fibromyalgia syndrome. Arthritis Rheum. 2008;59(9):1279-98.  
  30. Iranikhah M, Wensel TM, Thomason AR. Vilazodone for the treatment of major depressive disorder. Pharmacotherapy. 2012;32(10):958-65.
  31. Taylor WD.  Depression in the elderly. N Engl J Med. 2014;371:1228-36.  
  32. Clark MS, Jansen KL, Cloy JA. Treatment of childhood and adolescent depression. Am Fam Physician. 2012;86(5):442-8. 
  33. Bentley SM, Pagalilauan GL, Simpson SA. Major depression. Med Clin N Am. 2014;98:981-1005.
  34. Kovich H, DeJong A. Common questions about the pharmacologic management of depression in adults. Am Fam Physician. 2015;92(2):94-100.
  35. Texas Health and Human Services. Psychotropic medication utilization parameters for children and youth in Texas public behavioral health (6th version), June 2019. Available at: https://hhs.texas.gov/sites/default/files/documents/doing-business-with-hhs/provider-portal/facilities-regulation/psychiatric/psychotropic-medication-utilization-parameters.pdf. Accessed February 18, 2021. 

Anti-depressants, selective serotonin reuptake inhibitors

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Initially developed
    • March 2017
  • Revision history
    • April 23, 2021; March 2019

1.1. Adults

The FDA requires that all antidepressant drugs display a black box warning describing the potential for increased suicidal thinking and behavior when prescribed to young adults (18 to 24 years of age) with MDD and other psychiatric disorders. In short-term clinical trials, the suicide risk was increased in young adults managed with antidepressants compared to those receiving placebo in the first few months of treatment. Suicide risk was not shown to increase in adults over 24 years of age, and patients 65 years of age and older manifested a decreased suicide risk. Young adult patients prescribed antidepressant drugs should be closely monitored for changes in behavior.

Selective serotonin reuptake inhibitor (SSRI) antidepressant drugs are FDA-approved for use in major depressive disorder (MDD), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), premenstrual dysphoric disorder (PMDD), and posttraumatic stress disorder (PTSD). Recently, paroxetine has been approved to manage moderate to severe vasomotor symptoms associated with menopause (VMS). Combination therapy is FDA-approved for bipolar I disorder (BD) and treatment-resistant depression (TRD).

Maximum recommended daily doses for SSRI antidepressant drugs in adults, including the elderly population, are summarized in Tables 1 and 2 for both monotherapy and SSRI combination therapy, respectively. However, in all patients, the lowest effective antidepressant dose should be utilized to minimize unwanted adverse effects. Patient profiles with SSRI antidepressant dosages exceeding these recommendations will be reviewed.

Table 1: Oral SSRI Medications - Adult Maximum Recommended Dosages - Monotherapy

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage
MDD citalopram (Celexa®, generics) 10 mg, 20 mg, 40 mg tablets; 10 mg/ 5 mL oral solution
  • Less than or equal to 65 years:
    • 40 mg/day
  • Greater than 65 years:
    • 20 mg/day (older than 60 years)
GAD, MDD escitalopram (Lexapro®, generics) 5 mg, 10 mg, 20 mg tablets; 5 mg/5 mL oral solution
  • Less than or equal to 65 years:
    • 20 mg/day
  • Greater than 65 years:
    • 10 mg/day
MDD, OCD fluoxetine (Prozac®, generics) 10 mg, 20 mg, 40 mg capsules; 10 mg, 20 mg, 40 mg, 60 mg tablets; 20 mg/5 mL solution 
  • Less than or equal to 65 years:
    • 80 mg/day
  • Greater than 65 years:
    • 80 mg/day
BN, PD    
  • Less than or equal to 65 years:
    • 60 mg/day
  • Greater than 65 years:
    • 60 mg/day
MDD fluoxetine (Prozac® Weekly, generics) 90 mg delayed-release capsules
  • Less than or equal to 65 years:
    • 90 mg/week
  • Greater than 65 years:
    • 90 mg/week
BD, MDD fluoxetine (Prozac Pulvules®) 10 mg, 20 mg, 40 mg pulvules
  • Less than or equal to 65 years:
    • 75 mg/ day ^
  • Greater than 65 years:
    • 75 mg/ day ^
PMDD fluoxetine (generics) 10 mg, 20 mg capsules
  • Less than or equal to 65 years:
    • 80 mg/day
  • Greater than 65 years:
    • Not applicable
OCD fluvoxamine (generics) IR: 25 mg, 50 mg, 100 mg tablets
ER: 100 mg, 150 mg 24-hour ER capsules
  • Less than or equal to 65 years:
    • 300 mg/day*
  • Greater than 65 years:
    • 300 mg/day*
GAD, MDD paroxetine mesylate (Pexeva®) 10 mg, 20 mg, 30 mg, 40 mg tablets
  • Less than or equal to 65 years:
    • 50 mg/day++
  • Greater than 65 years:
    • 40 mg/day
OCD, PD    
  • Less than or equal to 65 years:
    • 60 mg/day
  • Greater than 65 years:
    • 40 mg/day
SAD, OCD, PD paroxetine HCl (Paxil®, generics) 10 mg, 20 mg, 30 mg, 40 mg tablets, 10 mg/ 5 mL suspension
  • Less than or equal to 65 years:
    • 60 mg/day++
  • Greater than 65 years:
    • 40 mg/day
GAD, MDD, PTSD    
  • Less than or equal to 65 years:
    • 50 mg/day++
  • Greater than 65 years:
    • 40 mg/day
MDD paroxetine HCl (Paxil CR®, generics) 12.5 mg, 25 mg, 37.5 mg 24-hour ER tablets
  • Less than or equal to 65 years:
    • 62.5 mg/day
  • Greater than 65 years:
    • 50 mg/day
PD    
  • Less than or equal to 65 years:
    • 75 mg/day
  • Greater than 65 years:
    • 50 mg/day
SAD    
  • Less than or equal to 65 years:
    • 37.5 mg/day
  • Greater than 65 years:
    • 50 mg/day
PMDD    
  • Less than or equal to 65 years:
    • 25 mg/day
  • Greater than 65 years:
    • Not applicable
VMS Paroxetine mesylate (Brisdelle®, generics) 7.5 mg capsule
  • Less than or equal to 65 years:
    • 7.5 mg/day at bedtime
  • Greater than 65 years:
    • 7.5 mg/day at bedtime
MDD, OCD, PD, SAD, PTSD sertraline (Zoloft®, generics) 25 mg, 50 mg, 100 mg tablets; 20 mg/mL oral concentrate
  • Less than or equal to 65 years:
    • 200 mg/day
  • Greater than 65 years:
    • 200 mg/day
PMDD    
  • Less than or equal to 65 years:
    • 150 mg/day
  • Greater than 65 years:
    • Not applicable

Legend:

  • BD = bipolar I disorder;
  • BN = bulimia nervosa
  • CR = controlled-release
  • ER = extended-release
  • GAD = generalized anxiety disorder
  • IR = immediate-release
  • MDD = major depressive disorder
  • OCD = obsessive-compulsive disorder
  • PD = panic disorder
  • PMDD = premenstrual dysphoric disorder
  • PTSD = posttraumatic stress disorder
  • SAD = social anxiety disorder
  • VMS = vasomotor symptoms associated with menopause
  • * Fluvoxamine IR doses greater than 100 mg daily should be administered in divided doses
  • ++ Data do not confirm that paroxetine doses greater than 20 mg/day are more effective
  • + Lower doses may be required in elderly patients
  • ^ In combination with olanzapine
     

Table 2: Oral SSRI Medications - Adult Maximum Recommended Dosages – Combination Therapy

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage 
BD, TRD olanzapine/ fluoxetine (Symbyax®, generics) 3 mg/ 25 mg, 6 mg/ 25 mg, 12 mg/25 mg, 6 mg/ 50 mg, 12 mg/ 50 mg capsules
  • Less than or equal to 65 years
    • 18 mg/ 75 mg per day
  • Greater than 65 years:
    • 18 mg/ 75 mg per day

Legend:

  • BD = bipolar I disorder
  • TRD = treatment-resistant depression

1.2. Pediatrics

The FDA requires that all antidepressant drugs display a black box warning describing the potential for increased suicidal thinking and behavior when prescribed to children and adolescents with MDD and other psychiatric disorders. In short-term clinical trials, the suicide risk occurred twice as frequently with antidepressant-treated children/adolescents compared to those receiving placebo (4% vs. 2%, respectively) in the first few months of treatment. Pediatric patients prescribed antidepressant drugs should be closely monitored for changes in behavior.

Citalopram and paroxetine are not FDA-approved for use in pediatric patients as safety and effectiveness in this age group have not been well established. The olanzapine/fluoxetine combination is FDA-approved in pediatric patients.

Maximum pediatric recommended doses for SSRI antidepressants approved for use as monotherapy and combination therapy are summarized in Tables 3 and 4, respectively. An additional column reflecting literature-based dosing included in the Texas Health and Human Services Psychotropic Medication Utilization Parameters for Children and Youth in Texas Public Behavioral Health (6th Version) is included in Tables 3 and 4. Dosages exceeding these recommendations will be reviewed.

Table 3: Recommended SSRI Antidepressant Drug Dosages for Pediatric Patients – Monotherapy

Treatment Indication Drug Name Available Dosage Strengths Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
  citalopram (Celexa®) 10 mg, 20 mg, 40 mg tablets; 10 mg/ 5 mL oral solution ≥6 years of age: 40 mg/ day Not FDA approved for children & adolescents
MDD escitalopram (Lexapro®, generics) 5 mg, 10 mg, 20 mg tablets; 5 mg/5 mL oral solution
  • 6-11 years of age:
    • 20 mg/ day
  • Greater than or equal to 12 years of age:
    • 30 mg/day
  • 12 to 17 years of age:
    • 20 mg/day
MDD fluoxetine (Prozac®, generics) 10 mg, 20 mg, 40 mg capsules; 10 mg, 20 mg, 40 mg, 60 mg tablets; 20 mg/5 mL solution Greater than or equal to 6 years of age: 60 mg/ day 8 to 17 years of age: 20 mg/day
OCD     Greater than or equal to 6 years of age: 60 mg/ day
  • 7 to 17 years of age:
    • lower weight children:
      • 30 mg/day
    • higher weight children:
      • 60 mg/day
BD fluoxetine (Prozac Pulvules®) 10 mg, 20 mg, 40 mg pulvules   10 to 17 years of age: 50 mg/ day^
OCD fluvoxamine (generics) IR: 25 mg, 50 mg, 100 mg tablets
  • Age 8-11 years:
    • 200 mg/day
  • Age 12-17 years:
    • 300 mg/day
  • 8-11 years of age:
    • 200 mg/day#
  • 12 to 17 years of age:
    • 300 mg/day#
OCD Fluvoxamine controlled release (Luvox CR®, generics) CR: 100 mg, 150 mg
  • Age 8-11 years:
    • 200 mg/day
  • Age 12-17 years:
    • 300 mg/day
  • 8-11 years of age:
    • 200 mg/day
  • 12 to 17 years of age:
    • 300 mg/day
OCD sertraline (Zoloft®, generics) 25 mg, 50 mg, 100 mg tablets; 20 mg/mL oral concentrate Age greater than or equal to 6 years: 200 mg/day 6 to 17 years of age: 200 mg/day

Legend:

  • BD = bipolar I disorder
  • IR = immediate-release
  • MDD = major depressive disorder
  • OCD = obsessive-compulsive disorder
  • # Fluvoxamine IR doses greater than 50 mg daily should be administered in divided doses
  • ^ In combination with olanzapine

1.3. Renal Impairment

Many antidepressants do not require significant dosage modifications in renal impairment. However, dosage guidelines for select SSRIs in renal impairment are available. Table 5 summarizes dosage modifications and/or restrictions for specific SSRI antidepressant medications.

Table 5: Select SSRI Antidepressant Dosage Modifications in Renal Impairment

Drug Name  Dosage in Renal Impairment
Citalopram Severe renal impairment (creatinine clearance less than 20 mL/min): use cautiously, as potential exists for active metabolites to accumulate with associated adverse effects
Escitalopram Severe renal impairment (creatinine clearance less than 20 mL/min):  use cautiously, as specific dosage guidelines not available
Paroxetine (Paxil®, Pexeva®, Paxil CR®) Serum levels, AUC increase as renal function declines; therefore, maximum doses when creatinine clearance less than 30 mL/min are:
  • IR: 40 mg/day
  • CR: 50 mg/day

Legend:

  • CR = controlled-release
  • IR = immediate-release

2. Duration of Therapy

There is no basis for limiting antidepressant therapy duration when used to manage MDD, OCD, GAD, PTSD, or PD as these disorders can all be characterized as chronic conditions.

Clinical trials have documented fluoxetine efficacy in BN management for up to 52 weeks. Fluoxetine has demonstrated efficacy in PMDD for up to 6 months when administered continuously and up to 3 months when administered intermittently. Paroxetine and sertraline have demonstrated efficacy in PMDD for up to 6 months and 12 months, respectively, in clinical trials. Patients should be assessed periodically to determine need for continued treatment. However, the potential exists for PMDD symptoms to worsen with advancing age until patients reach menopause. Patients responding to fluoxetine, paroxetine, or sertraline therapy for PMDD may benefit from chronic administration.

Paroxetine treatment for VMS exceeding 24 weeks has not been evaluated in clinical trials. Additionally, paroxetine dosages used to manage VMS are not FDA-approved to manage psychiatric conditions, as the dose contained in Brisdelle® is lower than the recommended doses used to manage psychiatric disorders. Patients requiring paroxetine for psychiatric disorders should discontinue Brisdelle® and initiate therapy with a paroxetine formulation FDA-approved for psychiatric use.

3. Duplicative Therapy

The concurrent use of two SSRI antidepressant medications with the same spectrum of activity may not be justified and will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. The following drug-drug interactions summarized in Table 6 are considered clinically relevant for SSRI antidepressants. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 6: Major Drug-Drug Interactions for SSRI Antidepressant Drugs
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
fluoxetine ergot derivatives increased risk of ergotism due to fluoxetine inhibition of CYP3A4-mediated ergot metabolism avoid concurrent use contraindicated (DrugReax) major (CP)
SSRIs anticoagulants co-administration may increase bleeding risk due to impaired platelet aggregation most likely resulting from platelet serotonin depletion patients should be monitored for signs/symptoms of bleeding (including INR) if combined therapy necessary major (DrugReax) 3-moderate (CP)
SSRIs drugs with serotonergic properties (e.g., antipsychotics, tramadol, triptans) or dopamine antagonist properties (e.g., phenothiazines, metoclopramide) combined use may increase risk of serotonin syndrome or neuroleptic malignant syndrome (NMS) cautiously administer concurrently and closely observe for signs/symptoms of serotonin syndrome or NMS, especially with treatment initiation or dosage increases major (DrugReax) 2-major (CP)
SSRIs MAOIs increased risk of serotonin syndrome (e.g., mental status changes, hyperpyrexia, restless, shivering, hypertonia, tremor) due to serotonin metabolism inhibition by monoamine oxidase allow 14 days after MAOI discontinuation before initiating other antidepressant therapy; wait 5 weeks after discontinuing fluoxetine before initiating MAOIs contraindicated (DrugReax) 1-severe (CP)
SSRIs tramadol increased risk of serotonin syndrome and seizures due to increased nervous system serotonin concentrations (additive effects on serotonin, SSRI inhibition of CYP2D6-mediated tramadol metabolism) as well as potential reduced seizure threshold with SNRIs, SSRIs avoid concurrent use major (DrugReax) 2-major (CP)
SSRIs pimozide increased risk of pimozide toxicity including cardiotoxicity (QT prolongation) due to elevated plasma concentrations or additive effects on QT interval avoid concurrent use contraindicated (DrugReax) 1-severe (CP)
SSRIs select phenothiazines (mesoridazine, thioridazine) increased risk of somnolence, bradycardia and serious cardiotoxicity (QT prolongation, torsades de pointes) due to potential additive effects on QT interval prolongation; increased thioridazine serum concentrations/ decreased thioridazine elimination and potential for serious cardiac arrhythmias due to CYP2D6 inhibition by duloxetine, fluoxetine, or paroxetine avoid concurrent use; if adjunctive use necessary, monitor for increased pharmacologic/toxic effects; adjust dose as necessary contraindicated (DrugReax) 1-severe (CP)

Legend:

  • MAOI = monoamine oxidase inhibitor
  • SNRI = serotonin-norepinephrine reuptake inhibitor
  • SSRI= selective serotonin reuptake inhibitor
  • # CP = Clinical Pharmacology

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: February 18, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed February 18, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; February 18, 2021.
  4. American Society of Health-System Pharmacists. 2021. AHFS Drug Information® - 2021st Ed. Bethesda, MD. American Society of Health-System Pharmacists®. ISBN-10: 1-58528-654-0, ISBN-13: 978-1-58528-654-6. ISSN: 8756-6028. STAT!Ref Online Electronic Medical Library.  https://online.statref.com/document/cQfe8yqMRNqgSGqm4Qo8Qj. Accessed February 18, 2021.
  5. Fluoxetine capsules, delayed-release capsules (Prozac®, Prozac® Weekly™) package insert. Eli Lilly and Company, April 2020.
  6. Fluoxetine pulvules package insert. Dista Products Company, April 2020.
  7. Paroxetine tablets (Pexeva®) package insert. Apotex Corp., June 2020.
  8. Paroxetine capsules (Brisdelle®) package insert. Sebela Pharmaceuticals Inc., October 2017.
  9. Olanzapine and fluoxetine (Symbyax®) package insert. Eli Lilly and Company, October 2020.
  10. U.S. Food and Drug Administration. FDA drug safety communication: revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses. Available at:  http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm. Accessed February 18, 2021.
  11. American Psychiatric Association. Work Group on Major Depressive Disorder.  Practice guideline for the treatment of patients with major depressive disorder Practice guideline for the treatment of patients with major depressive disorder, 3rd edition; 2010. Available at:  http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Accessed February 18, 2021.
  12. Zuckerbrot RA, Cheung A, Jensen PS, et al. Guidelines for adolescent depression in primary care (GLAD-PC): Part I. Practice preparation, identification, assessment, and initial management. Pediatrics. 2018;141(3):e20174081. 
  13. Cheung AH, Zuckerbrot RA, Jensen PS, et al. Guidelines for adolescent depression in primary care (GLAD- PC): Part II. Treatment and ongoing management. Pediatrics. 2018;141(3):e20174082. 
  14. Freeman EW, Rickels K, Sammel MD, et al. Time to relapse after short- or long-term treatment of severe premenstrual syndrome with sertraline. Arch Gen Psychiatry. 2009; 66(5):537-44.
  15. Steiner M, Ravindran AV, LeMelledo JM, et al. Luteal phase administration of paroxetine for the treatment of premenstrual dysphoric disorder: a randomized, double-blind, placebo-controlled trial in Canadian women. J Clin Psychiatry. 2008;69(6):991-8.
  16. Busti AJ, Lehew DS, Nuzum DS, Daves BJ. Part 1: How does the opioid analgesic tramadol (Ultram®; Ultram ER®, Ultracet®) increase the risk for developing serotonin syndrome in patients taking SSRI antidepressant medications? Pharmacol Wkly. 2009;1(9):1-4.
  17. Taylor WD. Depression in the elderly. N Engl J Med. 2014;371:1228-36.
  18. Clark MS, Jansen KL, Cloy JA. Treatment of childhood and adolescent depression. Am Fam Physician. 2012;86(5):442-8.
  19. Bentley SM, Pagalilauan GL, Simpson SA. Major depression. Med Clin N Am. 2014;98:981-1005.
  20. Kovich H, DeJong A. Common questions about the pharmacologic management of depression in adults. Am Fam Physician. 2015;92(2):94-100.
  21. Texas Health and Human Services. Psychotropic medication utilization parameters for children and youth in Texas public behavioral health (6th version), June 2019. Available at: https://hhs.texas.gov/sites/default/files/documents/doing-business-with-hhs/provider-portal/facilities-regulation/psychiatric/psychotropic-medication-utilization-parameters.pdf. Accessed February 18, 2021.

Anti-diabetic Agents (oral)

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • Oct. 22, 2021, Sept. 2019; Sept. 2017; Sept. 2015; Dec. 2013; Feb. 2012; June 2010; May 2010; March 2007; Dec. 2006; Oct. 2006; May 2003; April 2002; April 2001; April 2000; March 1999; March 1998.  
  • Initially developed
    • Feb. 1997

1.1. Adults

Oral atypical antipsychotics are FDA-approved for use in schizophrenia, bipolar I disorder (BD), bipolar disorder with mixed episodes or depressive episodes, bipolar mania, schizoaffective disorder (SD), adjunctive therapy in major depressive disorder (MDD), treatment-resistant schizophrenia, and irritability associated with autism 1-18. Cariprazine (Vraylar®) has been approved for schizophrenia and manic or mixed episodes associated with BD 1-4, 19. Aripiprazole tablets with sensors (Abilify MyCite®) have been approved to track if the medication has been taken 20.

Pimavanserin (Nuplazid®) is an oral atypical antipsychotic recently indicated for use to manage hallucinations and delusions seen with Parkinson’s disease psychosis 1-4, 21. Olanzapine combination therapy is FDA-approved for use in managing treatment-resistant depression as well as bipolar depression 1-4, 22. Secuado® (asenapine) Transdermal System is a topical patch that was approved by the FDA in 2019 for the management of schizophrenia in adult patients 1-4, 23. Additionally, Caplyta® (lumateperone) is a once daily oral capsule that was approved in 2019 for the management of schizophrenia in adult patients 1-4, 24.

Maximum recommended adult doses for atypical antipsychotics are summarized in Table 1 1-21, 23, 24. Dosages exceeding these recommendations will be reviewed.

Combination therapy with the atypical antipsychotic, olanzapine, and the selective serotonin reuptake inhibitor, fluoxetine, is FDA-approved for the management of depressive episodes associated with bipolar I disorder and treatment-resistant depression in adults 1-4, 22.

In May 2021, the FDA approved Lybalvi®, which is an oral combination product containing olanzapine and samidorphan, for the management of acute mixed or manic episodes in bipolar 1 disorder, maintenance therapy in bipolar 1 disorder, and for the management of schizophrenia 1-4, 25. Samidorphan that binds to mu, kappa, and delta opioid receptors. Samidorphan is a mu-opioid receptor antagonist, and it demonstrates partial agonist activity on kappa, and delta-opioid receptors. The major metabolites of samidorphan also have an affinity for opioid receptors, however, neither metabolite is thought to contribute to the pharmacologic effects of the drug 1-4, 25.

Doses exceeding the maximum adult recommended doses summarized in Table 2 1-4, 22, 25 will be reviewed.

Table 1: Oral Atypical Antipsychotics (Monotherapy) - Adult Maximum Recommended Dosages

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage
Schizophrenia, BD Aripiprazole (Abilify®, Abilify Discmelt®, Abilify MyCite® system)
  • 2 mg, 5 mg, 10mg, 15 mg, 20 mg, 30 mg immediate-release (IR) tablets
  • 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg IR tablets with sensor#  
  • 10 mg, 15 mg orally disintegrating tablets (ODTs)
  • 1 mg/ml oral solution
  • oral tablets: 30 mg/day
  • oral solution: 25 mg/day
MDD     15 mg/day
Schizophrenia, BD Asenapine (Saphris®, Secuado® Transdermal System)
  • 2.5 mg, 5 mg, 10 mg sublingual tablets
  • 3.8 mg/24 hr, 5.7 mg/24 hr, 7.6 mg/24 hr transdermal patch
  • 20 mg/day, in two divided doses
  • 7.6 mg/24 hr transdermally
Schizophrenia Brexpiprazole (Rexulti®) 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg tablets 4 mg once daily
MDD     3 mg once daily
Bipolar major depression Cariprazine (Vraylar®) 1.5 mg, 3 mg, 4.5 mg 6 mg capsules 3 mg once daily
BD (acute mixed/manic episodes), schizophrenia     6 mg once daily
Schizophrenia (treatment-resistant), reducing recurrent suicidal behavior in schizophrenia and schizoaffective disorder (SD) Clozapine (Clozaril®, generics, FazaClo®, Versacloz®)
  • 25 mg, 50 mg, 100 mg, 200 mg IR tablets
  • 12.5 mg, 25 mg, 100 mg, 150 mg, 200 mg ODTs
  • 50 mg/ml oral suspension
900 mg/day, in divided doses
Schizophrenia Iloperidone (Fanapt®) 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg 12 mg IR tablets 24 mg/day, in divided doses
Schizophrenia Lumateperone (Caplyta®) 42 mg capsules 42 mg/day
Schizophrenia Lurasidone (Latuda®) 20 mg, 40 mg, 60 mg, 80 mg, 120 mg IR tablets 160 mg/day, with food (at least 350 calories)
Bipolar depression     120 mg/day, with food (at least 350 calories)
Schizophrenia, BD, treatment-resistant depression Olanzapine (Zyprexa®, Zyprexa Zydis®, generics)
  • 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg IR tablets
  • 5 mg, 10 mg, 15 mg, 20 mg ODTs
20 mg/day, as a single dose
Schizophrenia, SD Paliperidone (Invega®) 1.5 mg, 3 mg, 6 mg, 9 mg extended-release (ER) tablets 12 mg/day
Parkinson disease psychosis Pimavanserin (Nuplazid®) 10 mg, 17 mg, 34 mg tablet 34 mg once daily
Schizophrenia, BD (acute manic episodes, maintenance) Quetiapine (Seroquel®, Seroquel XR®, generics)
  • 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg IR tablets
  • 50 mg, 150 mg, 200 mg, 300 mg, 400 mg ER tablets
  • IR: 800 mg/day, in two or three divided doses
  • ER: 800 mg/day, as a single dose
Bipolar depression    
  • IR: 300 mg/day, at bedtime
  • ER: 300 mg/day, as a single dose
MDD Quetiapine (Seroquel XR®, generics) 50 mg, 150 mg, 200 mg, 300 mg, 400 mg ER tablets ER: 300 mg/day, as a single dose
Schizophrenia Risperidone (Risperdal®, Risperdal M-TAB®, generics)
  • 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg IR tablets
  • 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg ODTs
  • 1 mg/ml oral solution
8 mg/day in 1 or 2 divided doses *
Bipolar mania     6 mg/day
Schizophrenia Ziprasidone (Geodon®, generics) 20 mg, 40 mg, 60 mg, 80 mg IR capsules 200 mg/day, in two divided doses +
BD     160 mg/day, in two divided doses

Legend:

  • # ingestible event marker (IEM) embedded in each MyCite® tablet; to be dispensed with MyCite® patch (wearable sensor that detects signal frim IEM sensor) and MyCite App
  • * doses up to 16 mg/day have demonstrated efficacy in clinical trials; however, doses of 4 to 8 mg/day tended to produce the maximal effect    
  • + doses up to 320 mg daily have been used safely but greater efficacy not noted with higher dosages
     

Table 2: Oral Atypical Antipsychotics (Combination Therapy) – Adult Maximum Recommended Dosages

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage 
Bipolar depression, treatment-resistant depression Olanzapine/ fluoxetine (Symbyax®)
  • Olanzapine 3 mg/fluoxetine 25 mg
  • olanzapine 6 mg/fluoxetine 25 mg
  • olanzapine 6 mg/fluoxetine 50 mg
  • olanzapine 12 mg/fluoxetine 25 mg
  • lanzapine 12 mg/fluoxetine 50 mg
Olanzapine 18 mg/fluoxetine 75 mg once daily in evening, without regard to meals
Schizophrenia, BD Olanzapine/ samidorphan (Lybalvi®)
  • Olanzapine 5 mg/ samidorphan 10 mg
  • olanzapine 10 mg/ samidorphan 10 mg
  • olanzapine 15 mg/ samidorphan 10 mg
  • olanzapine 20 mg, samidorphan 10 mg
Olanzapine 20 mg/samidorphan 10 mg once daily

1.2. Pediatrics

Risperidone has been FDA-approved to manage symptoms of irritability in autistic children greater than 5 years of age and adolescents, and has recently gained FDA-approved indications for bipolar mania in children and adolescents 10 to 17 years of age and schizophrenia in adolescents 13 to 17 years of age. Aripiprazole has received recent FDA approval for treating Tourette’s disorder in pediatric patients 6 to 18 years of age, and is also FDA-approved for managing schizophrenia in adolescents 13 to 17 years of age, bipolar disorder with or without psychotic features in children 10 to 17 years of age, and irritability associated with autistic disorder in children 6 to 17 years of age. Olanzapine has been granted FDA approval for bipolar disorder and schizophrenia in adolescents 13 years of age and older. Quetiapine is FDA approved for acute treatment of bipolar disorder mania episodes in children and adolescents 10 to 17 years of age and schizophrenia management in adolescents 13 to 17 years of age. Paliperidone is approved FDA for the management of schizophrenia in adolescents 12 to 17 years of age. Lurasidone is approved for the management of depressed phase bipolar disorder in children 10 to 17 years of age, and it is approved for the management of schizophrenia in patients 13 to 17 years of age. Brexpiprazole, cariprazine, clozapine, iloperidone, Lumateperone, ziprasidone, and aripiprazole tablets with sensors (Abilify MyCite®) are not recommended for use in pediatric patients as safety and efficacy have not been established in this patient population. Additionally, pimavanserin is not approved for use in pediatric patients as Parkinson’s disease is typically not observed in pediatric patients, and safety and efficacy data are not available for pimavanserin in the pediatric population 1-25.

Atypical antipsychotic pediatric dosages are summarized in Table 3. An additional column reflecting literature-based dosing included in the Texas Health and Human Services Psychotropic Medication Utilization Parameters for Children and Youth in Texas Public Behavioral Health (6th Version) is included in Tables 3 1-21, 23, 26 and 4 26.

The olanzapine/fluoxetine combination has been approved for use in pediatric patients 10-17 years of age with depression associated with BD 1-4, 22. Recommended pediatric dosages are summarized in Table 4 1-4, 22, 26.

Table 4: Oral Atypical Antipsychotics (Combination Therapy) – Pediatric Maximum Recommended Dosages

Treatment Indication Drug Name Available Dosage Strengths Literature Based Maximum Dosage Maximum Recommended Dosage per Age Group
Bipolar depression Olanzapine/fluoxetine (Symbyax®)
  • Olanzapine 3 mg/fluoxetine 25 mg
  • olanzapine 6 mg/fluoxetine 25 mg
  • olanzapine 6 mg/fluoxetine 50 mg
  • olanzapine 12 mg/fluoxetine 25 mg;
  • olanzapine 12 mg/fluoxetine 50 mg
Age 10-17 years: 12 mg olanzapine/50 mg fluoxetine once daily 10-17 years of age:  olanzapine 12 mg/ fluoxetine 50 mg once daily in evening, without regard to meals

 

2. Duration of Therapy

Atypical antipsychotics are indicated for use in the management of schizophrenia and psychotic disorders. Therefore, there is no basis for limiting treatment duration with these atypical antipsychotics as these agents are utilized in the management of chronic disorders1-44.

3. Duplicative Therapy

Combined therapy with multiple antipsychotic medications has been evaluated in patients with treatment-resistant schizophrenia. Open studies, case reports, and clinical trials have observed favorable results following concurrent therapy with either atypical antipsychotics plus conventional antipsychotic agents, or clozapine in conjunction with an additional atypical antipsychotic in clozapine-refractory patients. Further controlled trials are necessary to identify patients and circumstances in which combination therapy should be utilized as well as risks and benefits of concurrent therapy.

Neuroleptics should be used concomitantly during transitional periods lasting up to four weeks when switching patients to a different antipsychotic agent 1-44.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug interactions considered clinically relevant for atypical antipsychotics are summarized in Table 5 1-25. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 5: Select Drug-Drug Interactions for Oral Atypical Antipsychotics

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
Aripiprazole Citalopram Increased risk of QT prolongation and serotonin syndrome because aripiprazole is a partial agonist of 5-HT1A and citalopram is a selective serotonin reuptake inhibitor Avoid use Major (DrugReax) 2-major(CP)
Atypical antipsychotics (AAs) Antihypertensive agents Potential for enhanced antihypertensive effects due to AA-associated alpha1-adrenergic receptor antagonism Use cautiously together; monitor for amplified hypotensive effects 3-moderate (CP)
AAs CNS depressants Potential for additive CNS effects Use cautiously together; observe patients for enhanced CNS adverse effects Major (DrugReax) 3-moderate (CP)
AAs (except pimavanserin) Drugs affecting seizure threshold (e.g., tramadol) Increased seizure risk as AAs have been associated with seizures (incidence varies) Avoid drug combination if possible; if combination necessary, closely monitor patients for seizure activity and discontinue therapy as indicated Major (DrugReax) 2-major (CP)
AAs Metoclopramide Adjunctive therapy enhances potential for increased extrapyramidal symptoms (EPS) and neuroleptic malignant syndrome (NMS) as both agents block dopamine receptors Combination contraindicated by metoclopramide manufacturer; if combination necessary, monitor for signs/ symptoms of EPS or NMS-discontinue metoclopramide if symptoms develop Contraindicated (DrugReax) 1-severe (CP)
Clozapine Myelopsuppressive (antineoplastic) drugs Potential for additive bone marrow suppressive effects Concurrent administration contraindicated 1-severe (CP)
Clozapine Carbamazepine Increased risk of additive bone marrow-suppressing effects, including agranulocytosis Avoid concurrent use; choose alternative anticonvulsant     Major (DrugReax) 2-major (CP)
Samidorphan Opioids Concurrent use may decrease opioid efficacy and precipitate opioid withdrawal Concurrent administration is contraindicated Contraindicated (DrugReax) 1-severe (CP)
Select AAs (clozapine, olanzapine) CYP1A2 inducers (e.g., carbamazepine**, phenobarbital, phenytoin, ritonavir*, rifampin) Potential for reduced clozapine, olanzapine serum concentrations and worsening of psychosis Monitor clozapine, olanzapine efficacy in patients; adjust doses as necessary when CYP1A2 inducer added, deleted, or changed to therapeutic regimen Moderate (DrugReax) 2-major (CP)
Select AAs (asenapine, clozapine, olanzapine) CYP1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine) Potential for decreased AA clearance, increased AA serum concentrations and enhanced pharmacologic/ adverse effects (seizures, hypotension) as clozapine, olanzapine metabolized by CYP1A2 If drug combination necessary, used reduced clozapine dosages and closely monitor for adverse events Moderate (DrugReax) 2-major (CP)
Select AAs (aripiprazole, brexpiprazole, cariprazine, clozapine, iloperidone, pimavanserin, quetiapine, ziprasidone) CYP3A4 inhibitors (e.g., ketoconazole, ritonavir*) Potential for decreased AA clearance, increased AA serum concentrations, and enhanced pharmacologic/ adverse effects as select AAs metabolized by CYP3A4 Monitor for enhanced AA pharmacologic/ adverse effects and adjust doses as necessary (50% dose reduction recommended for aripiprazole,  brexpiprazole, iloperidone) Moderate (DrugReax) 2-major, 3-moderate (CP)
Select AAs (aripiprazole, brexpiprazole, clozapine, olanzapine, pimavanserin,  quetiapine, risperidone, ziprasidone) CYP3A4 inducers (e.g., carbamazepine**, phenytoin) Potential for significant reductions in AA plasma concentrations (by as much as 50%) due to enhanced AA hepatic microsomal metabolism Monitor AA efficacy in patients; adjust doses as necessary when CYP3A4 inducer added, deleted, or changed to therapeutic regimen (brexpiprazole dose should be doubled over 1-2 weeks when prescribed with CYP3A4 inducer) Moderate (DrugReax) 2-major, 3-moderate (CP)
Select AAs (aripiprazole, brexpiprazole, iloperidone, risperidone) CYP2D6 inhibitors (e.g., quinidine, select SSRIs, ritonavir) Potential for decreased AA clearance and increased AA serum concentrations and enhanced pharmacologic/ adverse effects as select AAs metabolized by CYP2D6 Monitor for enhanced AA pharmacologic/ adverse effects and adjust doses as necessary (recommended to reduce aripiprazole, brexpiprazole,  iloperidone doses by 50% when administered in conjunction with CYP2D6 inhibitor) Moderate (DrugReax) 2-major, 3-moderate (CP)
Select AAs (aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, pimavanserin, quetiapine, risperidone, ziprasidone) QTc interval-prolonging medications Potential for increased cardiotoxicity (e.g., torsades de pointes, cardiac arrest) due to additive QT interval prolongation Avoid concurrent use; if combination necessary, closely monitor cardiac function; discontinue therapy in patients with QTc measurements greater than 500 msec Major (DrugReax) 1-severe, 2-major (CP)

Legend:

  • #CP = Clinical Pharmacology
  • * Ritonavir inhibits clozapine metabolism through CYP3A4 inhibition, but induces olanzapine metabolism through CYP1A2 enzyme induction.  
  • ** Carbamazepine induces olanzapine metabolism through CYP1A2 enzyme induction and induces clozapine metabolism through CYP3A4 induction.

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited:  September 15, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed September 15, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; September 15, 2021.
  4. American Society of Health-System Pharmacists. 2021. AHFS Drug Information® - 2021st Ed. Bethesda, MD. American Society of Health-System Pharmacists®. STAT!Ref Online Electronic Medical Library. Available at: https://online.statref.com/document/cQfe8yqMRNqgSGqm4Qo8Qj. Accessed September 15, 2021.
  5. Clozapine tablets (Clozaril®) package insert. Mylan Pharmaceuticals Inc., February 2021.
  6. Clozapine orally disintegrating tablets (FazaClo®) package insert. Jazz Pharmaceuticals, Inc., November 2020.
  7. Clozapine oral suspension (Versacloz®) package insert. TruPharma, LLC, August 2020.
  8. Asenapine sublingual tablets (Saphris®) package insert. Allergan USA, Inc., February 2017.
  9. Ziprasidone capsules (Geodon®) package insert. Aurobindo Pharma Limited, June 2021.
  10. Risperidone tablets, orally disintegrating tablets, oral solution (Risperdal®) package insert.  Janssen Pharmaceuticals, Inc., February 2021.
  11. Iloperidone tablets (Fanapt®) package insert.  Vanda Pharmaceuticals Inc., September 2018.
  12. Paliperidone extended-release tablets (Invega®) package insert. Janssen Pharmaceuticals, Inc., February 2021.
  13. Aripiprazole tablet, orally disintegrating tablet, oral solution (Abilify®) package insert. Otsuka America Pharmaceutical, Inc., August 2021.
  14. Olanzapine tablet, orally disintegrating tablet (Zyprexa®, Zyprexa® Zydis®) package insert. Eli Lilly and Company, April 2020.
  15. Quetiapine tablets (Seroquel®) package insert. AstraZeneca Pharmaceuticals, September 2020.
  16. Quetiapine extended-release tablets (Seroquel XR®) package insert. AstraZeneca Pharmaceuticals, September 2020.
  17. Lurasidone tablets (Latuda®) package insert. Sunovion Pharmaceuticals Inc., November 2020.
  18. Brexpiprazole (Rexulti®) package insert. Otsuka America Pharmaceutical, Inc., August 2021.
  19. Cariprazine capsules (Vraylar®) package insert. Allergan USA, Inc., May 2019.
  20. Aripiprazole tablets with sensor (Abilify MyCite®) package insert. Otsuka America Pharmaceutical, Inc., August 2021.
  21. Pimavanserin tablets (Nuplazid®) package insert. Acadia Pharmaceuticals, Inc., November 2020.
  22. Olanzapine and fluoxetine hydrochloride capsule (Symbyax®) package insert. Eli Lilly and Company, March 2021.
  23. Asenapine (Secuado®) Transdermal System package insert. Noven Pharmaceuticals, LLC, February 2020.
  24. Lumateperone (Caplyta®) oral capsules package insert. Intra-Cellular Therapies, Inc., December 2019.
  25. Olanzapine and samidorphan (Lybalvi®) oral tablets package insert. Alkermes Inc., May 2021.
  26. The Parameters Workgroup of the Psychiatric Executive Formulary Committee, Health and Specialty Care Division, Texas Health and Human Services Commission. Psychotropic medication utilization parameters for children and youth in Texas public behavioral health (6th version). (June 2019) Available at: https://hhs.texas.gov/sites/default/files/documents/doing-business-with-hhs/provider-portal/facilities-regulation/psychiatric/psychotropic-medication-utilization-parameters.pdf. Accessed September 15, 2021.
  27. Komossa K, Rummel-Kluge C, Hunger H, et al. Ziprasidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2009, Issue 4. Art. No.: CD006627.
  28. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166(9):980-91.
  29. Cruz N, Sanchez-Moreno J, Torres F, et al. Efficacy of modern antipsychotics in placebo-controlled trials in bipolar depression: a meta-analysis. Int J Neuropsychopharmacol. 2010;13(1):5-14.
  30. Crossley NA, Constante M, McGuire P, Power P. Efficacy of atypical v. typical antipsychotics in the treatment of early psychosis: meta-analysis. Br J Psychiatry. 2010;196:434-9.
  31. Edwards SJ, Smith CJ. Tolerability of atypical antipsychotics in the treatment of adults with schizophrenia or bipolar disorder: a mixed treatment comparison of randomized controlled trials. Clin Ther. 2009;31(Part 1):1345-59.
  32. Vitiello B, Correll C, van Zwieten-Boot B, et al. Antipsychotics in children and adolescents: increasing use, evidence for efficacy and safety concerns. Eur Neuropsychopharmacol. 2009;19(9):629-35.
  33. Sernyak MJ, Rosenheck R. Clinicians’ reasons for antipsychotic coprescribing.  J Clin Psychiatry. 2004;65:1597-1600.
  34. Tapp AM, Wood AE, Kilzieh N, et al. Antipsychotic polypharmacy: do benefits justify the risks? Ann Pharmacother. 2005;39:1759-60.
  35. Tranulis C, Skalli L, Lalonde P, et al. Benefits and risks of antipsychotic polypharmacy: an evidence-based review of the literature. Drug Saf. 2008;31(1):7-20.
  36. Cheng-Shannon J, McGough JJ, Pataki C, McCracken JT. Second-generation antipsychotic medications in children and adolescents. J Child Adolesc Psychopharmacol. 2004;14:372-94.
  37. Barzman DH, DelBello MP, Kowatch RA, et al. The effectiveness and tolerability of aripiprazole for pediatric bipolar disorders: a retrospective chart review. J Child Adolesc Psychopharmacol. 2004;14:593-600.
  38. Kranzler H, Roofeh D, Gerbino-Rosen G, et al. Clozapine: its impact on aggressive behavior among children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry. 2005;44:55-63.
  39. Sikich L, Hamer RM, Bashford RA, et al. A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial. Neuropsychopharmacology. 2004;29:133-45.
  40. Mozes T, Greenberg Y, Spivak B, et al. Olanzapine treatment in chronic drug-resistant childhood-onset schizophrenia: an open-label study. J Child Adolesc Psychopharmacol. 2003;13:311-7.
  41. Delbello MP, Schwiers ML, Rosenberg HL, Strakowski SM. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry. 2002;41:1216-23.
  42. Barnett MS. Ziprasidone monotherapy in pediatric bipolar disorder. J Child Adolesc Psychopharmacol. 2004;14:471-7.
  43. Aman MG, Arnold LE, McDougle CJ, et al. Acute and long-term safety and tolerability of risperidone in children with autism. J Child Adolesc Psychopharmacol. 2005;15:869-84.
  44. Masi G, Liboni F. Management of schizophrenia in children and adolescents:  focus on pharmacotherapy. Drugs. 2011;71(2):179-208.
  45. Thomas T, Stansifer L, Findling RL. Psychopharmacology of pediatric bipolar disorders in children and adolescents. Pediatr Clin N Am. 2011;58:173-87.

Atypical Anti-psychotics (long-acting injectable)

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • Oct. 2021, Sept. 2019
  • Initially developed
    • Sept. 2017

1.1. Adults

Long-acting injectable (LAI) second generation (atypical) antipsychotics are FDA-approved drugs to treat psychiatric disorders. All of the LAI atypical antipsychotics are used to treat schizophrenia 1-13. Invega Sustenna® has an additional indication for treating schizoaffective disorder 1-5. Both Abilify Maintena® and Risperdal Consta® have an additional indication for treating bipolar I disorder 1-4, 6, 7. Invega Hafyera® was approved in September 2021 for the management of schizophrenia in adult patients, and it is administered every six months 1-4, 11. Perseris® is a monthly injection of risperidone approved for the management of schizophrenia in adults that was first approved in 2018 1-4, 13. Aristada Initio® was approved for the initiation of Aristada®, and is only given once in combination with a single 30 mg oral dose of aripiprazole 1-4, 9. Recommended treatment dosages for LAI atypical antipsychotics are summarized in Table 1 1-13.

Abilify Maintena® dosages must be modified in patients prescribed CYP3A4 or CYP2D6 inhibitors, or in those patients identified as CYP poor metabolizers. Abilify Maintena® should be avoided in patients prescribed CYP3A4 inducers concurrently 1-4, 6. Recommended Abilify Maintena® dosages when prescribed concurrently with CP450-modifying medications are summarized in Table 2 1-4, 6.

Aristada® dosages must be modified in patients prescribed CYP3A4 or CYP2D6 inhibitors as well as CYP3A4 inducers concurrently. Aristada Initio® only comes in one dosage strength, and it should be avoided in patients who are known CYP2D6 poor metabolizers or taking strong CYP3A4 inhibitors, strong CYP2D6 inhibitors, or strong CYP3A4 inducers 1-4, 8, 9. Recommended Aristada® dosages when prescribed concurrently with CP450-modifying medications are summarized in Table 3 1-4, 8, 9.

Table 1: Adult LAI Atypical Antipsychotic Recommended Dosages

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage
Schizophrenia, bipolar I disorder (maintenance therapy) Aripiprazole (Abilify Maintena®) 300 mg, 400 mg intramuscular (IM) injection 400 mg IM once monthly
Schizophrenia Aripiprazole lauroxil (Aristada®, Aristada Initio®) 441 mg, 662 mg, 675 mg, 882 mg, 1064 mg IM injection 1064 mg IM every two months
Schizophrenia Olanzapine (Zyprexa® Relprevv ™) 210 mg, 300 mg, 405 mg IM injection 300 mg IM every two weeks or 405 mg every 4 weeks
Schizophrenia in patients who have been treated on Invega Sustenna for at least four months or Invega Trinza for at least one three month cycle Paliperidone palmitate (Invega Hafyera®) 1,092 mg, 1,560 mg IM injection 1,560 mg IM every 6 months
Schizophrenia, schizoaffective disorder Paliperidone palmitate (Invega Sustenna®) 39 mg, 78 mg, 117 mg, 156 mg, 234 mg IM injection 234 mg IM once monthly
Schizophrenia in patients who have been treated on Invega Sustenna® for at least four months Paliperidone palmitate (Invega Trinza®) 273 mg, 410 mg, 546 mg, 819 mg IM injection 819 mg IM once every 3 months
Schizophrenia Risperidone (Perseris®) 90 mg, 120 mg IM injection 120 mg IM every month
Schizophrenia, bipolar I disorder (maintenance therapy) Risperidone (Risperdal Consta®) 12.5 mg, 25 mg, 37.5 mg, 50 mg IM injection 50 mg IM every 2 weeks

Table 2: Cytochrome P450-Associated Dosage Changes for Aripiprazole (Abilify Maintena®) (Adults)

Factors Dosage Adjustment
Abilify Maintena® 300 mg intramuscular administration  
Strong CYP3A4 or CYP2D6 inhibitor (greater than 14 days) Reduce to 200 mg
CYP3A4 and CYP2D6 inhibitor together (greater than 14 days) Reduce to 160 mg
CYP3A inducer (greater than 14 days) Avoid use
Abilify Maintena® 400 mg intramuscular administration  
Strong CYP3A4 or CYP2D6 inhibitor (greater than 14 days) Reduce to 300 mg
CYP3A4 and CYP2D6 inhibitor together (greater than 14 days) Reduce to 200 mg
CYP3A inducer (greater than 14 days) Avoid use
Abilify Maintena® in CYP2D6 poor metabolizers  
Known CYP2D6 poor metabolizers Reduce to 300 mg
Known CYP2D6 poor metabolizer taking a CYP3A4 inhibitor Reduce to 200 mg

Table 3: Cytochrome P450-Associated Dosage Changes for Aripiprazole Lauroxil (Aristada® & Aristada Initio®) (Adults)

Factors Dosage Adjustment
Strong CYP3A inhibitor Reduce Aristada® dose to the next lowest strength; if patient is taking 441 mg, no dosage adjustment required
Strong CYP2D6 inhibitor Reduce Aristada® dose to next lowest strength; if patient is taking 441 mg, no dosage adjustment required
Known CYP2D6 poor metabolizer taking a strong CYP3A inhibitor If patient is taking 662 or 882 mg, reduce the dose to 441 mg; if patient is taking 441 mg, no dosage adjustment required
Known CYP2D6 poor metabolizer taking a strong CYP2D6 inhibitor No dose adjustment needed
Both a strong CYP2D6 inhibitor and CYP3A inhibitor Avoid using in patients who are taking 662 or 882 mg; if patient is taking 441 mg, no dosage adjustment needed
CYP3A4 inducers No dose adjustment is needed for the 662 mg or 882 mg dosages; if patient is taking 441 mg, increase dose to 662 mg

1.2. Pediatrics

Safety and efficacy of LAI atypical antipsychotics for use in children younger than 18 years of age have not been established 1-14. The Psychotropic Medication Utilization Parameters for Children and Youth in Texas Public Behavioral Health (6th Version) does not provide dosing recommendations for long-acting injectable atypical antipsychotics 14.

2. Duration of Therapy

If the patient is tolerating the LAI atypical antipsychotic, then there is no basis for limiting treatment length for approved psychiatric disorders as schizophrenia, schizoaffective disorder, and bipolar I disorder are chronic, lifelong diseases 1-13.

3. Duplicative Therapy

Co-administration of two or more LAI atypical antipsychotics is not justified due to limited additional therapeutic benefit and increased risk of adverse effects 1-13.

Patient profiles containing concomitant prescriptions for two or more LAI atypical antipsychotics will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for LAI atypical antipsychotics are summarized in Table 6. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed 1-13.

Table 6: Select LAI Atypical Antipsychotic Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level
Aripiprazole Citalopram Increased risk of QT prolongation and serotonin syndrome because aripiprazole is a partial agonist of 5-HT1A and citalopram is a selective serotonin reuptake inhibitor Avoid use Major (DrugReax) 2-major(CP)
Aripiprazole Strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole) Increased risk of aripiprazole overexposure because aripiprazole is metabolized by CYP3A4 Monitor patient closely and adjust aripiprazole dosages as needed Major (DrugReax) 3-moderate (CP)
Long-acting injectable atypical antipsychotics (LAI AAs) CNS depressants Increased risk of respiratory and central nervous system depression due to additive pharmacologic effects Use cautiously together; observe patients for enhanced CNS adverse effects Major (DrugReax) 3-moderate (CP)
LAI AAs Metoclopramide Increased risk of extrapyramidal reactions or neuroleptic malignant syndrome Avoid use Contraindicated (DrugReax) 1-severe,2-major (CP)
LAI AAs QT interval- prolonging medications (e.g. posaconazole) Increased risk of QT interval prolongation Avoid use; if combined use necessary, administer cautiously together and monitor closely     Contraindicated (DrugReax) 1-severe,2-major,3-moderate (CP)
Olanzapine Agents that lower seizure threshold (e.g. clomipramine) Increased seizure risk because psychotropic drugs may reduce the seizure threshold Use caution when administered concomitantly Major (DrugReax) 3-moderate (CP)
Atypical antipsychotics CYP3A4 and CYP1A2 inducers (e.g. carbamazepine) Concomitant use can lead to decreased serum concentrations of atypical antipsychotics Monitor treat efficacy and adjust atypical antipsychotic dosages as needed Major (DrugReax) 2-major (CP)
Olanzapine (CYP1A2 substrate) CYP1A2 inhibitor (e.g. fluvoxamine) Increased olanzapine serum concentrations Monitor patient closely and adjust olanzapine dosages as needed Major (DrugReax) 2-major (CP)
Risperidone Serotonergic agents (e.g. linezolid) Increased risk of serotonin syndrome Monitor patients for serotonin syndrome Major (DrugReax) 2-major (CP)
Risperidone, Olanzapine Lithium Increased extrapyramidal symptoms; encephalopathy and brain damage have occurred in case reports due to unknown mechanism Monitor patients closely for symptoms and monitor lithium levels Major (DrugReax) 3-moderate (CP)

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited:  September 21, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at:  http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed September 21, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; September 21, 2021.
  4. American Society of Health-System Pharmacists. 2021. AHFS Drug Information® - 2021st Ed. Bethesda, MD. American Society of Health-System Pharmacists®. STAT!Ref Online Electronic Medical Library. Available at: https://online.statref.com/document/cQfe8yqMRNqgSGqm4Qo8Qj. Accessed September 15, 2021.
  5. Paliperidone palmitate extended-release injection suspension (Invega® Sustenna®) package insert. Janssen Pharmaceuticals, August 2021.
  6. Aripiprazole intramuscular extended-release injection (Abilify Maintena®) package insert. Otsuka America Pharmaceutical, Inc., September 2021.
  7. Risperidone long-acting injection (Risperdal Consta®) package insert. Janssen Pharmaceuticals, Inc., February 2021.
  8. Aripiprazole lauroxil intramuscular extended-release injection (Aristada®) package insert. Alkermes, Inc., March 2021.
  9. Aripiprazole lauroxil intramuscular extended-release (Aristada Initio®) package insert. Alkermes, Inc., March 2021.
  10. Olanzapine extended release injectable suspension (Zyprexa® Relprevv™) package insert. Eli Lilly and Company, May 2021.
  11. Paliperidone palmitate extended-release injection suspension (Invega Hafyera®) package insert. Janssen Pharmaceuticals, August 2021.
  12. Paliperidone palmitate extended release suspension (Invega Trinza®) package insert. Janssen Pharmaceuticals, August 2021.
  13. Risperidone long-acting injection (Perseris®) package insert. Indivior Inc., December 2019.
  14. The Parameters Workgroup of the Psychiatric Executive Formulary Committee, Health and Specialty Care Division, Texas Health and Human Services Commission. Psychotropic medication utilization parameters for children and youth in Texas public behavioral health (6th version). (June 2019) Available at: https://hhs.texas.gov/sites/default/files/documents/doing-business-with-hhs/provider-portal/facilities-regulation/psychiatric/psychotropic-medication-utilization-parameters.pdf. Accessed September 21, 2021. 
  15. Correll CU, Citrome L, Haddad PM, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77(suppl 3):1-24.
  16. Llorca PM, Abbar M, Courtet P, et al. Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness. BMC Psychiatry. 2013;13:340.

Atypical Anti-psychotics (oral)

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • Oct. 22, 2021, Sept. 2019; Sept. 2017; Sept. 2015; Dec. 2013; Feb. 2012; June 2010; May 2010; March 2007; Dec. 2006; Oct. 2006; May 2003; April 2002; April 2001; April 2000; March 1999; March 1998
  • Initially developed
    • Feb. 1997

1.1. Adults

Oral atypical antipsychotics are FDA-approved for use in schizophrenia, bipolar I disorder (BD), bipolar disorder with mixed episodes or depressive episodes, bipolar mania, schizoaffective disorder (SD), adjunctive therapy in major depressive disorder (MDD), treatment-resistant schizophrenia, and irritability associated with autism 1-18. Cariprazine (Vraylar®) has been approved for schizophrenia and manic or mixed episodes associated with BD.1-4, 19  Aripiprazole tablets with sensors (Abilify MyCite®) have been approved to track if the medication has been taken 20.

Pimavanserin (Nuplazid®) is an oral atypical antipsychotic recently indicated for use to manage hallucinations and delusions seen with Parkinson’s disease psychosis 1-4, 21. Olanzapine combination therapy is FDA-approved for use in managing treatment-resistant depression as well as bipolar depression 1-4, 22. Secuado® (asenapine) Transdermal System is a topical patch that was approved by the FDA in 2019 for the management of schizophrenia in adult patients 1-4, 23. Additionally, Caplyta® (lumateperone) is a once daily oral capsule that was approved in 2019 for the management of schizophrenia in adult patients 1-4, 24.

Maximum recommended adult doses for atypical antipsychotics are summarized in Table 1 1-21, 23, 24. Dosages exceeding these recommendations will be reviewed.

Combination therapy with the atypical antipsychotic, olanzapine, and the selective serotonin reuptake inhibitor, fluoxetine, is FDA-approved for the management of depressive episodes associated with bipolar I disorder and treatment-resistant depression in adults 1-4, 22.

In May of 2021 the FDA approved Lybalvi®, which is an oral combination product containing olanzapine and samidorphan, for the management of acute mixed or manic episodes in bipolar 1 disorder, maintenance therapy in bipolar 1 disorder, and for the management of schizophrenia 1-4, 25 Samidorphan that binds to mu, kappa, and delta opioid receptors. Samidorphan is a mu-opioid receptor antagonist, and it demonstrates partial agonist activity on kappa, and delta-opioid receptors. The major metabolites of samidorphan also have an affinity for opioid receptors, however, neither metabolite is thought to contribute to the pharmacologic effects of the drug 1-4, 25.

Doses exceeding the maximum adult recommended doses summarized in Table 2 1-4, 22, 25 will be reviewed.

Table 1: Oral Atypical Antipsychotics (Monotherapy) - Adult Maximum Recommended Dosages

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage
Schizophrenia, BD Aripiprazole (Abilify®, Abilify Discmelt®, Abilify MyCite® system)
  • 2 mg, 5 mg, 10mg, 15 mg, 20 mg, 30 mg immediate-release (IR) tablets
  • 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg IR tablets with sensor#  
  • 10 mg, 15 mg orally disintegrating tablets (ODTs)
  • 1 mg/ml oral solution
  • oral tablets: 30 mg/day
  • oral solution: 25 mg/day
MDD     15 mg/day
Schizophrenia, BD Asenapine (Saphris®, Secuado® Transdermal System)
  • 2.5 mg, 5 mg, 10 mg sublingual tablets
  • 3.8 mg/24 hr, 5.7 mg/24 hr, 7.6 mg/24 hr transdermal patch
  • 20 mg/day, in two divided doses
  • 7.6 mg/24 hr transdermally
Schizophrenia Brexpiprazole (Rexulti®) 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg tablets 4 mg once daily
MDD     3 mg once daily
Bipolar major depression Cariprazine (Vraylar®) 1.5 mg, 3 mg, 4.5 mg 6 mg capsules 3 mg once daily
BD (acute mixed/manic episodes), schizophrenia     6 mg once daily
Schizophrenia (treatment-resistant), reducing recurrent suicidal behavior in schizophrenia and schizoaffective disorder (SD) Clozapine (Clozaril®, generics, FazaClo®, Versacloz®)
  • 25 mg, 50 mg, 100 mg, 200 mg IR tablets
  • 12.5 mg, 25 mg, 100 mg, 150 mg, 200 mg ODTs
  • 50 mg/ml oral suspension
  • 900 mg/day, in divided doses
Schizophrenia Iloperidone (Fanapt®) 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg 12 mg IR tablets 24 mg/day, in divided doses
Schizophrenia Lumateperone (Caplyta®) 42 mg capsules 42 mg/day
Schizophrenia Lurasidone (Latuda®) 20 mg, 40 mg, 60 mg, 80 mg, 120 mg IR tablets 160 mg/day, with food (at least 350 calories)
Bipolar depression     120 mg/day, with food (at least 350 calories)
Schizophrenia, BD, treatment-resistant depression Olanzapine (Zyprexa®, Zyprexa Zydis®, generics) 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg IR tablets 5 mg, 10 mg, 15 mg, 20 mg ODTs    20 mg/day, as a single dose
Schizophrenia, SD Paliperidone (Invega®) 1.5 mg, 3 mg, 6 mg, 9 mg extended-release (ER) tablets 12 mg/day
Parkinson disease psychosis Pimavanserin (Nuplazid®) 10 mg, 17 mg, 34 mg tablet 34 mg once daily
Schizophrenia, BD (acute manic episodes, maintenance) Quetiapine (Seroquel®, Seroquel XR®, generics)
  • 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg IR tablets
  • 50 mg, 150 mg, 200 mg, 300 mg, 400 mg ER tablets
  • IR: 800 mg/day, in two or three divided doses
  • ER: 800 mg/day, as a single dose
Bipolar depression    
  • IR: 300 mg/day, at bedtime
  • ER: 300 mg/day, as a single dose
MDD Quetiapine (Seroquel XR®, generics) 50 mg, 150 mg, 200 mg, 300 mg, 400 mg ER tablets ER: 300 mg/day, as a single dose
Schizophrenia Risperidone (Risperdal®, Risperdal M-TAB®, generics)
  • 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg IR tablets
  • 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg ODTs
  • 1 mg/ml oral solution
8 mg/day in 1 or 2 divided doses *
Bipolar mania     6 mg/day
Schizophrenia Ziprasidone (Geodon®, generics) 20 mg, 40 mg, 60 mg, 80 mg IR capsules 200 mg/day, in two divided doses +
BD     160 mg/day, in two divided doses

Legend:

  • # ingestible event marker (IEM) embedded in each MyCite® tablet; to be dispensed with MyCite® patch (wearable sensor that detects signal frim IEM sensor) and MyCite App
  • * doses up to 16 mg/day have demonstrated efficacy in clinical trials; however, doses of 4 to 8 mg/day tended to produce the maximal effect    
  • + doses up to 320 mg daily have been used safely but greater efficacy not noted with higher dosages

Table 2: Oral Atypical Antipsychotics (Combination Therapy) – Adult Maximum Recommended Dosages

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage
Bipolar depression, treatment-resistant depression Olanzapine/ fluoxetine (Symbyax®)
  • Olanzapine 3 mg/fluoxetine 25 mg
  • olanzapine 6 mg/fluoxetine 25 mg
  • olanzapine 6 mg/fluoxetine 50 mg
  • olanzapine 12 mg/fluoxetine 25 mg
  • olanzapine 12 mg/fluoxetine 50 mg
Olanzapine 18 mg/ fluoxetine 75 mg once daily in evening, without regard to meals
Schizophrenia, BD Olanzapine/ samidorphan (Lybalvi®)
  • Olanzapine 5 mg/ samidorphan 10 mg
  • olanzapine 10 mg/ samidorphan 10 mg
  • olanzapine 15 mg/ samidorphan 10 mg
  • olanzapine 20 mg, samidorphan 10 mg
Olanzapine 20 mg/ samidorphan 10 mg once daily

1.2. Pediatrics

Risperidone has been FDA-approved to manage symptoms of irritability in autistic children greater than 5 years of age and adolescents, and has recently gained FDA-approved indications for bipolar mania in children and adolescents 10 to 17 years of age and schizophrenia in adolescents 13 to 17 years of age. Aripiprazole has received recent FDA approval for treating Tourette’s disorder in pediatric patients 6 to 18 years of age, and is also FDA-approved for managing schizophrenia in adolescents 13 to 17 years of age, bipolar disorder with or without psychotic features in children 10 to 17 years of age, and irritability associated with autistic disorder in children 6 to 17 years of age. Olanzapine has been granted FDA approval for bipolar disorder and schizophrenia in adolescents 13 years of age and older. Quetiapine is FDA approved for acute treatment of bipolar disorder mania episodes in children and adolescents 10 to 17 years of age and schizophrenia management in adolescents 13 to 17 years of age. Paliperidone is approved FDA for the management of schizophrenia in adolescents 12 to 17 years of age. Lurasidone is approved for the management of depressed phase bipolar disorder in children 10 to 17 years of age, and it is approved for the management of schizophrenia in patients 13 to 17 years of age. Brexpiprazole, cariprazine, clozapine, iloperidone, Lumateperone, ziprasidone, and aripiprazole tablets with sensors (Abilify MyCite®) are not recommended for use in pediatric patients as safety and efficacy have not been established in this patient population. Additionally, pimavanserin is not approved for use in pediatric patients as Parkinson’s disease is typically not observed in pediatric patients, and safety and efficacy data are not available for pimavanserin in the pediatric population 1-25.

Atypical antipsychotic pediatric dosages are summarized in Table 3 1-21, 23, 26. An additional column reflecting literature-based dosing included in the Texas Health and Human Services Psychotropic Medication Utilization Parameters for Children and Youth in Texas Public Behavioral Health (6th Version) is included in Tables 3 and 4 26.

The olanzapine/fluoxetine combination has been approved for use in pediatric patients 10-17 years of age with depression associated with BD 1-4, 22. Recommended pediatric dosages are summarized in Table 4 1-4, 22, 26.

Table 3: Atypical Antipsychotics (Monotherapy) – Pediatric Maximum Recommended Dosages

Treatment Indication Drug Name Available Dosage Strengths Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage 
Schizophrenia Aripiprazole (Abilify®, Abilify Discmelt®)
  • 2 mg, 5 mg, 10mg, 15 mg, 20 mg, 30 mg immediate-release (IR) tablets
  • 10 mg, 15 mg orally disintegrating tablets (ODTs)
  • 1 mg/ml oral solution
  • Age 4-11 years: 15 mg/day
  • Age greater than or equal to 12 years: 30 mg/day
13-17 years of age: 30 mg once daily
BD       10-17 years of age: 30 mg once daily
Tourette’s disorder       6-18 years of age:
  • Less than 50 kg: 10 mg/day
  • Greater than or equal to 50 kg: 20 mg/day
Irritability associated with autism       6-17 years of age: 15 mg/day as a single dose
BD Asenapine (Saphris®) 2.5 mg, 5 mg, 10 mg sublingual tablets Age greater than or equal to 10 years: 10 mg twice daily 10-17 years of age: 20 mg/day, in two divided doses
Reserved for treatment resistant psychosis, following two failed trials of antipsychotic therapy with adequate dose/ duration Clozapine (Clozaril®, generics, FazaClo®, Versacloz®)
  • 25 mg, 50 mg, 100 mg, 200 mg IR tablets
  • 12.5 mg, 25 mg, 100 mg, 150 mg, 200 mg ODTs
  • 50 mg/ml oral suspension
  • Age 8-11 years: 150- 300 mg/day
  • Age greater than or equal to 12 years: 600 mg/day
  • Target serum clozapine level of 350 ng/mL for optimal efficacy
Not approved for children or adolescents 
Schizophrenia, BD Lurasidone (Latuda®) 20 mg, 40 mg, 60 mg, 80 mg IR tablets
  • Schizophrenia (age 13-17 years): 80 mg/day
  • Bipolar I Depression (age 10-17 years): 80 mg/day
13 to 17 years of age: 80 mg/day, with food (at least 350 calories)
Schizophrenia, BD Olanzapine (Zyprexa®, Zyprexa Zydis®, generics)
  • 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg IR tablets
  • 5 mg, 10 mg, 15 mg, 20 mg orally disintegrating tablets
  • Age 4-5 years: 12.5 mg/day
  • Age 6-17 years: 20 mg/ day
13 to 17 years of age: 20 mg once daily
Schizophrenia Paliperidone (Invega®) 1.5 mg, 3 mg, 6 mg, 9 mg extended-release (ER) tablets Adolescents (age greater than or equal to 12 years), schizophrenia: 
  • Weight less than 51 kg: 6 mg/day
  • Weight greater than or equal to 51 kg: 12 mg/day
12-17 years of age:
  • Less than 51 kg: 6 mg/day
  • Greater than or equal to 51 kg: 12 mg/day
BD - acute manic episodes Quetiapine (Seroquel®, generics, Seroquel XR®)
  • 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg IR tablets
  • 50 mg, 150 mg, 200 mg, 300 mg, 400 mg ER tablets
  • Age 5- 9 years: 400 mg/day
  • Age 10-17 years: 800 mg/day
10 to 17 years of age: 600 mg daily, once daily (ER tablets) or in 2 to 3 divided doses (IR tablets)
Schizophrenia       13 to 17 years of age: 800 mg daily, once daily (ER tablets) or in 2 to 3 divided doses (IR tablets)
Bipolar mania Risperidone (Risperdal®, Risperdal M-TAB®, generics)
  • 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg IR tablets
  • 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg ODTs
  • 1 mg/ml oral solution
  • Age 4-11 years: 3 mg/day
  • Age greater than or equal to12 years:6 mg/day
10-17 years of age: 6 mg daily
Schizophrenia       13-17 years of age: 6 mg daily
Irritability in autistic disorder       5-17 years of age: 3 mg/day (no dosing data available for pediatric patients less than 15 kg)
BP Ziprasidone (Geodon®, generics) 20 mg, 40 mg, 60 mg, 80 mg IR capsules Bipolar Disorder (age10-17 years)
  • Weight less than or equal to 45 kg: 80 mg/day
  • Weight greater than 45 kg
Not approved for children or adolescents

Table 4: Oral Atypical Antipsychotics (Combination Therapy) – Pediatric Maximum Recommended Dosages

Treatment Indication Drug Name Available Dosage Strengths Literature Based Maximum Dosage Maximum Recommended Dosage per Age Group
Bipolar depression Olanzapine/ fluoxetine (Symbyax®)
  • Olanzapine 3 mg/fluoxetine 25 mg
  • olanzapine 6 mg/fluoxetine 25 mg
  • olanzapine 6 mg/fluoxetine 50 mg
  • olanzapine 12 mg/fluoxetine 25 mg
  • olanzapine 12 mg/fluoxetine 50 mg
Age 10-17 years: 12 mg olanzapine/50 mg fluoxetine once daily 10-17 years of age:  olanzapine 12 mg/ fluoxetine 50 mg once daily in evening, without regard to meals

2. Duration of Therapy

Atypical antipsychotics are indicated for use in the management of schizophrenia and psychotic disorders. Therefore, there is no basis for limiting treatment duration with these atypical antipsychotics as these agents are utilized in the management of chronic disorders 1-44.

3. Duplicative Therapy

Combined therapy with multiple antipsychotic medications were evaluated in patients with treatment-resistant schizophrenia. Open studies, case reports, and clinical trials have observed favorable results following concurrent therapy with either atypical antipsychotics plus conventional antipsychotic agents or clozapine in conjunction with an additional atypical antipsychotic in clozapine-refractory patients. Further, controlled trials are necessary to identify patients and circumstances in which combination therapy should be utilized and the risks and benefits of concurrent therapy.

Neuroleptics should be used concomitantly during transitional periods lasting up to four weeks when switching patients to a different antipsychotic agent 1-44.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug interactions considered clinically relevant for atypical antipsychotics are summarized in Table 5 1-25. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 5: Select Drug-Drug Interactions for Oral Atypical Antipsychotics

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
Aripiprazole Citalopram Increased risk of QT prolongation and serotonin syndrome because aripiprazole is a partial agonist of 5-HT1A and citalopram is a selective serotonin reuptake inhibitor Avoid use Major (DrugReax) 2-major(CP)
Atypical antipsychotics (AAs) Antihypertensive agents Potential for enhanced antihypertensive effects due to AA-associated alpha1-adrenergic receptor antagonism Use cautiously together; monitor for amplified hypotensive effects 3-moderate (CP)
AAs CNS depressants Potential for additive CNS effects Use cautiously together; observe patients for enhanced CNS adverse effects Major (DrugReax) 3-moderate (CP)
AAs (except pimavanserin) Drugs affecting seizure threshold (e.g., tramadol) Increased seizure risk as AAs have been associated with seizures (incidence varies) Avoid drug combination if possible; if combination necessary, closely monitor patients for seizure activity and discontinue therapy as indicated Major (DrugReax) 2-major (CP)
AAs Metoclopramide Adjunctive therapy enhances potential for increased extrapyramidal symptoms (EPS) and neuroleptic malignant syndrome (NMS) as both agents block dopamine receptors Combination contraindicated by metoclopramide manufacturer; if combination necessary, monitor for signs/ symptoms of EPS or NMS-discontinue metoclopramide if symptoms develop Contraindicated (DrugReax) 1-severe (CP)
Clozapine Myelopsuppressive (antineoplastic) drugs Potential for additive bone marrow suppressive effects Concurrent administration contraindicated 1-severe (CP)
Clozapine Carbamazepine Increased risk of additive bone marrow-suppressing effects, including agranulocytosis Avoid concurrent use; choose alternative anticonvulsant Major (DrugReax) 2-major (CP)
Samidorphan Opioids Concurrent use may decrease opioid efficacy and precipitate opioid withdrawal Concurrent administration is contraindicated Contraindicated (DrugReax) 1-severe (CP)
Select AAs (clozapine, olanzapine) CYP1A2 inducers (e.g., carbamazepine**, phenobarbital, phenytoin, ritonavir*, rifampin) Potential for reduced clozapine, olanzapine serum concentrations and worsening of psychosis Monitor clozapine, olanzapine efficacy in patients; adjust doses as necessary when CYP1A2 inducer added, deleted, or changed to therapeutic regimen Moderate (DrugReax) 2-major (CP)
Select AAs (asenapine, clozapine, olanzapine) CYP1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine) Potential for decreased AA clearance, increased AA serum concentrations and enhanced pharmacologic/ adverse effects (seizures, hypotension) as clozapine, olanzapine metabolized by CYP1A2 If drug combination necessary, used reduced clozapine dosages and closely monitor for adverse events Moderate (DrugReax) 2-major (CP)
Select AAs (aripiprazole, brexpiprazole, cariprazine, clozapine, iloperidone, pimavanserin, quetiapine, ziprasidone) CYP3A4 inhibitors (e.g., ketoconazole, ritonavir*) Potential for decreased AA clearance, increased AA serum concentrations, and enhanced pharmacologic/ adverse effects as select AAs metabolized by CYP3A4 Monitor for enhanced AA pharmacologic/ adverse effects and adjust doses as necessary (50% dose reduction recommended for aripiprazole,  brexpiprazole, iloperidone) Moderate (DrugReax) 2-major, 3-moderate (CP)
Select AAs (aripiprazole, brexpiprazole, clozapine, olanzapine, pimavanserin,  quetiapine, risperidone, ziprasidone) CYP3A4 inducers (e.g., carbamazepine**, phenytoin) Potential for significant reductions in AA plasma concentrations (by as much as 50%) due to enhanced AA hepatic microsomal metabolism Monitor AA efficacy in patients; adjust doses as necessary when CYP3A4 inducer added, deleted, or changed to therapeutic regimen (brexpiprazole dose should be doubled over 1-2 weeks when prescribed with CYP3A4 inducer) Moderate (DrugReax) 2-major, 3-moderate (CP)
Select AAs (aripiprazole, brexpiprazole, iloperidone, risperidone) CYP2D6 inhibitors (e.g., quinidine, select SSRIs, ritonavir) Potential for decreased AA clearance and increased AA serum concentrations and enhanced pharmacologic/ adverse effects as select AAs metabolized by CYP2D6 Monitor for enhanced AA pharmacologic/ adverse effects and adjust doses as necessary (recommended to reduce aripiprazole, brexpiprazole,  iloperidone doses by 50% when administered in conjunction with CYP2D6 inhibitor) Moderate (DrugReax) 2-major, 3-moderate (CP)
Select AAs (aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, pimavanserin, quetiapine, risperidone, ziprasidone) QTc interval-prolonging medications Potential for increased cardiotoxicity (e.g., torsades de pointes, cardiac arrest) due to additive QT interval prolongation Avoid concurrent use; if combination necessary, closely monitor cardiac function; discontinue therapy in patients with QTc measurements greater than 500 msec Major (DrugReax) 1-severe, 2-major (CP)

Legend:

  • # CP = Clinical Pharmacology
  • * Ritonavir inhibits clozapine metabolism through CYP3A4 inhibition, but induces olanzapine metabolism through CYP1A2 enzyme induction.  
  • ** Carbamazepine induces olanzapine metabolism through CYP1A2 enzyme induction and induces clozapine metabolism through CYP3A4 induction.

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited:  September 15, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed September 15, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; September 15, 2021.
  4. American Society of Health-System Pharmacists. 2021. AHFS Drug Information® - 2021st Ed. Bethesda, MD. American Society of Health-System Pharmacists®. STAT!Ref Online Electronic Medical Library. Available at: https://online.statref.com/document/cQfe8yqMRNqgSGqm4Qo8Qj. Accessed September 15, 2021.
  5. Clozapine tablets (Clozaril®) package insert. Mylan Pharmaceuticals Inc., February 2021.
  6. Clozapine orally disintegrating tablets (FazaClo®) package insert. Jazz Pharmaceuticals, Inc., November 2020.
  7. Clozapine oral suspension (Versacloz®) package insert. TruPharma, LLC, August 2020.
  8. Asenapine sublingual tablets (Saphris®) package insert. Allergan USA, Inc., February 2017.
  9. Ziprasidone capsules (Geodon®) package insert. Aurobindo Pharma Limited, June 2021.
  10. Risperidone tablets, orally disintegrating tablets, oral solution (Risperdal®) package insert. Janssen Pharmaceuticals, Inc., February 2021.
  11. Iloperidone tablets (Fanapt®) package insert. Vanda Pharmaceuticals Inc., September 2018.
  12. Paliperidone extended-release tablets (Invega®) package insert. Janssen Pharmaceuticals, Inc., February 2021.
  13. Aripiprazole tablet, orally disintegrating tablet, oral solution (Abilify®) package insert. Otsuka America Pharmaceutical, Inc., August 2021.
  14. Olanzapine tablet, orally disintegrating tablet (Zyprexa®, Zyprexa® Zydis®) package insert. Eli Lilly and Company, April 2020.
  15. Quetiapine tablets (Seroquel®) package insert. AstraZeneca Pharmaceuticals, September 2020.
  16. Quetiapine extended-release tablets (Seroquel XR®) package insert. AstraZeneca Pharmaceuticals, September 2020.
  17. Lurasidone tablets (Latuda®) package insert. Sunovion Pharmaceuticals Inc., November 2020.
  18. Brexpiprazole (Rexulti®) package insert. Otsuka America Pharmaceutical, Inc., August 2021.
  19. Cariprazine capsules (Vraylar®) package insert. Allergan USA, Inc., May 2019.
  20. Aripiprazole tablets with sensor (Abilify MyCite®) package insert. Otsuka America Pharmaceutical, Inc., August 2021.
  21. Pimavanserin tablets (Nuplazid®) package insert. Acadia Pharmaceuticals, Inc., November 2020.
  22. Olanzapine and fluoxetine hydrochloride capsule (Symbyax®) package insert. Eli Lilly and Company, March 2021.
  23. Asenapine (Secuado®) Transdermal System package insert. Noven Pharmaceuticals, LLC, February 2020.
  24. Lumateperone (Caplyta®) oral capsules package insert. Intra-Cellular Therapies, Inc., December 2019.
  25. Olanzapine and samidorphan (Lybalvi®) oral tablets package insert. Alkermes Inc., May 2021.
  26. The Parameters Workgroup of the Psychiatric Executive Formulary Committee, Health and Specialty Care Division, Texas Health and Human Services Commission. Psychotropic medication utilization parameters for children and youth in Texas public behavioral health (6th version). (June 2019) Available at: https://hhs.texas.gov/sites/default/files/documents/doing-business-with-hhs/provider-portal/facilities-regulation/psychiatric/psychotropic-medication-utilization-parameters.pdf. Accessed September 15, 2021.
  27. Komossa K, Rummel-Kluge C, Hunger H, et al. Ziprasidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2009, Issue 4. Art. No.: CD006627.
  28. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166(9):980-91.
  29. Cruz N, Sanchez-Moreno J, Torres F, et al. Efficacy of modern antipsychotics in placebo-controlled trials in bipolar depression: a meta-analysis. Int J Neuropsychopharmacol. 2010;13(1):5-14.
  30. Crossley NA, Constante M, McGuire P, Power P. Efficacy of atypical v. typical antipsychotics in the treatment of early psychosis: meta-analysis. Br J Psychiatry. 2010;196:434-9.
  31. Edwards SJ, Smith CJ. Tolerability of atypical antipsychotics in the treatment of adults with schizophrenia or bipolar disorder: a mixed treatment comparison of randomized controlled trials. Clin Ther. 2009;31(Part 1):1345-59.
  32. Vitiello B, Correll C, van Zwieten-Boot B, et al. Antipsychotics in children and adolescents: increasing use, evidence for efficacy and safety concerns. Eur Neuropsychopharmacol. 2009;19(9):629-35.
  33. Sernyak MJ, Rosenheck R. Clinicians’ reasons for antipsychotic coprescribing. J Clin Psychiatry. 2004;65:1597-1600.
  34. Tapp AM, Wood AE, Kilzieh N, et al. Antipsychotic polypharmacy: do benefits justify the risks? Ann Pharmacother. 2005;39:1759-60.
  35. Tranulis C, Skalli L, Lalonde P, et al. Benefits and risks of antipsychotic polypharmacy: an evidence-based review of the literature. Drug Saf. 2008;31(1):7-20.
  36. Cheng-Shannon J, McGough JJ, Pataki C, McCracken JT. Second-generation antipsychotic medications in children and adolescents. J Child Adolesc Psychopharmacol. 2004;14:372-94.
  37. Barzman DH, DelBello MP, Kowatch RA, et al. The effectiveness and tolerability of aripiprazole for pediatric bipolar disorders: a retrospective chart review. J Child Adolesc Psychopharmacol. 2004;14:593-600.
  38. Kranzler H, Roofeh D, Gerbino-Rosen G, et al. Clozapine: its impact on aggressive behavior among children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry. 2005;44:55-63.
  39. Sikich L, Hamer RM, Bashford RA, et al. A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial. Neuropsychopharmacology. 2004;29:133-45.
  40. Mozes T, Greenberg Y, Spivak B, et al. Olanzapine treatment in chronic drug-resistant childhood-onset schizophrenia: an open-label study. J Child Adolesc Psychopharmacol. 2003;13:311-7.
  41. Delbello MP, Schwiers ML, Rosenberg HL, Strakowski SM. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry. 2002;41:1216-23.
  42. Barnett MS. Ziprasidone monotherapy in pediatric bipolar disorder. J Child Adolesc Psychopharmacol. 2004;14:471-7.
  43. Aman MG, Arnold LE, McDougle CJ, et al. Acute and long-term safety and tolerability of risperidone in children with autism. J Child Adolesc Psychopharmacol. 2005;15:869-84.
  44. Masi G, Liboni F. Management of schizophrenia in children and adolescents:  focus on pharmacotherapy. Drugs. 2011;71(2):179-208.
  45. Thomas T, Stansifer L, Findling RL. Psychopharmacology of pediatric bipolar disorders in children and adolescents. Pediatr Clin N Am. 2011;58:173-87.

Benzodiazepines (Oral, Nasal, Rectal)

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

Refer to the Sedative/Hypnotics criteria for sedative and hypnotic benzodiazepines.

  • Revision history
    • April 22, 2022; March 2020; March 2018; May 2017; Dec. 2014; March 2013; June 2011; Jan. 2009; April 2003; Dec. 2001; Dec. 2000; Dec. 1999; Nov. 1998; Nov. 1997; Dec. 1996.
  • Initially developed
    • Oct. 1993

1.1. Adults

Non-sedative/hypnotic benzodiazepines and benzodiazepines with mixed indications are FDA-approved for use in the outpatient setting to manage anxiety (alprazolam, chlordiazepoxide, clorazepate, oral diazepam, lorazepam, oxazepam), panic disorder (alprazolam, clonazepam), acute musculoskeletal (MS) conditions including spasticity (oral diazepam), seizures [clobazam (Lennox-Gastaut syndrome), clonazepam, clorazepate, nasal, oral and rectal diazepam], and acute alcohol withdrawal (chlordiazepoxide, clorazepate, oral diazepam, oxazepam) 1-11. An oral film formulation of clobazam (Sympazan®) is FDA approved for adjunctive seizure management in Lennox-Gastaut syndrome 1,2,12. A diazepam nasal formulation (Valtoco®) is FDA-approved to treat intermittent frequent seizure episodes that differ from a patient’s usual seizure pattern 1,2,13. Nayzilam® is a nasal spray formulation of midazolam that is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient’s usual seizure pattern in patients with epilepsy 1,2,14. In November 2021, the FDA approved a once daily extended release formulation of lorazepam (Loreev XR®) that is approved for the treatment of anxiety disorders in adults who are already receiving three times daily dosing of lorazepam 1,2,15.

The chlordiazepoxide-amitriptyline combination is indicated for depression with associated anxiety symptoms, while chlordiazepoxide/clidinium is FDA-approved to control emotional and somatic factors in gastrointestinal disorders as well as adjunctive use in peptic ulcer disease, irritable bowel syndrome, and acute enterocolitis 1,2,16. Tables 1 1-15 and 2 1,2,16,17summarize the adult maximum recommended dosages for non-sedative/hypnotic benzodiazepines as monotherapy and combination therapy.

Table 1. Adult Benzodiazepine Maximum Recommended Daily Dosages: Monotherapy

Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage*
alprazolam (Xanax®, generics) 0.25 mg, 0.5 mg, 1 mg, 2 mg tablets, disintegrating tablets; 1 mg/ml oral solution anxiety Less than or equal to and greater than 65 years: 4 mg daily, in divided doses
alprazolam (Xanax®, Xanax XR®, generics) 0.25 mg, 0.5 mg, 1 mg, 2 mg tablets, disintegrating tablets; 0.5 mg, 1 mg, 2 mg, 3 mg extended-release tablets; 1 mg/ml oral solution panic Less than or equal to and greater than 65 years: 10 mg daily, in divided doses for immediate release formulations
chlordiazepoxide (generics) 5 mg, 10 mg, 25 mg capsule alcohol withdrawal (AW) Less than or equal to and greater than 65 years: 300 mg daily, in divided doses
    anxiety

Less than 65 years: mild, moderate: 40 mg daily, in divided doses severe: 100 mg daily, in divided doses

Greater than 65 years: 20 mg daily, in divided doses

clobazam (Onfi®, Sympazan®, generics) 10 mg, 20 mg tablets; 2.5 mg/mL suspension; 5 mg, 10 mg, 20 mg oral soluble film seizures associated with Lennox-Gastaut syndrome

Less than 65 years: 
weight greater than 30 kg:
40 mg/day in two divided doses weight less than or equal to 30 kg 20 mg/day in two divided doses

Greater than 65 years:
weight greater than 30 kg: 
40 mg/day in two divided doses weight less than or equal to  30 kg 20 mg/day in two divided doses 

clonazepam (Klonopin®, generics) 0.5 mg, 1 mg, 2 mg tablets; 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg disintegrating tablets panic Less than or equal to and greater than 65 years: 4 mg daily
    seizures Less than or equal to and greater than 65 years: 20 mg daily
clorazepate (Tranxene®, Tranxene T-Tab®, generics) 3.75 mg, 7.5 mg, 15 mg tablets AW Less than or equal to and greater than 65 years: 90 mg daily
    anxiety Less than or equal to and greater than 65 years: 60 mg daily
    seizures Less than or equal to and greater than 65 years: 90 mg daily
diazepam (nasal) (Valtoco®) 5 mg as one 5 mg device, 10 mg as one 10 mg device, 15 mg as 2 x 7.5 mg devices, 20 mg as 2 x 10 mg devices nasal liquid seizures 28-50 kg: 10 mg as one spray in one nostril (equates to 0.2 mg/kg dose)^
51-75 kg: 15 mg as 2 x 7.5 mg devices with one spray in each nostril (equates to 0.2 mg/kg dose)^
Greater than or equal to 76 kg^: 20 mg as 2 x 10 mg devices with one spray in each nostril (equates to 0.2 mg/kg dose)^
diazepam (oral) (Valium®, Diazepam Intensol®, generics) 2 mg, 5 mg, 10 mg oral tablets; 5 mg/mL, 5 mg/5 mL oral solution AW Less than or equal to and greater than 65 years: 40 mg daily
    anxiety Less than or equal to and greater than 65 years: 40 mg daily
    musculoskeletal conditions Less than or equal to and greater than 65 years: 40 mg daily
    seizures Less than or equal to and greater than 65 years: 40 mg daily
diazepam (rectal) (Diastat®, Diastat AcuDial®, generics) 2.5 mg, 10 mg, 20 mg rectal gel seizures

Less than or equal to and greater than 65 years: 0.2 mg/kg; may be repeated once 4-12 hours after initial dose+

lorazepam (Ativan®, Loreev XR®, generics) 0.5 mg, 1 mg, 2 mg tablets; 1 mg, 1.5 mg, 2 mg, 3 mg extended-release capsules;
2 mg/mL solution
anxiety Less than or equal to and greater than 65 years: 10 mg daily, in divided doses
lorazepam (Ativan®, generics)   insomnia due to anxiety or transient situational stress Less than or equal to and greater than 65 years: 4 mg at bedtime
Midazolam (nasal) (Nayzilam®) 5 mg nasal spray seizures Less than or equal to and greater than 65 years: 5 mg as one spray in one nostril!
oxazepam (generics) 10 mg, 15 mg, 30 mg capsule AW Less than or equal to 65 years: 120 mg daily in divided doses Greater than 65 years: 60 mg daily in divided doses#
oxazepam   anxiety Less than or equal to 65 years: mild, moderate: 60 mg daily in divided doses severe: 120 mg daily in divided doses Greater than 65 years: 60 mg daily in divided doses

Legend:

  • * Benzodiazepine doses should be reduced to lowest effective dose, if possible, in the elderly (patients greater than 65 years of age), to minimize oversedation; these patients are more sensitive to pharmacologic effects of these agents
  • ^May give second diazepam nasal dose at least 4 hours after first dose, if necessary; may not use more than 2 doses to treat single episode; may not treat more than 1 episode/5 days or more than 5 episodes/month
  • + Dose rounded up to nearest commercially available unit dose (in multiples of 2.5 mg); should not be administered by caregivers outside the hospital more frequently than one course every 5 days with a maximum of 5 courses per month; not for chronic administration to minimize potential for development of tolerance
  • ! May give second midazolam nasal dose 10 minutes after first dose, if necessary; may not use more than 2 doses to treat a single episode. Nasal midazolam should be used to treat no more than one episode every three days and no more than 5 episodes per month
  • # In elderly patients, doses up to 120 mg/day may be needed to treat AW

Table 2. Adult Benzodiazepine Maximum Recommended Dosages: Combination Therapy

Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage
chlordiazepoxide/ amitriptyline (Limbitrol®, generics) 5 mg/12.5 mg tablets 10 mg/25 mg double-strength tablets depression with concurrent anxiety symptoms 60 mg chlordiazepoxide/ 150 mg amitriptyline daily in divided doses
chlordiazepoxide/ clidinium (Librax®, generics) 5 mg/ 2.5 mg capsule emotional/ somatic factors in gastro-intestinal disorders; adjunctive therapy in peptic ulcer disease, irritable bowel syndrome, and acute enterocolitis 40 mg/20 mg per day (2 capsules 4 times daily)

1.2. Pediatrics

Safety and effectiveness of alprazolam and combination therapies, chlordiazepoxide/amitriptyline and chlordiazepoxide/clidinium, in children less than 18 years of age have not been established.1-3,16,17 Additionally, safety and effectiveness of Loreev XR® (lorazepam) has not been established in pediatric patients, and the safety and effectiveness of Nayzilam® (midazolam) has not been established in pediatric patients less than 12 years of age .1,2,14,15.

The oral tablet and oral film formulations of clobazam are approved for use in children 2 years of age and older to manage seizures associated with Lennox-Gastaut syndrome.1,2,11,12 The diazepam nasal formulation (Valtoco®) is FDA-approved for use in patients 6 years and older to treat intermittent frequent seizure episodes that differ from a patient’s usual seizure pattern .1,2,13.

Except for alprazolam, non-sedative/hypnotic benzodiazepines are indicated for use in pediatric patients to manage anxiety or seizures.1-15 Pediatric dosages and age limitations for benzodiazepines are summarized in Table 3 1,2,4-14.

Table 3. Pediatric Benzodiazepine Maximum Recommended Dosages

Drug Name Treatment Indication Maximum Recommended Dosage
chlordiazepoxide anxiety Greater than or equal to  6 years: 30 mg daily in divided doses
clobazam seizures associated with Lennox-Gastaut syndrome
  • 2 years and older, adolescents less than or equal to 30 kg:
    • 20 mg/day in two divided doses
  • 2 years and older, adolescents greater than 30 kg:
    • 40 mg/day in two divided doses
clonazepam seizures
  • Less than 10 years or less than or equal to 30 kg:
    • 0.2 mg/kg daily in divided doses
  • Greater than or equal to 10 years or greater than  30 kg:
    • 20 mg daily in divided doses
clorazepate seizures
  • 9-12 years: 60 mg daily in divided doses
  • Greater than 12 years: 90 mg daily in divided doses
diazepam (nasal) seizures
  • 6-11 years of age:
    • 10-18 kg: 5 mg as one spray in one nostril (equates to 0.3 mg/kg dose)^
    • 19-37 kg: 10 mg as one spray in one nostril (equates to 0.3 mg/kg dose)^
    • 38-55 kg: 15 mg as 2 x 7.5 mg devices with one spray in each nostril (equates to 0.3 mg/kg dose) ^
    • 56-74 kg: 20 mg as 2 x 10 mg devices with one spray in each nostril (equates to 0.3 mg/kg dose) ^
  • Greater than or equal to 12 years of age:
    • 14-27 kg: 5 mg as one spray in one nostril (equates to 0.2 mg/kg dose)^
    • 28-50 kg: 10 mg as one spray in one nostril (equates to 0.2 mg/kg dose)^
    • 51-75 kg: 15 mg as 2 x 7.5 mg devices with one spray in each nostril (equates to 0.2 mg/kg dose) ^
    • Greater than or equal to 76 kg: 20 mg as 2 x 10 mg devices with one spray in each nostril (equates to 0.2 mg/kg dose) ^
diazepam (oral) musculoskeletal conditions Greater than or equal to 6 months of age: 10 mg/day in divided doses have been used; dose may be increased as needed and tolerated – no maximum dose documented
diazepam (oral) seizures Greater than or equal to 6 months of age: 10 mg/day in divided doses have been used; dose may be increased as needed and tolerated – no maximum dose documented
diazepam (rectal) seizures+
  • 2-5 years: 0.5 mg/kg/dose^
  • 6-11 years: 0.3 mg/kg/dose^
  • Greater than or equal to 12 years: 0.2 mg/kg/dose^
lorazepam anxiety Greater than or equal to 12 years: 10 mg daily in divided doses (maximum, 2 mg/dose)
  insomnia due to anxiety or situational stress Greater than or equal to 12 years: 4 mg at bedtime
midazolam (nasal) seizures Greater than or equal to 12 years: 5 mg as one spray in one nostril!
oxazepam anxiety
  • 6-12 years: dose not established;
    • 1 mg/kg/day in divided doses has been adequate
  • Greater than 12 years:
    • mild, moderate: 60 mg daily, in divided doses
    • severe: 120 mg daily, in divided doses

Legend:

  • ^ May give second diazepam nasal or rectal dose at least 4 hours after first dose, if necessary; may not use more than 2 doses to treat single episode; may not treat more than 1 episode/5 days or more than 5 episodes/month
  • + Dose rounded up to nearest commercially available unit dose (in multiples of 2.5 mg); should not be administered by caregivers outside the hospital more frequently than one course every 5 days with a maximum of 5 courses per month; not for chronic administration to minimize potential for development of tolerance
  • ! May give second midazolam nasal dose 10 minutes after first dose, if necessary; may not use more than 2 doses to treat a single episode. Nasal midazolam should be used to treat no more than one episode every three days and no more than 5 episodes per month

2. Duration of Therapy

Anxiety disorders are considered chronic disorders with low spontaneous remission rates and high rates of relapse. Pharmacotherapy for generalized anxiety disorder (GAD) in adults includes antidepressants, benzodiazepines, buspirone, hydroxyzine and pregabalin. Treatment duration for GAD ranges from 3 to 12 months to accomplish treatment goals of symptom remission and improvement in quality of life. Although antidepressants are now considered drugs of choice for managing GAD, benzodiazepines are used frequently for short-term management of anxiety, as an adjunct to initiating antidepressant therapy, or improvement in sleep disturbances associated with GAD and/or antidepressant therapy. Benzodiazepines provide symptom improvement more rapidly than antidepressants and are more effective in managing somatic complaints rather than psychic symptoms. Although longer-term use is considered relatively safe and effective for benzodiazepines, the potential for abuse, dependence and withdrawal does exist 18-19.

In pediatric patients, selective serotonin reuptake inhibitors (SSRIs) are agents of choice to manage childhood anxiety disorders, with serotonin norepinephrine reuptake inhibitors (SNRIs) being recommended as another treatment option. The most recent guidelines published by the American Academy of Child & Adolescent Psychiatry state that there is insufficient evidence to draw conclusions about the benefits or harms of benzodiazepine therapy in pediatric patients with anxiety disorders20.

Panic disorder (PD) is a chronic, recurring condition requiring drug therapy suitable for prolonged use. The acute treatment phase for PD lasts approximately 12 weeks, and most patients require an additional 12 to 18 months of therapy to optimize treatment response and prevent relapse. SSRIs are the agents of choice to manage PD, although benzodiazepines are frequently prescribed as well, usually in combination with antidepressant therapy18. While benzodiazepines are effective in the short-term treatment of panic disorder due to rapid onset of action, long-term treatment may be less desirable due to the potential for dependence. Unlike anxiety disorder patients, patients with panic disorder are less successful at discontinuing benzodiazepine therapy. Additionally, there is a high prevalence of comorbid depression and/or bipolar disorder in patients with panic disorder. Benzodiazepines are less effective than other available agents when panic disorder coexists with other mood disorders. Therefore, patients with panic disorder and other psychiatric comorbidities may benefit from short-term therapy with a benzodiazepine, with chronic management incorporating mood stabilizing or antidepressant agents that are also effective in panic disorder19. Alprazolam has been studied more than other available benzodiazepines for the treatment of panic disorder, although clonazepam, lorazepam, and diazepam have also been evaluated. Most studies evaluating benzodiazepine use in panic disorder have been short-term studies (less than 8 weeks in duration). A few long-term panic disorder studies evaluating alprazolam have demonstrated sustained reductions in panic attack frequency when alprazolam has been administered for 6 to 8 months21. Benzodiazepines should be tapered when discontinued, as patients may experience a withdrawal syndrome if therapy is discontinued abruptly. Benzodiazepine elimination half-life and seizure history for the patient also influence the taper duration. Patients receiving benzodiazepines in lower doses for shorter times periods (less than six months) may be effectively tapered over two to eight weeks, while patients receiving benzodiazepines with a short elimination half-life, in higher doses, and/or for a longer duration (six months or longer) may require a slow taper over two to four months18,19,21.

Benzodiazepines should be prescribed on a short-term basis to manage anxiety disorders. Benzodiazepine doses should be tapered rather than discontinued abruptly to avoid withdrawal symptoms. Patients receiving benzodiazepines for up to 6 months should be tapered over 2 to 8 weeks, while patients treated with benzodiazepines for up to 12 months should be tapered over 2 to 4 months18,19,21<.

While concerns for benzodiazepine tolerance and withdrawal exist, patients may benefit from long-term use of benzodiazepines in panic disorder to minimize symptom recurrence. Additionally, significant problems with benzodiazepine dose escalation have not surfaced with chronic use for panic disorder18,19,21.

The use of benzodiazepines as an anti-epileptic is not limited in duration.

3. Duplicative Therapy

The combined use of two or more benzodiazepines is not supported in the literature and therefore is not recommended. The concurrent use of two or more benzodiazepines will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for nonsedative/hypnotic benzodiazepines are summarized in Table 4 1-17. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 4. Benzodiazepine (nonsedative/hypnotic) Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level*
alprazolam CYP3A4 inhibitors (e.g., azole anti-fungals, macro-lides, NNRT inhibitors, protease inhibitors) adjunctive administration may result in enhanced oxidized BZD pharmacologic effects and/or toxicity, including significant sedation and/or respiratory depression, as alprazolam is metabolized by CYP3A4 avoid combined therapy with most CYP3A4 inhibitors, if possible contraindicated -azole antifungals, NNRT inhibitors, protease inhibitors; moderate -macrolides (DrugReax) 1 – severe (azole antifungals, NNRT inhibitors, protease inhibitors); 3-moderate (macrolides) (CP)
alprazolam phenytoin combined use may induce alprazolam metabolism and decrease alprazolam pharmacologic effects monitor for reduced alprazolam clinical effects and adjust doses as necessary 3-moderate (CP)
benzodiazepines (BZDs) central nervous system (CNS) depressants concurrent administration may potentiate respiratory depression, especially with overdosage monitor for respiratory depression; adjust doses as necessary major (DrugReax) 2-major (CP)
BZDs sodium oxybate (Xyrem®) combined use may lead to increased respiratory depression due to additive CNS/ respiratory depressive effects adjunctive use should be avoided; if concurrent use necessary, closely monitor for respiratory depression; dosage reductions for one or both medications may be needed major (DrugReax) 1-severe (CP)
clobazam drugs metabolized by CYP2C19 (e.g., clopidogrel, cimetidine, fluconazole) co-administration may result in increased clobazam serum levels and increased pharmacologic and/or adverse effects as clobazam is partially metabolized by CYP2C19 monitor for enhanced clobazam pharmacologic/adverse effects; adjust clobazam dose as necessary moderate (DrugReax) 3-moderate (CP)
other oxidized BZDs (chlor-diazepoxide, clonazepam, diazepam) CYP3A4 inhibitors [e.g., azole antifungals, macrolides, non-nucleoside reverse transcriptase (NNRT) inhibitors, protease inhibitors] adjunctive administration may result in enhanced oxidized BZD pharmacologic effects and/or toxicity, including significant sedation and/or respiratory depression, as oxidized BZDs are metabolized by CYP3A4 avoid combined therapy, if possible; if concurrent with BZD necessary, monitor for increased sedation, respiratory depression, or consider a BZD metabolized by glucuronidation (e.g., oxazepam) moderate (DrugReax) 2-major (protease inhibitors); 3- moderate (azoles, macrolides, NNRT inhibitors) (CP)
oxidized BZDs (e.g., alprazolam, chlordiazepoxide, clonazepam, diazepam) CYP3A4 inducers (e.g., carbamazepine, rifamycins) combined use may result in increased oxidized BZD clearance, reduced oxidized BZD serum levels, and decreased pharmacologic effects; oxidized BZDs are metabolized by CYP3A4 monitor oxidized BZD clinical response and adjust dose as needed; may also consider substituting a BZD metabolized by glucuronidation (e.g., oxazepam) moderate (DrugReax) 2-major, 3-moderate (CP)
select BZDs (chlordiazepoxide,  diazepam) phenytoin concomitant use may result in unpredictable effects on serum phenytoin levels (may increase, decrease, or not change) due to unknown effect on phenytoin metabolism; phenytoin may induce BZD metabolism, reduce BZD serum levels, and decrease BZD pharmacologic effects closely monitor serum phenytoin levels and observed for altered pharmacologic effects (reduced efficacy, increased toxicity); monitor for reduced BZD clinical effects and adjust doses as necessary major (diazepam), moderate (chlordiazepoxide) (DrugReax) 3-moderate (CP)
chlordiazepoxide/amitriptyline amphetamines combined administration may increase potential for serotonin syndrome as both medications target the serotonin neurotransmitter system if adjunctive therapy is necessary, start with lower doses and monitor for signs/ symptoms of serotonin syndrome; discontinue both medications if serotonin syndrome develops major (DrugReax) 2-major (CP)
chlordiazepoxide/amitriptyline monoamine oxidase inhibitors increased risk of serotonin syndrome with amitriptyline (e.g., mental status changes, hyperpyrexia, restless, shivering, hypertonia, tremor) due to serotonin metabolism inhibition by monoamine oxidase allow 14 days after MAOI discontinuation before initiating other tricyclic antidepressant therapy contraindicated (DrugReax) 1-severe (CP)
chlordiazepoxide/amitriptyline QT interval-prolonging drugs co-administration with QT interval-prolonging drugs may increase risk of QT interval prolongation and torsades de pointes as amitriptyline also prolongs the QT interval avoid concurrent use; if adjunctive use necessary, monitor for increased pharmacologic/toxic effects; adjust dose as necessary or discontinue therapy contraindicated (DrugReax) 1-severe, 2-major (CP)
midazolam CYP3A4 inhibitors May result in prolonged sedation because of a decreased clearance of midazolam Avoid co-administration of midazolam with moderate or strong CYP3A4 inhibitors. Use with caution with co-administered with mild CYP3A4 inhibitors Contraindicated (strong CYP3A4 inhibitors), Major (moderate CYP3A4 inhibitors) (Micromedex)
  Opioids Concomitant use increases the risk of respiratory depression Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. Minimize dosages and durations to the minimum required Major (Micromedex)
  central nervous system depressants Concomitant use may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect Reserve concomitant use for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required Major (Micromedex)

Legend:

  • *CP = Clinical Pharmacology

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: March 27, 2022).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2022. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed March 27, 2022.
  3. Alprazolam (Xanax®) oral tablet package insert. Pharmacia & Upjohn Company, LLC. September 2021.
  4. Chlordiazepoxide oral capsule package insert. Epic Pharma, LLC. March 2022.
  5. Clorazepate oral tablet package insert. Mylan Pharmaceuticals, Inc. June 2020.
  6. Diazepam (Valium®) oral tablet package insert. Roche Laboratories, Inc. November 2019.
  7. Diazepam (Diastat®, Diastat® AcuDial™) rectal delivery system package insert. Bausch Health US, LLC. March 2021.
  8. Lorazepam (Ativan®) oral tablet package insert. Bausch Health US, LLC. February 2021.
  9. Oxazepam oral capsule package insert. Actavis Pharma, Inc. September 2021.
  10. Clonazepam (Klonopin®) package insert. Genentech, Inc. December 2019.
  11. Clobazam (Onfi®) Package Insert. Lundbeck Inc., February 2021.
  12. Clobazam oral film (Sympazan®) package insert. Aquestive Therapeutics, Inc., March 2021.
  13. Diazepam nasal spray (Valtoco®) package insert. Neurelis, Inc., February 2022.
  14. Midazolam (Nayzilam®) nasal spray package insert. UCB, Inc. February 2021.
  15. Lorazepam (Loreev XR®) extended-release capsule package insert. Almatica Pharma, LLC. February 2022.
  16. Chlordiazepoxide/amitriptyline package insert. Mylan Pharmaceuticals, Inc., December 2021.
  17. Chlordiazepoxide/clidinium (Librax®) package insert. Bausch Health US LLC, February 2021.
  18. Melton ST, Kirkwood CK. Chapter 87. Anxiety disorders I: generalized anxiety, panic, and social anxiety disorders (Chapter). In: DiPiro JT, Yee GC, Posey LM, et al. Pharmacotherapy: a pathophysiologic approach. 11th ed. New York, McGraw-Hill, 2019. Access Pharmacy Web site. Available at:  http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/content.aspx?bookid=1861&sectionid=146065193. Accessed March 28, 2022.
  19. Locke AB, Kirst N, Shultz CG. Diagnosis and management of generalized anxiety disorder and panic disorder in adults. AFP. 2015;91(9):617-624.
  20. Walter HJ, Bukstein OG, Abright AR, et al. Clinical practice guideline for the assessment and treatment of children and adolescents with anxiety disorders. Journal of the American Academy of Child & Adolescent Psychiatry. 2020;59(10):1107-1124.
  21. Work Group on Panic Disorder. American Psychiatric Association Practice Guidelines. Practice guideline for the treatment of patients with panic disorder, second edition. Available at:  http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/panicdisorder.pdf. Accessed March 28, 2022.

Complement Inhibitor and Enzyme/Protein Replacement Therapy

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • April 2022; March 2020; March 2018; March 2017; April 2015; March 2015; Feb. 2013. 
  • Initially developed
    • Dec. 2012

1. Dosage

  • Adenosine deaminase (ADA) deficiency in severe combined immunodeficiency (SCID)
  • Atypical hemolytic uremic syndrome (aHUS) 
  • Congenital sucrase isomaltase deficiency (CSID)
  • Fabry disease
  • Gaucher disease 
  • Hereditary angioedema (HAE)
  • Hypophosphatasia
  • Wolman disease (lysosomal acid lipase (LAL) deficiency)
  • Mucopolysaccharidoses (MPS) 
    • Hurler and Hurler-Scheie forms of MPS I; 
    • Hunter syndrome (MPS II); 
    • Morquio A syndrome (MPS IVA);
    • Maroteaux-Lamy syndrome (MPS VI);
    • Sly syndrome (MPS VII)
  • Myasthenia gravis
  • Neuromyelitis optica spectrum disorder
  • Paroxysmal nocturnal hemoglobinuria
  • Pompe disease
  • Severe congenital protein C deficiency

1.1. Adults

Recommended doses for complement inhibitor as well as enzyme/protein replacement therapy FDA-approved for use in adults are summarized in Tables 1-3.  Patient profiles containing doses exceeding maximum recommendations will be reviewed.

Table 1. Adult Complement Inhibitor Maximum Dosages1-14
Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage 
Berotralstat (Orladeyo®) Hereditary angioedema (HAE) prophylaxis 110 mg, 150 mg oral capsule 150 mg by mouth daily*
C1 esterase inhibitor, human (Berinert®) HAE treatment 500 international unit (IU) single-use vial for reconstitution 20 IU/kg by IV injection as a single dose
C1 esterase inhibitor, human (Cinryze®) HAE attacks, routine prevention 500 unit single-use vial for reconstitution 1000 U by IV infusion every 3-4 days+
C1 esterase inhibitor, human (Haegarda®) HAE attacks, routine prevention 2000, 3000 IU single-use vials for reconstitution 60 IU/kg subcutaneously twice weekly (every 3 to 4 days)
C1 esterase inhibitor, recombinant (Ruconest®) HAE treatment 2100 IU/14 mL single-use vial for reconstitution
  • Greater than or equal to  84 kg:
    • 4200 units as a single IV dose; may repeat x1 if attack symptoms persist in 24-hour period
  • Less than 84 kg:
    • 50 units/kg as single IV dose up to a maximum of 4200 units per dose; may repeat x1 if attack symptoms persist in 24-hour period
Ecallantide (Kalbitor®) HAE treatment 10 mg/ml single-use vials x 3 30 mg subcutaneously as three separate 10 mg injections; may repeat x1 in 24-hour period if attack symptoms persist
eculizumab (Soliris®) Atypical hemolytic uremic syndrome (aHUS) 300 mg/30 mL single-dose vial Initial 900 mg IV infusion once weekly for four weeks followed by a 1200 mg IV infusion one week later, maintenance 1200 mg IV infusion over 1-4 hours every two weeks thereafter 
  Myasthenia gravis, generalized   Initial 900 mg IV infusion once weekly for four weeks followed by a 1200 mg IV infusion one week later, maintenance 1200 mg IV infusion over 1-4 hours every two weeks
  Neuromyelitis optica spectrum disorder   Initial 900 mg IV infusion once weekly for four weeks followed by a 1200 mg IV infusion one week later, maintenance 1200 mg IV infusion over 1-4 hours every two weeks
  Paroxysmal nocturnal hemoglobinuria (PNH)   Initial 600 mg IV infusion once weekly for four weeks followed by a 900 mg IV infusion one week later, maintenance 900 mg IV infusion over 1-4 hours every two weeks thereafter
icatibant acetate (Firazyr®, Sajazir®) HAE treatment 30 mg/3 mL prefilled syringe, 30 mg/ 3 mL solution for injection 30 mg subcutaneously as single dose; may repeat x2 with 6 hours between doses in 24-hour period if attack symptoms persist (maximum 3 doses per 24-hour period) 
lanadelumab-flyo (Takhzyro®) HAE, routine prevention 300 mg/2 mL vial 300 mg subcutaneously every 2 weeks; every 4-week dosing possible in patients well-controlled for Greater than 6 months
pegcetacoplan (Empaveli®) PNH 1080 mg/ 20 mL solution for injection 1080 mg subcutaneously twice weekly
ravulizumab (Ultomiris®) aHUS^
PNH
300 mg/3 mL, 100 mg/11 mL intravenous solution in single-dose vial
  • Greater than or equal to 100 kg:
    • 3600 mg as intravenous infusion every 8 weeks starting 2 weeks after loading dose (loading dose = 3000 mg)
  • 60-99 kg:
    • 3300 mg as intravenous infusion every 8 weeks starting 2 weeks after loading dose (loading dose = 2700 mg)
  • 40-59 kg:
    • 3000 mg as intravenous infusion every 8 weeks starting 2 weeks after loading dose (loading dose = 2400 mg)
  • 30-39 kg:
    • 2700 mg as intravenous infusion every 8 weeks starting 2 weeks after loading dose (loading dose = 1200 mg)
  • 20-29 kg:
    • 2100 mg as intravenous infusion every 8 weeks starting 2 weeks after loading dose (loading dose = 900 mg)
  • 10-19 kg:
    • 600 mg as intravenous infusion every 4 weeks starting 2 weeks after loading dose (loading dose = 600 mg)
  • 5-9 kg:
    • 300 mg as intravenous infusion every 4 weeks starting 2 weeks after loading dose (loading dose = 600 mg)

Legend

  • * Berotralstat is dosed at 110 mg by mouth daily in patients with moderate to severe hepatic impairment, chronic use of P-glycoprotein (P-gp) or BCRP (breast cancer resistance protein) inhibitors, or patients with persistent gastrointestinal (GI) reactions 
  • + in patients not responding adequately, doses up to 2500 units (not exceeding 100 u/kg) every 3 or 4 days may be utilized based on individual patient response
  • ^ treat atypical hemolytic-uremic syndrome with ravulizumab for at least six months
Table 2. Adult Enzyme Replacement Therapy Maximum Dosages1,2,15-29
Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
agalsidase beta (Fabrazyme®) Fabry disease 5 mg, 35 mg single-use vials 1 mg/kg by intravenous (IV) infusion every 2 weeks
alglucosidase alfa (Lumizyme®) Pompe disease (lysosomal acid alpha-glucosidase (GAA) deficiency) 50 mg single-use vial 20 mg/kg as IV infusion every 2 weeks
Avalglucosidase alfa (Nexviazyme®) Late onset Pompe disease (lysosomal acid alpha-glucosidase (GAA) deficiency) 100 mg single use vial
  • Greater than or equal to  30 kg:
    • 20 mg/kg as IV infusion every 2 weeks
  • Less than 30 kg:
    • 40 mg/ kg as IV infusion every 2 weeks
elapegademase (Revcovi®) Adenosine deaminase severe combined immunodeficiency 2.4 mg/1.5 mL intramuscular solution
  • treatment naïve:
    • 0.2 mg/kg as intramuscular injection twice weekly for a minimum of 12 to 24 weeks; titrate up by 0.033 mg/kg/week to maintain ADA trough Greater than 30 mmol/hr/L, trough deoxyadenosine nucleotides less than 0.02 mmol/L, and maintain immune reconstitution
  • patients transitioning from pegademase:
    • Patients receiving pegademase doses less than or equal to 30 U/kg should receive elapegademase 0.2 mg/kg intramuscularly once weekly; patients with pegademase doses Greater than 30 U/kg should receive equivalent elapegademase dose*
elosulfase alfa (Vimizim®) Mucopoly-saccharidosis (MPS) IVA (Morquio A syndrome) 5 mg/5 mL single-use vial 2 mg/kg by IV infusion once weekly
galsulfase (Naglazyme®) MPS VI (Maroteaux-Lamy syndrome) 5 mg/5 mL preservative-free vials 1 mg/kg by IV infusion once weekly
idursulfase (Elaprase®) MPS II (Hunter syndrome) 6 mg/3 mL single-use vial 0.5 mg/kg as IV infusion once weekly
imiglucerase (Cerezyme®) Gaucher disease, type 1 (non-neuropathic) 400 mg vials for reconstitution 60 U/kg by IV infusion over 1-2 hours every 2 weeks
laronidase (Aldurazyme®) MPS 1 (Hurler, Hurler-Scheie forms; Scheie form with moderate to severe symptoms) 2.9 mg/5 mL single-use vials 0.58 mg/kg by IV infusion once weekly
migalastat (Galafold®) Fabry disease with amenable galactosidase alpha gene (GLA) variant 123 mg oral capsule 123 mg by mouth every other day
sacrosidase (Sucraid®) Congenital sucrase-isomaltase deficiency (CSID) 8500 international units/mL as 118 mL oral solution bottles, 8500 units/ mL as 2 mL oral solution Greater than 15 kg: 17,000 units orally mixed in 2-4 ounces of water or milk with each meal or snack
sebelipase alfa (Kanuma®) Wolman Disease (Lysosomal acid lipase (LAL) deficiency) 20 mg/10 mL single-use vial 3 mg/kg by IV infusion once every other week
taliglucerase alfa (Elelyso®) Gaucher disease, type 1 200 unit single-use vials for reconstitution
  • treatment-naïve:
    • 60 U/kg by IV infusion once every 2 weeks
  • previously treated with imiglucerase:
    • use same unit/kg dosage for taliglucerase that was prescribed for imiglucerase and administer every two weeks
velaglucerase alfa (Vpriv®) Gaucher disease, type 1 400 unit single-use vials for reconstitution
  • treatment-naïve:
    • 60 U/kg as IV infusion every 2 weeks
  • previously treated with imiglucerase:
    • use same unit/kg dosage for velaglucerase that was prescribed for imiglucerase and administer every two weeks
vestronidase alfa-vjbk (Mepsevii®) MPS VII (Sly syndrome), excluding central nervous system symptoms 10 mg/5 mL single-use vial 4 mg/kg as IV infusion every two weeks

Legend

  • * elapegademase equivalent dose to pegademase: pegademase dose (U/kg) divided by 150
Table 3. Adult Protein Replacement Therapy Maximum Dosages1,2,30
Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
protein C concentrate (Ceprotin®) Severe congenital protein C deficiency (acute episode*) 500 IU, 1000 IU single-use vial for reconstitution 100-120 IU/kg initial dose by IV infusion, followed by 60-80 IU/kg every 6 hours for 3 doses by IV infusion
  Severe congenital protein C deficiency (short-term prophylaxis/ maintenance dose*)   45-60 IU/kg every 6 to 12 hours by IV infusion
  Severe congenital protein C deficiency (long-term prophylaxis*)   45-60 IU/kg every 12 hours by IV infusion

Legend

  • * maximum protein C concentrate infusion rate: 2 ml/min

1.2. Pediatrics

Since the last update, several new therapies have been approved by the FDA, and several therapies had their approvals expanded to include a younger age demographic. Berotralstat was approved in 2020 for Hereditary Angioedema prophylaxis in patients 12 years of age and older1-3. Elapegademase is indicated for use in infants, children, adolescents and adults with ADA deficiency due to SCID; pegademase, an older agent used to manage ADA deficiency in pediatric SCID patients is no longer commercially available1,2,18. C1 esterase inhibitor safety and efficacy have not been determined in pediatric patients younger than 5 years of age, and in 2020 the FDA approval for Haegarda® was expanded to include patients six years of age and older1,2,4-7.

In 2021, agalsidase beta was approved for pediatric use in patients two years of age and older for the treatment of Fabry Disease, and avalglucosidase alfa was approved to treat Pompe Disease in patients one year of age and older1,2,15,17.

Alglucosidase alfa is FDA-approved and has been evaluated for early use to treat Pompe disease in all age groups from neonates to adolescents. In a small study, investigators found that alglucosidase therapy initiated early after diagnosis in neonates less than 1 month of age can improve clinical outcomes even before onset of clinical symptoms in infants with Pompe disease33 .

Maximum recommended dosages for complement inhibitor and protein/enzyme replacement therapies FDA-approved for use in pediatric patients are summarized in Tables 4-6. Dosages exceeding these recommendations will be reviewed.

Table 4. Pediatric Complement Inhibitor Maximum Dosages1-9,12,14
Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
berotralstat (Orladeyo®) Hereditary angioedema (HAE) prophylaxis 110 mg, 150 mg oral capsule 12 to 17 years: 150 mg daily
C1 esterase inhibitor, human (Berinert®) HAE treatment 500 unit single-use vial for reconstitution 5 to 17 years: 20 IU/kg by IV injection as a single dose
C1 esterase inhibitor, human (Cinryze®) HAE attacks, routine prevention 500 unit single-use vial for reconstitution
  • 12 to 17 years:
    • 1000 U by IV infusion every 3-4 days+
  • 6 to 11 years:
    • 500 U by IV infusion every 3-4 days+
C1 esterase inhibitor, human (Haegarda®) HAE attacks, routine prevention 2000, 3000 IU single-use vials for reconstitution 6 years and older: 60 IU/kg subcutaneously twice weekly (every 3 to 4 days)
C1 esterase inhibitor, recombinant (Ruconest®) HAE treatment 2100 IU/14 mL single-use vial for reconstitution
  • 13 to 17 years (less than 84 kg):
    • 50 units/kg as single IV dose up to a maximum of 4200 units per dose; may repeat x1 if attack symptoms persist in 24 hour period
  • 13 to 17 years (Greater than 84 kg):
    • 4200 units as a single IV dose; may repeat x1 if attack symptoms persist in 24 hour period
ecallantide (Kalbitor®) HAE treatment 10 mg/ml single-use vials x 3
  • 12 to 17 years:
    • 30 mg subcutaneously as three separate 10 mg injections; may repeat x1 in 24 hour period if attack symptoms persist
eculizumab (Soliris®) Atypical hemolytic uremic syndrome (aHUS) 300 mg/ 30 mL single-dose vial
  • 2 months to 17 years:
    • Greater than or equal to 40 kg:
      • Initial 900 mg IV infusion once weekly for four weeks followed by a 1200 mg IV infusion one week later, maintenance 1200 mg IV infusion over 1-4 hours every two weeks
    • 30-39 kg:
      • Initial 600 mg IV infusion once weekly for two weeks followed by a 900 mg IV infusion one week later, maintenance 900 mg IV infusion over 1-4 hours every two weeks
    • 20-29 kg:
      • Initial 600 mg IV infusion once weekly for three weeks, maintenance 600 mg IV infusion over 1-4 hours every two weeks
  • 10-19 kg:
    • Initial 600 mg IV infusion followed by 300 mg IV infusion one week later, maintenance 300 mg IV infusion over 1-4 hours every two weeks
  • 5-9 kg: Initial 300 mg IV infusion followed by 300 mg IV infusion one week later, maintenance dose of 300 mg IV infusion over 1-4 hours every 3 weeks
lanadelumab-flyo (Takhzyro®) HAE, routine prevention 300 mg/2 mL vial 12 years and older: 300 mg subcutaneously every 2 weeks; every 4-week dosing possible in patients well-controlled for greater than 6 months
ravulizumab (Ultomiris®) aHUS^
Paroxysmal nocturnal hemoglobinuria (PNH)
300 mg/3 mL, 1100 mg/11 mL intravenous solution
  • adolescents greater than or equal to  100 kg:
    • 3600 mg as intravenous infusion every 8 weeks starting 2 weeks after loading dose (loading dose = 3000 mg)
  • adolescents, children 60-99 kg:
    • 3300 mg as intravenous infusion every 8 weeks starting 2 weeks after loading dose (loading dose = 2700 mg)
  • adolescents, children 40-59 kg:
    • 3000 mg as intravenous infusion every 8 weeks starting 2 weeks after loading dose (loading dose = 2400 mg)
  • adolescents, children 30-39 kg:
    • 2700 mg as intravenous infusion every 8 weeks starting 2 weeks after loading dose (loading dose = 1200 mg)
  • children 20-29 kg:
    • 2100 mg as intravenous infusion every 8 weeks starting 2 weeks after loading dose (loading dose = 900 mg)
  • infants, children 10-19 kg:
    • 600 mg as intravenous infusion every 4 weeks starting 2 weeks after loading dose (loading dose = 600 mg)
  • infants, children 5-9 kg:
    • 300 mg as intravenous infusion every 4 weeks starting 2 weeks after loading dose (loading dose = 600 mg)

Legend

  • + in patients 6 to 11 years of age not responding adequately, doses up to 1000 units every 3 or 4 days may be utilized based on individual response. In patients 12 years of age and older not responding adequately, doses up to 2500 units (not exceeding 100 u/kg) every 3 or 4 days may be utilized based on individual patient response
  • ^ treat atypical hemolytic-uremic syndrome with ravulizumab for at least six months
Table 5. Pediatric Enzyme Replacement Therapy Maximum Dosages1,2,15-29,31,32
Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage 
agalsidase beta (Fabrazyme®) Fabry disease 5 mg, 35 mg single-use vials 2-17 years: 1 mg/kg by intravenous (IV) infusion every 2 weeks
alglucosidase alfa (Lumizyme®) Pompe disease 50 mg single-use vial Birth to any age: 20 mg/kg as IV infusion every 2 weeks
asfotase alfa (Strensiq®) hypophosphatasia (perinatal/infantile- or juvenile-onset) 18 mg/0.45 mL, 28 mg/0.7 mL, 40 mg/1 mL, or 80 mg/0.8 mL single-use vials
  • Hypophosphatasia (perinatal/infantile-onset): 
    • birth to any age: 9 mg/kg weekly as subcutaneous injection as 3 mg/kg three times weekly
  • Hypophosphatasia (juvenile-onset): 
    • 6 years and older: 6 mg/kg weekly as subcutaneous injection, given either as 2 mg/kg three times weekly or 1 mg/kg six times weekly
avalglucosidase alfa (Nexviazyme®) Late onset Pompe disease (lysosomal acid alpha-glucosidase (GAA) deficiency) 100 mg single use vial
  • 1 year of age and older:
    • Greater than or equal to  30 kg: 20 mg/kg as IV infusion every 2 weeks
    • Less than 30 kg: 40 mg/ kg as IV infusion every 2 weeks
cerliponase alfa (Brineura®) late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease 150 mg/5 ml as 2 single-use vials copackaged with intraventricular electrolytes 3 years and older: 300 mg every other week by intraventricular infusion, followed by intraventricular electrolytes
elapegademase (Revcovi®) Adenosine deaminase severe combined immunodeficiency 2.4 mg/1.5 mL intramuscular solution
  • treatment naïve:
    • 0.2 mg/kg as intramuscular injection twice weekly for a minimum of 12 to 24 weeks; titrate up by 0.033 mg/kg/week to maintain ADA trough greater than 30 mmol/hr/L, trough deoxyadenosine nucleotides less than 0.02 mmol/L, and maintain immune reconstitution
  • patients transitioning from pegademase:
    • Patients receiving pegademase doses less than or equal to 30 U/kg should receive elapegademase 0.2 mg/kg intramuscularly once weekly; patients with pegademase doses Greater than 30 U/kg should receive equivalent elapegademase dose*
elosulfase (Vimizim®) Mucopolysaccharidoses (MPS) IVA (Morquio A syndrome) 5 mg/5 mL single-use vial 5 years and older: 2 mg/kg by IV infusion over a minimum of 3.5-4.5 hours once weekly
galsulfase (Naglazyme®) MPS VI (Maroteaux-Lamy syndrome) 5 mg/5 mL preservative-free vials 3 months and older: 1 mg/kg by IV infusion once weekly
idursulfase (Elaprase®) MPS II (Hunter syndrome) 6 mg/3 mL single-use vial 16 months to 17 years: 0.5 mg/kg as IV infusion once weekly
imiglucerase (Cerezyme®) Gaucher disease, type 1 (nonneuropathic) 400 mg vials for reconstitution 2 to 16 years: 60 U/kg by IV infusion over 1-2 hours every 2 weeks
imiglucerase (Cerezyme®) Gaucher disease, type 1 (nonneuropathic) 400 mg vials for reconstitution 2 to 16 years: 60 U/kg by IV infusion over 1-2 hours every 2 weeks
laronidase (Aldurazyme®) MPS 1 (Hurler, Hurler-Scheie forms; Scheie form with moderate to severe symptoms) 2.9 mg/5 mL single-use vials 6 months of age and older: 0.58 mg/kg by IV infusion over 3-4 hours once weekly
sacrosidase (Sucraid®) Congenital sucrase-isomaltase deficiency (CSID) 8500 international units/mL as 118 mL oral solution bottles, 8500 units/ mL as 2 mL oral solution
  • 5 months to 17 years:
    • less than or equal to 15 kg:
      • 8500 units orally mixed in 2-4 ounces of water, milk, or infant formula with each meal or snack
    • Greater than 15 kg:
      • 7,000 units orally mixed in 2-4 ounces of water or milk with each meal or snack
sebelipase alfa (Kanuma®) Wolman Disease (Lysosomal acid lipase (LAL) deficiency) 20 mg/10 mL single-use vial Greater than or equal to  1 month of age to 17 years: 3 mg/kg by IV infusion once every other week
  Wolman Disease (Rapidly progressive LAL deficiency developing in first 6 months of life)   1-12 months of age: 5 mg/kg by IV infusion once weekly
taliglucerase alfa (Elelyso®) Gaucher disease, type 1 200 unit single-use vials for reconstitution    treatment-naïve (4 years and older): 60 U/kg by IV infusion once every 2 weeks previously treated with imiglucerase (4 years and older): use same unit/kg dosage for taliglucerase that was prescribed for imiglucerase and administer every two weeks
velaglucerase alfa (Vpriv®) Gaucher disease, type 1 400 unit single-use vials for reconstitution    treatment-naïve (4 years and older): 60 U/kg by IV infusion once every 2 weeks previously treated with imiglucerase (4 years and older): use same unit/kg dosage for velaglucerase that was prescribed for imiglucerase and administer every two weeks
vestronidase alfa-vjbk (Mepsevii®) MPS VII (Sly syndrome), excluding central nervous system symptoms 10 mg/5 mL single-use vial birth to 17 years: 4 mg/kg as IV infusion every two weeks

Legend

  • * elapegademase equivalent dose to pegademase: pegademase dose (U/kg) divided by 150
Table 6. Pediatric Protein Replacement Therapy Maximum Dosages1,2,32
Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
protein C concentrate (Ceprotin®) Severe congenital protein C deficiency (acute episode) 500 IU, 1000 IU single-use vial for reconstitution birth to 17 years:  100-120 IU/kg initial dose by IV infusion, followed by 60-80 IU/kg every 6 hours for 3 doses by IV infusion*
  Severe congenital protein C deficiency (short-term prophylaxis/ maintenance dose)   birth to 17 years:  45-60 IU/kg every 6 to 12 hours by IV infusion*
  Severe congenital protein C deficiency (long-term prophylaxis)   birth to 17 years:  45-60 IU/kg every 12 hours by IV infusion*

Legend

  • * maximum protein C concentrate infusion rate: 2 ml/min, except in children less than 10 kg, where infusion rate should not exceed 0.2 ml/kg/min

2. Duration of Therapy

There is no basis for limiting the duration of complement inhibitor and enzyme/protein replacement therapy as enzyme deficiencies represent chronic disorders and require sustained treatment1-32.

3. Duplicative Therapy

FDA-approved enzyme replacement therapies are indicated for specific enzyme deficiencies. Patients with multiple enzyme deficiencies may be prescribed multiple enzyme replacement therapies concurrently. Adjunctive administration of enzyme replacement therapies without multiple enzyme deficiency diagnoses is not clinically reasonable and will be evaluated.

4. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: March 9, 2022).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2022. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed March 9, 2022.
  3. Berotralstat oral capsules (Orladeyo®) package insert. BioCryst Pharmaceuticals, Inc., December 2020.
  4. C1 esterase inhibitor, human (Berinert®) package insert. CSL Behring, September 2021.
  5. C1 esterase inhibitor, human intravenous injection (Cinryze®) package insert. ViroPharma Biologics LLC, January 2021.
  6. C1 esterase inhibitor subcutaneous injection (Haegarda®) package insert. CSL Behring, October 2020.
  7. C1 esterase inhibitor, recombinant (Ruconest®) package insert.  Pharming Healthcare Inc., April 2020.
  8. Ecallantide subcutaneous injection (Kalbitor®) package insert. Takeda Pharmaceuticals America, Inc., November 2021.
  9. Eculizumab intravenous injection (Soliris®) package insert. Alexion Pharmaceuticals, Inc., April 2021.
  10. Icatibant subcutaneous injection (Firazyr®) package insert. Takeda Pharmaceuticals America, Inc., September 2020.
  11. Icatibant subcutaneous injection (Sajazir®) package insert. Cycle Pharmaceuticals LTD., June 2021.
  12. Lanadelumab subcutaneous injection (Takhzyro®) package insert. Takeda Pharmaceuticals America, Inc., February 2022.
  13. Pegcetacoplan subcutaneous solution (Empaveli®) package insert. Apellis Pharmaceuticals, Inc., August 2021.
  14. Ravulizumab intravenous injection (Ultomiris®) package insert. Alexion Pharmaceuticals, Inc., January 2022.
  15. Agalsidase beta injection (Fabrazyme®) package insert. Genzyme Corporation, August 2021.
  16. Alglucosidase alfa injection (Lumizyme®) package insert. Genzyme Corporation, July 2021.
  17. Avalglucosidase alfa intravenous injection (Nexviazyme®) package insert. Genzyme Corporation, August 2021.
  18. Elapegademase intramuscular injection (Revcovi®) package insert. Leadiant Biosciences, November 2021.
  19. Elosulfase injection (Vimizim®) package insert. BioMarin Pharmaceutical Inc., January 2021.
  20. Galsulfase injection (Naglazyme®) package insert. BioMarin Pharmaceutical Inc., April 2020.
  21. Idursulfase injection (Elaprase®) package insert. Shire Human Genetic Therapies, Inc., October 2021.
  22. Imiglucerase injection (Cerezyme®) package insert. Genzyme Corporation, January 2022.
  23. Laronidase intravenous infusion (Aldurazyme®) package insert.  Genzyme Corporation, December 2019.
  24. Migalastat oral capsules (Galafold®) package insert. Amicus Therapeutics US, LLC, December 2021.
  25. Sacrosidase oral solution (Sucraid®) package insert. QOL Medical, LLC, August 2021.
  26. Sebelipase injection (Kanuma®) package insert. Alexion Pharmaceuticals, Inc., November 2021. 
  27. Taliglucerase alfa injection (Elelyso®) package insert. Pfizer, July 2021.
  28. Velaglucerase alfa injection (Vpriv®) package insert. Takeda Pharmaceuticals America, Inc., October 2021.
  29. Vestronidase alfa-vjbk injection (Mepsevii®) package insert. Ultragenyx Pharmaceutical Inc., December 2020.
  30. Protein C concentrate (Ceprotin®) package insert. Baxalta US Inc., September 2021.
  31. Asfotase alfa injection (Strensiq®) package insert. Alexion Pharmaceuticals, Inc., April 2021.
  32. Cerliponase alfa injection (Brineura®) package insert. BioMarin Pharmaceutical Inc., July 2020.
  33. Ramaswami U, Parini R, Kampmann C, Beck M. Safety of agalsidase alfa in patients with Fabry disease under 7 years. Acta Paediatrica. 2011;100(4):605-11.

Cyclooxygenase-2 Inhibitors

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Initially developed
    • January 2002
  • Revision history
    • July 2021; July 2019; May 2019; May 2016; October 2014; February 2013; December 2012; March 2011; January 2011; October 2007; February 2006; January 2006; January 2004; January 2003

1. Dosage

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor nonsteroidal anti-inflammatory drug (NSAID), demonstrates anti-inflammatory, analgesic, and antipyretic effects through inhibiting prostaglandin synthesis, predominantly by inhibiting COX-2. Like nonselective NSAIDs, celecoxib is associated with an increased risk of potentially fatal thrombotic cardiovascular events, including myocardial infarction and stroke. Therefore, celecoxib should be used cautiously in patients with cardiovascular disease or with risk factors for cardiovascular disease.  To minimize the risk of celecoxib-associated cardiovascular events, the lowest celecoxib dose for the shortest treatment duration should be utilized. Celecoxib is FDA-approved to manage ankylosing spondylitis, juvenile rheumatoid arthritis, osteoarthritis, acute pain, primary dysmenorrhea, and rheumatoid arthritis. A new therapy came to market in 2019 that combines celecoxib with amlodipine (Consensi®), and it has been approved for use to manage hypertension in patients with osteoarthritis.

1.1. Adults

Maximum recommended celecoxib doses are listed in Table 1. Dosages exceeding these recommendations will be reviewed. Maximum recommended dosages for amlodipine/celecoxib combination therapy are summarized in Table 2.

Table 1: Adult Recommended COX-2 Inhibitor Daily Dosages (Monotherapy)

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
acute pain (including primary dysmenorrhea) celecoxib (Celebrex®) 50 mg, 100 mg, 200 mg, 400 mg capsules 400 mg/day*
ankylosing spondylitis     400 mg/day
osteoarthritis     200 mg/day
rheumatoid arthritis     400 mg/day

* An additional 200 mg dose may be given on the first day only to manage acute pain

1.2. Pediatrics

Celecoxib is FDA-approved for use in pediatric patients 2 years of age and older with a diagnosis of juvenile rheumatoid arthritis (JRA), now also known as juvenile arthritis (JA) or juvenile idiopathic arthritis (JIA). However, celecoxib long-term cardiovascular toxicity as well as extended treatment for greater than six months have not been evaluated in pediatric patients. Therefore, the lowest celecoxib dose for the shortest treatment duration should be employed. Celecoxib safety and efficacy have not been determined in pediatric patients younger than 2 years of age. Additionally, celecoxib/amlodipine (Consensi™) combination therapy is not approved for use in pediatric patients as safety and efficacy have not been established in this patient population. Recommended celecoxib pediatric dosages are summarized in Table 3.

Table 3: Recommended COX-2 Inhibitor Pediatric Daily Dosages

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
juvenile rheumatoid arthritis (JRA)/ juvenile arthritis (JA)/juvenile idiopathic arthritis (JIA)     celecoxib (Celebrex®) 50 mg, 100 mg capsules

Greater than or equal to 2 years of age:

  • 10 kg to less than or equal to 25 kg:
    • 50 mg twice daily
  • Greater than 25 kg:
    • 100 mg twice daily

 

1.3. Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh Class B), the celecoxib dose should be reduced by 50%. Celecoxib is not recommended for use in patients with severe hepatic impairment.

2. Duration of Therapy

Due to the potential for increased cardiovascular and gastrointestinal adverse events, celecoxib and amlodipine/celecoxib should be prescribed as the lowest effective dose for the shortest treatment duration that satisfies patient treatment goals. 

2.1. Therapy Limits

  1. Celecoxib is prescribed on an as needed basis in the management of acute pain or dysmenorrhea. However, treatment regimens extending beyond a two-week time period will be evaluated.
  2. Celecoxib dosages used in osteoarthritis, rheumatoid arthritis, familial adenomatous polyposis, and ankylosing spondylitis may be chronically administered based on patient need.
  3. Celecoxib safety and efficacy in pediatric patients 2 years of age and older with JRA for greater than a six-month treatment duration have not been established. Patient profiles containing prescriptions for JRA for greater than 6 months will be reviewed.

2.2. COX-2 Inhibitor Use in Elderly Patients

Elderly patients are frequently prescribed a COX-2 specific NSAID like celecoxib to manage acute and chronic pain. Several issues surface with COX-2 inhibitor use in elderly patients, including potential adverse effects and drug interactions. NSAID-induced gastrointestinal toxicity is prevalent in the elderly; therefore, COX-2 inhibitors like celecoxib or nonselective NSAIDs plus proton pump inhibitors may offer safer alternatives to these patients. Renal toxicity as well as adverse central nervous system effects are more prevalent in elderly patients due to changes in metabolism, underlying disease states, and concurrent drug therapy and should be considered prior to prescribing celecoxib, especially in higher doses. The potential for increased cardiovascular risk with COX-2 inhibitor use is also a factor when evaluating NSAID therapy in elderly patients. Elderly patients prescribed celecoxib, especially those at higher risk, should be evaluated for appropriateness of therapy as well as potential for drug-drug interactions. Appropriate therapy duration and dosages should also be assessed. Preventive measures such as gastric antisecretory agents administered should be considered in some individuals to reduce GI complications. Medication profiles of elderly patients greater than 60 years of age prescribed celecoxib in high doses or in patients with increased risk factors for adverse events or drug-drug interactions will be reviewed.

2.3. Selective NSAID Use and Cardiovascular Risk

Some clinical trials have shown that patients prescribed selective and nonselective NSAIDs may be at increased risk for serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, all of which can be fatal. Patients at greater risk are those with known CV disease or risk factors for CV disease. Due to the lack of long-term clinical trial data, CV risks associated with NSAID use remains controversial, especially in high-risk patients. Risk also varies between nonselective NSAIDs and cyclooxygenase-2 (COX-2) inhibitors, as well as between individual NSAIDs. The Center for Drug Evaluation and Research has determined that the increased risk of CV events associated with NSAID use should be considered a class effect for both selective and nonselective NSAIDs until more results are available. Patients should be prescribed the lowest effective NSAID dose for the shortest possible treatment duration to minimize the potential for cardiovascular adverse events.

NSAIDs may induce new onset hypertension or worsen pre-existing hypertension in some patients, which may contribute to the development of cardiovascular adverse events. Blood pressure should be routinely monitored in patients prescribed NSAIDs.

NSAIDs may cause fluid retention or edema in some patients and should be used cautiously in patients with a history of fluid retention or heart failure.

2.4. Selective NSAID use and Gastrointestinal Risk

Like nonselective NSAIDs, celecoxib use may be associated with an increased risk of serious gastrointestinal (GI) adverse events, including potentially fatal GI bleeding, ulceration, or gastric/intestinal perforation. The risk of NSAID-associated severe GI adverse events increases in patients with a history of peptic ulcer disease, GI bleeding, smoking, alcohol use, concurrent use of anticoagulants or oral corticosteroids, advanced age, poor health and prolonged NSAID use. However, celecoxib may be associated with fewer GI adverse events due to selective COX-2 inhibition. Short-term trials (3 to 6 months) have shown celecoxib to be associated with significantly fewer GI complications compared to a nonselective NSAID plus a proton pump inhibitor (PPI) (e.g., diclofenac plus omeprazole) and a Cochrane review found significantly fewer ulcer complications with COX-2 inhibitors compared to nonselective NSAIDs. Chan and cohorts, in a randomized, double-blind trial, found that celecoxib administered concurrently with the PPI, esomeprazole, was significantly better in preventing ulcer bleeding in high risk patients compared to celecoxib monotherapy. In a case-control study, Patterson et al. observed that outpatients in the United States using commonly prescribed nonselective NSAIDs and COX-2 inhibitors from 1999 to 2003 were two times more likely to be hospitalized for peptic ulcer bleeding and perforation following nonselective NSAID use compared to those receiving celecoxib. Additionally, a recent small study suggests that lower GI bleeding may occur less frequently following COX-2 inhibitor use compared to that seen with nonselective NSAIDs. This study was criticized, though, as investigators used hemoglobin decrease rather than documented lower GI bleeds to assess outcomes. Further long-term studies are necessary to substantiate the perceived lower GI risk associated with COX-2 inhibitors.

3. Duplicative Therapy

The combined use of specific COX-2 inhibitors and nonspecific COX-1, COX-2 inhibitors does not provide additional therapeutic benefit and may result in additive adverse effects, including gastrointestinal toxicity. However, because celecoxib lacks antiplatelet effects, celecoxib may be used concurrently with low-dose aspirin prescribed for cardiovascular prophylaxis. While an increased incidence of gastrointestinal adverse effects has been observed with combined celecoxib-aspirin therapy, the combination is cautiously warranted due to the potential cardiovascular benefits. Concurrent therapy with celecoxib and nonspecific COX-1, COX-2 inhibitors other than low-dose aspirin is not recommended and will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically significant for celecoxib are summarized in Table 4. Only those drug-drug interactions classified as clinical significance level 1/contraindicated or those considered life-threatening which have not yet been classified will be reviewed.

Table 4: COX-2 Inhibitor Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
amlodipine/celecoxib clopidogrel combined administration may reduce clopidogrel antiplatelet activity and increase risk of thrombotic events as both medications are metabolized by the CYP3A4 enzyme (CYP3A4 converts clopidogrel to active metabolite) administer cautiously together and observe patients for changes in clopidogrel efficacy major (DrugReax)
3 - moderate (CP)
amlodipine/celecoxib CYP3A4 inducers (e.g., rifampin) adjunctive administration may result in reduced amlodipine serum levels and therapeutic efficacy due to induction of amlodipine metabolism by CYP system observe patients for sustained therapeutic effects and adjust amlodipine dosages, if needed; may consider alternate therapy that does not induce CYP3A4 major (DrugReax)
3 – moderate (CP)
amlodipine/celecoxib CYP3A4 inhibitors (e.g., clarithromycin) co-administration may result in enhanced amlodipine pharmacologic and adverse effects, including hypotension and acute kidney injury, as amlodipine is metabolized by CYP3A4  use cautiously together, if at all; observe patients for amplified pharmacologic/ adverse effects; adjust dosages as necessary major (DrugReax)
2 - major (CP)
amlodipine/celecoxib simvastatin due to an unknown mechanism, combined use may cause enhanced simvastatin availability (increased area under curve, maximum concentration) and increased pharmacologic/ adverse effects including myopathy and rhabdomyolysis avoid combined use, if possible; if combined administration necessary, simvastatin dose should not exceed 20 mg/day; patients maintained on high-dose simvastatin who require amlodipine therapy should be converted to another statin with fewer interactions major (DrugReax) 2 - major (CP)
amlodipine/celecoxib tacrolimus increased tacrolimus serum levels with possible enhanced pharmacologic/ adverse effects may result with combined use; tacrolimus is a CYP3A4 substrate with a narrow therapeutic index and amlodipine is weak CYP3A4 inhibitor use cautiously together; monitor patients for tacrolimus adverse effects (e.g., renal dysfunction, cholestasis, paresthesias) major (DrugReax) 3 - moderate (CP)
celecoxib ACE inhibitors, angiotensin receptor blockers potential for decreased antihypertensive effects, increased renal impairment risk with combined therapy; NSAIDs may block production of  vasodilator and  natriuretic prostaglandins monitor blood pressure and renal function, modify therapy as needed; use combination cautiously in elderly; nonacetylated salicylates, sulindac,  may be alternative NSAIDS – have less inhibitory effect on prostaglandin synthesis moderate (DrugReax) 3 - moderate (CP)
celecoxib anticoagulants/ aspirin/ thrombolytic agents potential for increased gastrointestinal and bleeding adverse effects most likely due to either additive effects and/or decreased platelet function administer combination cautiously and observe for adverse bleeding events major (DrugReax) 2 - major (CP)
celecoxib corticosteroids potential for increased gastrointestinal adverse effects with combined therapy monitor for adverse effects; avoid prolonged concurrent administration 3 - moderate (CP)
celecoxib CYP2C9 inhibitors (e.g., fluconazole, amiodarone, delavirdine) celecoxib metabolized by CYP2C9; combination may increase celecoxib serum levels and potential for toxicity use cautiously together with lowest effective celecoxib dose; monitor for adverse effects moderate (DrugReax)
2 - major, 3 - moderate (CP)
celecoxib immune suppressants celecoxib may mask infection symptoms (e.g., fever, swelling) use combination cautiously 3 - moderate (CP)
celecoxib lithium NSAIDs may decrease lithium clearance by blocking renal tubular prostaglandins (may contribute to lithium clearance; may result in increased lithium levels and potential for adverse effects  avoid combination, if possible; if concurrent therapy necessary, monitor lithium levels and signs/ symptoms of lithium toxicity; sulindac, aspirin do not affect lithium clearance -may be alternative NSAIDS  moderate (DrugReax)
3 - moderate (CP)
celecoxib loop diuretics (e.g., furosemide) potential for impaired diuretic and antihypertensive activity of loop diuretic and increased risk of renal insufficiency due to NSAID-associated decreased renal prostaglandin production administer combination cautiously; monitor for signs/symptoms of renal dysfunction and reduced diuretic/ antihypertensive efficacy moderate (DrugReax)
3 - moderate (CP)
celecoxib methotrexate adjunctive administration may lead to increased methotrexate serum levels and the potential for adverse effects (e.g., hematologic, gastrointestinal toxicity), especially with higher methotrexate doses, due to NSAID- associated reductions in renal methotrexate clearance administer combination cautiously together; observe for enhanced methotrexate pharmacologic and adverse events major (DrugReax)
2 - major (CP)
 
celecoxib SNRIs/SSRIs concurrent administration may increase risk of enhanced bleeding activity as serotonin release from platelets necessary for adequate hemostasis monitor for signs/symptoms of bleeding with adjunctive administration major, moderate (DrugReax)
3 - moderate (CP)
celecoxib warfarin combined therapy may result in increased INR and increased risk of gastrointestinal adverse effects, especially in elderly, most likely due to competition for metabolism through CYP2C9 monitor anticoagulant activity, especially in first several days of combination therapy; adjust warfarin doses as necessary major (DrugReax)
2 - major (CP)

Legend:

  • * - Clinical Pharmacology
  • ACE - angiotensin converting enzyme
  • NSAIDs - nonsteroidal anti-inflammatory drugs
  • SNRIs - serotonin norepinephrine reuptake inhibitors
  • SSRIs - selective serotonin reuptake inhibitors

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: June 8, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed June 8, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; June 8, 2021. 
  4. Celecoxib (Celebrex®) package insert. Pfizer Inc., May 2021.
  5. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345:433-42.
  6. Frampton JE, Keating GM. Celecoxib: a review of its use in the management of arthritis and acute pain. Drugs. 2007;67:2433-72.
  7. Amlodipine besylate & celecoxib (Consensi®) oral tablet package insert. Burke Therapeutics, LLC., May 2021.
  8. Ringol S. Classification of juvenile idiopathic arthritis (JRA/JIA). In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA. (Accessed on June 16, 2021.)
  9. Foeldvari I, Szer IS, Zemel LS, et al. A prospective study comparing celecoxib with naproxen in children with juvenile rheumatoid arthritis. J Rheumatology. 2009;36:174-82.
  10. Bell GM, Schnitzer TJ. COX-2 inhibitors and other nonsteroidal anti-inflammatory drugs in the treatment of pain in the elderly. Clin Geriatr Med. 2001;17:489-502.
  11. Savage R. Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly? Drugs Aging. 2005;22:185-200.
  12. United States Food and Drug Administration. FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. (July 9, 2015) Available at:  http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm. Accessed June 8, 2021.
  13. Joshi GP, Gertler R, Fricker R. Cardiovascular thromboembolic adverse effects associated with cyclooxygenase-2 selective inhibitors and nonselective antiinflammatory drugs. Anesth Analg. 2007;105:1793–804.
  14. Sowers JR, White WB, Pitt B, et al. The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med. 2005;165:161-8.
  15. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352:1071-80
  16. Shaya FT, Blume SW, Blanchette CM, et al. Selective cyclooxygenase-2 inhibition and cardiovascular effects: An observational study of a Medicaid population. Arch Intern Med. 2005;165:181-6.
  17. Strand V. Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin? Lancet. 2007;370(9605):2138-51.
  18. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA.  2006;296(13):1633-44.
  19. Antman EM. Evaluating the cardiovascular safety of nonsteroidal anti-inflammatory drugs. Circulation. 2017;135(21):2062-72.
  20. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs. nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized trial. JAMA. 2000;284;1247-55.
  21. Singh G, Fort JG, Goldstein JL, et al. and SUCCESS-I Investigators.  Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med. 2006; 119(3):255–266.
  22. Chan FKL, Lanas A, Scheiman J, et al. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial.Lancet. 2010;376:173–79.
  23. Rostom A, Muir K, Dubé C, et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane collaboration systematic review. Clin Gastroenterol Hepatol 2007;5(7):818-28.
  24. Chan FKL, Wong VWS, Suen BY, et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial.  Lancet. 2007;369:1621–26.
  25. Patterson MK, Castellsague J, Walker AM. Hospitalization for peptic ulcer and bleeding in users of selective COX-2 inhibitors and nonselective NSAIDs with special reference to celecoxib. Pharmacoepidemiol Drug Saf. 2008;17:982-8.
  26. Rahme E, Bernatsky S. NSAIDs and risk of lower gastrointestinal bleeding. Lancet. 2010;376:146-7.
  27. Scheiman JM, Fendrick AM. Summing the risk of NSAID therapy. Lancet. 2007;369:1580-1.
  28. Mersfelder TL, Stewart LR. Warfarin and celecoxib interaction. Ann Pharmacother. 2000;34:325-7.

Direct Oral Anticoagulants

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • April 2022; March 2020; May 2018; Feb. 2018.
  • Initially developed
    • March 2017

1.1. Adults

Direct oral anticoagulants (DOACs) are FDA-approved to treat and prevent deep venous thrombosis (DVT) and pulmonary embolism (PE), reduce the risk of stroke and systemic embolism from non-valvular atrial fibrillation, and to be used as prophylaxis against DVT and PE after knee and hip surgery. DOACs work by interfering with pathways in the coagulation cascade: directly inhibiting thrombin (e.g., dabigatran); or selectively, reversibly inhibiting factor Xa (e.g., apixaban, edoxaban, rivaroxaban)1-7. In April 2020, Portola Pharmaceuticals removed Bevyxxa® (betrixaban) from the market for independent business reasons8 .

Maximum recommended adult dosages for DOACs are summarized in Tables 1 and 2. Medication profiles identifying patients prescribed dosages exceeding these recommendations will be reviewed.

Table 1. Maximum Daily Adult Dosages for DOACs: Direct Thrombin Inhibitors1-4
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage 
dabigatran (Pradaxa®) 75 mg, 110 mg, 150 mg capsules Reduction in risk of stroke and systemic embolism in non-valvular AF
  • CrCl greater than 30 mL/min:
    • 50 mg twice daily
  • CrCl 15-30 mL/min:
    • 75 mg twice daily
  • CrCl less than 15 mL/ min:
    • dosing recommendations cannot be provided
  • CrCl 30-50 mL/min with concomitant use of P-gp inhibitors:
    • 75 mg twice daily
  • CrCl less than 30 mL/min with concomitant use of P-gp inhibitors:
    • Avoid coadministration
dabigatran   Treatment of DVT and PE/reduction in the risk of recurrence of DVT and PE
  • CrCl greater than 30 mL/ min:
    • 150 mg twice daily*
  • CrCl less than or equal to 30 mL/ min:
    • dosing recommendations cannot be provided
  • CrCl less than 50 mL/ min with concomitant use of P-gp inhibitors:
    • Avoid coadministration
dabigatran   Prophylaxis of DVT and PE following hip replacement surgery
  • CrCl greater than 30 mL/min:
    • 110 mg for first day, then 220 mg once daily
  • CrCl less than or equal to 30 mL/ min:
    • dosing recommendations cannot be provided
  • CrCl less than 50 mL/ min with concomitant use of P-gp inhibitors:
    • Avoid coadministration
       

Legend:

  • AF = atrial fibrillation
  • DVT = deep venous thrombosis
  • PE = pulmonary embolism
  • *Requires 5 to 10 days parenteral therapy before initiation of therapy
Table 2. Maximum Daily Adult Dosages for DOACs: Factor Xa Inhibitors1,2,5-7
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage 
apixaban (Eliquis®) 2.5 mg, 5 mg tablets Reduction of risk of stroke and systemic embolism in patients with non-valvular AF 5 mg twice daily#
apixaban   Prophylaxis of DVT following hip or knee replacement surgery 2.5 mg twice daily
apixaban   Treatment of DVT and PE 10 mg twice daily for 7 days, then 5 mg twice daily
apixaban   Reduction in risk of recurrence of DVT and PE 2.5 mg twice daily^
edoxaban (Savaysa®) 15 mg, 30 mg, 60 mg tablets

Non-valvular AF: 

CrCl greater than 50 mL/min and less than or equal to 95 mL/min

60 mg once daily+
edoxaban  

Non-valvular AF:

CrCl 15-50 mL/min

30 mg once daily
edoxaban  

Treatment of DVT and PE:

greater than or equal to 60 kg

60 mg once daily*
edoxaban  

Treatment of DVT and PE:

less than 60 kg, CrCl 15-50 mL/min, adjunctive therapy with certain P-gp inhibitors

30 mg once daily*
rivaroxaban (Xarelto®) 2.5 mg, 10 mg, 15 mg, 20 mg tablets, 1 mg/ 1 mL granules for suspension Reduction in the risk of stroke in non-valvular AF, CrCl greater than 50 mL/min 20 mg once daily with evening meal
rivaroxaban   Reduction in the risk of stroke in non-valvular AF, CrCl less than or equal to 50 mL/min 15 mg once daily with evening meal
rivaroxaban   Treatment of DVT and PE, CrCl greater than or equal to 15 mL/min 15 mg twice daily for 21 days, then 20 mg once daily
rivaroxaban   Reduction in risk of recurrence of DVT and PE (following initial treatment), CrCl greater than or equal to 15 mL/min 10 mg once daily^
rivaroxaban   Prophylaxis of DVT following hip or knee replacement surgery, CrCl greater than or equal to 15 mL/min 10 mg once daily
rivaroxaban   VTE prophylaxis in hospitalized adults with acute illness and limited mobility and other risk factors for VTE, CrCl greater than or equal to 15 mL/min 10 mg once daily
rivaroxaban   Reduction of major cardiovascular event risk in patients with chronic coronary heart disease, peripheral artery disease 2.5 mg twice daily, plus aspirin 75-100 mg once daily

Legend

  • AF = atrial fibrillation
  • DVT = deep venous thrombosis
  • PE = pulmonary embolism
  • P-gp = P-glycoprotein
  • VTE = venous thromboembolism
  • + Avoid in patients with CrCl greater than 95 ml/min due to increased risk of ischemic stroke compared to warfarin
  • * Requires 5 to 10 days parenteral therapy before initiation of therapy
  • # Dose should be decreased to 2.5 mg twice daily in patients receiving strong inhibitors of both CYP3A4 and P-glycoprotein concurrently, or those with at least two of the following: age greater than or equal to 80 years, body weight less than or equal to 60 kg, or serum creatinine greater than or equal to 1.5 mg/dL
  • ^ Following at least 6 months of DVT or PE treatment

1.2. Pediatrics

Apixaban and edoxaban are not recommended for use in pediatric patients, as the safety and efficacy have not been established for these agents in this patient population .1,2,5,6 .

In June 2021, the FDA approved Pradaxa® (dabigatran) oral pellets to treat venous thromboembolism after receiving at least five days of injectable or intravenous treatment for blood clots and to reduce the risk of recurrent thromboembolism in patients 3 months to less than twelve years of age who have completed treatment for a previous venous thromboembolism9.

Dabigatran oral capsules were approved to treat venous thromboembolism after receiving at least five days of injectable or intravenous treatment for blood clots and to reduce the risk of recurrent thromboembolism in patients 8 years of age and older who have completed treatment for a previous venous thromboembolism9.

In December 2021, the FDA approved Xarelto® (rivaroxaban) tablets and oral suspension to treat venous thromboembolism and to reduce the risk of recurrent venous thromboembolism in patients less than 18 years of age who received at least five days of injectable or intravenous treatment for blood clots. Rivaroxaban was also approved to reduce the risk of blood clots in patients two years of age and older with congenital heart disease after the Fontan procedure10 .

Maximum recommended pediatric dosages for DOACs are summarized in Table 3 through Table 6. Medication profiles identifying patients prescribed dosages exceeding these recommendations will be reviewed.

Table 3. Maximum Daily Pediatric Dosages for DOACs in Pediatric Patients Less than 2 Years of Age: Direct Thrombin Inhibitors1,2,4
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage
dabigatran (Pradaxa®) oral pellets! 20 mg, 30 mg, 40 mg, 50 mg, 110 mg, 150 mg oral pellets Treatment of VTE and to reduce the risk of VTE recurrence: 3 months to less than or equal to 2 years of age
  • Actual Weight: 3kg to less than 4kg*^
    • 3 to less than 6 months: 30 mg twice daily
  • Actual Weight: 4 kg to less than 5 kg*^
    • 3 to less than 10 months: 40 mg twice daily
  • Actual Weight: 5 kg to less than 7 kg*^
    • 3 to less than 5 months: 40 mg twice daily
    • 5 to less than 24 months: 50 mg twice daily
  • Actual Weight: 7 kg to less than 9 kg*^
    • 3 to less than4 months: 50 mg twice daily
    • 4 to less than 9 months: 60 mg twice daily
    • 9 to less than24 months: 70 mg twice daily
  • Actual Weight: 9 kg to less than 11 kg*^
    • 5 to less than 6 months: 60 mg twice daily
    • 6 to less than 11 months: 80 mg twice daily
    • 11 to less than 24 months: 90 mg twice daily
  • Actual Weight: 11 kg to less than 13 kg*^
    • 8 to less than 18 months: 100 mg twice daily
    • 18 to less than 24 months: 110 mg twice daily
  • Actual Weight: 13 kg to less than 16 kg*^
    • 10 to less than 11 months: 100 mg twice daily
    • 11 to less than 24 months: 140 mg twice daily
  • Actual Weight: 16 kg to less than 21 kg*^
    • 12 to less than 24 months: 140 mg twice daily
  • Actual Weight: 21 kg to less than 26 kg*^
    • 18 to less than 24 months: 180 mg twice daily

Legend

  • VTE = venous thromboembolism
  • ! Avoid dabigatran in patients with a CrCl less than 50 mL/min
  • * Requires at least 5 days of parenteral therapy before initiation of therapy for the treatment of VTE
  • ^ Following appropriate treatment duration of DVT or PE treatment if used to reduce the risk of VTE recurrence
Table 4. Maximum Daily Pediatric Dosages for DOACs in Pediatric Patients 2 to Less than 12 Years of Age: Direct Thrombin Inhibitors1,2,4
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage 
dabigatran (Pradaxa®) oral pellets! 20 mg, 30 mg, 40 mg, 50 mg, 110 mg, 150 mg oral pellets Treatment of VTE and to reduce the risk of VTE recurrence: 2 to less than 12 years of age
  • Actual Weight: 7 kg to less than 9 kg*^
    • 70 mg twice daily
  • Actual Weight: 9 kg to less than 11 kg*^
    • 90 mg twice daily
  • Actual Weight: 11 kg to less than 13 kg*^
    • 110 mg twice daily
  • Actual Weight: 13 kg to less than 16 kg*^ 
    • 140 mg twice daily
  • Actual Weight: 16 kg to less than 21 kg*^
    • 170 mg twice daily
  • Actual Weight: 21 kg to less than 41 kg*^
    • 220 mg twice daily
  • Actual Weight: 41 kg or greater*^
    • 260 mg twice daily
       

Legend

  • VTE = venous thromboembolism
  • ! Avoid dabigatran in patients with a CrCl less than 50 mL/min
  • * Requires at least 5 days of parenteral therapy before initiation of therapy for the treatment of VTE
  • ^ Following appropriate treatment duration of DVT or PE treatment if used to reduce the risk of VTE recurrence
Table 5. Maximum Daily Pediatric Dosages for DOACs in Pediatric Patients 8 to Less than 18 Years of Age: Direct Thrombin Inhibitors1-3
Drug Name

 

Dosage Form/Strength

Treatment Indication Maximum Recommended Dosage
dabigatran (Pradaxa®) capsules! 75 mg, 110 mg, 150 mg oral capsules Treatment of VTE and to reduce the risk of VTE recurrence: 8 to less than 18 years of age 11 kg to less than 16 kg*^
75 mg twice daily
16 kg to less than 26 kg*^
110 mg twice daily
26 kg to less than 41 kg*^
150 mg twice daily
41 kg to less than 61 kg*^ 
185 mg twice daily
61 kg to less than 81 kg*^
220 mg twice daily
81 kg or greater*^
260 mg twice daily

Legend

  • VTE = venous thromboembolism
  • ! Avoid dabigatran in patients with a CrCl less than 50 mL/min
  • * Requires at least 5 days of parenteral therapy before initiation of therapy for the treatment of VTE
  • ^ Following appropriate treatment duration of DVT or PE treatment if used to reduce the risk of VTE recurrence
Table 6. Maximum Daily Pediatric Dosages for DOACs in Patients Less than 18 Years of Age: Factor Xa Inhibitors1,2,7
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage±
rivaroxaban (Xarelto®) 10 mg, 15 mg, 20 mg tablets, 1 mg/ 1 mL granules for suspension Treatment of VTE and to reduce the risk of VTE recurrence: less than 18 years of age
  • 2.6 kg to 2.9 kg*^#
    • 0.8 mg three times daily
  • 3 kg to 3.9 kg*^#
    • 0.9 mg three times daily
  • 4 kg to 4.9 kg*^#
    • 1.4 mg three times daily
  • 5 kg to 6.9 kg*^#
    • 1.6 mg three times daily
  • 7 kg to 7.9 kg*^#
    • 1.8 mg three times daily
  • 8 kg to 8.9 kg*^#
    • 2.4 mg three times daily
  • 9 kg to 9.9 kg*^#
    • 2.8 mg three times daily
  • 10 kg to 11.9 kg*^#
    • 3 mg three times daily
  • 12 kg to 29.9 kg*^#
    • 5 mg twice daily
  • 30 kg to 49.9 kg*^!
    • 15 mg once daily
  • greater than or equal to 50 kg*^!
    • 20 mg once daily
    Thromboprophylaxis in patients 2 years of age and older with congenital heart disease who have undergone Fontan procedure
  • 7 kg to 7.9 kg#
    • 1.1 mg twice daily
  • 8 kg to 9.9 kg#
    • 1.6 mg twice daily
  • 10 kg to 11.9 kg#
    • 1.7 mg twice daily
  • 12 kg to 19.9 kg#
    • 2 mg twice daily
  • 20 kg to 29.9 kg#
    • 2.5 mg twice daily
  • 30 kg to 49.9 kg#
    • 7.5 mg once daily
  • greater than or equal to 50 kg!
    • 10 mg once daily

Legend

  • VTE = venous thromboembolism
  • ± Patients less than 6 months of age should meet the following criteria: at birth at least 37 weeks gestation, have at least 10 days of oral feeding, and weigh greater than or equal to2.6 kg at the time of dosing
  • * Requires at least 5 days parenteral therapy before initiation of therapy for treatment of VTE
  • ^ Following appropriate treatment duration of DVT or PE treatment if used to reduce the risk of VTE recurrence
  • # May only use granules for suspension
  • ! May use granules for suspension or oral tablets

2. Duration of Therapy

There is no basis for limiting DOAC therapy when prescribed to prevent thromboembolic events associated with cardiovascular or cerebrovascular disease in those with a high risk of recurrence and low risk of bleeding (e.g., unprovoked proximal DVT, recurrent DVT). However, DOAC treatment duration varies, based on medication utilized, indication for use, underlying disease states, and patient factors11. The 2021 “Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guidelines and Expert Review Panel Report” indicates that extended-phase anticoagulation with DOACs does not have a defined stop date, and patients have been monitored for up to four years while on extended-phase anticoagulation. DOAC treatment durations are summarized in Table 7 through Table 10.

Table 7. DOAC Recommended Treatment Duration (Adults): Direct Thrombin Inhibitors1-3,11
Drug Name Indication Maximum Treatment Duration
dabigatran (Pradaxa®) Reduction of risk of stroke and systemic embolism in non-valvular AF indefinite
  DVT and PE treatment 3-12 months
  DVT and PE prevention indefinite
  Prophylaxis of DVT and PE following hip replacement surgery 28-35 days

Legend

  • AF = atrial fibrillation
  • DVT = deep venous thrombosis
  • PE = pulmonary embolism
Table 8. DOAC Recommended Treatment Duration (Adults): Factor Xa Inhibitors1,2,5-7,11
Drug Name Indication Maximum Treatment Duration
apixaban (Eliquis®) Reduction of risk of stroke and systemic embolism in patients with non-valvular AF indefinite
  Prophylaxis of DVT following hip or knee replacement surgery 35 days (hip); 12 days (knee)
  Treatment of DVT and PE 3-12 months
  Reduction in risk of recurrence of DVT and PE indefinite after at least 6 months of treatment
edoxaban (Savaysa®) Reduction of risk of stroke and systemic embolism in patients with non-valvular AF indefinite
  Treatment of DVT and PE maximum of 12 months after 5-10 days of initial therapy with a parenteral anticoagulant
rivaroxaban (Xarelto®) Reduction in the risk of stroke in non-valvular AF indefinite
  Treatment of DVT and PE 3-12 months
  Reduction in risk of recurrence of DVT and PE up to 12 months after an initial 6 months of treatment
  Prophylaxis of DVT following hip or knee replacement surgery 35 days (hip); 12 days (knee)
  VTE prophylaxis in hospitalized adults with acute illness and limited mobility and other risk factors for VTE 31 to 39 days
  Reduction of major cardiovascular event risk in patients with chronic coronary heart disease, peripheral artery disease indefinite

Legend

  • AF = atrial fibrillation
  • DVT = deep venous thrombosis
  • PE = pulmonary embolism

The DIVERSITY trial was conducted in pediatric populations to determine the safety and efficacy of dabigatran compared to the standard of care for the treatment of VTE. The median duration of dabigatran for VTE was 84.5 days12. An additional trial evaluated the safety and effectiveness of dabigatran in patients requiring secondary VTE prophylaxis who completed the DIVERSITY trial. Pediatric patients were treated with dabigatran for up to 12 months after the initial treatment for VTE13.

Table 9. DOAC Recommended Treatment Duration (Pediatrics): Direct Thrombin Inhibitors1-4,12-14
Drug Name Indication Maximum Treatment Duration
dabigatran (Pradaxa®) VTE treatment 3-12 months
  Reduction in risk of recurrence of DVT and PE up to 12 months after initial treatment for VTE

The EINSTEIN Junior trial studied the safety and efficacy of rivaroxaban compared to standard of care in pediatric patients with VTE. When appropriate, treatment for VTE and VTE risk reduction was extended to up to 12 months in duration15. The UNIVERSE trial assessed the safety and efficacy of rivaroxaban for thromboprophylaxis in pediatric patients with congenital heart disease who have undergone the Fontan procedure. Participants took rivaroxaban for up to 12 months in the study16. However, thromboembolic risk may persist for several years after the procedure, and further therapy with antiplatelet or anticoagulant drugs may be appropriate16.

Table 10. DOAC Recommended Treatment Duration (Pediatrics): Factor Xa Inhibitors1,2,7,14-16
Drug Name Indication Maximum Treatment Duration
rivaroxaban (Xarelto®) VTE treatment 3-12 months
  Reduction in risk of recurrence of VTE up to 12 months 
  Thromboprophylaxis in patients at least 2 years of age with congenital heart disease who have undergone Fontan procedure up to 12 months!

Legend

  • ! Specific patient factors may require a longer duration of antiplatelet or anticoagulant therapy

3. Duplicative Therapy

Combined administration of multiple DOACs should be avoided. Concomitant DOAC use results in additive factor Xa inhibition and prolonged prothrombin time (PT), which increases bleeding risk 1-7. No evidence demonstrating increased efficacy or augmentation of therapy from use of multiple DOACs currently exists.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Major drug-drug interactions considered clinically significant for DOACs are summarized in Table 11. Only those drug-drug interactions classified as clinical significance level 1/contraindicated or those considered life threatening which have not yet been classified will be reviewed.

Table 11. DOAC Drug-Drug Interactions1-7
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level#
dabigatran P-gp inhibitors (e.g., amiodarone, clarithromycin) increases dabigatran exposure and bleeding risk
  • Non-valvular AF:
    • avoid use with CrCl less than 30 mL/min; reduce dose to 75 mg twice daily with CrCl 30-50 mL/min (dronedarone, systemic ketoconazole only)
  • Treatment and prevention of DVT and PE:
    • avoid use with CrCl less than 50 mL/min
  • Prevention of DVT and PE after hip replacement surgery:
    • avoid use with CrCl less than 50 mL/min; separate by several hours with CrCl greater than 50 mL/min
dabigatran, major; itraconazole, contraindicated (DrugReax) 2 – major (CP)
dabigatran, edoxaban P-gp inducers (e.g., rifampin) reduces serum dabigatran, edoxaban serum levels and increases thrombosis risk avoid concurrent use major (DrugReax) 2 – major (CP)
DOACs anticoagulants, NSAIDs, aspirin, antiplatelet agents, fibrinolytics increases bleeding risk avoid concurrent use; if adjunctive administration necessary, use cautiously and monitor closely for signs/ symptoms of bleeding major (DrugReax) anticoagulants, 2 – major; fibrinolytics, 1 – severe (CP)
DOACs defibrotide enhances DOAC pharmacologic effects, increasing bleeding risk avoid concurrent use contraindicated (DrugReax) 1 – severe (CP)
DOACs selective serotonin reuptake inhibitors (SSRIs)/ serotonin norepinephrine reuptake inhibitors (SNRIs) may increase bleeding risk avoid concurrent use; if adjunctive administration necessary, use cautiously and monitor closely for signs/ symptoms of bleeding major (DrugReax) 2 – major (CP)
DOACs orlistat may increase INR due to decreased vitamin K absorption if adjunctive administration necessary, use cautiously and monitor closely for changes in coagulation factors major (DrugReax) 3 – moderate (CP)
rivaroxaban, apixaban dual P-gp and CYP3A4 inhibitors   (e. g., ritonavir, ketoconazole) increases serum rivaroxaban, apixaban levels, which increases bleeding risk avoid concurrent use; reduce dose of apixaban by 50%; avoid use in patients receiving apixaban 2.5 mg twice daily major (DrugReax) 2 – major (CP)
rivaroxaban, apixaban dual P-gp and CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine) decreases rivaroxaban exposure by 50%; rifampin decreases apixaban exposure by 50%; increases thrombosis risk avoid concurrent use major (DrugReax) 2 – major (CP)

5. References

  1. DRUGDEX® System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu/. Accessed March 1, 2022.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2022. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed March 1, 2022.
  3. Dabigatran etixilate mesylate capsules (Pradaxa®) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., June 2021.
  4. Dabigatran etixilate mesylate pellets (Pradaxa®) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., June 2021.
  5. Apixaban tablets (Eliquis®) package insert. Bristol-Myers Squibb Company, September 2021.
  6. Edoxaban tablets (Savaysa®) package insert. Daiichi Sankyo, Inc., September 2021.
  7. Rivaroxaban tablets and granules for suspension (Xarelto®) package insert. Janssen Pharmaceuticals, Inc., January 2022.
  8. Smith, I. Response to PREA non-compliance letter. Portola Pharmaceuticals. October 2020. Accessed March 1, 2022.
  9. U.S. Food and Drug Administration. FDA approved first oral blood thinning medication for children. June 2021. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-blood-thinning-medication-children#:~:text=Today%2C%20the%20U.S.%20Food%20and,by%20injection%20for%20at%20least. Accessed March 1, 2022. 
  10. U.S. Food and Drug Administration. FDA approved drug to treat, help prevent types of blood clots in certain pediatric populations. December 2021. Available at: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-treat-help-prevent-types-blood-clots-certain-pediatric-populations#:~:text=FDA%20has%20approved%20Xarelto%20(rivaroxaban,days%20of%20injectable%20or%20intravenous. Accessed March 1, 2022.
  11. Stevens SM, Woller SC, Kreuziger LB, et al. Executive summary: antithrombotic therapy for vte disease: second update of the chest guideline and expert panel report. CHEST. 2021;160(6):2247-2259.
  12. Halton J, Brandão LR, Luciani M, et al. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (Diversity): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial. The Lancet Haematology. 2021;8(1):e22-e33.
  13. Brandão LR, Albisetti M, Halton J, et al. Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children. Blood. 2020;135(7):491-504.
  14. Bosch A, Albisetti M. Management of venous thromboembolism in children: current recommendations and therapeutic options. Ther Clin Risk Manag. 2020;16:673-679.
  15. Male C, Lensing AWA, Palumbo JS, et al. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. The Lancet Haematology. 2020;7(1):e18-e27.
  16. McCrindle BW, Michelson AD, Van Bergen AH, et al. Thromboprophylaxis for children post‐fontan procedure: insights from the universe study. Journal of the American Heart Association. 2021;10(22):e021765.

Exogenous Insulin Products

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • Oct. 22, 2021; Sept. 2019.
  • Initially developed
    • June 2017

1.1. Background

Insulin is a hormone that is typically produced and secreted from pancreatic beta cells in response to elevated blood glucose by binding to receptors found on the liver, skeletal muscle, and adipose tissue cells. Carbohydrate, protein, and fat metabolism are regulated by insulin through suppressing hepatic glucose production, stimulating tissue glucose uptake, and suppressing free fatty acid release from adipose tissue. Subsequently, blood glucose levels are reduced through insulin’s mechanism. 1-3

However, there is inadequate or no insulin secretion in type 1 diabetes mellitus (DM), and there is insulin deficiency and resistance in type 2 DM. Therefore, patients with type 1 DM require insulin treatment to survive; patients with type 2 DM may require insulin when other antidiabetic agents are not able to effectively control blood glucose levels. If either type 1 or 2 DM are left untreated and/or uncontrolled, chronic hyperglycemia may lead to micro- and macrovascular complications, such as retinopathy, nephropathy, neuropathy, hypertension, dyslipidemia, and cardiovascular disease. 1-7

Exogenous insulin products are FDA-approved for use in type 1 and 2 DM. These products are used to mimic the physiologic pattern of insulin secretion. Phase 1 is basal insulin secretion, which suppresses hepatic glucose production in order to maintain blood glucose levels throughout the day. Phase 2 is increased insulin secretion in response to carbohydrate intake in order to lower postprandial blood glucose levels. Patients with type 1 DM require both basal and preprandial insulin boluses, while patients with type 2 DM may require basal and/or preprandial insulin boluses in addition to oral antidiabetic agents, diet, exercise, and weight reduction depending on the severity of their disease and glycemic control. 1-7

Glycemic targets recommended by the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) guidelines are summarized in Table 1 2, 8, 9. However, these targets should be individualized based on patient factors, such as life expectancy, severity of disease, comorbidities, and hypoglycemic risk. 2,8,9

Table 1: 2021 ADA & 2020 AACE/ACE General Glycemic Target Recommendations

Glycemic Targets ADA – Type 1 and 2 AACE/ACE – Adult Type 2
Hemoglobin A1c Adults & Pediatrics: less than 7%
Adults greater than 65 years:
  • Healthy: less than 7.0-7.5%
  • Complex/ intermediate health: less than 8.0%
  • Very complex/ poor health: Avoid hypoglycemia & symptomatic hyperglycemia
Greater than or less than 6.5%
Preprandial blood glucose Adults: 80–130 mg/dL
Pediatrics: 90–130 mg/dL*
Adults greater than 65 years:
  • Healthy: 80–130 mg/dL
  • Complex/intermediate health: 90-150 mg/dL
  • Very complex/ poor health: 100-180 mg/dL
Less than 110 mg/dL
Postprandial blood glucose Adults: less than 180 mg/dL Less than 140 mg/dL
Bedtime blood glucose Adults & Pediatrics: 90–150 mg/dL*
Adults Greater than 65 years:
  • Healthy: 80-180 mg/dL
  • Complex/ intermediate health: 100-180 mg/dL
  • Very complex/ poor health: 110-200 mg/dL
N/A

Legend:

  • * Recommendations carried over from 2019 ADA Standards of Medical Care in Diabetes since they are not presented in the 2021 guidelines.

1.2. Adults

Dosage forms, usual dosage regimen, and maximum recommended dosage of exogenous insulin products for adult patients, categorized by time of onset, peak, and duration of action, are summarized in the following:

  • Table 2 10-19
  • Table 3 10-13, 20-23
  • Table 4 10-13, 24, 25
  • Table 5 10-13, 26-31
  • Table 6 10-13, 32-36
  • Table 7 10-13, 37, 38

Lyumjev® and Lyumjev KwikPen® (insulin lispro) is a rapid-acting insulin that was approved in June 2020 for subcutaneous use as an injection or with an insulin pump. It is also approved for intravenous use.19 Semglee® (insulin glargine-yfgn) was approved by the FDA in July 2021, and it is the first FDA approved interchangeable biosimilar insulin product. Semglee® is interchangeable with Lantus® (insulin glargine)

Table 2: Adult Insulin Recommended Dosages for Single Insulin Products: Rapid-Acting

Drug Name Dosage Form Labeled Dosage Regimen for Type 1 Diabetes * Labeled Dosage Regimen for Type 2 Diabetes *
Insulin aspart
  • Fiasp® vial (100 units/mL – 10 mL)
  • Fiasp® FlexTouch (100 units/mL – 5 x 3 mL)
  • Fiasp® PenFill® cartridges (100 units/mL – 5 x 3 mL) for FlexTouch® device
  • NovoLog®, generic vial (100 units/mL – 10 mL)
  • NovoLog® FlexPen®, generic FlexPen® (100 units/mL – 5 x 3 mL)
  • NovoLog® PenFill®, generic cartridges (100 units/mL – 5 x 3 mL) for NovoPen Echo® device
  • 0.4-1.0 units/kg/day
  • Generally, 50% of daily dosing is given as basal insulin, usually at night
  • The other 50% is typically divided as prandial insulin
  • Administer Fiasp® at start of meal or within 20 minutes after starting meal
  • Administer NovoLog® and generics immediately before meals
  • 4 units or 10% of usual basal dose, given once daily before largest meal of the day, is recommended as initial dose
  • If a1c less than 8% and patient is on basal insulin when insulin aspart is initiated, consider decreasing basal insulin by same amount as initiated insulin aspart
  • Increase insulin aspart dose by 1-2 units, or 10-15%, twice weekly until blood glucose goals are met
  • Administer Fiasp at start of meals or within 20 minutes of starting meal
  • Administer NovoLog and generics immediately before meals
Insulin glulisine
  • Apidra® vial (100 units/mL – 10 mL)
  • Apidra® SoloStar® pen (100 units/mL – 5 x 3 mL)
  • 0.4-1.0 units/kg/day
  • Generally, 50% of daily dosing is given as basal insulin, usually at night
  • The other 50% is typically divided as prandial insulin
  • Administer insulin glulisine within 15 minutes before or 20 minutes after starting meal
  • 4 units or 10% of usual basal dose, given once daily before largest meal of the day, is recommended as initial dose
  • If a1c less than 8% & patient is on basal insulin when insulin glulisine is initiated, consider decreasing basal insulin by same amount as initiated insulin aspart
  • Increase insulin aspart dose by 1-2 units, or 10-15%, twice weekly until blood glucose goals are met
  • If hypoglycemia occurs, determine cause, & decrease dose by 10-20%
Insulin lispro
  • Admelog® vial (100 units/mL – 3 or 10 mL)
  • Admelog® SoloStar® pen (100 units/mL – 3 mL) 
  • HumaLog® cartridges (100 units/mL – 5 x 3 mL) for HumaPen® Luxura™ HD device
  • HumaLog®, generic vial (100 units/mL – 3 or 10 mL)
  • HumaLog® KwikPen®, generic (100 units/mL – 3 mL; 200 units/mL – 3 mL)
  • Lyumjev® (100 units/mL – 10 mL)
  • Lyumjev® KwikPen® (100 unit/ mL – 5 x 3 mL; 200 units/ mL – 2 x 3 mL)
  • 0.4-1.0 units /kg/day
  • Generally, 50% of daily dosing is given as basal insulin, usually at night
  • The other 50% is typically divided as prandial insulin
  • Administer Humalog® or Admelog® 15 minutes prior to eating meal or immediately after a meal
  • Administer Lyumjev® at the start of a meal or within 20 minutes after starting meal
  • 4 units or 10% of usual basal dose, given once daily before the largest meal of the day, is recommended as initial dose
  • If a1c less than 8% & patient is on basal insulin when insulin lispro is initiated, consider decreasing basal insulin by same amount as initiated insulin lispro
  • Increase insulin lispro dose by 1-2 units, or 10-15%, twice weekly until blood glucose levels are achieved
  • If hypoglycemia occurs, determine cause, & decrease dose by 10-20%
  • Administer Humalog® or Admelog® 15 minutes prior to eating meal or immediately after meal
  • Administer Lyumjev® at start of meal or within 20 minutes after starting meal

Legend:

  • Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; should be individualized for each patient 
  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
  • Total daily doses of ALL insulin formulations combined is typically: 0.5 to 1 units/kg/day 
  • Insulin needs may be affected by body weight; non-obese patients may require less insulin than obese patients
    • Non-obese: 0.4 to 0.6 units/kg/day
    • Obese: 0.8 to 1.2 units/kg/day 

Table 3: Adult Insulin Recommended Dosages for Insulin Combination Products: Short-Acting

Drug Name Dosage Form Labeled Dosage Regimen for Type 1 Diabetes * Labeled Dosage Regimen for Type 2 Diabetes *
Inhaled insulin
  • Afrezza® (4 units, 8 units, 12 units – single-use cartridges)
  • Insulin-naive patients: Start with 4 units at beginning of each meal
  • Insulin-experienced patients: Determine appropriate dose of inhaled insulin for each meal using conversions provided by manufacturer
  • Patients using pre-mixed insulin: Estimate mealtime dose by dividing half of total daily pre-mixed insulin dose equally among 3 daily meals. Convert to inhaled dose using manufacturer provided conversions
  • Administer half of total daily injected pre-mixed dose as injected basal insulin dose
  • In insulin-naive patients, start with 4 units at beginning of each meal
  • In patients using subcutaneous prandial insulin, determine appropriate dose of inhaled insulin for each meal using conversions provided by manufacturer
  • In patients using subcutaneous pre-mixed insulin, estimate mealtime injected dose by dividing half of total daily pre-mixed insulin dose equally among 3 daily meals. Convert to inhaled dose using manufacturer provided conversions
  • Administer half of total daily injected pre-mixed dose as injected basal insulin dose
  • Consider subcutaneous insulin in patients requiring high doses of inhaled insulin without adequate blood sugar control
Regular insulin
  • Humulin® R vial (100 units/mL – 10 mL; 500 units/mL – 20 mL)
  • Humulin® R KwikPen® (500 units/mL – 2 x 3 mL) 
  • Novolin® R vial (100 units/mL – 10 mL)
  • Novolin® R FlexPen® (100 units/mL – 5 x 3 mL)
  • 0.4-1.0 units /kg/day
  • Generally, 50% of daily dosing given as basal insulin, usually at night
  • The other 50% is typically divided as prandial insulin
  • Administer 30 minutes before meals
  • 4 units or 10% of usual basal dose, given once daily before largest meal of the day is recommended as initial dose
  • If a1c less than 8% & patient is on basal insulin when regular insulin is initiated, consider decreasing basal insulin by same amount as initiated regular insulin
  • Increase regular insulin dose by 1-2 units, or 10-15%, twice weekly until blood glucose goals are met
  • If hypoglycemia occurs, determine cause, & decrease dose by 10-20%

Legend:

  • Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; should be individualized for each patient 
  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
  • Total daily doses of ALL insulin formulations combined is typically: 0.5 to 1 units/kg/day 
  • Insulin needs may be affected by body weight; non-obese patients may require less insulin than obese patients
    • Non-obese: 0.4 to 0.6 units/kg/day
    • Obese: 0.8 to 1.2 units/kg/day

Table 4: Adult Insulin Recommended Dosages for Single Insulin Products: Intermediate-Acting

Drug Name Dosage Form Labeled Dosage Regimen for Type 1 Diabetes * Labeled Dosage Regimen for Type 2 Diabetes *
Isophane insulin (NPH)
  • Humulin® N vial (100 units/mL – 3 or 10 mL) 
  • Humulin® N KwikPen® (100 units/mL – 5 x 3 mL)
  • Novolin® N vial (100 units/mL – 10 mL)
  • Novolin® N KwikPen® (100 units/mL – 5 x 3 mL)
  • 0.4-1.0 units/kg/day
  • Generally, 50% of daily dosing given as basal insulin, usually at night
  • The other 50% typically divided as prandial insulin
  • Administer once daily before bed or divided into twice daily regimen given 30-60 minutes before meal
  • 10 units or 0.1 to 0.2 units/kg/day given once daily before bed or divided into twice daily regimen given 30-60 minutes before meal
  • Increase dosage by 2 units every 3 days until blood glucose goals are met
  • If hypoglycemia occurs, determine cause, & decrease the corresponding dose by 10% to 20%

Legend:

  • Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; should be individualized for each patient 
  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
  • Total daily doses of ALL insulin formulations combined is typically: 0.5 to 1 units/kg/day
  • Insulin needs may be affected by body weight; non-obese patients may require less insulin than obese patients
    • Non-obese: 0.4 to 0.6 units/kg/day
    • Obese: 0.8 to 1.2 units/kg/day

Table 5: Adult Insulin Recommended Dosages for Single Insulin Products: Long-Acting

Drug Name Dosage Form Labeled Dosage Regimen for Type 1 Diabetes * Labeled Dosage Regimen for Type 2 Diabetes *
Insulin degludec Tresiba® vial (100 units/mL – 10 mL)
Tresiba® FlexTouch® pen (100 units/mL – 5 x 3 mL; 200 units/mL – 3 x 3 mL)
Initially, administer 1/3 to 1/2 of total daily insulin dose once daily
Administer remainder as short-acting insulin & divided between each daily meal
Insulin naive patients generally require total daily insulin dose of 0.2 - 0.4 units/kg/day
Insulin degludec may be given any time of day; however, doses must be at least 8 hours apart
In adults naive to insulin, initiate with 10 units once daily
Insulin degludec may be given at any time of day; however, doses must be at least 8 hours apart
Titrate dosage every 3-4 days to achieve blood glucose & a1c goals in conjunction with short-acting insulin
Insulin detemir
  • Levemir® vial (100 units/mL – 10 mL)
  • Levemir® FlexTouch® pen (100 units/mL – 5 x 3 mL)
  • Initially, administer 1/3 to 1/2 of total daily insulin dose once or twice daily
  • For once daily dosing, give with evening meal or at bedtime
  • For twice daily dosing, give first dose in the morning and the second dose 12 hours later, with the evening meal, or at bedtime
  • Administer the remainder as short-acting insulin and divided between each daily meal
  • Insulin naive patients generally require a total daily insulin dose of 0.2 - 0.4 units/kg/day
  • Insulin degludec may be given at any time of day; however, doses must be given at least 8 hours apart
  • 10 units or 0.1 to 0.2 units/kg/day given once daily in the evening or divided twice daily
  • Increase dosage by 2 units every 3 days until blood glucose goals are achieved
  • If hypoglycemia occurs, decrease dose by 10-20%
  • For once daily dosing, give with evening meal or at bedtime
  • For twice daily dosing, give first dose in the morning and the second dose 12 hours later, with the evening meal, or at bedtime
  • Administer the remainder as short-acting insulin and divided between each daily meal
Insulin glargine
  • Basaglar® KwikPen® (100 units/mL)
  • Lantus® vial (100 units/mL – 10 mL)
  • Lantus® SoloStar® pen (100 units/mL – 5 x 3 mL)
  • Semglee® vial (100 units/mL – 10 mL)
  • Semglee® 100 units/mL pen (100 units/mL – 5 x 3 mL)
  • Toujeo® SoloStar® pen (300 units/mL – 3 x 1.5 mL)
  • Toujeo® Max SoloStar® pen (300 units/mL – 2 x 3 mL)
  • 0.4 to 1 unit/kg/day is the typical total daily insulin requirement
  • In general, 50% of daily insulin is given as basal insulin (intermediate-acting or long-acting), usually at night 
  • The other 50% is divided and given as prandial insulin (rapid-acting or short-acting) before a meal
  • Titrate dosage to achieve blood glucose and a1c goals in conjunction with short-acting insulin
  • 10 units or 0.1 to 0.2 units/kg/day once daily in patients not controlled on an oral antidiabetic medicine
  • Increase dosage by 2 units every 3 days until blood glucose goals are achieved
  • If hypoglycemia occurs, decrease dose by 10% to 20%

Legend:

  • Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; should be individualized for each patient 
  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
  • Total daily doses of ALL insulin formulations combined is typically: 0.5 to 1 units/kg/day
  • Insulin needs may be affected by body weight; non-obese patients may require less insulin than obese patients
    • Non-obese: 0.4 to 0.6 units/kg/day
    • Obese: 0.8 to 1.2 units/kg/day

Table 6: Adult Insulin Recommended Dosages for Insulin Combination Products

Drug Name Dosage Form Usual Dosage Regimen * Maximum Recommended Dosage *
Insulin aspart protamine/insulin aspart 
  • NovoLog® Mix 70/30, generic vial (100 units/mL – 10 mL)
  • NovoLog® Mix 70/30 FlexPen®, generic (100 units/mL – 5 x 3 mL)
  • Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; this should be individualized for each patient
  • Total daily doses of ALL insulin formulations combined: 0.5 to 1 units/kg/day
  • Insulin needs may be affected by body weight; nonobese patients may require less insulin than obese patients
  • Nonobese: 0.4 to 0.6 units/kg/day
  • Obese: 0.8 to 1.2 units/kg/day
  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
Isophane insulin (NPH)/ regular insulin
  • Humulin® 70/30 vial (100 units/mL – 3 or 10 mL)
  • Humulin® 70/30 KwikPen® (100 units/mL – 5 x 3 mL)
  • Novolin® 70/30 vial (100 units/mL – 10 mL)
  • Novolin® 70/30 FlexPen (100 units/mL – 5 x 3 mL)
  • Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; this should be individualized for each patient
  • Total daily doses of ALL insulin formulations combined: 0.5 to 1 units/kg/day
  • Insulin needs may be affected by body weight; nonobese patients may require less insulin than obese patients
  • Nonobese: 0.4 to 0.6 units/kg/day
  • Obese: 0.8 to 1.2 units/kg/day
  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
Insulin lispro protamine/insulin lispro
  • HumaLog® Mix 50/50 vial (100 units/mL – 10 units)
  • HumaLog® Mix 50/50 KwikPen® (100 units/mL – 5 x 3 mL)
  • HumaLog® Mix 75/25 vial (100 units/mL – 10 mL)
  • HumaLog® Mix 75/25 KwikPen®, generic (100 units/mL – 5 x 3 mL)
  • Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; this should be individualized for each patient
  • Total daily doses of ALL insulin formulations combined: 0.5 to 1 units/kg/day
  • Insulin needs may be affected by body weight; nonobese patients may require less insulin than obese patients
  • Nonobese: 0.4 to 0.6 units/kg/day
  • Obese: 0.8 to 1.2 units/kg/day
  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs

Legend:

  • Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; should be individualized for each patient
  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
  • Total daily doses of ALL insulin formulations combined is typically: 0.5 to 1 units/kg/day
  • Insulin needs may be affected by body weight; non-obese patients may require less insulin than obese patients
    • Non-obese: 0.4 to 0.6 units/kg/day
    • Obese: 0.8 to 1.2 units/kg/day 

Table 7: Adult Insulin Recommended Dosages for Insulin/GLP-1 Receptor Agonist Combination Products

Drug Name Dosage Form Usual Dosage Regimen Maximum Recommended Dosage
Insulin glargine/lixisenatide Soliqua® 100/33 pen (insulin glargine 100 units/mL and lixisenatide 33 mcg/mL – 5 x 3 mL) 15 – 60 units/day (15 – 60 units / 5 – 20 mcg)    60 units/20 mcg/day
Insulin degludec/liraglutide Xultophy® 100/3.6 pen (insulin degludec 100 units/mL and liraglutide 3.6 mg/mL – 5 x 3 mL) 10 – 50 units/day (10 – 50 units / 0.36 – 1.8 mg) 50 units/1.8 mg/day

Legend:

  • GLP-1 = glucagon-like peptide-1

1.3. Pediatrics

Safety and efficacy for inhaled insulin (Afrezza®), insulin lispro/lispro protamine combinations (HumaLog® Mix 50/50 and 75/25), insulin aspart/insulin aspart protamine combinations (NovoLog® Mix 70/30), and insulin-GLP-1 combinations (Soliqua® 100/33 and Xultophy® 100/3.6) have not been studied or established in pediatric patients. 10-13, 14, 19, 32, 35, 36-38

The insulin aspart formulation sold under the trade name Fiasp® was approved for pediatric use in patients 2 years of age or older in 2020.39

Recommended age requirements for insulin products approved in pediatric patients are summarized in the following:

  • Table 8 10-18
  • Table 9 10-13, 21, 23
  • Table 10 10-13, 24, 25
  • Table 11 10-13, 26-31
  • Table 12 10-13, 34

Usual dosage regimens and maximum recommended dosages are similar to adult patients.

Table 8: Pediatric Insulin Recommended Dosages for Single Insulin Products: Rapid-Acting

Drug Name Dosage Form Approved Age Requirements * Maximum Recommended Dosage *
Insulin aspart
  • Fiasp® vial (100 units/mL – 10 mL)
  • Fiasp® FlexTouch (100 units/mL – 5 x 3 mL)
  • Fiasp® PenFill® cartridges (100 units/mL – 5 x 3 mL) for FlexTouch® device
  • NovoLog® vial (100 units/mL – 10 mL)
  • NovoLog® FlexPen® (100 units/mL – 5 x 3 mL)
  • NovoLog® PenFill® cartridges (100 units/mL – 5 x 3 mL) for NovoPen Echo® device
Children greater than or equal to 2 years and adolescents No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
Insulin glulisine
  • Apidra® vial (100 units/mL – 10 mL)
  • Apidra® SoloStar® pen (100 units/mL – 5 x 3 mL)
Children greater than or equal to 4 years and adolescents No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
Insulin lispro
  • Admelog® vial (100 units/mL – 3 or 10 mL)
  • Admelog® SoloStar® pen (100 units/mL – 3 mL)
  • HumaLog® cartridges (100 units/mL – 5 x 3 mL) for 
  • HumaPen® Luxura™ HD device
  • HumaLog® vial (100 units/mL – 3 mL)
  • HumaLog® KwikPen® (100 units/mL – 3 mL; 200 units/mL – 3 mL)
Children greater than or equal to 3 years and adolescents No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs

Legend:

  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs

Table 9: Pediatric Insulin Recommended Dosages for Single Insulin Products: Short-Acting

Drug Name Dosage Form Approved Age Requirements * Maximum Recommended Dosage *
Regular insulin
  • Humulin® R vial (100 units/mL – 10 mL; 500 unit/mL – 20 mL)
  • Humulin® R KwikPen® (500 units/mL – 2 x 3 mL)
  • Novolin® R vial (100 units/mL – 10 units)
  • Novolin® R FlexPen® (100 units/mL – 5 x 3 mL
No specific age requirement reported No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs

Legend:

  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs

C-3.18. Table 10: Pediatric Insulin Recommended Dosages for Single Insulin Products: Intermediate-Acting

Drug Name Dosage Form Approved Age Requirements * Maximum Recommended Dosage *
Isophane insulin (NPH)
  • Humulin® N vial (100 units/mL – 3 or 10 mL)
  • Humulin® N KwikPen® (100 units/mL – 5 x 3 mL)
  • Novolin® N vial (100 units/mL – 10 mL)
  • Novolin® N KwikPen® (100 units/mL – 5 x 3 mL)
No specific age requirement reported No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs

Legend:

  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs

C-3.18. Table 11: Pediatric Insulin Recommended Dosages for Single Insulin Products: Long-Acting

Drug Name Dosage Form Approved Age Requirements * Maximum Recommended Dosage *
Insulin degludec
  • Tresiba® vial (100 units/mL – 10 mL)
  • Tresiba® FlexTouch® pen (100 units/mL – 5 x 3 mL; 200 units/mL – 3 x 3 mL)
  • Children greater than 1 year and adolescents
  • Not recommended if require less than 5 units
No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
Insulin detemir
  • Levemir® vial (100 units/mL – 10 mL)
  • Levemir® FlexTouch® pen (100 units/mL – 5 x 3 mL)
Children greater than 2 years and adolescents No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
Insulin glargine Basaglar® KwikPen® (100 units/mL)
Lantus® vial (100 units – 10 mL)
Lantus® SoloStar® pen (100 units/mL – 5 x 3 mL)
Semglee® vial (100 units/mL – 10 mL)
Semglee® 100 units/mL pen (100 units/mL – 5 x 3 mL)
Toujeo® SoloStar® pen (300 units/mL – 3 x 1.5 mL)
Toujeo® Max SoloStar® pen (300 units/mL – 2 x 3 mL)
Children greater than 6 years and adolescents No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs

Legend:

  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs

C-3.18. Table 12: Pediatric Insulin Age Requirements for Insulin Combination Products

Drug Name Dosage Form Approved Age Requirements * Maximum Recommended Dosage *
Isophane insulin (NPH) and regular insulin
  • Novolin® 70/30 vial (100 units/mL – 10 mL)
  • Novolin® 70/30 FlexPen (100 units/mL – 5 x 3 mL)
Children and adolescents No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs

Legend:

  • No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs

C-3.18.2. Duration of Therapy

Exogenous insulin products are indicated for the management of type 1 and 2 DM and may be continued indefinitely, as blood glucose control in DM is a chronic, lifelong process. 1-9

C-3.18.3. Duplicative Therapy

Adjunctive administration of multiple exogenous insulin products may be required or recommended to maintain adequate glycemic control. If multiple exogenous insulin products are required or recommended, the patients generally have one long-acting or intermediate-acting basal insulin product and one short- or rapid-acting preprandial insulin product 1-38. Patient profiles containing prescriptions for multiple short-acting or multiple long-acting exogenous insulin products will be reviewed.

C-3.18.4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for exogenous insulin products are summarized in Table 13 10-13. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

C-3.18. Table 13: Select Insulin Drug-Drug Interactions

Target Drug: all insulin products

Interacting Drug Interaction Recommendation Clinical Significance Level
angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) adjunctive use may increase hypoglycemia risk as ACE inhibitors, ARBS improve insulin sensitivity monitor blood glucose levels and observe for signs/symptoms of hypoglycemia moderate (DrugReax) 3-moderate (CP)
beta blockers combined use may increase or decrease blood glucose levels as beta blockers can alter glucose metabolism; beta blockade may also mask hypoglycemia signs/symptoms monitor patients for signs/ symptoms of hypo- or hyperglycemia with combined therapy; measure blood glucose levels moderate (DrugReax) 3-moderate (CP)
glucagon-like peptide-1 (GLP-1) receptor agonists concurrent use may increase hypoglycemia risk monitor blood glucose levels and consider insulin dose reductions or therapy modification; avoid combination of liraglutide and insulin if liraglutide is used primarily for weight loss liraglutide – major; others – moderate (DrugReax) 2-major (CP)
lithium combined use may increase risk of hypo- or hyperglycemia due to lithium varying effects on glucose metabolism monitor blood glucose levels, especially when adding, discontinuing, modifying therapy moderate (DrugReax) 3-moderate (CP)
metreleptin (Myalept®) concurrent use may increase risk of hypoglycemia use with caution and monitor blood glucose levels closely; potential large decreases in insulin dosage adjustments may be required, or consider therapy modification major (DrugReax) 3-moderate (CP)
peroxisome proliferator-activated receptor (PPAR)-gamma agonists insulin may enhance rosiglitazone, pioglitazone adverse effects (e.g., edema, heart failure); combined use may increase hypoglycemia risk avoid combination with rosiglitazone; if insulin is combined with pioglitazone, consider dose reductions or therapy modification; monitor patients for signs/symptoms of heart failure and hypoglycemia major (DrugReax) 2-major (CP)
pramlintide concurrent use may increase hypoglycemia risk decrease preprandial insulin dose by 50% or consider therapy modification; monitor blood glucose frequently and adjust insulin dose based on glycemic control major (DrugReax) 2-major (CP)
fluoroquinolone antibiotics concomitant use may increase risk of hypo- or hyperglycemia monitor blood glucose levels closely and adjust insulin dose as needed; further insulin dosage adjustments may be required upon fluoroquinolone discontinuation major (DrugReax) 3-moderate (CP)
somatostatin analogs concurrent use may diminish insulin therapeutic effects as somatostatin analogs associated with hyperglycemia monitor blood glucose levels frequently and adjust insulin dose as needed major (DrugReax) 3-moderate (CP)

C-3.18.5. References

  1. Trujillo J, Haines S. Diabetes Mellitus. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. DiPiro J.T., & Yee G.C., & Posey L, & Haines S.T., & Nolin T.D., & Ellingrod V(Eds.),Eds. Joseph T. DiPiro, et al.eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw Hill; 2020. Accessed September 13, 2021. https://accesspharmacy-mhmedical-com.ezproxy.lib.utexas.edu/content.aspx?bookid=2577&sectionid=228901946
  2. Garber AJ, Handelsman Y, Grunberger, et. al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm- 2020 executive summary. Endocr Pract. 2020 Jan;26(1):107-139. doi: 10.4158/CS-2019-0472. PMID: 32022600.
  3. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2021;44 (Suppl 1):S111-124.
  4. Weinstock RS. General principles of insulin therapy in diabetes mellitus. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed September 13, 2021.)
  5. Weinstock RS. Management of blood glucose in adults with type 1 diabetes mellitus. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed September 13, 2021.)
  6. Levitsky LL, Misra M. Management of type 1 diabetes mellitus in children and adolescents. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed September 13, 2021.)
  7. Wexler JW. Insulin therapy in type 2 diabetes mellitus. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed September 13, 2021.)
  8. American Diabetes Association. 6. Glycemic targets: Standards of medical care in diabetes – 2021. Diabetes Care. 2021;44 (Suppl 1): dc21-S0006. 
  9. American Diabetes Association. 13. Children and adolescents: Standards of medical care in diabetes – 2021. Diabetes Care. 2021;44 (Suppl 1)S180-S199.
  10. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: September 13, 2021).
  11. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed September 13, 2021.
  12. Lexicomp OnlineTM. Lexi-Comp OnlineTM. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021. Available at: http://online.lexi.com.ezproxy.lib.utexas.edu. Accessed September 13, 2021.
  13. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; Accessed September 1, 2021.
  14. Insulin aspart (Fiasp®) package insert. NovoNordisk, December 2019.
  15. Insulin aspart (NovoLog®) package insert. Novo Nordisk, March 2021.
  16. Insulin glulisine (Apidra®) package insert. Sanofi-Aventis, November 2020.
  17. Insulin lispro (Admelog®) package insert. Sanofi-Aventis, November 2020.
  18. Insulin lispro (Humalog®) package insert. Eli Lilly, May 2021.
  19. Insulin lispro (Lyumjev®) package insert. Eli Lilly and Company, August 2021.
  20. Regular insulin (Afrezza®) package insert. MannKind Corporation, March 2021.
  21. Regular insulin (Humulin® R) package insert. Eli Lilly, March 2020.
  22. Regular insulin (Humulin® R Concentrated U 500) package insert. Eli Lilly, November 2020.
  23. Regular insulin (Novolin® R) package insert. Novo Nordisk, November 2019.
  24. Insulin isophane (NPH) (Humulin® N) package insert. Eli Lilly, November 2020.
  25. Insulin isophane (NPH) (Novolin® N) package insert. Novo Nordisk, November 2019.
  26. Insulin degludec (Tresiba®) package insert. Novo Nordisk, November 2019.
  27. Insulin detemir (Levemir®) package insert. Novo Nordisk, April 2021.
  28. Insulin glargine (Basaglar®) package insert. Eli Lilly, July 2021.
  29. Insulin glargine (Lantus®) package insert. Sanofi-Aventis, January 2021.
  30. Insulin glargine (Semglee®) package insert. Mylan Specialty LP, June 2020.
  31. Insulin glargine (Toujeo®) package insert. Sanofi-Aventis, December 2020.
  32. Insulin aspart protamine and insulin aspart (NovoLog® Mix 70/30) package insert. Novo Nordisk, April 2021.
  33. Insulin isophane (NPH) and regular (Humulin® 70/30) package insert. Eli Lilly, November 2020.
  34. Insulin isophane (NPH) and regular (Novolin® 70/30) package insert. Novo Nordisk, November 2019.
  35. Insulin lispro (Humalog® Mix 50/50) package insert. Eli Lilly, March 2021.
  36. Insulin lispro (Humalog® Mix 75/25) package insert. Eli Lilly, June 2021.
  37. Insulin glargine and lixisenatide (Soliqua® 100/33) package insert. Sanofi-Aventis, August 2021.
  38. Insulin degludec and liraglutide (Xultophy® 100/3.6) package insert. Novo Nordisk, November 2019.
  39. Melillo G. FDA approves Fiasp for children with diabetes. Am J Manag Care. January 6, 2020. Available at: www.ajmc.com/view/fda-approves-fiasp-for-children-with-diabetes. Accessed September 13, 2021.

Fentanyl

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • July 23, 2021; May 24, 2019; May 2017; June 2015; October 2013; December 2011; January 2010
  • Initially developed
    • Feb. 2003

1.1. Adults

Fentanyl citrate intranasal spray as well as oral transmucosal lozenges, buccal tablets, sublingual tablets, sublingual spray, and transdermal patches are FDA-approved for managing breakthrough cancer pain in patients already receiving and tolerant to opioid therapy for persistent cancer pain. Patients are considered opioid tolerant if they are taking around-the-clock opioids consisting of at least 60 mg of oral morphine daily, 25 mcg of transdermal fentanyl/hour, 30 mg of oral oxycodone daily, 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer1-11.

Because of the risk of abuse, addiction, misuse, and overdose, all intranasal and oral fentanyl dosage forms are obtained solely through a restricted distribution program, the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Management Strategy (REMS) Access program, in which only outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors who have registered for the program can prescribe, dispense, and/or obtain intranasal and oral fentanyl1-5, 7-11.

Due to pharmacokinetic differences between intranasal, oral transmucosal, buccal, sublingual, and transdermal fentanyl citrate formulations, these products are not interchangeable on a mcg per mcg basis and should not be substituted on a mcg for mcg basis as enhanced or attenuated pharmacologic effects could occur1-11.

1.1.1. Transmucosal Lozenges (Actiq®, generic)

Patients receiving fentanyl oral transmucosal lozenges for breakthrough pain are prescribed an initial dose of 200 mcg with instructions to allow the lozenge to dissolve over 15 minutes as the product is not designed to be chewed. Until the appropriate dose is reached, patients may find it necessary to use an additional oral transmucosal unit during a single episode. Re-dosing may begin 30 minutes after the start of the previous unit. During the titration phase, no more than two units should be administered for each individual cancer breakthrough pain episode. Patients must wait at least 4 hours before administering fentanyl oral transmucosal lozenges for another episode of breakthrough pain. To limit the number of units during the titration period, patients should be prescribed a maximum supply of six 200 mcg fentanyl oral transmucosal lozenges. At each new dose of oral transmucosal lozenge required by a patient, it is recommended that no more than six units of the titration dose be prescribed. Once a successful dose is identified for a patient, the quantity of lozenges utilized by a patient should be limited to 4 or fewer units per day. If consumption increases to greater than 4 units per day, the dose of the long-acting opiate should be re-evaluated. To discontinue use of fentanyl oral transmucosal lozenges, a downward titration is recommended to minimize potential withdrawal adverse effects1, 7-15.

1.1.2. Buccal Tablets (Fentora®, generic)

Patients prescribed fentanyl buccal tablets for breakthrough pain should begin therapy with an initial dose of 100 mcg, with the exception of those previously treated with fentanyl oral transmucosal lozenges2, 7-11. Dose conversions between fentanyl oral transmucosal lozenges and buccal tablets are summarized in Table 1.

The tablet is placed in the buccal cavity (the space between the upper cheek and rear molar) or under the tongue and should be allowed to dissolve completely over a period of 30 minutes. Tablets should not be split, crushed, chewed or swallowed whole. If there are any tablet pieces remaining after 30 minutes, the patient may swallow them with a glass of water. The same dosage strength may be repeated once during a breakthrough pain episode, administered no sooner than 30 minutes after initiating buccal fentanyl tablet therapy, if pain is not relieved by the first buccal tablet dose. Patients must wait at least 4 hours before administering a fentanyl buccal tablet dose for another episode of breakthrough pain. The fentanyl buccal tablet dose should be increased in patients requiring greater than one breakthrough dose for several consecutive episodes. Patients requiring fentanyl buccal tablet doses higher than 100 mcg should be titrated in multiples of 100 mcg. Patients may receive up to four 100 mcg tablets at one time placed on each side of the mouth in each buccal cavity (2 tablets per side). Fentanyl buccal tablet dosages greater than 400 mcg should be titrated in 200 mcg increments. Doses should be titrated to achieve adequate analgesia with acceptable side effects, but no more than 4 tablets should be used concurrently for a breakthrough episode. Patients should receive only one buccal tablet dosage strength at a time to minimize confusion and the possibility of overdose. If more than four breakthrough pain episodes happen per day, the long-term opiate maintenance dose should be re-evaluated. To discontinue fentanyl buccal tablet use, a downward titration is recommended to minimize potential withdrawal adverse effects.

1.1.3. Sublingual Tablets (Abstral®)

Patients prescribed fentanyl sublingual tablets for breakthrough pain should begin therapy with an initial 100 mcg dose, with the exception of those previously treated with fentanyl oral transmucosal lozenges. Dose conversions between fentanyl oral transmucosal lozenges and sublingual tablets are summarized in Table 2.

To administer fentanyl sublingual tablets, the unwrapped tablet should be placed on the floor of the mouth, under the tongue and allowed to dissolve completely. Fentanyl sublingual tablets should not be chewed or swallowed. Patients should be advised to not eat or drink until the tablet is dissolved. In patients with xerostomia, the mouth should be moistened before the tablet is administered. If patients do not achieve adequate analgesia within 30 minutes, a second fentanyl sublingual tablet dose may be administered as directed. No more than two doses should be administered for any breakthrough pain episode. If pain relief for the breakthrough episode is not relieved with the 100 mcg dose, titrate using multiples of 100 mcg or 200 mcg tablets until adequate analgesia is achieved. Doses may be titrated upward to 200 mcg, 300 mcg, 400 mcg, 600 mcg, or 800 mcg per dose. Doses higher than 800 mcg have not been evaluated in clinical trials. If adequate pain relief is not achieved within 30 minutes of the first dose, a second dose of the same strength may be administered. Patients should not use more than 4 tablets at one time. Patients must wait at least 2 hours before administering fentanyl sublingual tablets for another episode of breakthrough pain. Once an effective fentanyl sublingual tablet dose has been determined, patients should be maintained on this dose. If pain is not effectively managed with this dose of fentanyl sublingual tablet, a patient may use a second dose as directed by their health care provider, with no more than two doses being used to treat any breakthrough pain episode. Again, patients must wait at least two hours before treating subsequent breakthrough pain episodes. Fentanyl sublingual tablets should be used for no more than four breakthrough pain episodes per day. If more than four breakthrough pain episodes happen per day, the long-term opiate maintenance dose should be re-evaluated. To discontinue fentanyl sublingual tablet use, a downward titration is recommended to minimize potential withdrawal adverse effects3, 7-11.

1.1.4. Sublingual Spray (Subsys®)

With the exception of patients previously treated with fentanyl transmucosal lozenges, treatment with fentanyl sublingual spray should be initiated with a 100 mcg dose. If patients do not achieve adequate analgesia within 30 minutes, a second fentanyl sublingual spray dose of the same strength may be administered. No more than two doses should be administered for any breakthrough pain episode. Patients must wait at least 4 hours before administering fentanyl sublingual spray for another episode of breakthrough pain. Patients should be prescribed only a titration supply of 100 mcg dose units during titration to minimize the number of available units during titration. If pain relief for the breakthrough episode is not relieved with the 100 mcg dose, titrate doses upward to 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, or 1600 mcg per dose. Patients previously treated with fentanyl transmucosal lozenges should receive a modified initial sublingual spray dose, based on the transmucosal lozenge dose that had previously been utilized. Dosage conversions between fentanyl transmucosal lozenges and sublingual spray are summarized in Table 3.

Once an effective fentanyl sublingual spray dose has been determined, patients should be maintained on this dose. If pain is not effectively managed with this dose of fentanyl sublingual spray, a patient may use a second dose as directed by their health care provider, with no more than two doses being used to treat any breakthrough pain episode. Again, patients must wait at least four hours before treating subsequent breakthrough pain episodes. Increase the fentanyl sublingual spray dose only when treatment at the current dose fails to provide pain relief for several episodes. To reduce the risk of overdose, patients should have only one fentanyl sublingual spray dosage strength available at any time. If more than four breakthrough pain episodes happen per day, the long-term opiate maintenance dose should be re-evaluated. In patients with Grade 1 mucositis, fentanyl sublingual spray may result in higher drug serum concentrations. For patients with Grade 2 mucositis, avoid sublingual fentanyl use unless the benefits outweigh the risks of increased drug exposure4, 7-11.

1.1.5. Intranasal Spray (Lazanda®)

Fentanyl intranasal spray should be initiated in all patients with a dose of 100 mcg (one spray in one nostril). If adequate analgesia is achieved, this dose will be used to manage future breakthrough pain episodes. If adequate pain relief is not achieved with the 100 mcg dose, titrate the dose upward in a stepwise manner to 200 mcg (2 x 100 mcg – one spray in each nostril), 400 mcg (4 x 100 mg – two sprays in each nostril or 1 x 400 mcg – one spray in one nostril), or 800 mcg (2 x 400 mcg – one spray in each nostril) per dose until adequate analgesia is achieved with minimal adverse effects. Patients must wait at least 2 hours before administering subsequent fentanyl intranasal spray doses. Safety and efficacy of doses greater than 800 mcg have not yet been determined in clinical trials. Once an effective dose has been established, fentanyl intranasal spray should be used to manage no more than four breakthrough episodes per day. If adequate analgesia is not achieved within 30 minutes of a fentanyl intranasal spray dose or a breakthrough pain episode occurs before the next fentanyl intranasal spray dose (i.e., within 2 hours of a fentanyl intranasal spray dose), a rescue medication may be utilized as dictated by the patient’s health care provider. If more than four breakthrough pain episodes happen per day, long-term opiate maintenance doses should be re-evaluated. To discontinue fentanyl intranasal spray use, a downward titration is recommended to minimize potential withdrawal adverse effects5, 7-11.

1.1.6. Transdermal Patch (Duragesic®, generics)

To initiate fentanyl transdermal patch therapy in patients prescribed other opioids, discontinue all other around-the-clock opioid therapy. Short-acting opioid agonists may be used as needed for the first 24 hours after initial application. Breakthrough pain may require supplemental doses even after a transdermal dose is established. Conversion doses from an oral or parenteral fentanyl preparation to fentanyl transdermal patches is summarized in Table 46-11. Conversion doses from daily oral morphine dosages to fentanyl transdermal patches is provided in Table 56-11. This table does NOT represent equianalgesic doses and is only intended to provide dosage conversions from other opioids to fentanyl transdermal patches, but does NOT provide dosage conversions from fentanyl transdermal patches to other fentanyl/opioid dosage forms as the new opioid dose would be overestimated and may potentially result in a fatal drug overdose.

Patients requiring fentanyl transdermal patch therapy and taking an opiate not listed in Table 4 should calculate the previous 24-hour analgesic requirement and convert the quantity to an equianalgesic oral morphine dose and use Table 4 or an additional dosage conversion chart such as the “Table 2. Morphine Milligram Equivalent (MME) Doses for Commonly Prescribed Opioids” table provided in the “CDC Guideline for Prescribing Opioids for Chronic Pain- United States, 2016” to identify an appropriate transdermal fentanyl patch conversion dose. The fentanyl transdermal patch dose should be titrated to a dose that provides adequate analgesia and minimal adverse reactions. The patch should be changed every 72 hours. If adequate analgesia is not achieved, the initial dose can be titrated after three days; subsequent dosage titrations should not be made more frequently than every six days. In the event that breakthrough pain occurs, a dosage adjustment may be necessary as well as rescue medication administration with an immediate-release analgesic. A small percentage of adult patients may not have adequate pain control with an every 72 hour dosage scheme and may require an every 48 hour dosing regimen. The patch should be applied to non-irritated, non-irradiated skin on a flat surface; avoid exposing the patch to external heat sources6, 7-11.

Table 4: Opioid Dosage Conversion to Fentanyl Transdermal Patch

Current Analgesic Daily Dosages (mg/day)
Oral morphine
  • 60–134
  • 135–224
  • 225–314
  • 315–404
Intravenous or intramuscular morphine
  • 10–22
  • 23–37
  • 38–52
  • 53–67
Oral oxycodone
  • 30–67
  • 67.5–112
  • 112.5–157
  • 157.5–202
Oral codeine
  • 150–447
Oral hydromorphone
  • 8–17
  • 17.1-28
  • 28.1-39
  • 39.1-51
Intravenous hydromorphone
  • 1.5-3.4
  • 3.5–5.6
  • 5.7–7.9
  • 8–10
Intramuscular meperidine
  • 75–165
  • 166–278
  • 279–390
  • 391–503
Oral methadone
  • 20–44
  • 45–74
  • 75–104
  • 105–134
Recommended fentanyl transdermal patch dose
  • 25 mcg/hour
  • 50 mcg/hour
  • 75 mcg/hour
  • 100 mcg/hour

1.1.7. Off-Label Uses

Although not FDA-approved, a few small studies have evaluated oral transmucosal fentanyl lozenge use for migraine headache pain management refractory to conventional treatment in patients with a history of parenteral opioid use in the Emergency Department (ED). These studies found the drug to be effective in reducing pain intensity scores and number of ED visits. Additional outpatient off-label use has been investigated in opioid-naïve patients with cancer, moderate to severe osteoarthritis with an inadequate response to weak opioid analgesic therapy, and pain associated with sickle cell anemia. The use of fentanyl patches in opioid-naïve patients with cancer is contraindicated, but two studies demonstrated successful use in this patient population. Short-term treatment with transdermal fentanyl significantly improved pain and functionality in patients with moderate to severe pain due to knee or hip osteoarthritis in two trials. However, opioid medications are conditionally recommended against for use in patients with osteoarthritis of the knee, hand, or hip while recognizing use may be appropriate when alternative options have failed. Current recommendations for the management of pain in sickle cell disease recommend against the use of chronic opioid therapy (COT) in children and adults unless the pain is refractory to multiple other therapies. Shared decision making should be used to determine the continuation of COT in patients who are well functioning and receiving a perceived benefit in therapy. Continuation of COT is not recommended in patients who are functioning poorly or are at high risk for opioid abuse or toxicity7, 17-19.

1.1.8. Dosage Limits

The lowest effective fentanyl transmucosal, buccal, intranasal, or sublingual dose should be administered to patients with renal or hepatic dysfunction, as well as those patients receiving concurrent CYP3A4 inhibitor drugs.

Patient profiles containing prescriptions for greater than 6 units of fentanyl oral transmucosal lozenges during a transition phase will be reviewed. Patient profiles containing prescriptions for more than one strength of buccal, nasal, sublingual, or transmucosal fentanyl concurrently for greater than two months will be reviewed.  Patient profiles containing prescriptions for greater than four doses per day of fentanyl intranasal spray or fentanyl sublingual tablets will be reviewed. Patient profiles documenting treatment of more than 4 breakthrough episodes daily with fentanyl buccal, transmucosal, or sublingual dosage forms will be reviewed (see Table 61-11)1-5, 7-11.

Table 6: Adult Maximum Oral/Intranasal/Transdermal Fentanyl Dosages

Fentanyl Dosage Form Dosage Strengths Maximum Dose
buccal tablet (Fentora®, generic) 100 mcg, 200 mcg, 400 mcg, 600 mcg, or 800 mcg per tablet 800 mcg/dose; no more than 4 tablets at one time per breakthrough episode, and no more than 2 doses per breakthrough pain episode; if more than 4 breakthrough episodes per 24 hours occur once maintenance dose determined, long-acting opioid dose should be re-evaluated
intranasal spray (Lazanda®) 100 mcg, 300 mcg, or 400 mcg per actuation 800 mcg/dose; if more than 4 breakthrough episodes per 24 hours occur once maintenance dose determined, long-acting opioid dose should be re-evaluated
sublingual tablet (Abstral®) 100 mcg, 200 mcg, 300 mcg, 400 mcg, 600 mcg, or 800 mcg per tablet 800 mcg/dose; no more than 4 tablets at one time per breakthrough episode, and no more than 2 doses per breakthrough pain episode; if more than 4 breakthrough episodes per 24 hours occur once maintenance dose determined, long-acting opioid dose should be re-evaluated
sublingual spray (Subsys®) 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, or 1600 mcg per spray 1600 mcg/dose; no more than 2 doses per breakthrough pain episode; if more than 4 breakthrough episodes per 24 hours occur once maintenance dose determined, long-acting opioid dose should be re-evaluated
transmucosal lozenge (Actiq®, generic) 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, or 1600 mcg per lozenge no more than 2 units/lozenges per breakthrough pain episode; no more than 4 lozenge units/day; if more than 4 breakthrough episodes per 24 hours occur once maintenance dose determined, long-acting opioid dose should be re-evaluated 
transdermal patch (Duragesic®, generic) 12 mcg/hr, 25 mcg/hr, 37.5 mcg/hr, 50 mcg/hr, 75 mcg/hr, 100 mcg/hr maximum dose not identified; dosages titrated every 3 days after initial dose, then every 6 days thereafter; most patients controlled with every 72 hour administration; a small percentage require every 48 hour administration

1.2. Pediatrics

Fentanyl citrate transmucosal lozenges are FDA-approved for use in adolescents 16 years and older. Fentanyl transdermal patch is FDA-approved for use to manage chronic severe pain in opioid-tolerant pediatric patients 2 years of age and older requiring around-the-clock opiate therapy. Fentanyl nasal spray as well as oral fentanyl buccal tablet, sublingual spray, and sublingual tablet safety and efficacy have not been established in patients below 18 years of age. Pediatric fentanyl maximum dosage recommendations are summarized in Table 71-11.

Although not FDA-approved, oral fentanyl citrate has been studied in non-opioid tolerant patients as young as 2 years of age for various indications including surgical procedure pain, wound dressing changes in burn patients, and sedation in single doses ranging from 10-20 mcg/kg given prior to procedures with mixed efficacy rates. Similarly, intranasal fentanyl has been effectively utilized in pediatric patients as young as 6 months of age for non-FDA approved uses (e.g., analgesia, burns, postoperatively) at doses of 1-2 mcg/kg with success20-29.

Table 7: Pediatric Maximum Transmucosal/Transdermal Fentanyl Dosages

Fentanyl Dosage Form Dosage Strengths Maximum Dose
transmucosal lozenge (Actiq®, generic) 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, or 1600 mcg per lozenge 16 years and older: no more than 2 units/lozenges per breakthrough pain episode; no more than 4 lozenge units/day; if more than 4 breakthrough episodes per 24 hours occur once maintenance dose determined, long-acting opioid dose should be re-evaluated
transdermal patch (Duragesic®, generic) 12 mcg/hr, 25 mcg/hr, 37.5 mcg/hr, 50 mcg/hr, 75 mcg/hr, 100 mcg/hr 2 years and older: maximum dose not identified; dosages titrated every 3 days after initial dose, then every 6 days thereafter

1.3. Opioid Reversal Agents

Naloxone is an opioid receptor antagonist that is FDA approved for reversal of opioid-induced respiratory and central nervous system depression. Naloxone is supplied as a nasal spray marketed as Narcan® 4 mg/0.1 mL nasal spray, Kloxxado® 8 mg/ 0.1 mL nasal spray, Evzio® 0.4 mg/ 0.4 mL auto-injector solution for injection, LifEMS Naloxone® 2 mg/2 mL solution for injection, and generic formulations of the solution for injection are available.

In July of 2020 the U.S. Food and Drug Administration made the recommendations that healthcare professionals should discuss the availability of naloxone products and consider prescribing naloxone to patients who are prescribed opioid pain relievers and are at increased risk of opioid overdose. Patients at risk of opioid overdose include patients who are co-prescribed benzodiazepines or other drugs that depress the central nervous system, patients with a history of opioid use disorder (OUD), or who have experienced a previous opioid overdose. Healthcare professionals should also consider prescribing naloxone to patients who have other household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. In 2016, the state of Texas, in association with the Texas Pharmacy Association, obtained a physician-signed standing order that allows pharmacists to dispense naloxone products to patients after completing Texas-accredited training. This allows for the sale and possession of naloxone products without a prescription in the state of Texas30-35.

2. Duration of Therapy

Therapy duration for fentanyl oral transmucosal lozenges, fentanyl buccal tablets, fentanyl sublingual tablets, fentanyl sublingual spray, fentanyl nasal spray, and fentanyl transdermal patches is limited to the need for pain management in patients with cancer already receiving opioids and tolerant to opioid therapy1-11.

3. Duplicative Therapy

Concurrent therapy with fentanyl oral transmucosal lozenges, buccal tablets, sublingual tablets, sublingual spray, or nasal spray and other forms of fentanyl as well as other CNS depressants should be prescribed cautiously, if at all. If concurrent therapy is necessary, patients should be monitored for signs of respiratory depression as well as excessive sedation1-11.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for fentanyl are summarized in Table 8. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed1-11, 36.

Table 8: Fentanyl Drug-Drug Interactions

Interacting Drug Interaction Recommendation Clinical Significance Level#
amiodarone concurrent use may result in cardiac toxicity (e.g., bradycardia, low cardiac output) and increased risk of fentanyl toxicity (e.g., respiratory and CNS depression) as amiodarone inhibits CYP3A4 if combination utilized, monitor patients closely for enhanced pharmacologic/toxic effects major (DrugReax) 3-moderate (CP)
CNS depressants (e.g., skeletal muscle relaxants,  haloperidol, other opioids) potential for additive CNS effects, including respiratory depression, excessive sedation or coma     use cautiously together; modify fentanyl doses as necessary and observe patients for enhanced CNS adverse effects major (DrugReax) 2-major (CP)
CYP3A4 inducers (e.g., rifampin, barbiturates, carbamazepine, phenytoin, aprepitant, efavirenz) may increase fentanyl clearance and reduce fentanyl systemic concentrations leading to decrease effectiveness as fentanyl is a CYP3A4 substrate monitor fentanyl efficacy in patients prescribed CYP3A4 inducers concurrently; adjust doses as necessary when CYP3A4 inducer added, deleted, or changed to therapeutic regimen moderate (DrugReax) 2-major, 3-moderate (CP)
CYP3A4 inhibitors (e.g., aprepitant, protease inhibitors, macrolides, azole antifungals, efavirenz) may decrease fentanyl clearance and increase fentanyl systemic concentrations leading to potential for enhanced pharmacologic/toxic effects as fentanyl is a CYP3A4 substrate monitor for enhanced fentanyl pharmacologic/toxic effects and adjust doses as necessary strong inhibitors - contraindicated, inhibitors - major  (DrugReax) 2-major, 3-moderate (CP)
MAOIs (e.g., phenelzine, procarbazine, linezolid) concurrent administration may potentiate severe, unpredictable opioid effects including CNS depression and hypotension fentanyl should not be prescribed during or within 14 days of MAOI administration major (DrugReax) 2-major (CP)
mifepristone adjunctive administration may result in increased fentanyl serum levels and the potential for enhanced pharmacologic/ serious adverse effects as fentanyl is a CYP3A4 substrate and mifepristone is a CYP3A4 inhibitor avoid concurrent administration contraindicated (DrugReax) 1-severe (CP)
nasal decongestants (e.g., oxymetazoline) and intranasal fentanyl combined administration of intranasal fentanyl with vasoconstrictive nasal decongestants results in reduced fentanyl absorption through the nasal mucosa, reduced Cmax and delayed Tmax, and the potential for reduced effectiveness in pain management use combination cautiously; avoid intranasal fentanyl dose titration in patients using vasoconstrictive decongestants as inappropriate maintenance dose may be calculated; interaction does not occur with other fentanyl dosage forms 2-major (CP)
opioid antagonists (e.g., naloxone, naltrexone) may precipitate withdrawal symptoms and/or decrease fentanyl effectiveness use with caution only when necessary and monitor for signs of fentanyl withdrawal/loss of efficacy naltrexone: contraindicated (DrugReax) 2-major (CP)
serotonergic agents (e.g., selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors) concurrent use increases risk for serotonin syndrome or neuroleptic malignant syndrome-like reactions as both agents have serotonergic properties administer cautiously together; observe for signs/symptoms of serotonin syndrome (e.g., agitation, confusion, hyperthermia, shivering) major (DrugReax) 2-major (CP)

Legend:

  • #CP = Clinical Pharmacology
  • CNS = central nervous system
  • Cmax = maximum serum concentration
  • CYP = cytochrome P450
  • MAOIs = monoamine oxidase inhibitors
  • Tmax = time when maximum serum concentration is reached

5. References

  1. Fentanyl citrate oral transmucosal lozenge (Actiq®) package insert. Cephalon, Inc. March 2021.
  2. Fentanyl buccal tablet (Fentora®) package insert. Cephalon, Inc. March 2021.
  3. Fentanyl sublingual tablets (Abstral®) package insert. Sentynl Therapeutics, Inc., December 2019.
  4. Fentanyl sublingual spray (Subsys®) package insert. Insys Therapeutics, Inc., May 2021.
  5. Fentanyl nasal spray (Lazanda®) package insert. West Therapeutic Development, LLC, March 2021.
  6. Fentanyl transdermal system (Duragesic®) package insert. Janssen Pharmaceuticals, Inc., July 2021.
  7. DRUGDEX® System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu/. Accessed November 18, 2021.
  8. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed November 18, 2021.
  9. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021. Available at: https://fco-factsandcomparisons-com.ezproxy.lib.utexas.edu. Accessed November 18, 2021. 
  10. American Society of Health-System Pharmacists. 2021. AHFS Drug Information® - 2021st Ed. Bethesda, MD. American Society of Health-System Pharmacists®. STAT!Ref Online Electronic Medical Library. Available at: https://online.statref.com/document/cQfe8yqMRNqgSGqm4Qo8Qj. Accessed November 18, 2021.
  11. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; November 18, 2021.
  12. Christie JM, Simmonds M, Patt R, et al. Dose-titration, multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. J Clin Oncol. 1998;16:3238-45.
  13. Mystakidou K, Katsouda E, Parpa E, Tsiatas ML, Vlahos L. Oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients:  an overview of its pharmacological and clinical characteristics. Am J Hosp Palliat Care. 2005;22:228-32.
  14. Coluzzi PH, Schwartzberg L, Conroy JD, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain. 2001;91:123-30.
  15. Burton AW, Drive LC, Mendoza TR, Syed G. Oral transmucosal fentanyl citrate in the outpatient management of severe cancer pain crises. A retrospective case series. Clin J Pain. 2004;20:195-7.
  16. CDC guideline for prescribing opioids for chronic pain — united states, 2016. MMWR Recomm Rep. 2016;65.
  17. Oral transmucosal fentanyl citrate used to reduce emergency department visits in migraine patients: a prospective open label trial. [abstract]. Pain Medicine. 2003:4:104. Abstract no. 536
  18. Landy SH. Oral transmucosal fentanyl citrate for the treatment of migraine headache pain in outpatients: a case series. Headache. 2004;44:762-6.
  19. Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4(12):2656-2701.
  20. Binstock W, Rubin R, Bachman C, et al. The effect of premedication with OTFC, with or without ondansetron, on postoperative agitation and nausea and vomiting in pediatric ambulatory patients. Paediatr Anaesth. 2004;14:759-67.
  21. Dsida RM, Wheeler M, Birmingham PK, et al. Premedication of pediatric tonsillectomy patients with oral transmucosal fentanyl citrate. Anesth Analg. 1998;86:66-70.
  22. Epstein RH, Mendel HG, Witkowski TA, et al. The safety and efficacy of oral transmucosal fentanyl citrate for preoperative sedation in young children.  Anesth Analg. 1996;83:1200-5.
  23. Howell, TK, Smith S, Rushman SC, et al. A comparison of oral transmucosal fentanyl and oral midazolam for premedication in children. Anaesthesia. 2002;57:798-805.
  24. Mahar PJ, Rana JA, Kennedy CS, et al. A randomized clinical trial of oral transmucosal fentanyl citrate versus intravenous morphine sulfate for initial control of pain in children with extremity injuries. Pediatr Emerg Care. 2007;23:544-8.
  25. Robert R, Brack A, Blakeney P, et al. A double-blind study of the analgesic efficacy of oral transmucosal fentanyl citrate and oral morphine in pediatric patients undergoing burn dressing change and tubbing. J Burn Care Rehabil. 2003;24:351-355.
  26. Schechter NL, Weisman SJ, Rosenblum M, et al. The use of oral transmucosal fentanyl citrate for painful procedures in children. Pediatrics. 1995;95:335-9.
  27. Sharar SR, Bratton SL, Carrougher GJ, et al. A comparison of transmucosal fentanyl citrate and oral hydromorphone for inpatient pediatric burn wound care analgesia. J Burn Care Rehabil. 1998;19:516-21.
  28. Sharar SR, Carrougher GJ, Selzer K, et al. A comparison of oral transmucosal fentanyl citrate and oral oxycodone for pediatric outpatient wound care. J Burn Care Rehabil. 2002;23:27-31.
  29. Mudd S. Intranasal fentanyl for pain management in children: a systematic review of the literature. J Pediatr Health Care. 2011;25:316-322.
  30. Naloxone hydrochloride (Narcan®) 4 mg/ 0.1 mL nasal spray package insert. Emergent Devices Inc., March 25, 2021. 
  31. Naloxone hydrochloride (Kloxxado®) 8 mg/ 0.1 mL nasal spray package insert. Hikma Specialty USA Inc., April 2021.
  32. Naloxone hydrochloride (Evzio®) 0.4 mg/ 0.4 mL pre-filled syringe autoinjector package insert. HF Acquisition Co LLC, DBA HealthFirst, February 2020.
  33. Naloxone hydrochloride (LifEMS®) 2 mg/ 2 mL solution for injection convenience kit package insert. Lifsa Drugs LLC, November 2020.
  34. U.S. Food and Drug Administration. FDA recommends health care professionals discuss naloxone with all patients when prescribing opioid pain relievers or medicines to treat opioid use disorder. FDA Drug Safety Communication. Published online July 23, 2020. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-health-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioid-pain. Accessed November 19th, 2021.
  35. Texas Pharmacy Association. Texas pharmacist naloxone standing order application. October 2016. Available at: https://www.texaspharmacy.org/page/TXPHARMNALOX. Accessed November 19th, 2021.
  36. Turkel SB, Nadala JGB, Wincor MZ. Possible serotonin syndrome in association with 5-HT3 antagonist agents. Psychosomatics. 2001;42:258-260.

Fluoroquinolones (oral)

Last Updated

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Vendor Drug Program formulary coverage.

  • Revision history
    • July 2022, June 2020; May 2018; Nov. 2015; Feb. 2014; June 2012; Oct. 2010; Sept. 2007; May 2007; Sept. 2006; Aug. 2006; Aug. 2003; Sept. 2002; Sept. 2001; Aug. 2000; Nov. 1999; Oct. 1999; Sept. 1999; Sept. 1998; Sept. 1997.
  • Initially developed
    • Oct. 1996

1.1. Adults

Maximum recommended adult daily doses for fluoroquinolones are summarized in Table 1. Prescribed dosages exceeding these recommendations will be reviewed.

Table 1. Adult Oral Fluoroquinolone Maximum Dosage Recommendations1-9
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage 
ciprofloxacin (Cipro®, generics) immediate-release (IR)#: 100 mg, 250 mg, 500 mg, 750 mg tablets; 250 mg/5 mL, 500 mg/5 mL suspension acute sinusitis 500 mg twice daily
    bone and joint infections 750 mg twice daily
    chronic bacterial prostatitis 500 mg twice daily
    complicated intra-abdominal infections (in combination with metronidazole) 500 mg twice daily
    complicated, uncomplicated skin/skin structure infections 750 mg twice daily
    infectious diarrhea 500 mg twice daily
    inhalational anthrax (post-exposure) 500 mg twice daily
    lower respiratory tract infections 750 mg twice daily
    moderate, complicated urinary tract infection (UTI) 500 mg twice daily
    plague 1500 mg/day
    typhoid fever 500 mg twice daily
    uncomplicated cervical, urethral gonococcal infections* 250 mg as single dose
    Uncomplicated UTI 250 mg twice daily
ciprofloxacin (Cipro® XR, generics) extended-release (ER)#:  500 mg, 1000 mg tablets acute uncomplicated pyelonephritis 1000 mg/day
    complicated UTI 1000 mg/day
    uncomplicated UTI 500 mg/day
delafloxacin (Baxdela®) 450 mg tablets acute bacterial skin/skin structure infections 450 mg twice daily
    community acquired bacterial pneumonia (CABP) 450 mg twice daily
gemifloxacin (Factive®) 320 mg tablets chronic bronchitis (acute bacterial exacerbation) 320 mg daily
    Community acquired pneumonia (CAP) 320 mg daily
levofloxacin (Levaquin®, generics) 250 mg, 500 mg, 750 mg tablets, 25 mg/mL solution acute bacterial sinusitis 750 mg once daily
    acute pyelonephritis 750 mg once daily
    chronic bacterial prostatitis 500 mg once daily
    chronic bronchitis (acute bacterial exacerbation) 500 mg once daily
    CAP 750 mg once daily
    complicated skin/skin structure infections 750 mg once daily
    inhalational anthrax 500 mg once daily
    mild/moderate complicated UTI 750 mg once daily
    nosocomial pneumonia 750 mg/day
    plague or plague prophylaxis 500 mg once daily
    uncomplicated skin/skin structure infections 500 mg once daily
    uncomplicated UTI 250 mg once daily
moxifloxacin (Avelox®, generics) 400 mg tablets acute bacterial sinusitis 400 mg once/day
    chronic bronchitis (acute bacterial exacerbation) 400 mg once/day
    CAP 400 mg once/day
    complicated intra-abdominal infections 400 mg once/day
    complicated skin/skin structure infections 400 mg once/day
    plague or plague prophylaxis 400 mg once/day
    uncomplicated skin/skin structure infections 400 mg once/day
ofloxacin (generics) 200 mg, 300 mg, 400 mg tablets acute pelvic inflammatory disease (PID)^ 400 mg twice daily
    acute, uncomplicated urethral, cervical gonorrhea* 400 mg as single dose
    chronic bronchitis (acute bacterial exacerbation) 400 mg twice daily
    CAP 400 mg twice daily
    complicated UTI 200 mg twice daily
    mixed infection of urethra, cervix due to C. trachomatis and N. gonorrhoeae* 300 mg twice daily
    nongonococcal cervicitis/urethritis due to Chlamydia trachomatis 300 mg twice daily
    prostatitis due to E. coli 300 mg twice daily
    uncomplicated cystitis due to E. coli or K. pneumoniae 200 mg twice daily
    uncomplicated cystitis due to other organisms 200 mg twice daily
    uncomplicated skin and skin structure infections 400 mg twice daily

Legend:

  • # ciprofloxacin immediate-release and extended-release tablets are not interchangeable
  • * CDC no longer recommends fluoroquinolones for treatment of infections due to N. gonorrhoeae
  • ^ CDC no longer recommends fluoroquinolones for treating PID; may be considered in combination with metronidazole if parenteral therapy not feasible

1.2. Pediatrics

Fluoroquinolones are not drugs of choice in pediatric patients due to an increased incidence of musculoskeletal adverse reactions, including arthralgias and events related to surrounding joints and tissues10. However, ciprofloxacin and levofloxacin have been evaluated for use in pediatric patients and are FDA-approved for use in select circumstances. Recommended dosage guidelines for fluoroquinolones in pediatric patients are summarized in Table 2.

Table 2. Fluoroquinolone Recommended Dosage Guidelines in Pediatric Patients1-3,7
Drug Name Treatment Indication Maximum Recommended Dosage 
ciprofloxacin complicated urinary tract infection (UTI) or pyelonephritis 10-20 mg/kg orally every 12 hours (not to exceed 750 mg/dose)
  inhalational anthrax (postexposure prophylaxis) 15 mg/kg orally every 12 hours (not to exceed 500 mg/dose)
  plague 15 mg/kg orally every 8-12 hours (not to exceed 500 mg/dose)
levofloxacin inhalational anthrax (postexposure prophylaxis)

Greater than or equal to 6 months of age and less than 50 kg: 8 mg/kg orally every 12 hours (not to exceed 250 mg/dose)

Greater than or equal to 6 months of age and greater than 50 kg: 500 mg orally once daily

  plague

Greater than or equal to 6 months of age and less than 50 kg: 8 mg/kg orally every 12 hours (not to exceed 250 mg/dose)

Greater than or equal to 6 months of age and greater than 50 kg: 500 mg orally once daily

2. Duration of Therapy

Therapy duration for antibiotics like fluoroquinolones is based on the type and severity of infection. Recommendations for usual or documented therapy durations for adults are summarized in Table 3. However, severe or complicated infections may require prolonged therapy.

Table 3. Adult Oral Fluoroquinolone Maximum Recommended Therapy Duration1-9
Drug Name Treatment Indication Maximum Therapy Duration
ciprofloxacin, IR acute sinusitis 10 days
  bone and joint infections 4 to 8 weeks
  chronic bacterial prostatitis 28 days
  complicated intra-abdominal infections (in combination with metronidazole) 7 to 14 days
  complicated, uncomplicated skin/skin structure infections 7 to 14 days
  infectious diarrhea 5 to 7 days
  inhalational anthrax (post-exposure) 60 days
  lower respiratory tract infections 7 to 14 days
ciprofloxacin, IR or ER moderate, complicated UTI 7 to 14 days
Ciprofloxacin, IR typhoid fever 10 days
  uncomplicated cervical, urethral gonococcal infections* single dose
ciprofloxacin, IR or ER uncomplicated UTI 3 days
delafloxacin acute bacterial skin/skin structure infections 5-14 days
  community acquired bacterial pneumonia (CABP) 5-10 days
gemifloxacin chronic bronchitis (acute bacterial exacerbation) 5 days
  CAP 5 to 7 days
levofloxacin acute bacterial sinusitis 10 to 14 days (500 mg dose); 5 days (750 mg dose)
  acute pyelonephritis 10 days (250 mg dose); 5 days (750 mg dose)
  chronic bacterial prostatitis 28 days
  chronic bronchitis (acute bacterial exacerbation) 7 days
  CAP 7 to 14 days (500 mg dose); 5 days (750 mg dose)
  complicated skin/skin structure infections 7 to 14 days (750 mg dose)
  inhalational anthrax 60 days+
  mild/moderate complicated UTI 10 days (250 mg dose); 5 days (750 mg dose)
  hospital acquired pneumonia 7 to 14 days
  plague or plague prophylaxis 10 to 14 days (500 mg dose; 750 mg dose considered if clinically warranted)
  uncomplicated skin/skin structure infections 7 to 10 days (500 mg dose)
  uncomplicated UTI 3 days (250 mg dose)
moxifloxacin acute bacterial sinusitis 10 days (5 to 7 days IDSA guidelines)
  chronic bronchitis (acute bacterial exacerbation) 5 days
  CAP 7 to 14 days
  complicated intra-abdominal infections 5 to 14 days
  complicated skin/skin structure infections 7 to 21 days
  plague or plague prophylaxis 10 to 14 days
  uncomplicated skin/skin structure infections 7 days
ofloxacin acute pelvic inflammatory disease (PID) 10 to 14 days^
  acute, uncomplicated urethral, cervical gonorrhea* (400 mg dose) 1 day
  chronic bronchitis (acute bacterial exacerbation) 10 days
  CAP 10 days
  complicated UTI 10 days
  mixed infection of urethra, cervix due to C. trachomatis and N. gonorrhoeae* 7 days
  nongonococcal cervicitis/urethritis due to Chlamydia trachomatis 7 days
  prostatitis due to E. coli 6 weeks
  uncomplicated cystitis due to E. coli or K. pneumoniae 3 days
  uncomplicated cystitis due to other organisms 7 days
  uncomplicated skin and skin structure infections 10 days

Legend:

  • +Levofloxacin safety greater than 28 days in adults and greater than 14 days in pediatric patients to manage anthrax has not been studied; use for greater than 28 days in adults and greater than 14 days in pediatrics when benefits outweigh risks
  • * CDC no longer recommends fluoroquinolones for treatment of infections due to N. gonorrhoeae
  • ^CDC no longer recommends fluoroquinolones for treating PID; may be considered in combination with metronidazole if parenteral therapy not feasible

Fluoroquinolone therapy duration in pediatric patients is summarized in Table 4.

Table 4. Pediatric Oral Fluoroquinolone Maximum Recommended Therapy Duration1-3,7

 

Drug Name

Treatment Indication Maximum Therapy Duration
ciprofloxacin UTI, pyelonephritis 10 to 21 days
  inhalational anthrax (postexposure prophylaxis) 60 days
  plague 14 days
levofloxacin inhalational anthrax (postexposure prophylaxis) 60 days+
  plague 10 to 14 days

Legend:

  • UTI = urinary tract infection
  • +Levofloxacin safety when used for longer than 14 days in pediatric patients has not been studied; use for greater than 14 days when benefit outweighs risk

3. Duplicative Therapy

The adjunctive use of two or more fluoroquinolones is not recommended. Additional therapeutic benefit is not realized when fluoroquinolones are administered in combination. Patient profiles containing concurrent prescriptions for multiple fluoroquinolones will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for oral fluoroquinolones are summarized in Table 5. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 5. Oral Fluoroquinolone Drug-Drug Interactions2-9
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level#
ciprofloxacin drugs metabolized by CYP1A2 (e.g., alosetron, caffeine, clozapine, duloxetine, mexiletine, ropinirole, tizanidine) concurrent administration ciprofloxacin, a known CYP1A2 inhibitor, with drugs metabolized by CYP1A2 may result in increased serum levels of drugs metabolized by CYP1A2 and potentially increased pharmacologic/adverse effects if combination necessary, monitor for increased adverse effects; alternative FQ that does not affect CYP1A2 enzymes may be considered contraindicated,  major, moderate (DrugReax) 2-major, 3-moderate (CP)
ciprofloxacin methotrexate co-administration may result in reduced methotrexate renal tubular transport and potential for increased methotrexate levels and increased pharmacologic/adverse effects measure methotrexate concentrations and observe patients for increased adverse effects moderate (DrugReax) 3-moderate (CP)
ciprofloxacin mycophenolate concurrent administration may decrease mycophenolic acid concentrations monitor response to therapy when ciprofloxacin is started or stopped moderate (DrugReax) 3-moderate (CP)
ciprofloxacin phenytoin concurrent use may result in increased or decreased phenytoin concentrations ; mechanism unknown measure phenytoin concentrations and observe patients for increased or decreased pharmacologic  effects moderate (DrugReax) 3-moderate (CP)
ciprofloxacin phosphodiesterase type 5 (PDE5) inhibitors concurrent administration may increase PDE5 inhibitor plasma levels and risk of adverse reactions during coadministration, consider lower dose of PDE5 inhibitor or withholding PDE5 inhibitor in patients at high risk of developing PDE5 inhibitor adverse reactions moderate (DrugReax)
ciprofloxacin probenecid co-administration may result in increased serum ciprofloxacin levels due to probenecid inhibition of renal tubular secretion monitor patients for increased ciprofloxacin adverse effects moderate (DrugReax) 4-minor (CP)
ciprofloxacin theophyllines adjuvant administration may result in decreased theophylline clearance and potential for increased serum theophylline levels and enhanced pharmacologic/toxic effects as ciprofloxacin interferes with theophylline clearance if adjunctive therapy necessary, closely monitor theophylline levels and observe for increased adverse effects; may consider alternative FQ that does not interfere with theophylline clearance major (DrugReax) 3-moderate (CP)
ciprofloxacin tizanidine (Ziaflex®) combined administration may result in enhanced tizanidine pharmacologic effects and/or adverse effects (e.g., sedation, hypotension) due to ciprofloxacin inhibition of CYP1A2-mediated tizanidine metabolism avoid concurrent administration; use alternative spasticity medication contraindicated  (DrugReax) 1-severe (CP)
fluoroquinolones (FQ) antacids simultaneous administration may result in reduced absorption/bioavailability and clinical effectiveness of the FQ due to chelation of the antacid cations with the quinolone molecule avoid concurrent administration; give FQ 2 hours before or 6 hours after giving antacids; may consider H2 receptor antagonist as alternative to antacids (e.g., ranitidine) in some clinical situations moderate (DrugReax) 2-major (CP)
FQ antidiabetic agents adjunctive administration may result in altered blood glucose levels and increased risk for hypo- or hyperglycemia monitor serum glucose levels closely with concurrent administration major (DrugReax) 3-moderate (CP)
FQ corticosteroids concurrent therapy may increase risk for tendon rupture, especially in patients over 60 years of age discontinue FQ therapy with any signs of tendon inflammation or pain moderate (DrugReax) 3-moderate (CP)
FQ didanosine (Videx®) oral solution didanosine buffers consist of magnesium-aluminum cations; concomitant administration with FQ may result in reduced FQ absorption/ bioavailability and clinical effectiveness due to chelation of the antacid cations with the quinolone molecule avoid concurrent administration; give FQ 2 hours before or 6 hours after giving didanosine moderate (DrugReax) 2-major (CP)
FQ iron salts (including iron in multivitamins) iron salts may bind FQ in GI tract forming insoluble, unabsorbable complexes with resultant reduced FQ serum concentrations/pharmacologic effects avoid concurrent administration; give FQ 2 hours before or 6 hours after giving drugs containing iron moderate (DrugReax) 2-major (CP)
FQ nonsteroidal anti-inflammatory drugs (NSAIDs) concurrent administration may increase risk of central nervous system (CNS) stimulation and convulsive seizures administer cautiously together and monitor patients closely for increased CNS adverse effects moderate (DrugReax) 3-moderate (CP)
FQ QTc interval-prolonging medications (e.g., class IA, III anti-arrhythmics, tricyclic antidepressants, clozapine, cyclobenzaprine, macrolide antibiotics, cisapride, ziprasidone) concurrent administration may increase risk of significant cardiotoxicity (e.g., life-threatening arrhythmias, cardiac arrest) as FQ may cause QTc interval prolongation and, rarely, torsades de pointes adjunctive administration should be avoided contraindicated, major (DrugReax) 1-severe, 2-major (CP)
FQ sevelamer (Renagel®) concurrent administration may cause decreased FQ bioavailability and potential for reduced pharmacologic effects avoid concurrent administration; administer FQ 1 hour before or 3 hours after sevelamer moderate (DrugReax) 2-major (CP)
FQ sucralfate concurrent administration may result in decreased FQ efficacy due to FQ chelation by sucralfate in GI tract avoid concurrent administration; give FQ 2 hours before or 6 hours after giving sucralfate moderate (DrugReax) 2-major (CP)
FQ warfarin concomitant administration may result in enhanced hypoprothrombinemic effects and increased bleeding risk;  mechanism of this interaction not identified; changes in PT/INR may occur 2-16 days after addition of FQ to warfarin therapy if combination cannot be avoided, monitor PT/INR closely and observe for increased adverse effects major (DrugReax) 2-major (CP)
FQ zinc salts, calcium zinc salts or calcium may bind FQ in GI tract forming insoluble, unabsorbable complexes with resultant reduced FQ serum concentrations/ pharmacologic effects avoid concurrent administration; give FQ 2 hours before or 6 hours after giving drugs containing zinc moderate (DrugReax)
select FQ (ciprofloxacin, levofloxacin) cyclosporine adjunctive administration has resulted in transiently increased serum creatinine levels and/or increased cyclosporine levels monitor serum creatinine and cyclosporine levels; observe patients for cyclosporine adverse effects moderate (DrugReax)

5. References

  1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2022. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu. Accessed May 17th, 2022.
  2. IBM Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu/  (cited: May 17th, 2022).
  3. Ciprofloxacin tablets (Cipro®) package insert. Bayer Healthcare Pharmaceuticals, Inc., November 2021.
  4. Ciprofloxacin extended-release tablets (Cipro® XR) package insert. Mylan Pharmaceuticals, Inc., May 2019.
  5. Delafloxacin tablets (Baxdela®) package insert. Melinta Therapeutics, LLC. June 2021.
  6. Gemifloxacin tablets (Factive®) package insert. Merus Labs International, Inc., August 2016.
  7. Levofloxacin tablets (Levaquin®) package insert. Cipla USA Inc., July 2020.
  8. Moxifloxacin tablets (Avelox®) package insert. Bayer Healthcare Pharmaceuticals Inc., July 2016.
  9. Ofloxacin tablets package insert. Dr. Reddy’s Laboratories Limited, December 2018.
  10. Jackson MA, Schutze GE, for the Committee on Infectious Diseases. The use of systemic and topical fluoroquinolones. Pediatrics. 2016;138(5):e1-e13 (doi: 10.1542/peds.2016-2706).

Gabapentin

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • Jan. 2022, Nov. 2019; Nov. 2017; Sept. 2015; Dec. 2013; Jan. 2012; Dec. 2011; April 2010; Aug. 2006.
  • Initially developed
    • June 2006

1.1. Adults

Gabapentin (Neurontin®, Gralise®) is FDA-approved for use in adults with postherpetic neuralgia pain and as adjunctive therapy for managing partial seizures with or without secondary generalization in epileptic patients.1-6 Gabapentin enacarbil (Horizant®) has been FDA-approved for management of moderate-to-severe restless legs syndrome (RLS) in adults, and is also approved for pain reduction in postherpetic neuralgia (PHN).1-4, 7 Gralise® and Horizant® are not interchangeable with Neurontin® and available generics due to differing chemical forms and pharmacokinetic properties. Maximum recommended adult dosages are summarized in Table 11-7. The maximum time interval between gabapentin immediate-release doses should not exceed 12 hours. Patient profiles containing doses that exceed the maximum recommended dose will be reviewed1-15.

While not FDA-approved, gabapentin has also been evaluated in adult clinical trials for use in neuropathic pain, fibromyalgia, and vasomotor symptoms with favorable results1-3.

Table 1: Maximum Recommended Adult Gabapentin Dosages

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
Partial seizures with/without secondary generalized tonic-clonic seizures gabapentin (Neurontin®, generics) 100 mg, 300 mg, 400 mg immediate-release (IR) capsules 600 mg, 800 mg IR tablet 250 mg/5 mL, 300 mg/ 6 mL oral solution 2400 mg/day (in three divided doses*)
Postherpetic neuralgia-associated neuropathic pain gabapentin (Neurontin®, generics) 100 mg, 300 mg, 400 mg IR capsules 600 mg, 800 mg IR tablet 250 mg/5 mL, 300 mg/ 6 mL oral solution 3600 mg daily in divided doses+
Postherpetic neuralgia-associated neuropathic pain gabapentin (Gralise®) 300 mg, 600 mg extended-release (ER) tablets 1800 mg once daily
Postherpetic neuralgia-associated neuropathic pain gabapentin enacarbil (Horizant®) 300 mg, 600 mg ER tablet 1200 mg daily in two divided doses
Restless legs syndrome gabapentin enacarbil (Horizant®) 300 mg, 600 mg ER tablet 600 mg daily at 5 pm^

Legend:

  • *Doses of 3600 mg/day have also been well tolerated in small numbers of patients for abbreviated treatment durations.
  • +Doses up to 3600 mg/day have been administered with therapeutic effect; however, additional benefit with doses greater than 1800 mg/day may not be observed.
  • ^Gabapentin enacarbil doses up to 1200 mg daily have been used in clinical trials with no additional benefit and increased adverse reactions.

1.2. Pediatrics

Gabapentin is FDA-approved for use as adjunctive therapy for partial seizures with or without generalization in pediatric epileptic patients 12 years of age and older, as well as adjunctive therapy for partial seizures in pediatric patients 3 years to 12 years of age1-5. Gabapentin extended-release formulations are not approved for use in pediatric patients as safety and efficacy in this patient population have not been established1-4, 6, 7. Maximum recommended pediatric gabapentin dosages are summarized in Table 25. The maximum time interval between gabapentin doses should not exceed 12 hours. Patient profiles containing gabapentin doses greater than maximum recommendations will be reviewed.

Table 2: Maximum Recommended Pediatric Gabapentin Dosages

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
Partial seizures with/without secondary generalized tonic-clonic seizures gabapentin (Neurontin®, generics) 100 mg, 300 mg, 400 mg immediate-release (IR) capsules
600 mg, 800 mg IR tablet
250 mg/5 mL, 300 mg/ 6 mL oral solution
  • 12 years and older: 2400 mg/day (in three divided doses*)
  • 5-11 years of age: 35 mg/kg/day (in 3 divided doses+)
  • 3-4 years of age:  40 mg/kg/day (in 3 divided doses+)

Legend:

  • +Doses up to 50 mg/kg/day have been well tolerated in an extended clinical trial.
  • *Doses of 3600 mg/day have also been well tolerated in small numbers of patients for abbreviated treatment durations.

1.3. Renal Impairment

Gabapentin dosing guidelines for adult with renal impairment are summarized in Table 3. Dosing guidelines for gabapentin immediate-release are also applicable for adolescents 12 years of age and older with renal impairment. Gabapentin use in pediatric patients younger than 12 years of age with impaired renal function has not been evaluated1-7.

Table 3: Gabapentin Dosage Guidelines in Adults, Adolescents 12 Years of Age and Older with Renal Impairment

  Creatinine Clearance (CrCl) Recommended Dosage Adjustments
Gabapentin immediate-release    
  60 ml/min or greater 900 mg to 3600 mg daily, in three divided doses
  30-59 ml/min 400 mg to 1400 mg daily, in two divided doses
  15-29 ml/min 200 mg to 700 mg once daily
  15 ml/min 100 mg to 300 mg once daily
  Less than less than 15 ml/min daily dose decreased in proportion to CrCl (e.g., CrCl = 7.5 ml/min – administer 50% of dose for CrCl of 15 ml/min)
  anephric patients maintenance doses based on CrCl estimates, with supplemental doses of 125 mg to 350 mg administered after every 4-hour hemodialysis session
Gabapentin extended-release    
Gralise®    
  60 ml/min or greater no dosage adjustment needed – 1800 mg once daily with evening meal
  30 – 59 ml/min 600 mg to 1800 mg once daily with evening meal
  Less than 30 ml/min avoid administering Gralise®
  hemodialysis patients avoid administering Gralise®
Horizant®    
Restless legs syndrome 60 ml/min or greater no dosage adjustment needed
  30 – 59 ml/min start with 300 mg daily with evening meal (~ 5 pm), increasing to 600 mg daily with evening meal as needed
  15-29 ml/min 300 mg daily with evening meal (~ 5 pm) 
  Less than 15 ml/min 300 mg every other day with evening meal (~ 5 pm)
  15-29 ml/min 300 mg daily with evening meal (~ 5 pm) 
  Less than 15 ml/min on hemodialysis Horizant® not recommended for use
Postherpetic neuralgia 60 ml/min or greater no dosage adjustment needed
  30 – 59 ml/min
  • Titration: 300 mg in morning for 3 days
  • Maintenance: 300 mg twice daily; increase to 600 mg twice daily if needed
  • Taper: reduce current maintenance dose to once daily in morning for 1 week before drug discontinuation
  15-29 ml/min
  • Titration: 300 mg in morning on day 1 and day 3
  • Maintenance: 300 mg in morning; increase to 300 mg twice daily if needed
  • Taper: if taking 300 mg twice daily, decrease to 300 mg once daily in morning for 1 week; if taking 300 mg once daily in morning, no taper needed
  Less than 15 ml/min
  • Titration: none
  • Maintenance: 300 mg every other day in morning; increase to 300 mg once daily in morning if needed
  • Taper: none
  Less than 15 ml/min on hemodialysis
  • Titration: none
  • Maintenance: 300 mg following every dialysis; increase to 600 mg after every dialysis if needed
  • Taper: none

2. Duration of Therapy

There is no basis for limiting the duration of gabapentin therapy since patients may suffer from epilepsy or RLS on a chronic basis, and postherpetic neuralgia management may require weeks to months of therapy8.

3. Duplicative Therapy

Gabapentin dosage formulations are not interchangeable due to variations in chemical forms and pharmacokinetic properties. Concurrent administration of two or more gabapentin formulations is not recommended due to lack of additional therapeutic benefit and increased risk of adverse effects. Patient profiles containing concomitant prescriptions for two or more gabapentin dosage formulations for more than two months will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for gabapentin are summarized in Table 41-7. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 4: Gabapentin Drug-Drug Interactions

Interacting Drug Interaction Recommendation Clinical Significance Level #
antacids decreased gabapentin oral availability by approximately 20% administer gabapentin at least two hours after antacids to avoid bioavailability problems moderate (DrugReax) 3-moderate (CP)
hydrocodone potential for decreased hydrocodone peak concentrations and AUC with concomitant gabapentin-hydrocodone administration in dose-dependent fashion; minor increases in gabapentin AUC observe patients for decreased hydrocodone efficacy or additive drowsiness 3-moderate (CP)
morphine concurrent administration may result in increased gabapentin serum levels (gabapentin AUC increased by 44% when morphine 60 mg controlled- release given 2 hours prior to gabapentin 600 mg) monitor patients for increased CNS depression; adjust gabapentin and/or morphine doses as necessary moderate (DrugReax) 3-moderate (CP)

Legend:

  • #CP = Clinical Pharmacology

5. References

  1. DRUGDEX® System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu/. Accessed November 23, 2021.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2017. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed November 23, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021. Available at: https://fco-factsandcomparisons-com.ezproxy.lib.utexas.edu. Accessed November 23, 2021. 
  4. American Society of Health-System Pharmacists. 2021. AHFS Drug Information® - 2021st Ed. Bethesda, MD. American Society of Health-System Pharmacists®. STAT!Ref Online Electronic Medical Library. Available at:  https://online.statref.com/document/cQfe8yqMRNqgSGqm4Qo8Qj. Accessed November 23, 2021. 
  5. Gabapentin (Neurontin®) package insert. Pfizer, October 2021.
  6. Gabapentin extended-release tablets (Gralise®) package insert. Almatica Pharma LLC, February 2021.
  7. Gabapentin enacarbil extended-release tablets (Horizant®) package insert. Arbor Pharmaceuticals, LLC, September 2021.
  8. The US Gabapentin Study Group. The long-term safety and efficacy of gabapentin (Neurontin) as add-on therapy in drug-resistant partial epilepsy. Epilepsy Res. 1994;18(1):67–73. 
  9. Appleton R, Fichtner K, LaMoreaux L, et al. Gabapentin as add-on therapy in children with refractory partial seizures: a 12-week, multicentre, double-blind, placebo-controlled study. Gabapentin Paediatric Study Group. Epilepsia. 1999;40(8):1147–54. 
  10. Marson AG, Kadir ZA, Hutton JL, Chadwick DW. Gabapentin add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev. 2000;(3):CD001415. 
  11. Ortega E. Postherpetic neuralgia. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com (Accessed on November 23, 2021.)
  12. Wiffen PJ, Derry S, Bell RF, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6(6):CD007938. Published 2017 Jun 9. doi:10.1002/14651858.CD007938.pub4.
  13. Johnson RW, Rice AS. Clinical practice. Postherpetic neuralgia. N Engl J Med. 2014;371(16):1526-33. 
  14. Trenkwalder C, Allen R, Högl B, et al. Comorbidities, treatment, and pathophysiology in restless legs syndrome. Lancet Neurol. 2018;17(11):994–1005. doi:10.1016/S1474-4422(18)30311-9.
  15. Kim ES, Deeks ED. Gabapentin enacarbil: a review in restless legs syndrome. Drugs. 2016;76(8):879–87. 

Hepatitis C Direct-Acting Antivirals

Last Updated

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Vendor Drug Program formulary coverage.

Note: This retrospective drug use criteria provides information from each respective therapies FDA approved package insert. Further guidance for patient specific treatments can be found within the continuously updated American Association for the Study of Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA) “HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C” guidelines at www.hcvguidelines.org. It is recommended to consult these guidelines prior to initiating therapy to treat hepatitis C infection.

  • Revision history
    • July 22, 2022
  • Initially developed
    • March 2018

1.1. Adults

Direct acting antivirals (DAA) for hepatitis are FDA-indicated for treatment of chronic infections caused by hepatitis C virus (HCV). Individual agents have varying FDA indications and treatment durations based on genotype (1-6), subtype (1a vs. 1b), liver function, HIV co-infection and/or previous treatment history1.

Table 1 provides DAA information for treatment naïve patients with or without cirrhosis.

Table 1: DAAs for treatment of adult chronic HCV infection: Treatment naïve and patients with or without cirrhosis2-12
Drug Name Dosage Form/Strength Treatment Indication Duration and Coadministration Maximum Recommended Dosage
elbasvir/ grazoprevir (Zepatier®) 50 mg/100 mg tablet

Chronic HCV treatment:

  • genotypes 1a 
    • without cirrhosis or with compensated cirrhosis (Child-Pugh A) with baseline NS5A polymorphisms
16 weeks with ribavirin 50 mg elbasvir and 100 mg grazoprevir once daily
   
  • without cirrhosis or with compensated cirrhosis (Child-Pugh A) without baseline NS5A polymorphisms
12 weeks  
   
  • genotype 1b without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks  
   
  • genotype 4 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks  
glecaprevir/pibrentasvir (Mavyret®) 100 mg/40 mg tablets

Chronic HCV treatment:

  • genotypes 1, 2, 3, 4, 5, and 6 without cirrhosis or with compensated cirrhosis (Child-Pugh A)    
8† weeks 300 mg glecaprevir and 120 mg pibrentasvir once daily
ledipasvir/ sofosbuvir (Harvoni®, generics) 90 mg/400 mg tablet

Chronic HCV treatment:

  • genotype 1
    • without cirrhosis
8* weeks or 12 weeks 90 mg ledipasvir and 400 mg sofosbuvir once daily
   
  • with compensated cirrhosis (Child-Pugh A)
12 weeks  
   
  • decompensated  cirrhosis (Child-Pugh B and C)
12 weeks plus ribavirin      
   
  • liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin  
   

genotype 4

  • liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin  
   
  • genotypes 4, 5, or 6 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks  
sofosbuvir/ velpatasvir (Epclusa®, generics) 400 mg/100 mg tablets

Chronic HCV treatment:

  • genotypes 1, 2, 3, 4, 5, and 6 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks 400 mg sofosbuvir and 100 mg velpatasvir once daily
   
  • genotypes 1, 2, 3, 4, 5, and 6 with decompensated cirrhosis (Child-Pugh B or C)
12 weeks plus ribavirin  
sofosbuvir (Sovaldi®) 400 mg tablet

Chronic HCV treatment:

  • genotypes 1 and 4 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin and peginterferon 400 mg once daily
   
  • genotype 2 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin  
   
  • genotype 3 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
24 weeks plus ribavirin  

Legend:

  • HCV = hepatitis C virus;
  • NS5A inhibitors = Nonstructural protein 5A (NS5A) inhibitors
  • NS3/4A protease inhibitors = Nonstructural protein 3/4A protease inhibitors
  • † = For HIV/HCV-coinfected patients, a treatment duration of 12 weeks is recommended with compensated cirrhosis (Child-Pugh A) for genotypes 1-4 and genotypes 5 and 6 regardless of liver status
  • * = 8 weeks of treatment can be considered in treatment naïve genotype 1 patients without cirrhosis who have pretreatment HCV RNA less than 6 million IU/mL
Table 2: DAAs for treatment of adult chronic HCV Infection: Treatment experienced patients with or without cirrhosis2-12
Drug Name Dosage Form/Strength Treatment Indication Duration and Coadministration Maximum Recommended Dosage
elbasvir/grazoprevir (Zepatier®) 50 mg/100 mg tablet

Chronic HCV treatment:

  • genotypes 1a:
    • that is peginterferon/ ribavirin experienced without baseline NS5A polymorphisms without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks 50 mg elbasvir and 100 mg grazoprevir once daily
   
  • that is peginterferon/ ribavirin experienced with baseline NS5A polymorphisms without cirrhosis or with compensated cirrhosis (Child-Pugh A)
16 weeks plus ribavirin  
   
  • that is peginterferon/ ribavirin and/or NS3/4A protease experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin  
   

genotype 1b:

  • that is peginterferon/ ribavirin experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks  
   
  • that is peginterferon/ ribavirin and/or NS3/4A protease experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin  
   
  • genotype 4 that is peginterferon/ribavirin experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)
16 weeks plus ribavirin  
glecaprevir/ pibrentasvir (Mavyret®) 100 mg/40 mg tablets

Chronic HCV treatment:

  • genotype 1
  • who have previously been treated with a regimen containing an HCV NS5A inhibitor without cirrhosis
16 weeks 300 mg glecaprevir and 120 mg pibrentasvir once daily
   
  • who have previously been treated with a regimen containing an HCV or an NS3/4A protease inhibitor with or without compensated cirrhosis (Child-Pugh A)
12 weeks  
   
  • genotypes 1,2, 4, 5, or 6 with prior treatment with a peg interferon, ribavirin and/or sofosbuvir, but no prior treatment with an NS3/4A PI or NS5A inhibitor without cirrhosis
8 weeks  
   
  • genotypes 1,2, 4, 5, or 6 with prior treatment with a peg interferon, ribavirin and/or sofosbuvir, but no prior treatment with an NS3/4A PI or NS5A inhibitor with compensated cirrhosis (Child-Pugh A)
12 weeks  
   
  • genotype 3 with prior treatment with a peg interferon, ribavirin and/or sofosbuvir, but no prior treatment with an NS3/4A PI or NS5A inhibitor without cirrhosis or with compensated cirrhosis (Child-Pugh A)
16 weeks  
ledipasvir/sofosbuvir (Harvoni®, generics) 90 mg/400 mg tablet

Chronic HCV treatment:

  • genotype 1 who have failed peginterferon and/or ribavirin-based regimen with or without a protease inhibitor
    • without cirrhosis
12 weeks 90 mg ledipasvir and 400 mg sofosbuvir once daily
   
  • with compensated cirrhosis (Child-Pugh A)
24 weeks or 12 weeks in combination with ribavirin†  
   
  • decompensated cirrhosis (Child-Pugh B or C) plus ribavirin
12 weeks plus ribavirin  
   
  • liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin      
   
  • genotype 4 who have failed peginterferon and/or ribavirin-based regimen with or without a protease inhibitor
    • in liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin      
   
  • genotype 4, 5, or 6 without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have failed peginterferon and/or ribavirin-based regimen with or without a protease inhibitor
12 weeks  
sofosbuvir/velpatasvir (Epclusa®, generics) 400 mg/100 mg tablets

Chronic HCV treatment:

  • genotype 1, 2, 3, 4, 5, or 6 treated with peginterferon/ribavirin and/or NS3/4A protease inhibitor
    • without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks 400 mg sofosbuvir and 100 mg velpatasvir once daily
   
  • with decompensated cirrhosis (Child-Pugh B or C)
12 weeks plus ribavirin  
sofosbuvir (Sovaldi®) 400 mg tablet

Chronic HCV treatment:

  • genotype 2 previously treated with an interferon-based regimen without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin 400 mg once daily
   
  • genotype 3 previously treated with an interferon-based regimen without cirrhosis or with compensated cirrhosis (Child-Pugh A)
24 weeks plus ribavirin  
sofosbuvir, velpatasvir, and voxilaprevir (Vosevi®) 400 mg/100 mg/100 mg

Chronic HCV treatment:

  • genotypes 1, 2, 3, 4, 5, or 6 previously treated with an NS5A inhibitor without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir once daily
   
  • genotypes 1a or 3 previously treated with sofosbuvir without a NS5A inhibitor
12 weeks  

Histamine H2 - Receptor Antagonists

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Initially developed
    • December 2001
  • Revision history
    • July 23, 2021; May 2019; December 2016; March 2015; June 2013; November 2011; September 2011; September 2009; June 2009; December 2005; November 2003; October 2002.

1. Dosage

Histamine H2-receptor antagonists (H2RAs) are FDA-approved for use in gastric ulcer, duodenal ulcer, gastroesophageal reflux disease (GERD), esophagitis, hypersecretory conditions, and non-ulcer indigestion/heartburn.

In April 2020, the Food and Drug Administration requested that manufacturers remove all prescription and over-the-counter (OTC) formulations of ranitidine from the market. The request for removal was precipitated by the discovery of N-nitrosodimethylamine (NDMA), a probable human carcinogen, in various ranitidine products. Zantac® is one of several trade names for ranitidine, and in June 2021, Sanofi Pharmaceuticals released Zantac 360°® as an OTC product. However, this new formulation contains famotidine rather than ranitidine.

1.1. Adults

The maximum adult H2RA daily doses when prescribed for acute and maintenance FDA-approved conditions are summarized in Table 1 and Table 2. Dosage regimens exceeding these maximum recommended values will be reviewed.

Current American College of Gastroenterology guidelines no longer include H2RAs as part of Helicobacter pylori treatment regimens as H2RAs are associated with lower compliance and efficacy rates compared to other available proton pump inhibitor (PPI) regimens.

Currently, famotidine is available as a combination product with ibuprofen, and it is marketed under the trade name Duexis®. Duexis® is FDA approved for the prophylaxis against upper gastrointestinal ulcers in adult patients with osteoarthritis or rheumatoid arthritis. Dosing for this agent is provided in Table 3.

Table 1: Adult Maximum Daily Acute Doses for Histamine H2-Receptor Antagonists - Monotherapy

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage 
duodenal ulcer cimetidine (generics) 200 mg, 300 mg, 400 mg, 800 mg tablets; 300 mg/5 mL oral solution 1200 mg/day ^
gastric ulcer     1200 mg/day
gastroesophageal reflux disease (GERD) - nonerosive     1600 mg/day
heartburn     400 mg/day
hypersecretory conditions     2400 mg/day
duodenal ulcer famotidine (Pepcid®, Zantac 360°® (20 mg), generics) 10 mg, 20 mg, 40 mg tablets; 40 mg/5 mL oral suspension 40 mg/day
erosive esophagitis (EE)     80 mg/day
gastric ulcer     40 mg/day
GERD - nonerosive     40 mg/day
heartburn     40 mg/day
hypersecretory conditions     640 mg/day
duodenal ulcer nizatidine (generics) 150 mg, 300 mg capsules; 15 mg/mL oral solution  300 mg/day in single or divided doses
gastric ulcer     300 mg/day in single or divided doses
GERD - nonerosive     300 mg/day in single or divided doses

^ Patients who are heavy smokers with duodenal ulcers greater than 1 cm may benefit from cimetidine 1600 mg at bedtime.

Table 2: Adult Maximum Daily Maintenance Dose for Histamine H2-Receptor Antagonists - Monotherapy

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage 
duodenal ulcer cimetidine (generics) 200 mg, 300 mg, 400 mg, 800 mg tablets; 300 mg/5 mL oral solution 400 mg/day
hypersecretory conditions     2400 mg/day
duodenal ulcer famotidine (Pepcid®, generics) 10 mg, 20 mg, 40 mg tablets; 40 mg/5 mL oral suspension 20 mg/day
hypersecretory conditions     640 mg/day
duodenal ulcer nizatidine (generics) 150 mg, 300 mg capsules; 15 mg/mL oral solution  150 mg/day at bedtime
duodenal ulcer ranitidine (Zantac®, generics) 150 mg, 300 mg capsules; 75 mg, 150 mg, 300 mg tablets; 15 mg/mL oral syrup 150 mg/day at bedtime
erosive esophagitis     300 mg/day in two divided doses
hypersecretory conditions     6 g/day in divided doses

1.2. Pediatrics

Maximum recommended pediatric H2RA daily doses for acute and maintenance therapy are summarized in Table 4. Dosages exceeding these recommendations will be reviewed.

Table 4: Pediatric Maximum Daily Acute Doses for Histamine H2-Receptor Antagonists - Monotherapy

Treatment Indication Drug Name Patient Characteristics Maximum Recommended Dosage
duodenal ulcer cimetidine (generics) Greater than or equal to 16 years of age 1200 mg/day ^
gastric ulcer   Greater than or equal to 16 years of age 1200 mg/day
gastroesophageal reflux disease (GERD) - nonerosive   Greater than or equal to 16 years of age 1600 mg/day
heartburn   Greater than or equal to 12 years of age 400 mg/day
hypersecretory conditions   Greater than or equal to 16 years of age 2400 mg/day
duodenal ulcer famotidine (Pepcid®, generics) 1 to 17 years of age 40 mg/day
erosive esophagitis (EE)   1 to 17 years of age 80 mg/day
gastric ulcer   1 to 17 years of age 40 mg/day
GERD - nonerosive   1 to 16 years of age
  • tablet: 40 mg/day
  • suspension: 80 mg/day
GERD – nonerosive   3 months to 1 year of age suspension: 0.5 mg/kg twice daily
GERD - nonerosive   Less than 3 months of age suspension: 0.5 mg/kg once daily
heartburn famotidine (Pepcid®, Zantac 360°® (20 mg),  generics) Greater than or equal to 12 years of age 40 mg/day
EE nizatidine (generics) Greater than or equal to 12 years of age 300 mg/day in single or divided doses
GERD - nonerosive   Greater than or equal to 12 years of age 300 mg/day in single or divided doses

^ Patients who are heavy smokers with duodenal ulcers greater than 1 cm may benefit from cimetidine 1600 mg at bedtime.

Table 6: H2RA Dosage Modifications in Renal Impairment

Drug Name Dosage Adjustments in Renal Impairment
cimetidine
  • moderate impairment (CrCl 10-50 ml/min): 50% of total daily dose
  • severe impairment (CrCl less than 10 ml/min): 300 mg orally every 12 hours; may increase to every 8 hours cautiously based on patient response
famotidine moderate to severe impairment (CrCl less than 50 ml/min): reduce total daily dose by 50%; alternately, dosing interval may be lengthened to 36-48 hours based on patient response and degree of renal impairment
nizatidine

active treatment:

  • CrCl 20-50 ml/min: 150 mg/day orally 
  • CrCl less than 20 ml/min: 150 mg orally every other day

maintenance therapy:

  • CrCl 20-50 ml/min: 150 mg every other day orally
  • CrCl less than 20 ml/min: 150 mg every 3 days orally

2. Duration of Therapy

Adult and Pediatric Patients

Clinical trials document a maximum treatment duration of 56 days (eight weeks) for anti-ulcer therapy in treating acute duodenal and gastric ulcers. In pediatric patients, an 8-week maximum GERD acute treatment duration is recommended.  H2RA treatment regimens at acute dosage levels lasting longer than four months will be reviewed.

When used for nonulcer indigestion/heartburn, H2RA treatment duration should not exceed 14 days at the maximum dose, unless directed by a physician.

Maintenance therapy, at recommended daily maintenance doses (Tables 2, 3, and 5), may be continued indefinitely based on patient need.

H2RAs may be used in conjunction with PPIs in GERD patients experiencing nocturnal breakthrough symptoms.

3. Duplicative Therapy

The current literature does not support the combination of two or more H2RAs. Therefore, concurrent use of this combination will be reviewed as there is no clinical evidence to suggest that adjunctive administration improves outcomes.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Table 7 summarizes major drug-drug interactions considered clinically relevant for H2RAs. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 7: Major H2RA Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
cimetidine clopidogrel (Plavix®) co-administration may result in decreased clopidogrel active metabolite levels, platelet inhibition, and clopidogrel efficacy; clopidogrel requires metabolism through CYP2C19 to active metabolite and cimetidine is CYP2C19 inhibitor
 
cimetidine-clopidogrel combination should be avoided; H2RA alternatives (e.g., famotidine, ranitidine) that are not CYP2C19 inhibitors can be substituted for cimetidine
 
major (DrugReax) 2 - major (CP)
cimetidine dofetilide (Tikosyn®) concurrent use may potentially increase dofetilide serum levels/ enhance pharmacologic effects (e.g., torsades de pointes) as dofetilide metabolized by CYP3A4, eliminated through renal and hepatic mechanisms; cimetidine inhibits dofetilide clearance through interference with active tubular secretion and moderate CYP3A4 inhibition dofetilide manufacturer states that concurrent administration of dofetilide and cimetidine is contraindicated; medications without effect on dofetilide pharmacokinetics (e.g., omeprazole, ranitidine, antacids) are potential alternatives to cimetidine contraindicated (DrugReax) 1 - severe (CP)
cimetidine theophylline adjunctive use may cause theophylline toxicity as cimetidine inhibits theophylline hepatic metabolism adjunctive use possible if proper monitoring and/or dosage adjustments are made; order in which therapy initiated important - adding theophylline to existing cimetidine drug regimen can be safe as theophylline dosage titrated to acceptable serum concentrations, but adding cimetidine to existing theophylline regimen may enhance theophylline pharmacologic/ adverse effects; other available H2RAs do not significantly interact with theophylline and may be appropriate alternatives for cimetidine major (DrugReax) 2 - major (CP)
cimetidine warfarin combined use may result in increased INR and moderate to severe bleeding in some patients as cimetidine stereoselectively inhibits hepatic metabolism of warfarin R-isomer adjunctive use possible if proper monitoring and/or dosage adjustments are made;  order in which therapy is initiated is important - adding warfarin to existing cimetidine drug regimen can be safe as warfarin dosage titrated to acceptable monitoring parameter (e.g., INR), but adding cimetidine to existing warfarin regimen may enhance warfarin-induced hypoprothrombinemic response;  other H2RAs do not significantly interact with warfarin - may be appropriate alternatives for cimetidine moderate (DrugReax) 2 - major (CP)
H2RAs atazanavir (Reyataz®) concurrent use may cause reduced atazanavir efficacy and increased resistance, as increased gastric pH with H2RAs causes decreased atazanavir solubility/ absorption/plasma levels administer atazanavir either with and/or at least 10 hours after H2RA dose and monitor for decreased efficacy/increased resistance major (DrugReax) 2 - major (CP)
H2RAs select azole antifungals (itraconazole (Sporanox®), ketoconazole, posaconazole (Noxafil®) combined use may result in reduced azole antifungal  bioavailability,  decreased maximum azole antifungal serum levels, and attenuated azole antifungal pharmacologic effects, as H2RAs increase gastric pH and azole antifungal oral absorption is dependent on acidic environment posaconazole manufacturer recommends avoiding the posaconazole-cimetidine drug combination unless benefits outweigh risks; if H2RA-azole antifungal combination necessary, monitor patients carefully for reduced antifungal activity major, moderate (DrugReax) 2 - major (CP)
H2RAs drugs pH- dependent for solubility (e.g., dasatinib- Sprycel®; erlotinib – Tarceva®) adjunctive administration for extended duration may result in reduced exposure and serum levels in select medications dependent on acidic gastric pH for solubility and absorption combined use not recommended; alternative acid suppressives (e.g., antacids) should be administered 2 hours before or 2 hours after pH-dependent medication for optimal efficacy major (DrugReax) 2 - major (CP)
H2RAs delavirdine (Rescriptor®) combined use for extended treatment duration may result in reduced delavirdine absorption, decreased delavirdine serum levels, and attenuated delavirdine efficacy as delavirdine is dependent on an acidic gastric pH for absorption; separating drug doses may not improve delavirdine absorption as H2RAs affect gastric pH for prolonged time concomitant use not recommended; antacids may be alternative acid suppressive therapy, with  antacid and delavirdine doses separated by at least one hour major (DrugReax) 2 - major (CP)

Legend:

  • *CP = Clinical Pharmacology
  • H2RAs = histamine (H2) receptor antagonists
  • INR = International Normalized Ratio

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: June 11, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed June 11, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; June 11, 2021.
  4. AHFS Drug Information 2021. Jackson, WY: Teton Data Systems.Stat!Ref Electronic Medical Library. Available at: http://online-statref-com.libproxy.uthscsa.edu/. Accessed June 11, 2021.
  5. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; June 11, 2021.
  6. Nizatidine capsule package insert. Actavis Pharma Inc., March 2016.
  7. Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. Lancet.  2009;374(9699):1449-61. 
  8. Moayyedi P, Talley NJ. Gastro-esophageal reflux disease. Lancet. 2006;367(9528):2086-100.
  9. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG clinical guideline: treatment of Helicobacter pylori infection. Am J Gastroenterol. 2017;112:212-38.  
  10. Anonymous. Drugs for GERD and peptic ulcer disease. Med Lett Drugs Ther. 2018; 60(1538):9-16.
  11. Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: A controlled study in normal subjects.  Gastroenterology.1998;115:1335-9.
  12. Xue S, Katz PO, Banerjee P, Tutuian R, Castell DO. Bedtime H2 blockers improve nocturnal gastric acid control in GERD patients on proton pump inhibitors. Aliment Pharmacol Ther. 2001;15:1351-6.
  13. Cross LB, Justice LN. Combination drug therapy for gastroesophageal reflux disease. Ann Pharmacother. 2002;36:912-6.
  14. Robinson M, Rodriguez-Stanley S, Ciociola AA, et al. Control of nocturnal gastric acidity: a role for low dose bedtime ranitidine to supplement daily omeprazole. Dig Dis Sci. 2002;47:265-73.
  15. United States Food and Drug Administration. FDA News Release: FDA requests removal of all ranitidine products (Zantac) from the market. (April 1, 2021). Available at: https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market. Accessed 6/11/2021.
  16. Famotidine (Zantac 360°®) oral tablets. Sanofi Pharmaceuticals. Available at: https://www.zantacotc.com/en-us/heartburn-medicine/maximum-strength/. Accessed 6/11/2021.
  17. Duexis® (ibuprofen/ famotidine) oral tablet package insert. Horizon Therapeutics USA, Inc., June 2021.

Hydrocodone Bitartrate/Hydrocodone Polistirex

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • Jan. 2022; Nov. 2019; Nov. 2017; Dec. 2016; Oct. 2014; Feb. 2013; June 2011; Jan. 2009; March 2003; April 2002; March 2001; March 2000; Feb. 1999; Feb. 1998; March 1997; Sept. 1995.  
  • Initially developed
    • April 1994

1. Dosage

In August 2014, the Drug Enforcement Administration published a final ruling to reschedule hydrocodone combination products from Schedule III to Schedule II due to their high potential of abuse. Beginning October 6, 2014, all hydrocodone combination products will be Schedule II. Single-entity hydrocodone products were already classified as Schedule II1.

Hydrocodone bitartrate, as combination therapy, is FDA-approved as an opioid antitussive and analgesic used for the relief of cough and moderate to moderately severe pain2-7. Hydrocodone bitartrate is available in fixed combinations with non-opiate drugs (e.g., acetaminophen, acetylsalicylic acid, chlorpheniramine, guaifenesin, ibuprofen, phenylephrine, and pseudoephedrine)2,3,6,7. This drug should be given in the smallest effective dose and as infrequently as possible to minimize the development of tolerance and physical dependence. Hydrocodone bitartrate is available in the United States as a single entity, extended-release capsule (Zohydro® ER), formulated with abuse-deterrent beads .2,3,8. This hydrocodone product is FDA-approved for managing pain requiring daily, long-term, around-the-clock opiate therapy not responsive to other treatment options. Hydrocodone bitartrate extended-release tablets with abuse deterrent properties (Hysingla® ER) have also been FDA-approved to manage severe pain requiring chronic, around-the-clock opiate treatment unresponsive to other treatment regimens 2,3,8,9.

The use of hydrocodone when prescribed by multiple physicians will be reviewed.

Hydrocodone/acetaminophen combination products containing greater than 325 mg of acetaminophen have been discontinued due to increased potential for liver toxicity.

1.1. Adults

Analgesic hydrocodone dosages should be determined based on pain severity and patient response/ tolerance. In individuals with severe pain or those who have become tolerant to the analgesic effects of hydrocodone, it may be necessary to exceed the usual dosage. Reduced hydrocodone dosages are indicated in high-risk patients and the elderly. The maximum daily dosage for the acetaminophen/ hydrocodone combination is restricted by the maximum acetaminophen dose of 4 g daily to limit the risk of hepatic damage and severe hypersensitivity reactions associated with acetaminophen use 2-4.

Hydrocodone exerts antitussive effects by directly acting on receptors in the cough center at dosages lower than those required for analgesia 2,3,6,7.

Recommended adult hydrocodone dosages as monotherapy and combination therapy are summarized in Tables 12,3,8,9 and 22-7,10. Dosages exceeding these recommendations will be reviewed.

Table 1: Recommended Adult Hydrocodone Dosages: Monotherapy

Drug/Indication Dosage Forms/Strengths Usual Dosage Regimen Maximum Recommended Dose
Analgesic hydrocodone extended-release capsule (Zohydro® ER, generics) 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg extended-release, abuse-deterrent capsules 20 mg to 100 mg every 12 hours maximum dose not defined; doses should be titrated per patient to maximize analgesia and minimize adverse drug reactions
Analgesic hydrocodone extended-release tablet (Hysingla® ER, generics) 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg extended-release, abuse-deterrent tablets 20 mg to 120 mg every 24 hours maximum dose not defined; doses should be titrated per patient to maximize analgesia and minimize adverse drug reactions

Table 2: Recommended Adult Hydrocodone Dosages: Combination Therapy

Drug/Indication Dosage Forms/Strengths Usual Dosage Regimen Maximum Recommended Dose
Analgesic hydrocodone bitartrate/ acetaminophen (Lortab®, Norco®, generics) 5 mg/300 mg, 7.5 mg/300 mg, 10 mg/300 mg, 2.5 mg/325 mg, 5 mg/325 mg, 7.5 mg/325 mg, 10 mg/325 mg tablets; 7.5 mg/325 mg/15 ml or 10 mg/325 mg/15 ml solution; 10 mg/300 mg/15 ml elixir 2.5-10 mg every 4-6 hours as needed 60 mg/4000 mg daily*
Analgesic hydrocodone bitartrate/ ibuprofen (Vicoprofen®, Ibudone®, Reprexain®, generics) 2.5 mg/200 mg, 5 mg/200 mg, 7.5 mg/200 mg, 10 mg/200 mg tablets 2.5-10 mg every 4-6 hours as needed 5 tablets per day [maximum hydrocodone dose (10mg/200 mg): 50 mg daily]**
Antitussive hydrocodone bitartrate/homatropine (Hydromet®, generics) 5 mg/1.5 mg/5ml solution or 5 mg/1.5 mg tablet 5 mg every 4-6 hours as needed 30 mg daily
Antitussive hydrocodone polistirex/chlorpheniramine polistirex (TussiCaps®) 10 mg/ 8 mg extended-release capsules 1 capsule every 12 hours 20 mg/16 mg every 24 hours
Antitussive hydrocodone polistirex/chlorpheniramine polistirex (Tussionex® Pennkinetic®, generics) 10 mg/8 mg+/5 ml extended-release oral suspension 10 mg/8 mg+ every 12 hours 20 mg/16 mg+ daily

Legend:

  • *dosage limit based on maximum acetaminophen daily dose; varies by product
  • **short-term use (less than 10 days) recommended
  • +dosed as hydrocodone bitartrate and chlorpheniramine maleate    

1.2. Pediatrics

Prior to 2018, Hydrocodone was not FDA-approved for use as an antitussive in pediatric patients younger than 6 years of age as safety and efficacy have not been established. In January 2018 the U.S. Food and Drug Administration changed the labeling to indicate that opioid cough and cold medicines containing codeine or hydrocodone are no longer indicated for patients less than 18 years of age.11 For analgesia, safety and efficacy of the hydrocodone/acetaminophen combination have not been established in children younger than 2 years of age, while the hydrocodone/ibuprofen combination is not indicated for use in children younger than 16 years of age due to lack of safety and efficacy data.2-5 The hydrocodone single-entity products, Zohydro® ER and Hysingla® ER are not FDA-approved in the pediatric population (less than 18 years of age) as safety and efficacy in this age group have not been established .2,3,8,9.

Analgesic hydrocodone dosages should be determined based on pain severity and patient response/ tolerance. In individuals with severe pain or those who have become tolerant to the analgesic effects of hydrocodone, it may be necessary to exceed the usual dosage. Reduced hydrocodone dosages are indicated in very young patients. Like adult patients, the maximum daily dosage for the acetaminophen/ hydrocodone combination is restricted by the maximum acetaminophen dose (as determined by age and weight – see Table 3) to limit the risk of hepatic damage and severe hypersensitivity reactions associated with acetaminophen use 2-10.

Recommended pediatric hydrocodone dosages as combination therapy are summarized in Table 32-5 . Dosages exceeding these recommendations will be reviewed.

Table 3: Recommended Pediatric Hydrocodone Dosages: Combination Therapy

Drug/Indication     Usual Dosage Regimen Maximum Recommended Dose
Analgesic hydrocodone bitartrate/acetaminophen (APAP) (Lortab®, Norco®, generics)
  • 2-3 years of age (12 to 15 kg): 
    • 1.875 mg every 4-6 hours as needed
  • 4-6 years of age (16 to 22 kg):  
    • 2.5 mg every 4-6 hours as needed
  • 7-9 years of age (23 to 31 kg):
    • 3.75 mg every 4-6 hours as needed
  • 10-13 years of age (32 to 45 kg):      
    • 5 mg every 4-6 hours as needed
  • Greater than or equal to 14 years of age (greater than or equal to 46 kg): 
    • 7.5 mg every 4-6 hours as needed
  • 750 mg daily (APAP+)*
  • 1 g daily (APAP)*
  • 1.5 g daily (APAP)*
  • 2 g daily (APAP)*
  • 3 g daily (APAP)*
Analgesic hydrocodone bitartrate/ibuprofen (Vicoprofen®, Ibudone®, Reprexain®, generics) 16 years and older: 2.5-10 mg/200 mg every 4-6 hours as needed 5 tablets daily**

Legend:

  • +APAP = acetaminophen
  • *dosage limit based on maximum acetaminophen daily dose
  • **short-term use (less than 10 days) recommended

1.3. Opioid Reversal Agents

Naloxone is an opioid receptor antagonist that is FDA approved for reversal of opioid-induced respiratory and central nervous system depression. Naloxone is supplied as a nasal spray marketed as Narcan® 4 mg/0.1 mL nasal spray, Kloxxado® 8 mg/ 0.1 mL nasal spray, Evzio® 0.4 mg/ 0.4 mL auto-injector solution for injection, LifEMS Naloxone® 2 mg/ 2 mL solution for injection, and generic formulations of the solution for injection are available12-15.

In July 2020, the U.S. Food and Drug Administration made the recommendations that healthcare professionals should discuss the availability of naloxone products and consider prescribing naloxone to patients who are prescribed opioid pain relievers and are at increased risk of opioid overdose. Patients at risk of opioid overdose include patients who are co-prescribed benzodiazepines or other drugs that depress the central nervous system, patients with a history of opioid use disorder (OUD), or who have experienced a previous opioid overdose. Healthcare professionals should also consider prescribing naloxone to patients who have other household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose.16 In 2016, the state of Texas, in association with the Texas Pharmacy Association, obtained a physician-signed standing order that allows pharmacists to dispense naloxone products to patients after completing Texas-accredited training17.

2. Duration of Therapy

When used as an analgesic, there is no basis for limiting hydrocodone therapy duration as hydrocodone may be utilized to manage chronic painful conditions as well as acute pain events. As an antitussive, hydrocodone is prescribed for a limited duration to manage cough and upper respiratory symptoms associated with the common cold or allergies in adults and pediatric patients 6 years of age and older. In isolated cases, hydrocodone may be prescribed for an extended time period in those adult patients requiring nonspecific therapy for a chronic, nonproductive cough, such as advanced cancer 18,19. In all patients, the smallest effective hydrocodone dose should be administered as infrequently as possible to minimize the development of tolerance and physical dependence2-10.

3. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for hydrocodone are summarized in Table 42-10, 20. Only those drug-drug interactions classified as clinical significance level 1/contraindicated or those considered life threatening which have not yet been classified will be reviewed.

Table 4: Hydrocodone Drug-Drug Interactions

Interacting Drug Interaction Recommendation Clinical Significance Level
anticholinergics (e.g., antidiarrheals) co-administration may lead increased risk of urination retention, severe constipation, including paralytic ileus, especially with chronic use, and CNS depression due to additive anticholinergic effects observe for chronic constipation, urinary retention, and CNS depression; adjust doses and/or discontinue therapy as needed 2-major (CP)
CYP3A4 inducers (e.g., rifampin, barbiturates) adjunctive use may result in decreased hydrocodone plasma levels/reduced therapeutic effects, including withdrawal, as hydrocodone is CYP3A4 substrate monitor for effective therapeutic effects; modify doses as necessary major (DrugReax) 3-moderate (CP)
CYP3A4 inhibitors concurrent administration with CY3A4 inhibitors may result in increased hydrocodone serum levels and the potential for enhanced pharmacologic/ adverse effects through inhibition of CYP3A4-mediated hydrocodone metabolism monitor for effective analgesia and signs/symptoms of adverse effects (e.g., enhanced sedation, respiratory depression); modify doses as necessary major (DrugReax) 2-major (CP)
gabapentin potential for decreased hydrocodone peak concentrations and AUC with concomitant gabapentin-hydrocodone administration in dose-dependent fashion; minor increases in gabapentin AUC observe patients for decreased hydrocodone efficacy or additive drowsiness minor (DrugReax) 3-moderate (CP)
monoamine oxidase inhibitors (MAOIs) combined administration may result in severe, unpredictable additive effects although no specific adverse interactions have been reported with the hydrocodone-MAOI combination, hydrocodone should not be administered in patients who have received MAOIs within 14 days major (DrugReax) 2-major (CP)
opiate agonist/ antagonists (OAAs) (e.g., buprenorphine, pentazocine) concomitant administration may result in partial blockade of hydrocodone pharmacologic effects and may precipitate a withdrawal syndrome in some patients requiring chronic hydrocodone therapy; antagonist effects are more likely to occur when OAAs used concurrently with low to moderate doses of a pure opioid agonist;  adjunctive therapy may be required in some instances, which may result in additive CNS depressant, respiratory, and hypotensive effects patients requiring concurrent therapy with hydrocodone and a mixed OAA should be monitored for enhanced or attenuated pharmacologic effects, which may necessitate hydrocodone dosage adjustments and/or pharmacotherapy modifications major (DrugReax) 2-major (CP)
opiate agonists (OAs) concurrent administration of pure OAs and narcotic analgesics like hydrocodone, or administration of OAs within 7 to 10 days of narcotic analgesic therapy may induce an acute abstinence syndrome unless clinically significant respiratory depression is present, OAs should not be administered concurrently with hydrocodone contraindicated (DrugReax) 2-major (CP)

Legend:

  • *CP = Clinical Pharmacology
  • AUC = area under the curve
  • CNS = central nervous system

4. References

  1. Department of Justice. Drug Enforcement Administration. Schedules of controlled substances: rescheduling of hydrocodone combination products from schedule III to schedule II. Fed Regist. 2014;79(163):49661-82.
  2. DRUGDEX® System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu/. Accessed December 7th, 2021.
  3. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed December 7th, 2021.
  4. Hydrocodone bitartrate/ acetaminophen oral tablets package insert. H.J. Harkins Company, Inc. September 2018.
  5. Hydrocodone bitartrate/ ibuprofen oral tablets package insert. Amneal Pharmaceuticals of New York, LLC, March 2021.
  6. Hydrocodone polistirex/chlorpheniramine polistirex extended-release suspension (Tussionex® Pennkinetic®) package insert. UCB, Inc., June 2018.
  7. Hydrocodone polistirex/chlorpheniramine polistirex extended-release capsules (TussiCaps®) package insert. Valeant Pharmaceuticals North America LLC, March 2018.
  8. Hydrocodone bitartrate extended-release capsules (Zohydro® ER) package insert. Currax Pharmaceuticals LLC, March 2021.
  9. Hydrocodone bitartrate extended-release tablets (Hysingla® ER) package insert. Purdue Pharma LLP, March 2021.
  10. Hydrocodone bitartrate/ homatropine methylbromide (Hydromet®) oral solution package insert. Actavis Pharma, Inc., August 2020.
  11. U.S. Food and Drug Administration FDA News Release. FDA acts to protect kids from serious risks of opioid ingredients contained in some prescription cough and cold products by revising labeling to limit pediatric use. January 2018.
  12. Naloxone hydrochloride (Narcan®) 4 mg/ 0.1 mL nasal spray package insert. Emergent Devices Inc., March 25, 2021. 
  13. Naloxone hydrochloride (Kloxxado®) 8 mg/ 0.1 mL nasal spray package insert. Hikma Specialty USA Inc., April 2021.
  14. Naloxone hydrochloride (Evzio®) 0.4 mg/ 0.4 mL pre-filled syringe autoinjector package insert. HF Acquisition Co LLC, DBA HealthFirst, February 2020.
  15. Naloxone hydrochloride (LifEMS®) 2 mg/ 2 mL solution for injection convenience kit package insert. Lifsa Drugs LLC, November 2020.
  16. U.S. Food and Drug Administration. FDA recommends health care professionals discuss naloxone with all patients when prescribing opioid pain relievers or medicines to treat opioid use disorder. FDA Drug Safety Communication. Published online July 23, 2020. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-health-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioid-pain. Accessed November 19th, 2021.
  17. Texas Pharmacy Association. Texas pharmacist naloxone standing order application. October 2016. Available at: https://www.texaspharmacy.org/page/TXPHARMNALOX. Accessed November 19th, 2021.
  18. Homsi J, Walsh D, Nelson KA, et al. A phase II study of hydrocodone for cough in advanced cancer. Am J Hospice Palliat Med. 2002;19(1):49-56.
  19. Estfan B, LeGrand S. Management of cough in advanced cancer. J Support Oncol. 2004;2(6):523-7.
  20. Armstrong SC, Cozza KL. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part II.  Psychosomatics. 2003;44:515-20.

Hydroxy-Methylglutaryl Coenzyme A Reductase Inhibitors

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • April 2022, March 2020; March 2018; March 2017; Dec. 2014; March 2013; April 2011; March 2011; Nov. 2008; Sept. 2008; July 2008; March 2008; Sept. 2001; Sept. 2000; Aug. 2000; Nov. 1999; Oct. 1999; Sept. 1998; Sept. 1997; Oct. 1996.
  • Initially developed
    • Nov. 1994

1.1. Adults

HMG-CoA reductase inhibitors, or statins, are lipid-lowering agents that competitively inhibit HMG-CoA reductase, the enzyme that catalyzes cholesterol biosynthesis. Inhibiting this enzyme results in decreases in total cholesterol, low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and apoprotein B (Apo B), increases in high-density lipoprotein cholesterol (HDL-C), as well as increases in the number of LDL receptors on hepatic and extrahepatic tissues. Clinical and epidemiologic studies have documented that low HDL-C, high LDL-C and elevated TG augment atherosclerosis development and are risk factors for cardiovascular disease, while higher HDL-C levels and lower LDL-C concentrations are associated with reduced cardiovascular risk1-14.

Statins are FDA-approved to manage hyperlipidemia (including hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia, and primary dysbetalipoproteinemia) in adults, treat homozygous familial hypercholesterolemia in adults, reduce the risk of coronary heart disease mortality and cardiovascular events in patients at high risk for coronary events, slow the progression of coronary atherosclerosis in patients with coronary artery disease by reducing total cholesterol and LDL-C levels, provide primary prevention of coronary artery disease in patients with risk factors for coronary artery disease but without symptomatic cardiovascular disease, promote secondary prevention of coronary events in patients with cardiovascular disease, and treat adolescents with heterozygous familial hypercholesterolemia unresponsive to diet therapy1-14.

Statin combination therapies are FDA-approved to manage primary hyperlipidemia/mixed dyslipidemia and homozygous familial hypercholesterolemia (Vytorin®) when monotherapy is deemed inadequate. Caduet® is FDA-approved in those patients requiring both amlodipine and atorvastatin1,2,15,16. In 2021 the combination product Roszet® (ezetimibe/ rosuvastatin) was approved for the management of homozygous familial hypercholesterolemia alone or in combination with other LDL-C lowering therapies and primary nonfamilial hyperlipidemia1,2,17.

Higher statin doses may be necessary in patients who respond poorly to initial prescribed amounts. Doses may be escalated incrementally every four weeks at minimum, based on patient need and tolerance, to the maximum recommended dose. However, the FDA now recommends limiting use of the highest simvastatin dose (80 mg) to only those patients who have been taking the dose for 12 months or more without evidence of myopathy, due to greater risks for muscle injury compared to lower simvastatin doses or other statins1,2,11,12.

Recommended adult statin maintenance doses as mono- and combination therapy should not exceed the maximum doses listed in Tables 1 and 2.

Table 1. HMG-CoA Reductase Inhibitor Monotherapy – Maximum Recommended Adult Dosages1-14
Drug Dosage Form/Strength Maximum Recommended Dosage
atorvastatin (Lipitor®, generic) 10 mg, 20 mg, 40 mg, 80 mg tablets
  • 80 mg once daily
  • concurrent administration with nelfinavir:
    • 40 mg once daily
  • concurrent administration with itraconazole, clarithromycin, saquinavir plus ritonavir, darunavir plus ritonavir, or fosamprenavir alone or in combination with ritonavir, elbasvir plus grazoprevir, letermovir:
    • 20 mg once daily
fluvastatin (generics, Lescol® XL, generics) 20 mg, 40 mg capsules; 80 mg extended-release tablets
  • 80 mg once daily, as single dose or two divided doses
  • concurrent administration with cyclosporine, fluconazole:
    • do not exceed 20 mg twice daily
lovastatin (generics) 10 mg, 20 mg, 40 mg tablets
  • 80 mg once daily with evening meal 
  • concurrent administration with amiodarone: 
    • 40 mg once daily with evening meal 
  • concurrent administration with danazol, diltiazem, or verapamil: 
    • 20 mg once daily with evening meal
lovastatin (Altoprev®) 20 mg, 40 mg, 60 mg extended-release tablets
  • 60 mg once daily at bedtime
  • concurrent administration with amiodarone:
    • 40 mg once daily at bedtime
  • concurrent administration with danazol, diltiazem, or verapamil:
    • 20 mg once daily at bedtime
pitavastatin calcium (Livalo®) 1 mg, 2 mg, 4 mg tablets
  • 4 mg once daily
  • concurrent administration with rifampin:
    • 2 mg once daily
  • concurrent administration with erythromycin:
    • 1 mg once daily
pitavastatin magnesium (Zypitamag®) 1 mg, 2 mg, 4 mg tablets
  • 4 mg once daily
  • concurrent administration with rifampin:
    • 2 mg once daily
  • concurrent administration with erythromycin:
    • 1 mg once daily
pravastatin (Pravachol®, generics) 10 mg, 20 mg 40 mg, 80 mg tablets
  • 80 mg once daily
  • concurrent administration with immunosuppressives (e.g., cyclosporine):  
    • 20 mg once daily
  • concurrent administration with clarithromycin:
    • 40 mg once daily
rosuvastatin (Crestor®, generics) 5 mg, 10 mg, 20 mg, 40 mg tablets
  • 40 mg once daily
  • concurrent administration with gemfibrozil, lopinavir/ritonavir, or atazanavir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir::
    • 10 mg once daily
  • concurrent administration with cyclosporine or darolutamide:
    • 5 mg once daily
rosuvastatin (Ezallor Sprinkle®) 5 mg, 10 mg, 20 mg, 40 mg sprinkle capsules
  • 40 mg once daily
  • concurrent administration with gemfibrozil, lopinavir/ritonavir, atazanavir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir:
    • 10 mg once daily
  • concurrent administration with cyclosporine or darolutamide:
    • 5 mg once daily
simvastatin (Zocor®, FloLipid®, tablet generics) 5 mg, 10 mg, 20 mg, 40 mg, 80 mg tablets; 20 mg/5 mL, 40 mg/5 mL suspension
  • 40 mg once daily in evening for most patients*
  • concurrent administration with amiodarone, amlodipine, or ranolazine:
    • 20 mg once daily in evening
  • concurrent administration with verapamil, diltiazem, or dronedarone:
    • 10 mg once daily in evening
  • concurrent lomitapide: simvastatin dose should be reduced by 50%; simvastatin dose should not exceed 20 mg/day for most patients prescribed lomitapide concurrently (40 mg/day in patients on 80 mg/day dose for at least 1 year)
    • *80 mg dose restricted to those patients chronically maintained on 80 mg without evidence of myopathy
Table 2. HMG-CoA Reductase Inhibitor Combination Therapy – Maximum Recommended Adult Dosages1,2,15-17
Drug Dosage Form/Strength Maximum Recommended Dosage
amlodipine/atorvastatin (Caduet®, generics) 2.5 mg/10 mg, 2.5 mg/20 mg, 2.5 mg/40 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 5 mg/80 mg, 10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, 10 mg/80 mg tablets
  • 10 mg/80 mg once daily
  • concurrent administration with nelfinavir:
    • 10 mg/40 mg once daily
  • concurrent administration with itraconazole, clarithromycin, saquinavir plus ritonavir, darunavir plus ritonavir, or fosamprenavir alone or in combination with ritonavir, elbasvir plus grazoprevir, letermovir:
    • 10 mg/20 mg once daily
ezetimibe/ rosuvastatin (Roszet®) 10 mg/5 mg, 10 mg/ 10mg, 10 mg/20 mg, 10 mg/40 mg oral tablets
  • 10 mg/40 mg once daily
  • concurrent administration with darolutamide:
    • 10 mg/ 5mg once daily
  • Concurrent administration with regorafenib:
    • 10 mg/10 mg once daily
  • Concurrent administration with sofosbuvir/velpatasvir/voxilaprevir and ledipasvir/sofosbuvir:
    • Avoid use
  • Concurrent administration with elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, atazanavir/ritonavir, and lopinavir/ritonavir:
    • 10 mg/10 mg once daily
ezetimibe/ simvastatin (Vytorin®, generics) 10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, 10 mg/80 mg tablets
  • 10 mg/40 mg once daily in evening for most patients*
  • concurrent administration with amiodarone, amlodipine, or ranolazine:
    • 10 mg /20 mg once daily in evening
  • concurrent administration with verapamil, diltiazem, or dronedarone:
    • 10 mg/10 mg once daily in evening
  • concurrent lomitapide: simvastatin dose should be reduced by 50%; simvastatin dose should not exceed 10 mg/20 mg daily for most patients prescribed lomitapide concurrently (10 mg/40 mg daily in patients on 80 mg/day dose for at least 1 year)
    • *10 mg/80 mg dose restricted to those patients chronically maintained on 80 mg without evidence of myopathy

1.2. Pediatrics

HMG-CoA reductase inhibitors are FDA-approved for use as a dietary adjunct to reduce total cholesterol, LDL-C, TG, and Apo B in adolescent boys, and girls who are at least one-year post-menarche, (for pravastatin, children and adolescents 8-18 years of age regardless of menarchal status) with elevated LDL-C due to heterozygous familial hypercholesterolemia. Pitavastatin calcium (Livalo®) is FDA-approved for use in children/adolescents over 8 years of age as an adjunct to diet to manage heterozygous familial hypercholesterolemia by lowering total cholesterol, LDL-C, and apo B1,2,13. Rosuvastatin has expanded FDA approval for use in children as young as 8 years of age with heterozygous familial hypercholesterolemia, and has gained FDA approval for homozygous familial hypercholesterolemia in pediatric patients 7-17 years of age.1,2,10 Simvastatin oral suspension (FloLipid®) has been approved for use in conjunction with diet to improve total cholesterol, LDL-C, and ApoB in pediatric patients 10-17 years (females at least one year post-menarche) with heterozygous familial hypercholesterolemia1,2,12. Safety and efficacy of pitavastatin magnesium (Zypitamag®) or rosuvastatin sprinkle capsules (Ezallor Sprinkle™) in pediatric patients have not been established1,2,13,14 . Safety and effectiveness of HMG-CoA reductase inhibitors in pre-menarchal girls or children younger than 10 years of age (for pravastatin and rosuvastatin in heterozygous familial hypercholesterolemia, younger than 8 years of age regardless of menarchal status; for rosuvastatin in homozygous familial hypercholesterolemia, younger than 7 years of age) have not been well established1,2,9,10.

Ezetemibe/simivastatin (Vytorin®) combination therapy has been effectively used to manage children and adolescents with heterozygous familial hypercholesterolemia 1,2,15. The amlodipine/atorvastatin (Caduet®) combination has not been FDA-approved for the pediatric population as safety and efficacy have not been established with this combination therapy1,2,16. The safety and efficacy of ezetimibe/ rosuvastatin (Roszet®) in children has not been established, and it is currently not FDA-approved in the pediatric population 1,2,17.

Maximum recommended doses for HMG-CoA reductase inhibitors as both monotherapy and combination therapy in pediatric patients are summarized in Tables 3 and 4.

Table 3. Maximum Recommended HMG-CoA Reductase Inhibitor Pediatric Dosages: Monotherapy1-6, 8-12
Treatment Indication Drug Name Maximum Recommended Dosage
Heterozygous familial hypercholesterolemia atorvastatin 10-17 years of age:  
20 mg once daily
Heterozygous familial hypercholesterolemia fluvastatin 10-17 years of age:  
80 mg daily, as single evening dose or two divided doses
Heterozygous familial hypercholesterolemia lovastatin (immediate-release only) 10-17 years of age:  
40 mg once daily with evening meal
Heterozygous familial hypercholesterolemia pitavastatin Greater than 8 years to 17 years of age:
4 mg once daily
Heterozygous familial hypercholesterolemia pitavastatin Greater than 8 years to 17 years of age:
4 mg once daily
Heterozygous familial hypercholesterolemia pravastatin

8-13 years of age:  
20 mg once daily

14-17 years of age:  
40 mg once daily

Heterozygous familial hypercholesterolemia rosuvastatin (tablets only)

8-9 years of age:
10 mg once daily

10-17 years of age:
20 mg once daily

Homozygous familial hypercholesterolemia rosuvastatin (tablets only) 7-17 years of age:
20 mg once daily
Heterozygous familial hypercholesterolemia simvastatin 10-17 years of age:
40 mg once daily in evening
Table 4. Maximum Recommended HMG-CoA Reductase Inhibitor Pediatric Dosages: Combination Therapy1,2,15
Treatment Indication Drug Name Maximum Recommended Dosage
Heterozygous familial hypercholesterolemia ezetimibe/simvastatin 10-17 years of age (females postmenarchal):
10 mg/40 mg once daily

2. Duration of Therapy

There is no basis for limiting therapy duration for HMG-CoA reductase inhibitors as control of cholesterol and other coronary heart disease risk factors is a life-long process1-17.

3. Duplicative Therapy

The use of two or more HMG-CoA reductase inhibitors in combination is not justified. Additional therapeutic benefit is not realized when HMG-CoA reductase inhibitors are used concomitantly and may result in increased adverse reactions such as myopathy and rhabdomyolysis. Patients receiving multiple HMG-CoA reductase inhibitors concurrently will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered most significant for HMG-CoA reductase inhibitors are summarized in Table 4. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:

Table 4. Significant Drug-Drug Interactions for HMG-CoA Reductase Inhibitors1-31
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level
HMGs cyclosporine co-administration may lead to increased HMG concentrations and potential for enhanced pharmacologic/ adverse effects (e.g., MYO, RHAB) due to inhibition of HMG metabolism (CYP3A4; OATP1B1) by cyclosporine  (CYP3A4, OATP1B1 inhibitor) avoid adjunctive therapy, if possible; if combined therapy necessary, monitor for signs/symptoms of MYO, RHAB; use lowest recommended HMG doses; fluvastatin may be alternative as  metabolized by CYP2C9 and not affected by OATP1B1 major, moderate (DrugReax) 2-major (CP)
HMGs fibric acid derivatives (e.g., fenofibrate, gemfibrozil) adjunctive administration may elevate HMG serum levels, with increased risk of severe MYO, RHAB, due to inhibition of HMG metabolism (CYP2C8; OATP1B1) by gemfibrozil  (CYP2C8, OATP1B1 inhibitor), or additive myopathy risk (fibrates) avoid combination, if possible; if concurrent therapy necessary, use cautiously, closely monitor creatine kinase and observe for MYO, RHAB; use lowest recommended HMG doses major (DrugReax) 2-major (CP)
HMGs protease inhibitors adjunctive administration may increase HMG serum levels and elevate potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB) due to CYP3A4 inhibition and other unknown mechanisms avoid combination therapy, if possible; if combined therapy necessary, monitor for increased adverse effects (e.g., MYO, RHAB) and use lowest recommended HMG dose; may consider pravastatin, an HMG not metabolized by CYP3A4 contraindicated, major, moderate (DrugReax) 1-severe, 2-major, 3-moderate (CP)
Select HMGs amiodarone combined administration may increase risk of  HMG adverse effects [e.g., myopathy (MYO), rhabdomyolysis (RHAB)] most likely due to inhibition of HMG metabolism (CYP3A4, CYP2C9) by amiodarone (CYP3A4, CYP2C9 inhibitor) monitor for MYO, RHAB; use lowest recommended HMG doses; consider using HMG not metabolized by CYP3A4 or CYP2C9, such as pravastatin, if drug combination necessary major, moderate (DrugReax) 2-major, 3-moderate (CP)
Select HMGs azole antifungals combined administration may lead to increased HMG concentrations and potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB) due to inhibition of HMG metabolism (CYP3A4) by azole antifungals  (CYP3A4 inhibitor); fluvastatin with increased risk of adverse effects when prescribed with fluconazole, voriconazole (CYP2C9 inhibitors) posaconazole-HMG combination is contraindicated due to increased risk of MYO/RHAB; avoid adjunctive therapy, if possible with other combinations; if combined therapy necessary, monitor for signs/symptoms of MYO, RHAB; may consider using HMG not metabolized by CYP3A4, CYP2C9 such as pravastatin contraindicated, major (DrugReax) 1-severe, 2-major, 3-moderate (CP)
Select HMGs macrolide antibiotics macrolides (CYP3A4, OATP1B1 inhibitors) prescribed with HMGs metabolized by CYP3A4 or OATP1B1 may increase HMG serum levels and elevate potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB) avoid macrolides with HMGs metabolized by CYP3A4, OATP1B1, if possible; pravastatin, rosuvastatin not metabolized by CYP3A4 and may be alternative HMGs; if combination necessary, monitor for MYO, RHAB major (DrugReax) 1-severe, 2-major (CP)
Select HMGs other CYP3A4 inhibitors (e.g., diltiazem, imatinib, nefazodone, verapamil) CYP3A4 inhibitors administered with HMGs metabolized by CYP3A4  may increase HMG serum levels and elevate potential for enhanced pharmacologic/ adverse effects (e.g., MYO, RHAB) avoid CYP3A4 inhibitors with HMGs metabolized by CYP3A4, if possible; pravastatin, rosuvastatin not metabolized by CYP3A4 and may be alternative HMGs; if combination necessary, use lowest recommended dose and monitor for MYO, RHAB contraindicated, major, moderate (DrugReax) 1-severe, 2-major, 3-moderate (CP)
Select HMGs select NNRT inhibitors (delavirdine, efavirenz) combined administration of delavirdine (CYP3A4 inhibitor) with HMGs metabolized by CYP3A4 may increase HMG serum levels and elevate potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB); alternately, concurrent administration of efavirenz (CYP3A4 inducer) with HMGs metabolized by CYP3A4 may decrease HMG serum levels and potentially decrease therapeutic efficacy monitor for increased adverse effects (e.g., MYO, RHAB) or decreased HMG efficacy; may alter HMG dose or add other lipid-lowering therapy; consider alternative HMGs not metabolized by CYP3A4 major, moderate (DrugReax) 1-severe, 2-major, 3-moderate (CP)

Legend:

  • *CP = Clinical Pharmacology
  • HMG = HMG CoA reductase inhibitor
  • MYO = myopathy
  • NNRT = non-nucleoside reverse transcriptase
  • RHAB = rhabdomyolysis

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: February 21, 2022).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2022. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed February 21, 2022.
  3. Atorvastatin tablets (Lipitor®) package insert. Parke-Davis Division of Pfizer, November 2021.
  4. Fluvastatin capsules package insert. Teva Pharmaceuticals USA, Inc., August 2020.
  5. Fluvastatin extended-release tablets (Lescol® XL) package insert. Novartis Pharmaceuticals Corporation, July 2021.
  6. Lovastatin immediate-release tablets package insert. Teva Pharmaceuticals USA, Inc., August 2020.
  7. Lovastatin extended-release tablets (Altoprev®) package insert. Covis Pharma US, Inc., December 2021.
  8. Pitavastatin calcium tablets (Livalo®) package insert. Kowa Pharmaceuticals America, Inc., May 2019.
  9. Pravastatin tablets (Pravachol®) package insert. Accord Healthcare Inc., May 2021.
  10. Rosuvastatin tablets (Crestor®) package insert. AstraZeneca, September 2020.
  11. Simvastatin tablets (Zocor®) package insert. Merck & Co., Inc., December 2020.
  12. Simvastatin oral suspension (FloLipid®) package insert. Salerno Pharmaceuticals, February 2022.
  13. Pitavastatin magnesium (Zypitamag™) package insert. Medicure Pharma, September 2020.
  14. Rosuvastatin sprinkle capsules (Ezallor Sprinkle™) package insert. Sun Pharmaceutical Industries, September 2020.
  15. Ezetimibe/simvastatin tablet (Vytorin®) package insert. Merck & Co., Inc., December 2020.
  16. Amlodipine/atorvastatin tablets (Caduet®) package insert. Pfizer, March 2021.
  17. Ezetimibe/ Rosuvastatin (Roszet®) package insert. Althera Pharmaceuticals, LLC. September 2021.
  18. Tobert JA, East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA.  Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation. N Engl J Med. 1988;318:47-8.
  19. Spach DH, Bauwens JE, Clark CD, Rhabdomyolysis associated with lovastatin and erythromycin use. West J Med. 1991;154:213-15.
  20. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA. 1990;264:71-5.
  21. Neuvonen PJ, Jalava KM. Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther. 1996;60:54-61.
  22. Neuvonen PJ. Niemi M. Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80:565-81.
  23. Bottorff MB. Statin safety and drug interactions: clinical implications. Am J Cardiol. 2006;97(8A):27C-31C.
  24. Armitage J. The safety of statins in clinical practice. Lancet. 2007;37:1781-90.
  25. Anonymous. Which statin, what dose? Drug Ther Bull. 2007;45:33-7.
  26. Neuvonen PJ, Niemi N, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80:565-81.
  27. Shitara Y, Sugiyama Y.  Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug–drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther. 2006;112:71-105.
  28. Dixit V, Hariparsad N, Li F, et al. Cytochrome P450 enzymes and transporters induced by anti-human immunodeficiency virus protease inhibitors in human hepatocytes: implications for predicting clinical drug interactions. Drug Metab Dispos. 2007;35:1853-9.
  29. Kiser JJ, Gerber JG, Predhomme JA, et al. Drug/drug interaction between loprenavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr.  2008;47:570-8.
  30. Busti AJ, Bain AM, Hall RG II, et al. Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol. 2008;51:605-10.
  31. Winston A, Boffito M. The management of HIV-1 protease inhibitor pharmacokinetic interactions. J Antimicrob Chemother. 2005;56:1-5.

Ivacaftor (Kalydeco) and Lumacaftor/Ivacaftor (Orkambi)

Last Updated

All criteria may be applied retrospectively and each set identifies prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document.

  • Revision history
    • April 22, 2022; Feb. 2020; Jan. 2020; Nov. 2019; Dec. 2017; Feb. 2016; June 2014.
  • Initially developed
    • Oct. 2012

1. Dosage

Ivacaftor is categorized as a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator. Cystic fibrosis (CF) occurs because of CFTR genetic mutations causing mucosal obstruction of the distal lung airway and submucosal glands.  Malfunction of the CFTR alters electrolyte homeostasis, which changes cell potentials and can lead to organ damage in CF patients. Patient genotyping shows that approximately 4% of the 30,000 CF patients in America are believed to have a G551D-CFTR mutation. Kalydeco® (Ivacaftor) targets multi-organ chloride channels at the surface of epithelial cells to enhance the opening of the CFTR protein.

Kalydeco® (ivacaftor) is FDA approved for use in patients 4 months or older who have one mutation in the CFTR gene that is responsive to ivacaftor therapy based on clinical and/ or in vitro assay data. If the patient’s genotype is unknown then an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use 1,2,4. A list of CF mutations indicated for the treatment of CF in patients 4 months of age and older are provided in the list below.

List of CFTR Gene Mutations that Produce Protein and are Responsive to Kalydeco®

  • 711+3A→G*
  • 2789+5G→A*
  • 3272-26A→G*
  • 3849+10kbC→T*
  • A120T
  • A234D
  • A349V
  • A455E*
  • A1067T
  • D110E
  • D110H
  • D192G
  • D579G*
  • D924N
  • D1152H*
  • D1270N
  • E56K
  • E193K
  • E822K
  • E831X*
  • F311del
  • F311L
  • F508C
  • F508C;S1251N†
  • F1052V
  • F1074L
  • G178E
  • G178R*
  • G194R
  • G314E
  • G551D*
  • G551S*
  • G576A
  • G970D
  • G1069R
  • G1244E*
  • G1249R
  • G1349D*
  • H939R
  • H1375P
  • I148T
  • I175V
  • I807M
  • I1027T
  • I1139V
  • K1060T
  • L206W*
  • L320V
  • L967S
  • L997F
  • L1480P
  • M152V
  • M952I
  • M952T
  • P67L*
  • Q237E
  • Q237H
  • Q359R
  • Q1291R
  • R74W
  • R75Q
  • R117C*
  • R117G
  • R117H*
  • R117L
  • R117P
  • R170H
  • R347H*
  • R347L
  • R352Q*
  • R553Q
  • R668C
  • R792G
  • R933G
  • R1070Q
  • R1070W*
  • R1162L
  • R1283M
  • S549N*
  • S549R*
  • S589N
  • S737F
  • S945L*
  • S977F*
  • S1159F
  • S1159P
  • S1251N*
  • S1255P*
  • T338I
  • T1053I
  • V232D
  • V562I
  • V754M
  • V1293G
  • W1282R
  • Y1014C
  • Y1032C

Legend

  • * Clinical data exists for these mutations.
  • † Complex/compound mutations. Most people with CF have 2 CF mutations, 1 on each copy of the CF gene. However, in rare instances, 1 copy of the CF gene can have more than 1 mutation. This is called a compound, or complex, mutation.

A combination product containing lumacaftor and ivacaftor (Orkambi®) was approved in July 2015 for use in patients 2 years and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, then an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. The F508del mutation is the most common cause of CF, with approximately half of the CF population in the U.S. being homozygous for the mutation. The combined effect of lumacaftor and ivacaftor increases the quantity (lumacaftor) and function (ivacaftor) of the F508del-CFTR ion channel, resulting in improved channel function and clinical benefit. The efficacy and safety of lumacaftor and ivacaftor combination therapy has not been established in patients with cystic fibrosis other than those homozygous for the F508del mutation1-3.

Tezacaftor/ivacaftor (Symdeko®) combination therapy is FDA-approved for CF in patients six years of age and older homozygous for the F508del mutation or who have at least one mutation in the CFTR gene responsive to tezacaftor/ivacaftor. If the patient’s genotype is unknown, then an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use. Tezacaftor increases the amount of mature CFTR at the cell surface by expediting cellular processing and trafficking of normal and select mutant forms of CFTR, while ivacaftor enhances channel-opening probability of CFTR proteins at the cell surface. Combined therapy improves CFTR function at the cell surface and increases chloride transport, resulting in clinical benefit1-3, 7. All CFTR protein producing CFTR mutations that are responsive to Symdeko® are listed in the following list8 .

CFTR Mutations that Produce CFTR Protein and Are Responsive to Symdeko®

  • 546insCTA§
  • 711+3A→G*
  • 2789+5G→A*
  • 3272-26A→G*
  • 3849+10kbC→T*
  • A120T§
  • A234D§
  • A349V§
  • A455E*
  • A554E§
  • A1006E§
  • A1067T
  • D110E
  • D110H*
  • D192G§
  • D443Y§
  • D443Y;G576A;R668C‡§
  • D579G*
  • D614G§
  • D836Y§
  • D924N§
  • D979V§
  • D1152H*
  • D1270N
  • E56K
  • E60K§
  • E92K§
  • E116K§
  • E193K
  • E403D§
  • E588V§
  • E822K§
  • E831X
  • F191V§
  • F311del§
  • F311L§
  • F508C§
  • F508C;S1251N‡§
  • F508del†
  • F575Y§
  • F1016S§
  • F1052V
  • F1074L
  • F1099L§
  • G126D§
  • G178E§
  • G178R§
  • G194R§
  • G194V§
  • G314E§
  • G551D§
  • G551S§
  • G576A§
  • G576A;R668C‡§
  • G622D§
  • G970D§
  • G1069R§
  • G1244E§
  • G1249R§
  • G1349D§
  • H939R§
  • H1054D§
  • H1375P§
  • I148T§
  • I175V§
  • I336K§
  • I601F§
  • I618T§
  • I807M§
  • I980K§
  • I1027T§
  • I1139V§
  • I1269N§
  • I1366N§
  • K1060T
  • L15P§
  • L206W*
  • L320V§
  • L346P§
  • L967S§
  • L997F§
  • L1324P§
  • L1335P§
  • L1480P§
  • M152V§
  • M265R§
  • M952I§
  • M952T§
  • P5L§
  • P67L*
  • P205S§
  • Q98R§
  • Q237E§
  • Q237H§
  • Q359R§
  • Q1291R§
  • R31L§
  • R74Q§
  • R74W
  • R74W; D1270N‡§
  • R74W;V201M‡§