Retrospective Drug Use Criteria

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.

C-3. Drug Use Criteria

C-3.1. 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

C-3.1.1. Dosage

C-3.1.1.1. 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.

C-3.1. 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

C-3.1. 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.

C-3.1.1.1.1. 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.

C-3.1.1.2. 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.

C-3.1.2. 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.

C-3.1.3. 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.

C-3.1.4. 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.

C-3.1. 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)

C-3.1.5. 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.
     

C-3.2. 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

C-3.2.1. Dosage

C-3.2.1.1. 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.

C-3.2. 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)

 

C-3.2. 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)

 

C-3.2.1.2. 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.

C-3.2. Table 3: Maximum Recommended Anticholinergic Metered-Dose Inhaler Pediatric Daily Dose

Treatment Indication Drug Name Dosage Form/Strength Patient Age/Maximum Recommended Dosage
asthma tiotropium (Spiriva® Respimat®) inhalation cartridge (1.25 mcg/ actuation) 6-17 years of age: 2 inhalations of 1.25 mcg/ actuation once daily (total dose = 2.5 mcg)

 

C-3.2.2. 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.

C-3.2. 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

C-3.2. 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

C-3.2.3. 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.

C-3.2.4. 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.

C-3.2. 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 

C-3.2.5. 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.

C-3.3. 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

C-3.3.1. 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.

C-3.3.1.1. 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.

C-3.3. 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

C-3.3. 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

C-3.3.1.2. 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.

C-3.3. 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

C-3.3.2. 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. 

C-3.3. 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

C-3.3. 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

C-3.3.3. 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.

C-3.3.4. 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.

C-3.3. 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

C-3.3.5. 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.)

C-3.4. 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

C-3.4.1. 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.

C-3.4.1.1. 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.

C-3.4. 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

 

C-3.4. 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.
     

C-3.4.1.2. 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.

C-3.4. Table 3: Pediatric LABA Maximum Daily Dosage Recommendations for Asthma - Monotherapy

Drug Name Dosage Form/Strength Patient Age/Maximum Recommended Dosage
salmeterol (Serevent® Diskus®) inhalation powder: 50 mcg/inhalation Greater than or equal to 4 years of age: 2 actuations/day (1 actuation twice daily); total dose = 100 mcg/day

C-3.4. 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.

C-3.4.2. 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.

C-3.4. 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

C-3.4. 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

C-3.4.3. 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.

C-3.4.4. 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.

C-3.4. 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

C-3.4.5. 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.

C-3.5. 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

C-3.5.1. Dosage

C-3.5.1.1. 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)

 

C-3.5. Table 2: Maximum Adult Daily Dose for Inhalational Beta2-Adrenergic Agents (Short-Acting) – Combination Therapy

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
chronic obstructive pulmonary disease ipratropium/ albuterol (Combivent Respimat®) inhalation spray (20 mcg ipratropium/ 100 mcg albuterol/ actuation) 6 actuations/day (total dose = 120 mcg ipratropium/ 600 mcg albuterol)

 

C-3.5.1.2. 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.

C-3.5. 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)

 

C-3.5.2. 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.

C-3.5. 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)

C-3.5. Table 5: Days’ Supply for Available Short-Acting Beta2-Adrenergic Agent Metered-Dose Inhalers (Adult Patients) – Combination Therapy

Drug # of Actuations Per Canister Days Supply (based on maximum dose per day) +
Ipratropium/albuterol (Combivent® Respimat®) (4 g cartridge) 120 20 days

 

C-3.5.3. 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.

C-3.5.4. 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.

C-3.5. 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

C-3.5.5. 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.

C-3.6. 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

C-3.6.1. Dosage

C-3.6.1.1. 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.

C-3.6. 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.

C-3.6. 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

C-3.6.1.2. 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.

C-3.6. Table 3: Pediatric Maximum Recommended Dosages for ACE inhibitors in Hypertension

Drug Patient Characteristics Maximum Daily Dosage
benazepril 6 to 17 years of age   0.6 mg/kg/day up to 40 mg/day
enalapril 1 month of age to 17 years of age 0.58 mg/kg/day up to 40 mg/day
fosinopril 6 to 17 years of age (greater than 50 kg)  40 mg daily
lisinopril 6 to 17 years of age 0.6 mg/kg/day up to 40 mg/day

 

C-3.6.2. 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.

C-3.6.3. 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.

C-3.6.4. 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.

C-3.6. 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

C-3.6.5. 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.

C-3.7. 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

C-3.7.1. Dosage

C-3.7.1.1. 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. 

C-3.7. 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

C-3.7. 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

C-3.7.1.2. 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.

C-3.7. 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

C-3.7.2. 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.

C-3.7.3. 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.

C-3.7.4. 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.

C-3.7. 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

C-3.7.5. 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.

C-3.8. 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

C-3.8.1. Dosage

C-3.8.1.1. 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.

C-3.8. 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

C-3.8. 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
     

C-3.8. 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

C-3.8. 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.

C-3.8. 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 

C-3.8. 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

C-3.8. 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.

C-3.8.1.2. 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.

C-3.8. 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

C-3.8. 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

C-3.8. 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

C-3.8. Table 11: Pediatric Maximum Recommended Antidepressant Drug Dosages (Monotherapy) - Tetracyclic Antidepressants

Treatment Indication Drug Name Available Dosage Strengths Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
Major depressive disorder mirtazapine (Remeron®, generics) 7.5 mg, 15 mg, 30 mg, 45 mg tablets; 15 mg, 30 mg, 45 mg orally disintegrating tablets Age ≥ 3 years: 45 mg/day Not approved for pediatric use

 

C-3.8.1.3. 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.

C-3.8. Table 12: Select non-SSRI Antidepressant Dosage Modifications in Renal Impairment – Tetracyclic Antidepressants

Drug Name Dosage in Renal Impairment 
Mirtazapine Initiate with the lowest dosage and titrate slowly as renal clearance reduced by approximately 30% in moderate (CrCl 11-39 ml/min) and 50% in severe (CrCl less than 10 ml/min) renal impairment

 

C-3.8. Table 13: Select non-SSRI Antidepressant Dosage Modifications in Renal Impairment – Monoamine Oxidase Inhibitors

Drug Name Dosage in Renal Impairment 
Isocarboxazid Contraindicated in severe renal impairment; use cautiously in moderate renal impairment due to potential accumulation of active metabolites
Phenelzine Contraindicated for use in severe renal impairment
Tranylcypromine Use cautiously in renal impairment due to potential for cumulative effects

 

C-3.8. 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 

C-3.8. 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

C-3.8.2. 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.

C-3.8.3. 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.

C-3.8.4. 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.

C-3.8. 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

C-3.8.5. 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. 

C-3.9. 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

C-3.9.1. Dosage

C-3.9.1.1. 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.

C-3.9. 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
     

C-3.9. 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

C-3.9.1.2. 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.

C-3.9. 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

C-3.9. Table 4: Recommended SSRI Antidepressant Drug Dosages for Pediatric Patients – Combination Therapy

Treatment Indication Drug Name Available Dosage Strengths Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
BD 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 Age 10-17 years: 12 mg olanzapine/50 mg fluoxetine once daily 10 to 17 years of age: 12 mg/50 mg per day

Legend:

  • BD = bipolar I disorder

C-3.9.1.3. 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.

C-3.9. 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

C-3.9.2. 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.

C-3.9.3. Duplicative Therapy

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

C-3.9.4. 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.

C-3.9. 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

C-3.9.5. 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.

C-3.10. 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

C-3.10.1. Dosage

C-3.10.1.1. 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.

C-3.10. 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
     

C-3.10. 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

C-3.10.1.2. 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.

C-3.10. 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

 

C-3.10.2. 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.

C-3.10.3. 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.

C-3.10.4. 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.

C-3.10. 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.

C-3.10.5. 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.

C-3.12. 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

C-3.12.1. Dosage

C-3.12.1.1. 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.

C-3.12. 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

C-3.12. 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

C-3.12. 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

C-3.12.1.2. 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.

C-3.12.2. 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.

C-3.12.3. 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.

C-3.12.4. 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.

C-3.12. 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)

C-3.12.5. 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.

C-3.13. 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

C-3.13.1. Dosage

C-3.13.1.1. 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.

C-3.13. 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

C-3.13. 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

C-3.13.1.2. 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.

C-3.13. 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

C-3.13. 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

C-3.13.2. 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.

C-3.13.3. 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.

C-3.13.4. 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.

C-3.13. 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.

C-3.13.5. References

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  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.
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  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.
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C-3.16. 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

C3.16.1. 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.

C3.16.1.1. 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.

C3.16. 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

C3.16. Table 2: Adult Recommended COX-2 Inhibitors Maximum Daily Dosages Combination Therapy)

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
hypertension in patients with osteoarthritis amlodipine/celecoxib (Consensi®) 2.5 mg/ 200 mg, 5 mg/ 200 mg, 10 mg/ 200 mg tablets 10 mg/ 200 mg/day

 

C3.16.1.2. 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.

C3.16. 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

 

C3.16.1.3. 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.

C3.16.2. 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. 

C3.16.2.1. 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.

C3.16.2.2. 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.

C3.16.2.3. 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.

C3.16.2.4. 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.

C3.16.3. 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.

C3.16.4. 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.

C3.16. 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

C3.16.5. 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.

C-3.18. 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

C-3.18.1. Dosage

C-3.18.1.1. 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

C-3.18. 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.

C-3.18.1.2. 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)

C-3.18. 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 

C-3.18. 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

C-3.18. 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

C-3.18. 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

C-3.18. 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 

C-3.18. 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

C-3.18.1.3. 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.

C-3.18. 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

C-3.18. 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.

C-3.23. 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.

C3.23.1. 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.

C3.23.1.1. 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.

C3.23. 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.

C3.23. 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

C3.23. Table 3: Adult Maximum Daily Dose for Histamine H2-Receptor Antagonists - Combination Therapy

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
gastric ulcer prophylaxis in osteoarthritis or rheumatoid arthritis famotidine/ ibuprofen (Duexis®) 26.6 mg/ 800 mg oral tablets 79.8 mg / 2400 mg/day in three divided doses

C3.23.1.2. Pediatrics

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

C3.23. 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.

C3.23. Table 5: Pediatric Maximum Daily Maintenance Doses for Histamine H2-Receptor Antagonists

Treatment Indication Drug Name Patient Characteristics Maximum Recommended Dosage
duodenal ulcer cimetidine (generics) Greater than or equal to 16 years of age 400 mg at bedtime
hypersecretory conditions   Greater than or equal to 16 years of age 2400 mg/day

 

C3.23.1.3. Dosage in Renal Impairment

H2RAs are primarily renally excreted. Dosage modifications for H2RA use in renal impairment are summarized in Table 6.

C3.23. 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

C3.23.2. 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.

C3.23.3. 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.

C3.23.4. 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.

C3.23. 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

C3.23.5. 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.

C-3.28. Ketorolac (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.

  • Revised
    • July 23, 2021; May 24, 2019; May 2016; December 2014; March 2013; May 2011; January 2009; October 2003; October 2002; September 2001; October 2000; September 1999; September 1998; September 1997; October 1996; October 1995
  • Initially developed
    • February 1995

C3.28.1. Dosage

C3.28.1.1. Adults

Intranasal or oral ketorolac, a nonsteroidal anti-inflammatory drug (NSAID), is FDA-approved for short-term (no more than 5 days) management of acute moderate to severe pain, usually in the postoperative setting, that requires pain management at the opioid level.

Oral ketorolac is only approved for use after therapy initiation with intravenous or intramuscular ketorolac. Therefore, a prescription for a parenteral form of ketorolac should precede treatment with oral ketorolac to satisfy manufacturer and FDA recommendations.

The maximum recommended dosage for oral ketorolac is 40 mg/24 hours given in divided doses every 4 to 6 hours. Dosages exceeding this recommendation will be reviewed.

Intranasal ketorolac is dosed as one spray (15.75 mg) in each nostril every 6 to 8 hours for a maximum total of 8 sprays (126 mg) in a 24-hour period for patients less than 65 years of age. In patients with renal impairment, age greater than or equal to 65 years, or those weighing less than 50 kg, intranasal ketorolac should be dosed as one spray (15.75 mg) in one nostril every 6 to 8 hours for a total of 4 doses (63 mg) per 24-hour period.   Discard the intranasal ketorolac bottle after 24 hours, even if liquid is still present in the bottle, as the delivery system is not designed to deliver the intended dose after 24 hours.

C3.28.1.2. Pediatrics

Oral ketorolac is not FDA-approved for pediatric patients younger than 17 years of age as safety and efficacy in this age group have not been established. In adolescents 17 years of age and older, the maximum oral daily ketorolac dose is 40 mg in divided doses as continuation from parenteral ketorolac therapy. The maximum intranasal dose in pediatric patients 17 years of age and older is 126 mg per 24 hours in divided doses [one spray (15.75 mg) in each nostril (31.5 mg total) every 6 to 8 hours]. Discard the intranasal ketorolac bottle after 24 hours, even if liquid is still present in the bottle, as the delivery system is not designed to deliver the intended dose after 24 hours.

C3.28.2. Duration of Therapy

C3.28.2.1. Therapy Limits

The maximum treatment duration for oral and parenteral ketorolac, combined, is 5 days due to increased frequency and severity of adverse effects associated with extended use. The maximum treatment period for nasal ketorolac when used as monotherapy or sequentially with other ketorolac dosage forms is also 5 days.  Treatment regimens exceeding these requirements will be reviewed.

C3.28.2.2. NSAID Use and Elderly Patients

Elderly patients frequently utilize prescription and nonprescription NSAIDs to manage acute and chronic pain. Several issues surface with NSAID use in elderly patients, including potential adverse effects and drug interactions. NSAID-induced gastrointestinal and 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. The majority of fatal gastrointestinal events associated with ketorolac use have been seen in elderly or debilitated patients. The potential for increased cardiovascular risk with NSAID use is also a factor when evaluating NSAID therapy in elderly patients. Elderly patients prescribed NSAIDs, especially those at higher risk, should be evaluated for appropriateness of therapy as well as potential for drug-drug interactions. Appropriate ketorolac therapy duration as well as appropriate dosages should also be evaluated.

C3.28.2.3. 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.

C3.28.2.4. NSAID use and Gastrointestinal Risk

All NSAIDs 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. Ketorolac has a greater incidence of gastritis, gastric ulceration with or without perforation and gastric bleeding compared to other NSAIDs and is contraindicated for use in patients with a history of or active peptic ulcer disease, GI bleeding, or perforation, and should be used cautiously in patients with other types of GI disease (e.g., inflammatory bowel disease). Additionally, total systemic use for ketorolac is limited to 5 days due to increased incidence of severe adverse events, including GI events, with prolonged use.

C3.28.3. Duplicative Therapy

Adjunctive use of ketorolac with other ketorolac dosage forms, aspirin or other NSAIDs is contraindicated as combined therapy may result in an increased risk of gastrointestinal (GI) adverse effects and may also increase serum ketorolac levels. Therefore, concurrent ketorolac use with these agents will be reviewed.

C3.28.4. 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 ketorolac are summarized in Table 1. 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.

C3.28. Table 1: Ketorolac Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
ketorolac pentoxifylline adjunctive administration may increase bleeding risk, due to unknown mechanism combined therapy contraindicated contraindicated (DrugReax) 1 - severe (CP)
ketorolac phenytoin concurrent administration increases seizure risk due to unknown mechanism; ketorolac may displace phenytoin from binding sites monitor for seizures, signs/symptoms of phenytoin toxicity; adjust phenytoin doses as necessary major (DrugReax) 3 - moderate (CP)
ketorolac probenecid combined administration may increase ketorolac serum concentrations and potential for enhanced pharmacologic/adverse effects due to decreased ketorolac clearance adjunctive administration contraindicated contraindicated (DrugReax) 1 - severe (CP)
NSAIDs antihypertensive agents (e.g., angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, diuretics) potential for decreased antihypertensive effects, increased renal impairment risk (especially in patents dependent on renal prostaglandins for perfusion), with combined therapy; increased hyperkalemia risk with potassium-sparing diuretics; NSAIDs may block production of vasodilator and natriuretic prostaglandins monitor blood pressure, renal function; observe for hyperkalemia with potassium-sparing diuretics; modify therapy as necessary; use combination cautiously in elderly; sulindac, nonacetylated salicylates may be alternative NSAIDS – have less inhibitory effect on prostaglandin synthesis moderate (DrugReax) 3 - moderate (CP)
NSAIDs antiplatelet drugs (e.g., clopidogrel, prasugrel) potential for increased bleeding risk due to additive inhibitory effects on platelet aggregation administer cautiously together; monitor for increased bleeding, especially gastrointestinal (GI) bleeding clopidogrel –major;
prasugrel - moderate (DrugReax) 3-moderate (CP)
NSAIDs bisphosphonates combined therapy may result in additive GI, renal toxicity; NSAIDs also decrease bone mineral density, may attenuate bone mineral stabilizing effects by bisphosphonates administer combination cautiously; monitor for increased GI/renal adverse effects, reduced bone mineral density 2-major (CP)
NSAIDs corticosteroids potential for increased GI adverse effects with combined therapy monitor for adverse effects; avoid prolonged concurrent administration 3-moderate (CP)
NSAIDs cyclosporine increased risk for additive renal dysfunction with concurrent administration; potential for reduced cyclosporine elimination/ increased pharmacologic and adverse effects due to NSAID effects on renal prostaglandins; NSAIDs may mask signs of infection (e.g., fever, swelling) use cautiously together; monitor clinical status and signs/symptoms of cyclosporine toxicity (e.g., renal dysfunction, cholestasis, paresthesias) moderate (DrugReax) 3 - moderate (CP)
NSAIDs fluoroquinolones increased risk for seizures, potentially due to inhibition of gamma aminobutyric acid (GABA) which results in CNS stimulation administer cautiously together; consider alternative therapy in patients with predisposition to seizures moderate (DrugReax) 3-moderate (CP)
NSAIDs lithium NSAIDs like ketorolac decreases lithium clearance by blocking renal tubular prostaglandins; 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 when ketorolac therapy initiated or discontinued moderate (DrugReax) 3 - moderate (CP)
NSAIDs low molecular weight heparins potential for additive bleeding adverse effects; NSAIDs inhibit platelet aggregation and have increased GI bleeding risk, prolonged bleeding time avoid concurrent therapy, if possible; if drug combination necessary, use cautiously, monitor for signs/symptoms of bleeding  major (DrugReax) 2-major (CP)
NSAIDs methotrexate (MTX) potential for increased MTX serum levels, risk of enhanced pharmacologic/toxic effects as NSAIDs like ketorolac can reduce MTX clearance avoid concurrent NSAIDs prior to, concurrently or following intermediate or high-dose MTX; use cautiously together with low-dose MTX; monitor for increased myelopsuppressive, GI adverse effects; may consider using longer leucovorin rescue major (DrugReax) 1 - severe (CP)
NSAIDs SSRIs/SNRIs (e.g., milnacipran) increased bleeding risk with combined therapy, especially GI bleeding;  SSRIs/SNRIs deplete platelet serotonin, which may impair platelet aggregation monitor for signs/ symptoms of bleeding; may consider shorter treatment duration, adding proton pump inhibitor, or substituting tricyclic antidepressant for SSRI/SNRI or acetaminophen for NSAID major, moderate (DrugReax) 3 - moderate (CP)
NSAIDs sulfonylureas increased risk for additive hypoglycemia due to inhibition of sulfonylurea metabolism monitor serum glucose concentrations; adjust doses as necessary moderate (DrugReax)
NSAIDs tacrolimus potential for additive nephrotoxicity with combined therapy due to NSAID inhibitory effects on renal prostaglandins avoid combination, if possible; if concurrent therapy necessary, closely monitor renal function major (DrugReax) 3 - moderate (CP)
NSAIDs warfarin combined therapy may increase risk of GI bleeding as NSAIDs, including ketorolac, inhibit platelet aggregation and may cause gastric erosion monitor anticoagulant activity and signs of bleeding, especially in first several days of combination therapy; adjust warfarin doses as necessary moderate (DrugReax) 2 - major (CP)

Legend:

  • * Clinical Pharmacology
  • NSAIDs = nonsteroidal anti-inflammatory drugs
  • SNRIs = serotonin-norepinephrine reuptake inhibitors
  • SSRIs = selective serotonin reuptake inhibitors

C3.28.5. 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 10, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed June 10, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; June 10, 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 10, 2021.
  5. Ketorolac tromethamine nasal spray (Sprix®) package insert. Zyla Life Sciences US Inc., April 2021.
  6. 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;1633-44.
  7. Garnock-Jones K. Intranasal ketorolac for short-term pain management. Clin Drug Investig. 2012;32(6):361-71.
  8. 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 10, 2021.
  9. 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.

C-3.29. Leukotriene Receptor Antagonists

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 2019; March 2016; June 2014; October 2012; November 2010; October 2010; September 2007; June 2007; March 2007
  • Initially developed
    • February 2007

C3.29.1. Dosage

Leukotrienes are inflammatory molecules released by mast cells in response to inhaled allergens. Cysteinyl leukotrienes bind to receptors on airway smooth muscle and macrophages and activate a number of airway effects, ultimately resulting in bronchoconstriction and inflammation associated with asthma, as well as the pathophysiologic effects associated with allergic rhinitis. Leukotriene receptor antagonists (LTRAs) prevent binding of cysteinyl leukotrienes to active receptors. Currently available LTRAs include montelukast and zafirlukast, with montelukast FDA-approved for prevention and chronic management of asthma in adults and children 12 months of age and older, seasonal allergic rhinitis in adults and children 2 years of age and older, perennial allergic rhinitis in adults and children 6 months of age and older, and prevention of exercise-induced bronchoconstriction in adults and children 6 years of age and older. Zafirlukast is only FDA-approved for use in preventing and managing chronic asthma in adults and children 5 years of age and older.

The Expert Panel created by the National Heart, Lung and Blood Institute considers LTRAs to be alternative, not preferred, treatment options for mild to moderate persistent asthma, and alternative, not preferred, adjunctive therapy with inhaled corticosteroids for mild to moderate persistent asthma. The GINA guidelines consider LTRAs to be an option for children > 5 years of age, adolescents, and adults at all levels of severity, although clinical benefit is not as significant as that seen with low-dose inhaled corticosteroids. In adult patients, LTRAs may be used as an alternative therapy for mild persistent asthma; however, when used as monotherapy, LTRAs are less effective than low-dose inhaled corticosteroids and may contribute to loss of asthma control if substituted in patients already maintained on inhaled corticosteroid therapy. LTRAs may also be utilized as add-on treatment in patients not adequately controlled on low-dose inhaled corticosteroids and may contribute to inhaled corticosteroid dosage reductions in adults with moderate persistent or severe asthma. However, most studies have shown that long-acting inhaled beta2-agonists are more effective than LTRAs as add-on therapy. In pediatric asthma patients, GINA guidelines state that LTRAs provide partial protection against exercise-induced bronchoconstriction and provide moderate clinical improvement with reduced exacerbations when used as adjunctive therapy in patients inadequately controlled with low-dose inhaled corticosteroids. In moderate persistent asthma, however, increasing inhaled corticosteroid doses is more effective than adding LTRAs to existing therapy, and in moderate-to-severe persistent asthma, the addition of montelukast has not been shown to decrease the use of inhaled corticosteroids.

C3.29.1.1. Adults

Adult dosage recommendations for LTRAs are summarized in Table 1. Patient profiles containing dosages not conforming to these recommendations will be reviewed.

C3.29. Table 1: LTRA Adult Dosage Recommendations

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
asthma montelukast (Singulair®, generics) 10 mg tablets, 4 mg, 5 mg chewable tablets, 4 mg oral granule packets 10 mg once daily in the evening 
prophylaxis, exercise-induced bronchoconstriction     10 mg as a single dose, at least 2 hours before exercise; dose should not be repeated within 24 hours of previous dose
perennial and/or seasonal allergic rhinitis     10 mg daily
asthma zafirlukast (Accolate®, generics) 10 mg, 20 mg tablets 20 mg twice daily

 

C3.29.1.2. Pediatrics

Pediatric dosage recommendations for LTRAs are summarized in Table 2. Patient profiles containing dosages not conforming to these recommendations will be reviewed.

C3.29. Table 2: LTRA Pediatric Dosage Recommendations

Treatment Indication Drug Nam Dosage Form/Strength Maximum Recommended Dosage
asthma montelukast (Singulair®, generics) 10 mg tablets, 4 mg, 5 mg chewable tablets, 4 mg oral granule packets
  • adolescents greater than or equal to 15 years of age:
    • 10 mg once daily in the evening (as tablet)
  • children 6-14 years of age:
    • 5 mg once daily in the evening (as chewable tablet)
  • children 2-5 years of age:
    • 4 mg once daily in the evening (as chewable tablet or oral granules)
  • children 12–23 months of age:
    • 4 mg once daily in the evening (as oral granules)
prophylaxis, exercise-induced bronchoconstriction    
  • adolescents greater than or equal to 15 years of age:
    • 10 mg as a single dose, at least 2 hours before exercise; dose should not be repeated within 24 hours of previous dose
  • children 6 to 14 years of age:
    • 5 mg (as chewable tablet) as a single dose, at least 2 hours before exercise; dose should not be repeated within 24 hours of previous dose
seasonal allergic rhinitis    
  • adolescents greater than or equal to 15 years of age:
    • 10 mg daily (as tablet)
  • children 6-14 years of age:
    • 5 mg daily (as chewable tablet)
  • children 2-5 years of age:
    • 4 mg daily (as chewable tablet or oral granules)
perennial allergic rhinitis
 
   
  • adolescents greater than or equal to 15 years of age:
    • 10 mg daily (as tablet)
  • children 6-14 years of age:
    • 5 mg daily (as chewable tablet)
  • children 2-5 years of age:
    • 4 mg daily (as chewable tablet or oral granules)
  • children 6-23 months of age:
    • 4 mg daily (as oral granules)
asthma zafirlukast (Accolate®, generics) 10 mg, 20 mg tablets
  • adolescents greater than or equal to 12 years of age:
    • 20 mg twice daily
  • children 5-11 years of age:
    • 10 mg twice daily

C3.29.2. Duration of Therapy

LTRAs are indicated for the management of chronic asthma and seasonal allergic rhinitis and may be continued indefinitely, as both allergic rhinitis and asthma are chronic, lifelong processes.

C3.29.3. Duplicative Therapy

Zileuton (Zyflo®), a 5-lipoxygenase inhibitor, inhibits formation of cysteinyl leukotrienes. Concurrent administration of LTRAs with zileuton does not provide additional clinical benefit and may increase risk of developing adverse events. Concurrent administration of LTRAs with zileuton is not recommended and will be reviewed.

Adjunctive administration of montelukast and zafirlukast does not provide additional clinical benefit and may result in additive adverse effects. Combined administration of montelukast and zafirlukast is not recommended and will be reviewed.

C3.29.4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.

No dosage adjustments are necessary when montelukast is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, digoxin, warfarin, thyroid hormones, sedative hypnotics, nonsteroidal anti-inflammatory agents, benzodiazepines, decongestants, and cytochrome P450 enzyme inducers. Continuous monitoring for montelukast efficacy is recommended when concurrently taking cytochrome P450 enzyme inducers.

Drug-drug interactions considered clinically relevant for zafirlukast are summarized in Table 3. 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.

C3.29. Table 3: Zafirlukast Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
zafirlukast erythromycin, clarithromycin decreased zafirlukast concentrations; mechanism unknown monitor patient for lack of response to zafirlukast therapy; may consider azithromycin or montelukast as alternatives 3-moderate (CP) moderate (DrugReax)
zafirlukast drugs metabolized by CYP2C9 (e.g., warfarin, phenytoin) increased concentrations of drugs metabolized by CYP2C9 due to zafirlukast enzyme inhibition; prothrombin time increased by 35% with warfarin-zafirlukast combination monitor for increased adverse events (e.g., regularly assess PT or INR with warfarin-zafirlukast combination, phenytoin levels) 2-major (CP) moderate (DrugReax)
zafirlukast other drugs metabolized by CYP3A4 (e.g., dofetilide, ergot alkaloids, aripiprazole, cilostazol) increased concentration of drugs metabolized by CYP3A4 due to CYP3A4 inhibition by zafirlukast carefully monitor patient therapy for potentially enhanced pharmacologic effects and toxicity 2-major (CP) minor (DrugReax)
zafirlukast pimozide increased pimozide concentrations resulting in QTc prolongation and ventricular arrhythmias due to CYP3A4 inhibition by zafirlukast contraindicated 1-severe (CP)
zafirlukast saquinavir (boosted with ritonavir) saquinavir and zafirlukast are CYP3A4 inhibitors; combined use may increase saquinavir serum levels and potentially result in life-threatening arrhythmias (including torsades de pointes) contraindicated 1-severe (CP)
zafirlukast theophylline increased theophylline concentration due to CYP 1A2 inhibition by zafirlukast and/or decreased zafirlukast serum levels monitor for theophylline toxicity and/or reduced zafirlukast efficacy 3-moderate (CP) moderate (DrugReax)

Legend:

  • *CP = Clinical Pharmacology

C3.29.5. 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. Montelukast (Singulair®) package insert. Merck & Co., February 2021.
  5. Zafirlukast (Accolate®) package insert. Par Pharmaceutical Companies, Inc., November 2018.
  6. U.S. Department of Health and Human Services. National Institutes of Health. National Heart, Lung and Blood Institute. National Asthma Education and Prevention Program. Expert Panel 3: guidelines for the diagnosis and management of asthma. Full report 2007. NIH Publication No. 08-4051. Available at: Accessed June 11, 2021.
  7. 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 June 11, 2021. 
  8. Global Initiative for Asthma. Global strategy for asthma management and prevention. Updated 2021. Available at: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf. Accessed June 11, 2021.
  9. Currie GP, McLaughlin K. The expanding role of leukotriene receptor antagonists in chronic asthma. Ann Allergy Asthma Immunol. 2006;97:731-42.
  10. Ducharme FM, Lasserson TJ, Cates CJ. Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma. Cochrane Database Syst Rev. 2011; Issue 5. Art. No.: CD003137. DOI:10.1002/14651858.CD003137.pub4.
  11. Li JT, Oppenheimer J, Bernstein IL, et al, and the Joint Task Force on Practice Parameters for the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Attaining optimal asthma control: a practice parameter. J Allergy Clin Immunol. 2005;116(5 Suppl):S3-S11.
  12. Nassef M, Shapiro G, Casale TB, on behalf of the Respiratory & Allergic Disease Foundation. Identifying and managing rhinitis and its subtypes: allergic and nonallergic components – a consensus report and materials from the Respiratory & Allergic Disease Foundation.  Curr Med Res Opin. 2006;22:2541-48.
  13. Jiang RS. Efficacy of a leukotriene receptor antagonist in the treatment of perennial allergic rhinitis. J Otolaryngol. 2006;35:117-21.
  14. Mucha SM, deTineo M, Naclerio RM, Baroody FM. Comparison of montelukast and pseudoephedrine in the treatment of allergic rhinitis.  Arch Otolaryngol Head Neck Surg. 2006;132:164-72.
  15. Di Lorenzo G, Pacor ML, Pellitteri ME, et al. Randomized placebo-controlled trial comparing fluticasone aqueous nasal spray in monotherapy, fluticasone plus cetirizine, fluticasone plus montelukast and cetirizine plus montelukast for seasonal allergic rhinitis. Clin Exp Allergy.  2004;34:259-67.
  16. Nayak A, Langdon RB. Montelukast in the treatment of allergic rhinitis: an evidence-based review.  Drugs. 2007;67:887-901.
  17. Strunk RC, Bacharier LB, Phillips BR, et al.  Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe childhood asthma study. J Allergy Clin Immunol. 2008;122(6):1138-44.
  18. Lofdahl CG, Reiss TF, Leff JA, et al. Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ.1999;319(7202):87-90.
  19. Miligkos M, Bannuru RR, Alkofide H, et al. Leukotriene-receptor antagonists versus placebo in the treatment of asthma in adults and adolescents: a systematic review and meta-analysis. Ann Intern Med. 2015;163(10):756-67.

C-3.31. Mecasermin

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 2019; May 2016; August 2015; December 2013; February 2012; June 2010; May 2010; May 2007
  • Initially developed
    • December 2006

C3.31.1. Dosage

Mecasermin (Increlex®) is the recombinant DNA form of human insulin-like growth factor-1 (rhIGF-1). In normal circulation, over 98% of rhIGF-1 is available in bound form to IGFBP-3, which allows IGF-1 to remain inactive until released to target tissues. This reduces the potential for adverse events associated with free levels of IGF-1. In patients with growth hormone insensitivity syndrome, the serum half-life of unbound IGF-1 is decreased, as these patients have lower rhIGFBP-3 concentrations. Patients with IGF-1 gene deletion have normal levels of rhIGFBP-3. Mecasermin is FDA-approved for use in treating growth failure in children with severe primary IGF-1 deficiency (primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. Mecasermin has also been evaluated for use in short children with low IGF-1 levels; results showed improvement in height velocities following mecasermin use compared to untreated patients after one year of treatment.1-4

C3.31.1.1. Pediatrics

Mecasermin is approved for use in children 2 years of age and older but has not been studied in adults. Mecasermin should not be used in children whose bone growth plates are closed (epiphyseal closure), as linear growth is no longer possible in these patients. Additionally, mecasermin safety and efficacy have not been determined in children younger than 2 years of age. The recommended initial mecasermin dosage is 0.04 to 0.08 mg/kg twice daily subcutaneously, which can be titrated up in increments of 0.04 mg/kg, if tolerated, to a maximum dose of 0.12 mg/kg twice daily (total: 0.24 mg/kg/day). Patient profiles containing prescriptions for doses exceeding these recommendations will be reviewed.1-4

Mecasermin should be administered with food or a snack as IGF-1 decreases hepatic glucose production and increase peripheral glucose utilization and may induce hypoglycemia. Mecasermin administration should be withheld in patients unable or unwilling to eat a meal prior to mecasermin dosing.1-4

C3.31.2. Duration of Therapy

Five clinical studies evaluated mecasermin use in 71 pediatric patients with severe primary IGF-1 deficiency (one double-blind, placebo-controlled trial and four open-label trials). Results revealed 61 patients completed at least one year of treatment and 13 patients received mecasermin therapy for 8 years. The mean change in height velocity significantly increased from baseline in mecasermin-treated patients for treatment years 1 through 6. Therapy continuation is recommended until epiphyses fuse and full growth potential is reached. However, a maximum treatment duration has not been defined for mecasermin.4-8

C3.31.3. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: May 17, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed May 17, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; May 17, 2021.
  4. Mecasermin [rDnA origin] injection (Increlex®) package insert. Ipsen Biopharmaceuticals, Inc., May 2020.
  5. Chernausek SD, Backeljauw PF, Frane J, et al for the GH Insensitivity Syndrome Collaborative Group. Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol Metab. 2007;92(3):902-10.
  6. Bright GM, Mendoza JR, Rosenfeld RG. Recombinant human insulin-like growth factor-1 treatment: ready for primetime. Endocrinol Metab Clin N Am. 2009;38:625-38.
  7. Midyett LK, Rogol AD, Van Meter QL, et al. Recombinant insulin-like growth factor (IGF)-I treatment in short children with low IGF-I levels:  first-year results from a randomized clinical trial. J Clin Endocrinol Metab.  2010;95: 611–9.
  8. Cohen J, Blethen S, Kuntze J, et al. Managing the child with severe primary insulin-like growth factor-1 deficiency (IGFD): IGFD diagnosis and management. Drugs R D. 2014;14:25-9.

C-3.32. Memantine

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 2019; May 2017; November 2015; March 2014; March 2012
  • Initially developed
    • April 2010

C3.32.1. Dosage

C3.32.1.1. Adults

Memantine, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist, is FDA-approved for use in the palliative management of moderate-to-severe Alzheimer’s disease. Glutamate, the key excitatory neurotransmitter in the central nervous system, 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. Memantine exerts pharmacologic effects by blocking glutamate activity. However, memantine has not been shown to delay or prevent neurodegeneration in Alzheimer’s disease patients.

Memantine is available as an immediate-release (IR) tablet and solution as well as extended-release (ER) capsule. A combination product containing donepezil and memantine extended-release (Namzaric®) is also available for use in patients with moderate to severe Alzheimer’s dementia stabilized on donepezil. Acetylcholinesterase inhibitors like donepezil exert pharmacologic effects by increasing availability of intrasynaptic acetylcholine in the presence of intact cholinergic neurons. 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.

Recommended memantine and memantine/donepezil dosages are summarized in Table 1. Patient profiles documenting dosages exceeding these recommendations will be reviewed.

In patients with severe renal impairment (creatinine clearance 5-29 mL/min, based on Cockcroft-Gault equation), the memantine target IR dose should be reduced to 5 mg orally twice daily, while memantine ER maximum dosages should not exceed 14 mg once daily. 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 may utilize memantine/donepezil combination therapy in doses not exceeding 14 mg/10 mg daily.

While Tariot et al. have shown beneficial improvements in cognitive and behavioral performance when memantine is administered in combination with donepezil, a recent trial by Howard and cohorts and systematic review by Tricco et al. revealed that monotherapy with memantine or donepezil was significantly better than no therapy, but combined therapy did not produce significant improvements in cognitive and functional outcomes compared to donepezil alone. Although not FDA-approved, memantine therapy has demonstrated some efficacy in treating mild-to-moderate vascular dementia and Parkinson’s disease dementia. Memantine has been approved as an extended-release formulation to simplify the dosage regimen and improve compliance/adherence.

C3.32. Table 1: Approved Memantine Adult Dosage Recommendations - Monotherapy

Drug Name Dosage Form/Strength Titration Dose ^ Maximum Recommended Dosage
memantine IR* (Namenda®) 5 mg, 10 mg tablets
2 mg/ml oral solution
Week 1: 5 mg orally once daily
Week 2: 5 mg orally twice daily
Week 3: 10 mg in am, 5 mg in pm
Week 4: 10 mg orally twice daily 
20 mg/day, in divided doses
memantine ER+ (Namenda XR®) 7 mg, 14 mg, 21 mg, 28 mg capsules Week 1: 7 mg orally once daily
Week 2: 14 mg orally once daily
Week 3: 21 mg orally once daily
Week 4: 28 mg orally once daily
28 mg/day as a single dose

Legend:

  • *IR = immediate-release
  • +ER = extended-release
  • ^Titrate in weekly intervals to next dose, only if previous dose tolerated

C3.32. Table 2: Approved Memantine Adult Dosage Recommendations - Combination Therapy

Drug Name Dosage Form/Strength Titration Dose^ Maximum Recommended Dosage
memantine extended-release/donepezil (Namzaric®) 7 mg/10 mg, 14 mg/ 
10 mg, 21 mg/ 10 mg, 
28 mg/ 10 mg capsules
NA 28 mg/10 mg once daily

Legend:

  • ^Titrate in weekly intervals to next dose, only if previous dose tolerated

C3.32.1.2. Pediatrics

Memantine is not recommended for use in children and adolescents as safety and efficacy have not been established in the pediatric population.

C3.32.2. Duration of Therapy

Memantine may be prescribed chronically until the dementia associated with Alzheimer’s disease becomes unresponsive to therapy.

C3.32.3. Duplicative Therapy

Adjunctive administration of memantine with other NMDA antagonists, such as amantadine and dextromethorphan, has not been clinically evaluated. Therefore, memantine should be prescribed cautiously, if at all, with other available NMDA antagonists. 

C3.32.4. 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 memantine are summarized in Table 3. 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.

C3.32. Table 3: Memantine Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
memantine, memantine/ donepezil alkalinizing agents (e.g., select carbonic anhydrase inhibitors, sodium bicarbonate) memantine clearance reduced by about 80% in alkaline conditions (pH greater than or equal to 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)
memantine, memantine/ donepezil 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)

Legend:

  • #CP = Clinical Pharmacology

C3.32.5. References

  1. Memantine tablets/oral solution (Namenda®) package insert. Allegan USA, Inc., November 2018.
  2. Memantine extended-release capsules (Namenda XR®) package insert. Allergan USA, Inc., November 2019.
  3. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: May 17, 2021).
  4. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed May 17, 2021.
  5. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; May 17, 2021.
  6. AHFS Drug Information 2021. Jackson, WY: Teton Data Systems.  Stat!Ref Electronic Medical Library. Available at: http://online-statref-com.libproxy.uthscsa.edu/. Accessed May 17, 2021.
  7. Memantine and donepezil extended-release capsules (Namzaric) package insert. Allergan USA, Inc., January 2019.
  8. Anonymous. Namzaric--a combination of 2 old drugs for Alzheimer's disease. Med Lett Drugs Ther. 2015;57(1473):105-6.
  9. Pharmacotherapy choices for patients with dementia. Pharmacist's Letter/Prescriber's Letter 2008;24(5):240510.
  10. Qaseem A, Snow V, Cross JT, et al, and the Joint American College of Physicians/American Academy of Family Physicians Panel on Dementia.  Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American College of Family Physicians. Ann Intern Med. 2008;148:370-378.
  11. Reisberg B, Doody R, Stoffler A, et al, for the Memantine Study Group.  Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med.  2003;348:1333-41.
  12. Reisberg B, Doody R, Stoffler A, et al. a 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol. 2006;63:49-54.
  13. Farlow MR, Cummings JL. Effective pharmacologic management of Alzheimer’s disease. Am J Med. 2007;120:388-97.
  14. Shah RS, Lee HG, Xiongwei Z, et al. Current approaches in the treatment of Alzheimer’s disease. Biomed Pharmacother. 2008;62:199-207.
  15. Cummings JL, Mackell J, Kaufer D.  Behavioral effects of current Alzheimer’s disease treatments: a descriptive review.  Alzheimers Dement. 2008;4:49-60.
  16. 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.
  17. Peron EP, Zimmerman KM, Crouse EL, Slattum PW, Hobgood SE. Alzheimer Disease. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill; Accessed May 18, 2021. https://accesspharmacy-mhmedical-com.ezproxy.lib.utexas.edu/content.aspx?bookid=2577&sectionid=226724147.
  18. Tariot PN, Farlow MR, Grossberg GT, et al, for the Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291:317-24.
  19. Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med. 2012;366:893-903.
  20. Tricco AC, Ashoor HM, Soobiah C, et al. Comparative effectiveness and safety of cognitive enhancers for treating Alzheimer’s disease: systematic review and network metaanalysis. J Am Geriatr Soc. 2018;66(1):170–8.
  21. Emre M, Tsolaki M, Bonuccelli U, et al.  Memantine for patients with Parkinson’s disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9:969–77.
  22. Leroi I, Overshott R, Byrne EJ, et al.  Randomized controlled trial of memantine in dementia associated with Parkinson's disease.  Mov Disord. 2009;24(8):1217-21.
  23. Grossberg GT, Manes F, Allegri RF, et al. The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer's disease taking cholinesterase inhibitors. CNS Drugs. 2013;27:469-78.
  24. US Preventive Services Task Force. Screening for Cognitive Impairment in Older Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2020;323(8):757–763. doi:10.1001/jama.2020.0435.
  25. World Health Organization. (‎2015)‎. mhGAP : Mental Health Gap Action Programme: cholinesterase inhibitors and memantine for treatment of dementia. Geneva : World Health Organization. https://www.who.int/mental_health/mhgap/evidence/dementia/q1/en/
     

C-3.34. Nitazoxanide (Alinia®)

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; Sept. 2017; Aug. 2015; Dec. 2013; Feb. 2012; April 2010; March 2007.  
  • Initially developed
    • Jan. 2007

C-3.34.1. Dosage

Nitazoxanide is available as a 500 mg tablet and a 100 mg/5 ml oral suspension. The 500 mg tablet contains greater than recommended amounts of nitazoxanide for pediatric dosing and should not be used in pediatric patients younger than 11 years of age.

C-3.34.1.1. Adults

Nitazoxanide is FDA-approved for the management of diarrhea caused by Giardia lamblia or Cryptosporidium parvum in adults. Adult dosage recommendations for nitazoxanide are summarized in Table 1. Dosages exceeding these recommendations will be reviewed.

Although not FDA-approved, nitazoxanide 500 mg twice daily for 10 days has demonstrated comparable efficacy to metronidazole in managing Clostridioides difficile colitis in both patients responsive and resistant to metronidazole therapy. Additionally, nitazoxanide may be proven comparable in efficacy to vancomycin in treating C. difficile colitis, although current sample sizes are too small to assess clinical significance. Although several studies have demonstrated possible efficacy and off-label use occurs, nitazoxanide is not currently a guideline recommended therapy for C. diff. infection.

Nitazoxanide has also shown benefit in treating diarrhea caused by intestinal parasites other than G. lamblia as well as rotavirus but does not yet possess FDA approval for these indications.

Nitazoxanide has improved eradication rates compared to standard triple therapy when used as part of a four-drug treatment regimen for Helicobacter pylori in treatment-naïve patients but is not FDA-approved for this indication.

Nitazoxanide, while not FDA-approved, may be considered as an alternative treatment to manage Cryptosporidium-associated diarrhea in adult and adolescent human immunodeficiency virus patients. Dosages utilized are 500 mg to 1000 mg orally twice daily for 14 days to 8 weeks in conjunction with optimized antiretroviral therapy, electrolyte replacement and symptomatic treatment as well as rehydration.

C-3.34. Table 1: Adult Nitazoxanide Dosage Recommendations

Treatment Indication Available Dosage Strengths Maximum Recommended Dosage 
Diarrhea caused by G. lamblia or C. parvum 500 mg tablet, 100 mg/5ml suspension 1 tablet (500 mg) or 25 ml of oral suspension every 12 hours with food for 3 days

 

C-3.34.1.2. Pediatrics

Nitazoxanide is FDA-approved for the management of diarrhea caused by G. lamblia or C. parvum in pediatric patients 1 year of age and older. Nitazoxanide pediatric dosage recommendations are summarized in Table 2. Patient profiles containing dosages exceeding these recommendations will be reviewed.

C-3.34. Table 2: Pediatric Nitazoxanide Dosage Recommendations

Treatment Indication Available Dosage Strengths Maximum Recommended Dosage Per Age Group *
Diarrhea caused by G. lamblia or C. parvum Diarrhea caused by G. lamblia or C. parvum
  • 1-3 years of age:
    • 100 mg (5 ml as oral suspension) every 12 hours (with food) for 3 days
  • 4-11 years of age:
    • 200 mg (10 ml as oral suspension) every 12 hours (with food) for 3 days
  • Greater than or equal to 12 years of age:
    • 500 mg tablet (or 25 ml as oral suspension) every 12 hours (with food) for 3 days

Legend:

  • * Tablets are only approved for use in children 12 years of age and older

C-3.34.2. Duration of Therapy

Nitazoxanide is FDA-approved for three days of therapy to manage cryptosporidiosis and giardiasis in immunocompetent adult and pediatric patients, as documented in clinical trials. Treatment durations exceeding these recommendations will be reviewed.

C-3.34.3. Duplicative Therapy

Concurrent administration of nitazoxanide with other approved antibiotic therapies for cryptosporidiosis and giardiasis (i.e., paromomycin, metronidazole, tinidazole, paromomycin + azithromycin) is not recommended as these combinations do not provide additional therapeutic benefit and may result in enhanced adverse events. Patient profiles containing adjunctive prescriptions for nitazoxanide and additional cryptosporidiosis or giardiasis therapy will be reviewed.

C-3.34.4. 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 are considered clinically relevant for nitazoxanide. 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.

C-3.34.4.1. Highly Plasma Protein-Bound Medications

(e.g., hydantoins, salicylates, warfarin) [clinical significance level – 3- moderate (CP)]

Nitazoxanide is rapidly metabolized to tizoxanide following oral administration. Because tizoxanide is highly bound to plasma proteins (>99.9%), caution should be exercised when dosing nitazoxanide concurrently with other drugs highly protein bound possessing narrow therapeutic indices as competition for binding sites may occur with potential for toxicity. However, in an open-label, randomized, crossover study, investigators assessed nitazoxanide effects on warfarin pharmacokinetics and pharmacodynamics after a single warfarin 25 mg dose in 14 adult male volunteers and found that warfarin pharmacokinetic/pharmacodynamic parameters did not change significantly following nitazoxanide administration. Until further confirmatory data are available, it may be prudent to monitor patients for signs of warfarin toxicity and changes in INR when warfarin and nitazoxanide are administered concurrently. Similarly, until contrasting data are available, monitor patients for signs and symptoms of hydantoin or salicylate toxicity when nitazoxanide is administered adjunctively.

C-3.34.5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: August 3, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed August 3, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; August 3, 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 August 3, 2021.
  5. Nitazoxanide (Alinia®) package insert. Romark Laboratories, January 2021.
  6. Musher DM, Logan N, Bressler AM, et al. Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double-blind study. Clin Infect Dis. 2009;48(4):e41-6.
  7. Musher DM, Logan N, Mehendiratta V, et al. Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide. J Antimicrob Chemother. 2007;59(4):705-10.
  8. Musher DM, Logan N, Bressler AM, et al. Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double-blind study. Clin Infect Dis. 2009;48(4):e41-6.
  9. Abaza H, El-Zayadi AR, Kabil SM, et al. Nitazoxanide in the treatment of patients with intestinal protozoan and helminthic infections: a report on 546 patients in Egypt. Curr Ther Res. 1998;59(2):116-21.
  10. Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Giardia intestinalis and Entamoeba histolytica or E. dispar: a randomized, double-blind, placebo-controlled study of nitazoxanide. J  Infect Dis. 2001;184(3):381-4.
  11. Rossignol JF, Kabil SM, El-Gohary Y, Younis AM.  Nitazoxanide in the treatment of amoebiasis. Trans R Soc Trop Med Hyg. 2007;101(10):1025-31.
  12. Rossignol JF, Abu-Zekry M, Hussein A, Santoro MG. Effect of nitazoxanide for treatment of severe rotavirus diarrhoea: randomised double-blind placebo-controlled trial. Lancet. 2006;368(9530):124-9.
  13. Rossignol JF, El-Gohary YM. Nitazoxanide in the treatment of viral gastroenteritis: a randomized double-blind placebo-controlled clinical trial. Aliment Pharmacol Ther. 2006;24(10):1423-30, 2006.
  14. Basu PP, Rayapudi K, Pacana T, et al. A randomized study comparing levofloxacin, omeprazole, nitazoxanide and doxycycline for the eradication of Helicobacter pylori. Am J Gastroenterol. 2011;106(11):1970-5.
  15. Leder K, Weller PF.  Treatment and prevention of cryptosporidiosis.  Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com (Accessed on August 3, 2021.)
  16. Ortiz JJ, Ayoub A, Gargala G, et al. Randomized clinical study of nitazoxanide compared to metronidazole in the treatment of symptomatic giardiasis in children from Northern Peru. Aliment Pharmacol Ther. 2001;15:1409-15.
  17. Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of nitazoxanide. J Infect Dis. 2001;184:103-6.
  18. Bailey JM, Erramouspe J. Nitazoxanide treatment for giardiasis and cryptosporidiosis in children. Ann Pharmacother. 2004;38:634-40.
  19. Vets E, Rossignol JF, Jackson AS. Effects of nitazoxanide on pharmacokinetics and pharmacodynamics of a single dose of warfarin.  Am J Health Syst Pharm. 2009;66(9):838-42. 
  20. Stuart Johnson, Valéry Lavergne, Andrew M Skinner, Anne J Gonzales-Luna, Kevin W Garey, Ciaran P Kelly, Mark H Wilcox, Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults, Clinical Infectious Diseases, 2021.
  21. Sukdong Lee, Gregory T. Sneed & Jamie N. Brown (2020) Treatment of Helicobacter pylori with nitazoxanide-containing regimens: a systematic review, Infectious Diseases, 52:6, 381-390.

C-3.37. Platelet Aggregation 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
    • January 22, 2021; March 2019
  • Initially developed
    • December 2016

C-3.37.1. Dosage

C-3.37.1.1. Adults

Platelet aggregation inhibitors (PAIs) are FDA-approved to reduce thrombotic cardiovascular events in patients with a history of ischemic stroke, or to prevent stroke in patients with predisposing factors for atherosclerosis or symptomatic cerebrovascular disease.1-12 PAIs work by interfering with pathways that promote normal platelet function: inhibiting cyclooxygenase-1 (e.g., aspirin); inhibiting adenosine uptake into platelets, resulting in increased cyclic-3’,5’-adenosine monophosphate (cAMP) and adenosine levels (e.g., dipyridamole); inhibiting the adenosine diphosphate (ADP) P2Y12 receptor on the platelet surface and blocking activation of the glycoprotein GPIIb/IIIa complex (e.g., clopidogrel, prasugrel, ticagrelor); antagonizing protease-activated receptor 1 (PAR-1), which inhibits thrombin and thrombin receptor agonist peptide activity (e.g., vorapaxar); or inhibiting phosphodiesterase lll (e.g., cilostazol).2-4, 13

Aspirin is available in combination with omeprazole, a proton pump inhibitor, to reduce the risk of aspirin-associated gastric ulcers in those patients requiring aspirin for secondary prevention of cardiovascular and cerebrovascular events.2-4, 10 Aspirin is also available as combination therapy with dipyridamole, pairing two antiplatelet agents with different mechanisms of action for secondary stroke prevention.2-4, 11 Maximum recommended adult dosages for PAIs are summarized in Tables 1 (1-3, 5-12) and 2 (1-3, 5-12). Medication profiles identifying patients prescribed dosages exceeding these recommendations will be reviewed.

C-3.37. Table 1. Maximum Daily Adult Dosages for PAIs: Monotherapy

Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
reduce risk of death and recurrent stroke or recurrent MI in patients with a history of ischemic stroke or TIA, and/or a history of chronic coronary artery disease ACS (STEMI, NSTE-ACS) aspirin (Durlaza®)* 162.5 mg extended-release capsule 162.5 mg once daily
intermittent claudication cilostazol (generics) 50 mg, 100 mg tablets 100 mg twice daily
ACS, including UA/NSTEMI and STEMI clopidogrel (Plavix®, generics) 75 mg, 300 mg tablets Initial: 300 mg or 600 mg loading dose, followed by 75 mg once daily for up to 12 months in combination with aspirin, followed by aspirin indefinitely
thromboembolism prophylaxis in patients with recent MI or stroke, or established peripheral vascular disease     75 mg/day
prevention of postoperative thrombotic complications in patients with prosthetic heart valves dipyridamole (generics) 25 mg, 50 mg, 75 mg tablets 400 mg/day (divided doses, in combination with warfarin) or 400 mg/day (divided doses, in combination with aspirin)
ACS in patients to be managed with PCI prasugrel (Effient®, generics) 5 mg, 10 mg tablets following a 60 mg loading dose, 10 mg/day+ in combination with aspirin
reduce risk of death, MI, and stroke in patients with ACS, history of MI, or acute ischemic stroke/high risk transient ischemic attack ticagrelor (Brilinta®) 60 mg, 90 mg tablets following a 180 mg loading dose, 90 mg twice daily^ in combination with aspirin
reduce risk of first MI or stroke in patients with CAD at high risk of events     60 mg twice daily in combination with aspirin
MI, stroke, thrombosis prophylaxis in patients with a history of MI or PAD vorapaxar (Zontivity®) 2.08 mg tablet 2.08 mg/day in combination with aspirin or clopidogrel

Legend:

  • ACS = acute coronary syndrome;
  • CAD = coronary artery disease
  • MI = myocardial infarction
  • NSTE-ACS = non-ST-elevation acute coronary syndrome
  • NSTEMI = non-ST-elevation myocardial infarction
  • PAD = peripheral arterial disease
  • PCI = percutaneous coronary intervention
  • STEMI = ST-elevation myocardial infarction
  • TIA = transient ischemic attack
  • UA = unstable angina
  • * Durlaza is not currently available by the manufacturer. It is expected to be reintroduced to the U.S. market by the middle of 2021. 
  • + patients 75 years or older or weigh less than 60 kg may use prasugrel 5 mg/day as maintenance therapy in combination with aspirin to reduce bleeding risk
  • ^ ticagrelor dosages are decreased to 60 mg twice daily after 12 months

C-3.37. Table 2. Maximum Daily Adult Dosages for PAIs – Combination Therapy

Treatment Indication Drug Name Dosage Form/ Strength Maximum Recommended Dosage
secondary prevention of cardiovascular and cerebrovascular events in patients predisposed to gastric ulcers aspirin/omeprazole (Yosprala®) 81 mg/40 mg, 325 mg/40 mg delayed-release tablets 325 mg/40 mg once daily
secondary stroke prevention dipyridamole/aspirin (Aggrenox®, generics) 200 mg/25 mg extended-release capsule 200 mg/25 mg twice daily

C-3.37.1.2. Pediatrics

Dipyridamole is FDA-approved for use in pediatric patients 12 years of age and older as adjunctive therapy to prevent thromboembolism following cardiac valve replacement. The maximum recommended dose is 100 mg four times daily in combination with warfarin. Dosages exceeding these recommendations will be reviewed.

Aspirin as Durlaza®, cilostazol, prasugrel, ticagrelor, vorapaxar, aspirin/omeprazole, and dipyridamole/aspirin are not recommended for use in pediatric patients as safety and efficacy have not been established for these agents in this patient population. Although not FDA-approved, clopidogrel has effectively been used in pediatric patients to reduce thrombosis risk in infants and children with select types of heart disease, or as an alternative in patients with Kawasaki disease or ischemic stroke when aspirin is not tolerated.2, 3, 14-17

C-3.37.2. Duration of Therapy

There is no basis for limiting PAI therapy duration when prescribed to prevent thromboembolic events associated with cardiovascular or cerebrovascular disease. However, PAI therapy duration varies based on medication utilized and indication for use. PAI treatment durations are summarized in Tables 3 (1-3, 5-12) and 4 (1-3, 5-12).

C-3.37. Table 3. PAI Recommended Treatment Duration (Adults): Monotherapy

Drug Name Treatment Indication Maximum Treatment Duration
aspirin (Durlaza®) reduce risk of death and recurrent stroke or recurrent MI in patients with a history of ischemic stroke or TIA, and/or a history of chronic CAD indefinite
cilostazol intermittent claudication indefinite
clopidogrel acute coronary syndrome (NSTE-ACS and STEMI) up to 1 year, in combination with aspirin; aspirin then continued indefinitely +
  thromboembolism prophylaxis indefinite
prasugrel ACS in patients to be managed with PCI at least 12 months, in combination with aspirin, after stent placement
ticagrelor ACS 90 mg twice daily x 1 year in combination with aspirin; then, 60 mg twice daily in combination with aspirin indefinitely
vorapaxar MI, stroke, thrombosis prophylaxis in patients with a history of MI or PAD indefinite, in combination with aspirin or clopidogrel

Legend:

  • ACS = acute coronary syndrome
  • CAD = coronary artery disease
  • MI = myocardial infarction
  • NSTE-ACS = non-ST-elevation acute coronary syndrome
  • NSTEMI = non-ST-elevation myocardial infarction
  • PAD = peripheral arterial disease
  • PCI = percutaneous coronary intervention
  • STEMI = ST-elevation myocardial infarction
  • TIA = transient ischemic attack
  • + in patients with aspirin allergy, clopidogrel monotherapy may be continued indefinitely

C-3.37. Table 4. Adult PAI Recommended Combination Therapy Treatment Duration

Drug Name Treatment Indication Maximum Treatment Duration
aspirin/omeprazole secondary prevention of cardiovascular and cerebrovascular events in patients predisposed to gastric ulcers indefinite
dipyridamole/aspirin stroke prevention indefinite

C-3.37.3. Duplicative Therapy

Adjunctive therapy with aspirin and clopidogrel, dipyridamole, prasugrel, ticagrelor, or vorapaxar has documented efficacy for acute coronary syndrome or thrombotic event prevention; concurrent therapy with clopidogrel and ticagrelor or vorapaxar is also FDA-approved for thromboembolic event prophylaxis or acute coronary syndrome (see Tables 1-4).1-11,18-19

C-3.37.4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens that may result in clinically significant drug-drug interactions. Major drug-drug interactions considered clinically significant for platelet aggregation inhibitors are summarized in Table 5 (1-3, 5-11, 20-22). 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.

C-3.37. Table 5. Major Platelet Aggregation Inhibitor Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level
aspirin methotrexate (MTX) potential for increased MTX serum levels, risk of enhanced pharmacologic/ toxic effects as NSAIDs can reduce MTX clearance avoid concurrent aspirin use within 10 days of high-dose MTX; otherwise, use cautiously together; monitor for increased myelosuppressive, GI adverse effects; may consider using longer leucovorin rescue major (DrugReax) 1-severe (CP)
cilostazol, dipyridamole riociguat (Adempas®) concurrent administration may result in increased hypotension risk avoid concurrent use contraindicated (DrugReax) dipyridamole: 1-severe; cilostazol: 3-moderate (CP) 
cilostazol, ticagrelor, vorapaxar itraconazole, strong CYP3A4 inhibitors co-administration may result in elevated serum concentrations of select platelet aggregation inhibitors (PAIs) and potential bleeding complications as cilostazol, ticagrelor, and vorapaxar metabolized by CYP3A4 avoid use; ticagrelor therapy should not be initiated for at least 2 weeks after itraconazole discontinuation; if adjunctive administration necessary, use cautiously and monitor patient closely for enhanced pharmacologic/ adverse effects, especially bleeding ticagrelor: contraindicated; cilostazol, vorapaxar: major (DrugReax) 
ticagrelor: 1-severe; cilostazol, vorapaxar: 2-major (CP)
clopidogrel dasabuvir/ombitasvir/paritaprevir/ritonavir (Viekira®) adjunctive administration with clopidogrel (strong CYP2C8 inhibitor) contraindicated by manufacturer, as dasabuvir metabolized by CYP2C8, which increases risk for dasabuvir-induced QT interval prolongation; ritonavir, a CYP3A4 inhibitor, may limit clopidogrel conversion to active metabolite avoid concurrent use 1-severe (CP)
clopidogrel omeprazole strong CYP2C19 inhibitor (e.g. omeprazole) may result in reduced plasma concentrations of clopidogrel active metabolite and diminish antiplatelet activity avoid concurrent use; consider alternative proton pump inhibitor (e.g. pantoprazole) major (DrugReax) 2-major (CP)
PAIs defibrotide increased risk of hemorrhage when used adjunctively with  antithrombotic/ fibrinolytic drugs like PAIs avoid concurrent use contraindicated (DrugReax) 1-severe (CP)
PAIs, including aspirin low molecular weight heparins potential for additive bleeding adverse effects; PAIs inhibit platelet aggregation and have increased bleeding risk, prolonged bleeding time avoid concurrent therapy, if possible; if drug combination necessary, use cautiously, monitor for signs/symptoms of bleeding major, moderate (DrugReax) 2-major, 3-moderate (CP)
PAIs, including aspirin selective serotonin reuptake inhibitors (SSRIs)/,  serotonin norepinephrine reuptake inhibitors (SNRIs) increased bleeding risk with combined therapy;  SSRIs/SNRIs deplete platelet serotonin, which may impair platelet aggregation monitor for signs/symptoms of bleeding; may consider substituting tricyclic antidepressant for SSRI/SNRI SSRIs –major; SNRIs-major (DrugReax) 3-moderate (CP)
PAIs, including aspirin anticoagulants combined administration may increase bleeding risk, due to additive effects if combined therapy necessary, monitor patients closely for bleeding signs/symptoms major (DrugReax) 2-major, 3-moderate (CP)
PAIs nonsteroidal anti-inflammatory drugs (NSAIDs) concurrent use may increase risk for bleeding especially with chronic NSAID use monitor for signs of bleeding with concurrent use major (DrugReax) 3-moderate (CP)
ticagrelor, vorapaxar strong CYP3A inducers (e.g., rifampin) strong inducers substantially reduce ticagrelor, vorapaxar exposure and efficacy as both are CYP3A4 substrates avoid use major (DrugReax) 2–major (CP)
ticagrelor simvastatin, lovastatin adjunctive use may increase lovastatin, simvastatin serum levels as ticagrelor is CYP3A4 inhibitor and lovastatin and simvastatin are metabolized by CYP3A4 avoid lovastatin, simvastatin doses higher than 40 mg; observe for adverse effects if combined use necessary moderate (DrugReax)  2–major (CP)

C-3.37.5. References

  1. DRUGDEX® System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu. Accessed December 22, 2020.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2020. Available at: http://www.clinicalpharmacology.com. Accessed December 22, 2020.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2020. Available at:  http://eanswers.factsandcomparisons.com.ezproxy.lib.utexas.edu/.  Accessed December 22, 2020.
  4. Cucchiara BL, Messé SR. Antiplatelet therapy for secondary prevention of stroke. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on December 22, 2020.)
  5. Aspirin extended-release capsules (Durlaza®) package insert. New Haven Pharmaceuticals, September 2015.
  6. Clopidogrel tablets (Plavix®) package insert. Sanofi-Aventis, April 2020.
  7. Prasugrel tablets (Effient®) package insert. Eli Lilly and Company, September 2020.
  8. Ticagrelor (Brilinta®) package insert. AstraZeneca, November 2020.
  9. Vorapaxar tablets (Zontivity®) package insert. Aralez Pharmaceuticals Us Inc., November 2019. 
  10. Aspirin/omeprazole extended-release tablets (Yosprala®) package insert.  Aralez Pharmaceuticals US Inc., June 2018.
  11. Aspirin/extended-release dipyridamole capsules (Aggrenox®) package insert.  Boehringer Ingelheim Pharmaceuticals, Inc., December 2019.
  12. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio:Wolters Kluwer Clinical Drug Information, Inc.; 2020; December 22, 2020. 
  13. Coutre S. Congenital and acquired disorders of platelet function. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on December 22, 2020.)
  14. Li JS, Yow E, Berezny KY, et al. Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On cLOpidogrel (PICOLO) trial. Circulation 2008;117:553-9.
  15. Soman T, Rafay MF, Hune S, et al. The risks and safety of clopidogrel in pediatric arterial ischemic stroke. Stroke. 2006;37(4):1120-2.
  16. Giglia TM, Massicotte MP, Tweddell JS, et al., for the American Heart Association Congenital Heart Defects Committee of the Council on Cardiovascular Disease in the Young, Council on Cardiovascular and Stroke Nursing, Council on Epidemiology and Prevention, and Stroke Council. Prevention and treatment of thrombosis in pediatric and congenital heart disease: a scientific statement from the American Heart Association. Circulation. 2013;128:2622-2703.
  17. McCrindle Brian W., Rowley Anne H., Newburger Jane W., et al. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the american heart association. Circulation. 2017;135(17):e927-e999.
  18. DiDomenico RJ, Dobesh PP, Finks SW.  Chapter 33. Acute coronary syndromes. (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: http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/book.aspx?bookid=689. Accessed December 23, 2020.
  19. Stacy Z, Chow S.  Chapter 34. Peripheral arterial 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: http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/book.aspx?bookid=689. Accessed December 23, 2020.
  20. Ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets co-packaged for oral use (Viekira Pak®) package insert. AbbVie Inc., November 2020.
  21. Food and Drug Administration. Current and Resolved Drug Shortages and Discontinuations Reported to FDA: dasabuvir, ombitasvir, paritaprevir, and ritonavir extended-release tablets (Viekira XR). May 22, 2018. Available at: https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Dasabuvir%20Sodium;%20Ombitasvir;%20Paritaprevir;%20Ritonavir%20(Viekira%20XR)%20Tablets&st=d. Accessed December 22, 2020.

C-3.39. Promethazine Use In Children Less Than 2 Years of Age

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; Sept. 2017; Aug. 2015; Dec. 2013; Feb. 2012; May 2010
    • Initially developed
      • Oct. 2006

    C-3.39.1. Dosage

    C-3.39.1.1. Pediatrics

    In 2004, promethazine received a “black box” warning with contraindications for use in children under two years of age and strengthened warnings for use in children two years of age and older. These revisions resulted from repeated reports to the Food and Drug Administration (FDA) of serious, life-threatening adverse events in children. Between 1969 and 2003, the FDA received 125 reports of adverse events in the pediatric population including respiratory depression, apnea, or cardiac arrest (n = 38); dystonic reactions (n = 29); unspecified central nervous system reactions (n = 24); seizures or seizure-like activity (n = 15); dermatologic reactions (n = 12); and neuroleptic malignant syndrome (n = 5). All routes of administration were responsible for the outcomes observed with these events, which included hospitalization, life-threatening events, disability, and death. 1-6

    Due to the limitations placed on promethazine prescribing, all profiles for patients under two years of age containing prescriptions for promethazine will be reviewed.

    C-3.39.2. References

    1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: August 23, 2021).
    2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed August 23, 2021.
    3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; August 23, 2021.
    4. Starke PR, Weaver J, Chowdhury BA. Boxed warning added to promethazine labeling for pediatric use. N Engl J Med. 2005;352:2653.
    5. U.S. Department of Health and Human Services. U.S. Food and Drug Administration. Promethazine (marketed as Phenergan) information. (April 2006). Available at:  http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm109364.htm. Accessed August 23, 2021.
    6. Promethazine hydrochloride solution package insert. Nostrum Laboratories, Inc., December 2020.
    7. Promethazine suppositories package insert. Padagis Israel Pharmaceuticals, August 2021.

    C-3.40. Proton Pump 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
      • January 22, 2021; December 2016; March 2015; June 2013; November 2011; September 2011; September 2009; June 2009; December 2005; November 2003; October 2002
    • Initially developed
      • December 2001

    C-3.40.1. Dosage

    Proton pump inhibitors (PPIs) are FDA-approved for managing duodenal and gastric ulcers, erosive esophagitis (EE), gastroesophageal reflux disease (GERD), hypersecretory conditions, and heartburn, preventing nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers, and eradicating Helicobacter pylori (as a component of combination therapy).

    Omeprazole/sodium bicarbonate combination therapy is FDA-approved for managing gastric and duodenal ulcer, EE, GERD, and upper gastrointestinal bleed risk reduction in critically ill patients.

    Esomeprazole combined with naproxen is FDA-approved for use in osteoarthritis (OA), rheumatoid arthritis (RA), or ankylosing spondylitis (AS) in adult patients at greater risk for developing NSAID-induced gastric ulcers.

    C-3.40.1.1. Adults

    Maximum daily adult doses for PPIs when prescribed as acute and maintenance therapy, as well as components of combination treatments, are summarized in Tables 1-4. Dosages exceeding these recommended values will be reviewed.

    C-3.40. Table 1. Adult Maximum Daily Acute Doses for Proton Pump Inhibitors: Monotherapy

    Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage 
    erosive esophagitis (EE) dexlansoprazole (Dexilant®) 30 mg, 60 mg delayed-release capsules 60 mg/day
    gastroesophageal reflux disease (GERD)-nonerosive     30 mg/day
    EE esomeprazole magnesium (Nexium®, generics) 20 mg, 40 mg delayed-release capsules; 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg delayed-release powder for suspension 40 mg/day
    GERD-nonerosive     20 mg/day
    Helicobacter pylori eradication     80 mg/day
    heartburn     20 mg/day
    hypersecretory conditions     240 mg/day in divided doses
    duodenal ulcer lansoprazole (Prevacid®, generics) 15 mg, 30 mg delayed-release capsules, 15 mg, 30 mg orally disintegrating tablets 15 mg/day
    EE     30 mg/day
    gastric ulcer     30 mg/day
    GERD-nonerosive     15 mg/day
    H. pylori eradication     90 mg/day (in divided doses)
    heartburn     15 mg/day
    hypersecretory conditions     180 mg/day in divided doses
    NSAID-associated gastric ulcer     30 mg/day
    duodenal ulcer omeprazole (Prilosec®, generics) 10 mg, 20 mg, 20.6 mg, 40 mg delayed-release capsule; 20 mg delayed-release orally disintegrating tablet; 2 mg/mL oral suspension 20 mg/day
    EE     20 mg/day
    gastric ulcer     40 mg/day
    GERD-nonerosive     20 mg/day
    heartburn     20 mg/day
    H. pylori eradication    
    • triple therapy: 40 mg/day in divided doses
    • dual therapy: 40 mg/day
    hypersecretory conditions     360 mg/day in divided doses
    duodenal ulcer omeprazole magnesium (Prilosec®) 2.5 mg, 10 mg packet with delayed-release granules for suspension 20 mg/day
    EE     20 mg/day
    gastric ulcer     40 mg/day
    GERD-nonerosive     20 mg/day
    H. pylori eradication    
    • triple therapy: 40 mg/day in divided doses
    • dual therapy: 40 mg/day
    hypersecretory conditions     360 mg/day in divided doses
    EE pantoprazole (Protonix®, generics) 20 mg, 40 mg delayed-release tablets; 40 mg delayed-release granules for suspension 40 mg/day
    hypersecretory conditions     240 mg/day in divided doses
    duodenal ulcer rabeprazole (Aciphex®, generics) 20 mg delayed-release tablet; 5 mg, 10 mg delayed-release sprinkle capsule 20 mg/day
    EE     20 mg/day
    GERD-nonerosive     20 mg/day
    H. pylori eradication     40 mg/day (in divided doses)
    hypersecretory conditions     120 mg/day in divided doses

    C-3.40. Table 2. Adult Maximum Daily Acute Doses for Proton Pump Inhibitors: Combination Therapy

    Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
    duodenal ulcer omeprazole/ sodium bicarbonate (Zegerid®, generics) 20 mg/1100 mg, 40 mg/1100 mg capsules; 20 mg/1680 mg, 40 mg/1680 mg packets for suspension 20 mg/day (as mg of omeprazole)
    EE     20 mg/day (as mg of omeprazole)
    gastric ulcer     40 mg/day (as mg of omeprazole)
    GERD-nonerosive     20 mg/day (as mg of omeprazole)
    heartburn     20 mg/day (as mg of omeprazole)
    upper GI bleed risk reduction in critically ill (suspension only)     40 mg/day (as mg of omeprazole)

    C-3.40. Table 3. Adult Maximum Daily Maintenance Dose for Proton Pump Inhibitors: Monotherapy

    Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
    erosive esophagitis (EE) dexlansoprazole 30 mg, 60 mg delayed- release capsules 30 mg/day
    heartburn     30 mg/day
    EE esomeprazole magnesium (Nexium®, generics) 20 mg, 40 mg delayed-release capsules; 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg delayed-release powder for suspension 20 mg/day
    hypersecretory conditions     240 mg/day in divided doses
    risk reduction of NSAID-associated gastric ulcer     40 mg/day
    duodenal ulcer lansoprazole (Prevacid®, generics) 15 mg, 30 mg delayed-release capsules, 15 mg, 30 mg orally disintegrating tablets 15 mg/day
    EE     15 mg/day
    hypersecretory conditions     180 mg/day in divided doses
    risk reduction of NSAID-associated gastric ulcer     15 mg/day
    EE omeprazole (Prilosec®, generics) 10 mg, 20 mg, 40 mg delayed-release capsule; 20 mg delayed-release orally disintegrating tablet; 2 mg/mL oral suspension 20 mg/day
    hypersecretory conditions     360 mg/day in divided doses
    EE omeprazole magnesium (Prilosec®) 2.5 mg, 10 mg packet with delayed-release granules for suspension 20 mg/day
    hypersecretory conditions     360 mg/day in divided doses
    EE pantoprazole (Protonix®, generics) 20 mg, 40 mg delayed-release tablets; 40 mg delayed-release granules for suspension 40 mg/day
    hypersecretory conditions     240 mg/day in divided doses
    EE rabeprazole (Aciphex®, generics) 20 mg delayed-release tablet; 5 mg, 10 mg delayed-release sprinkle capsule 20 mg/day
    hypersecretory conditions     120 mg/day in divided doses

    C-3.40. Table 4. Adult Maximum Daily Maintenance Dose for Proton Pump Inhibitors: Combination Therapy

    Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage 
    prevention of NSAID-associated gastric ulcer in patients with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis esomeprazole/ naproxen (Vimovo®) 20 mg immediate-release/375 mg delayed-release, 20 mg immediate-release/500 mg delayed-release tablets 40 mg/1000 mg/day in divided doses
    EE omeprazole/ sodium bicarbonate (Zegerid®, generics) 20 mg/1100 mg, 40 mg/1100 mg capsules; 20 mg/1680 mg, 40 mg/1680 mg packets for suspension 20 mg/day (as mg of omeprazole)

    C-3.40.1.2. Pediatrics

    The safety and efficacy of dexlansoprazole and esomeprazole/naproxen in patients less than 12 years of age as well as omeprazole/sodium bicarbonate in patients less than 18 years of age have not been established.

    Esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole are FDA-approved for acute use in pediatric patients; doses are age-dependent. Omeprazole is the only PPI approved for erosive esophagitis maintenance therapy in pediatric patients. The maximum recommended daily pediatric doses for these PPIs are summarized in Tables 5-7. Dosages exceeding these recommendations will be reviewed.

    Although not FDA-approved due to limited availability of guidelines and well-designed clinical trials, select proton pump inhibitors have been utilized in combination with antibiotic therapy to manage H. pylori in pediatric patients. The 2016 European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) guidelines for H. pylori management in pediatric patients recommend PPI doses of 1-2 mg/kg/day for 10 to 14 days as combination therapy or sequential therapy. Pediatric dosage recommendations for H. pylori management are summarized in Table 8.

    C-3.40. Table 5. Pediatric Maximum Daily Acute Doses for Proton Pump Inhibitors: Monotherapy

    Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage 
    erosive esophagitis (EE) dexlansoprazole (Dexilant®) 30 mg, 60 mg delayed- release capsules 12 to 17 years of age: 60 mg/day
    gastroesophageal reflux disease (GERD) - nonerosive     12 to 17 years of age: 30 mg/day
    EE due to only acid-mediated GERD esomeprazole magnesium (Nexium®, generics) 20 mg, 40 mg delayed-release capsules; 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg delayed-release powder for suspension
    • 1 to 11 months of age:
      • 3 kg to 5 kg: 2.5 mg once daily
      • 5 kg to 7.5 kg:  5 mg once daily
      • 7.5 kg to 12 kg:  10 mg once daily
    EE    
    • 1 to 11 years of age:
      • greater than equal to 20 kg: 20 mg/day 
      • Less than 20 kg:  10 mg/day
    • 12 to 17 years of age:
      • 40 mg/day
    GERD-nonerosive    
    • 1 to 11 years of age:
      • 10 mg/day
    • 12 to 17 years of age:
      • 20 mg/day
    EE lansoprazole (Prevacid®, generics) 15 mg, 30 mg delayed-release capsules, 15 mg, 30 mg orally disintegrating tablets
    • 1 to 11 years of age:
      • Greater than or equal to 30 kg: 30 mg/day* 
      • Less than 30 kg: 15 mg/day
    • Greater than or equal to 12 years of age: 30 mg/day*
    GERD-nonerosive    
    • 1 to 11 years of age:
      • Less than 30 kg: 15 mg/day
      • Greater than or equal to 30 kg: 30 mg/day 
    • Greater than or equal to 12 years of age:
      • 15 mg/day
    EE omeprazole (Prilosec®, generics) 10 mg, 20 mg, 40 mg delayed-release capsule; 20 mg delayed-release orally disintegrating tablet
    • 1 month to Less than 1 year of age:
      • 3 kg to Less than 5 kg: 2.5 mg once daily
      • 5 kg to Less than 10 kg: 5 mg once daily
      • Greater than or equal to 10 kg: 10 mg once daily
    • 1 to 16 years of age:
      • 5 kg to Less than 10 kg: 5 mg once daily
      • 10 kg to Less than 20 kg:  10 mg once daily
      • Greater than or equal to 20 kg: 20 mg once daily
    GERD-nonerosive    
    • 1 to 16 years of age:
      • 5 kg to Less than 10 kg: 5 mg once daily
      • 10 kg to Less than 20 kg:  10 mg once daily
    • Greater than or equal to 20 kg: 20 mg once daily
    EE omeprazole magnesium (Prilosec®) 2.5 mg, 10 mg packet with delayed-release granules for suspension
    • 1 month to Less than 1 year of age:
      • 3 kg to Less than 5 kg: 2.5 mg once daily
      • 5 kg to Less than 10 kg: 5 mg once daily
      • Greater than or equal to 10 kg: 10 mg once daily
    • 1 to 16 years of age:
      • 5 kg to Less than 10 kg: 5 mg once daily
      • 10 kg to Less than 20 kg:  10 mg once daily
      • Greater than or equal to 20 kg: 20 mg once daily
    GERD-nonerosive    
    • 1 to 16 years of age:
      • 5 kg to Less than 10 kg: 5 mg once daily
      • 10 kg to Less than 20 kg:  10 mg once daily
      • Greater than or equal to 20 kg: 20 mg once daily
    EE pantoprazole (Protonix®, generics) 20 mg, 40 mg delayed-release tablets; 40 mg delayed-release granules for suspension
    • Greater than or equal to 5 years of age:
      • 15 kg to less than 40 kg: 20 mg/day
      • Greater than or equal to 40 kg: 40 mg/day 
    GERD-nonerosive rabeprazole (Aciphex®, generics) 20 mg delayed-release tablet; 5 mg, 10 mg delayed-release sprinkle capsule
    • 1 to 11 years of age: 
      • less than 15 kg: 5 mg/day+
      • greater than or equal to 15 kg: 10 mg/day 
    • Greater than of equal to 12 years of age:
      • 20 mg/day

    Legend:

    • * dose increased to 30 mg twice daily in some children who remained symptomatic after 2 weeks of therapy at lower doses conditions
    • + may increase to 10 mg daily in those with inadequate response to 5 mg dose

    C-3.40. Table 6. Pediatric Maximum Daily Maintenance Doses for Proton Pump Inhibitors: Monotherapy

    Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
    erosive esophagitis (EE) dexlansoprazole (Dexilant®) 30 mg, 60 mg delayed- release capsules 12 to 17 years of age: 30 mg/day
    EE omeprazole (Prilosec®, generics) 10 mg, 20 mg, 40 mg delayed-release capsule; 20 mg delayed-release orally disintegrating tablet
    • 1 to 16 years of age:
      • 5 kg to less than 10 kg: 5 mg once daily
      • 10 kg to less than 20 kg: 10 mg once daily
      • Greater than or equal to 20 kg: 20 mg once daily

    C-3.40. Table 7. Pediatric Maximum Daily Maintenance Doses for Proton Pump Inhibitors: Combination Therapy

    Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
    juvenile idiopathic arthritis esomeprazole/ naproxen (Vimovo®) 20 mg immediate-release/375 mg delayed-release, 20 mg immediate-release/500 mg delayed-release tablets Greater than or equal to 12 years: 
    • 38 kg to less than 50 kg: 40 mg/750 mg/day in two divided doses
    • Greater than 50 kg: 40 mg/1000 mg/day in two divided doses

     

    C-3.40. Table 8. ESPGHAN/NASPGHAN Pediatric H. pylori Treatment Recommendations

    Treatment Option Maximum Recommended Dosage

    Option 1:  
    amoxicillin

    clarithromycin

    PPI

    15-24 kg: 500 mg twice daily
    25-34 kg: 750 mg twice daily
    greater than or equal to 35 kg: 1 g twice daily

    15-24 kg: 250 mg twice daily
    25-34 kg: 500 mg in morning, 250 mg in evening; greater than or equal to 35 kg: 500 mg twice daily

    15-24 kg: 20 mg twice daily
    25-34 kg: 30 mg twice daily
    Greater than or equal to 35 kg: 40 mg twice daily

    Option 2:  
    amoxicillin

    metronidazole

    PPI

    15-24 kg: 500 mg twice daily
    25-34 kg: 750 mg twice daily
    Greater than or equal to 35 kg: 1 g twice daily

    15-24 kg: 250 mg twice daily
    25-34 kg: 500 mg in morning, 250 mg+ in evening; greater than or equalt to 35 kg: 500 mg twice daily

    15-24 kg: 20 mg twice daily
    25-34 kg: 30 mg twice daily
    Greater than or equal to 35 kg: 40 mg twice daily

    Option 3:
    bismuth salts

    amoxicillin

    metronidazole

    Less than 10 years:  262 mg four times daily
    Greater than or equal to  10 years: 524 mg four times daily
    15-24 kg: 500 mg twice daily; 25-34 kg: 750 mg twice daily
    Greater than 35 kg: 1 g twice daily
    15-24 kg: 250 mg twice daily
    25-34 kg: 500 mg in morning, 250 mg+ in evening; greater than 35 kg: 500 mg twice daily

    Sequential therapy*:

    PPI + amoxicillin

    followed by PPI + metronidazole + clarithromycin

    15-24 kg: 20 mg twice daily
    25-34 kg: 30 mg twice daily
    Greater than 35 kg: 40 mg twice daily 1
    15-24 kg: 500 mg twice daily
    25-34 kg: 750 mg twice daily
    Greater than 35 kg: 1 g twice daily
    15-24 kg: 20 mg twice daily
    25-34 kg: 30 mg twice daily
    Greater than 35 kg: 40 mg twice daily 1
    15-24 kg: 250 mg twice daily; 25-34 kg: 500 mg in morning, 250 mg+ in evening;
    Greater than 35 kg: 500 mg twice daily
    15-24 kg: 250 mg twice daily
    25-34 kg: 500 mg in morning, 250 mg in evening; greater than 35 kg: 500 mg twice daily

    Legend:

    • * sequential therapy = PPI + amoxicillin x 5 days followed by PPI + metronidazole + clarithromycin x 5 days
    • + if oral metronidazole suspension used, dose may be divided equally every 12 hours

    C-3.40.1.3. Dosage in Renal Impairment

    Dosage adjustments are not necessary when PPIs are prescribed as monotherapy to patients with renal impairment. Omeprazole/sodium bicarbonate therapy also does not require dosage adjustments in renally impaired patients. However, the esomeprazole/naproxen combination is not recommended for use in patients with a creatinine clearance below 30 ml/min due to the potential for naproxen/naproxen metabolite accumulation and increased risk for adverse events.

    C-3.40.2. Duration of Therapy

    PPI acute treatment durations for both adult and pediatric patients based on FDA-approved indications are summarized in Tables 9-11.

    In the acute setting in both adult and pediatric patients older than 11 months of age, 8 weeks of PPI therapy will treat EE and will heal most non-H. pylori duodenal and gastric ulcers. The prescribing health care provider may continue acute dosage regimens for longer than 8 weeks in patients with hypersecretory disease states, esophagitis, or GERD, as well as those patients with risk factors for gastric ulcer treatment failure such as smoking. PPI acute dosage regimens may also exceed 8 weeks in patients with risk factors for delayed duodenal ulcer healing such as daily ethanol use, large ulcers, signs of upper GI bleeding, and/or a previous history of duodenal ulcer. Patients with refractory ulcers, defined as ulcers that do not respond to up to 12 weeks of anti-ulcer therapy, may also require extended PPI therapy. Treatment regimens at acute dosage levels lasting longer than four months (16 weeks) in patients with a diagnosis of acute duodenal or gastric ulcer will be reviewed.

    Clinical trials support dexlansoprazole efficacy for maintenance of healed EE and heartburn relief for up to six months in adults and up to 16 weeks in pediatric patients 12 to 17 years of age.

    Esomeprazole, when prescribed for risk reduction of NSAID-associated gastric ulcer, may be administered for up to six months, as controlled studies for this indication do not extend beyond this time. Treatment regimens for NSAID-associated gastric ulcers extending beyond designated treatment times for esomeprazole and lansoprazole will be reviewed.

    Unless otherwise specified, maintenance therapy, at the recommended daily maintenance dose (Tables 2 and 4), may be continued indefinitely based on patient need. Omeprazole treatment for EE and GERD in pediatric patients may continue indefinitely.

    PPI treatment duration in adults for H. pylori eradication is summarized in Table 12. PPI therapy is prescribed for a maximum of 14 days in most patients, as treatment durations exceeding 14 days do not significantly increase eradication rates. In treatment failures, retreatment with an alternate antibiotic regimen has been beneficial. In these circumstances, patients may receive PPI therapy for a maximum of 28 days.

    Pediatric treatment regimens for H. pylori eradication reported in guidelines and clinical trials should be administered for 10 to 14 days. Pediatric sequential therapy for H. pylori eradication is comprised of a PPI plus amoxicillin administered for 5 days, followed by a PPI plus metronidazole plus clarithromycin given for 5 days.

    C-3.40. Table 10. PPI Acute Duration of Therapy for Adult Patients: Combination Therapy

    Treatment Indication Drug Name Maximum Therapy Duration
    duodenal ulcer omeprazole/sodium bicarbonate (Zegerid®, generics) 4 weeks+
    EE   8 weeks#
    gastric ulcer   8 weeks
    GERD   4 weeks

    Legend:

    • + may consider an additional 4-week treatment course in patients who do not heal with initial treatment
    • # may consider an additional 8-week treatment course in patients with incomplete healing or EE recurrence after initial treatment

    C-3.40. Table 11. PPI Acute Duration of Therapy for Pediatric Patients: Monotherapy

    Treatment Indication Drug Name Maximum Therapy Duration
    erosive esophagitis (EE) dexlansoprazole (Dexilant®) 12 to 17 years of age: 8 weeks
    EE due to only acid-mediated GERD esomeprazole magnesium (Nexium®, generics) 1 to 11 months of age: 6 weeks
    EE  

    1 to 11 years of age: 8 weeks

    12 to 17 years of age: 8 weeks

    symptomatic GERD-nonerosive  

    1 to 11 years of age: 8 weeks

    12 to 17 years of age: 4 weeks

    EE lansoprazole (Prevacid®, generics)

    1 to 11 years of age: 12 weeks

    12 to 17 years of age: 8 weeks

    GERD  

    1 to 11 years of age: 12 weeks

    12 to 17 years of age: 8 weeks

    EE omeprazole (Prilosec®, generics) 1 month to less than 1 year of age: 6 weeks
    1 to 16 years of age: 12 weeks ∞
    EE omeprazole magnesium (Prilosec®) 1 month to less than 1 year of age: 6 weeks
    1 to 16 years of age: 8 weeks ^
    GERD   1 to 16 years of age: 4 weeks
    EE pantoprazole (Protonix®, generics) Greater than or equal to 5 years of age: 8 weeks
    GERD rabeprazole (Aciphex®, generics)

    1 to 11 years of age: 12 weeks

    12 to 17 years of age: 8 weeks

    Legend:

    • ∞ may consider additional 4- to 8-week treatment course with EE or GERD recurrence
    • ^ may consider an additional 4- to 8-week treatment course in patients who do not heal with initial treatment

    C-3.40. Table 12. Proton Pump Inhibitor Recommended Therapy Duration in Adults for H. pylori Eradication

    Drug Name Recommended Therapy Duration
    esomeprazole
    • with triple therapy: 10 days
    lansoprazole
    • with dual therapy: 14 days
    • with triple therapy: 10-14 days
    omeprazole
    • with ulcer present at treatment initiation
      • dual or triple therapy: 28 days
    • without ulcer present at treatment initiation
      • dual therapy: 14 days
      • triple therapy: 10 days
    rabeprazole with triple therapy: 7 days

    C-3.40. Table 9. PPI Acute Duration of Therapy for Adult Patients: Monotherapy

    Treatment Indication Drug Name Maximum Therapy Duration
    erosive esophagitis (EE) dexlansoprazole (Dexilant®) 8 weeks
    gastroesophageal reflux disease (GERD) - nonerosive   4 weeks
    EE esomeprazole magnesium (Nexium®, generics) 8 weeks^
    GERD   4 weeks+
    heartburn   14 days*
    EE esomeprazole strontium 8 weeks^
    GERD   4 weeks+
    duodenal ulcer lansoprazole (Prevacid®, generics) 4 weeks
    EE   8 weeks#
    gastric ulcer   8 weeks
    GERD   8 weeks
    heartburn   14 days*
    NSAID-associated gastric ulcer  
    • without prior gastric ulcer:
      • 8 weeks
    • with prior gastric ulcer:
      • 12 weeks
    duodenal ulcer omeprazole (Prilosec®, generics) 4 weeks+
    EE   8 weeks#
    EE gastric ulcer 8 weeks
    GERD   4 weeks
    heartburn   14 days*
    duodenal ulcer omeprazole magnesium (Prilosec®) 4 weeks+
    EE   8 weeks#
    gastric ulcer   8 weeks
    GERD   4 weeks
    EE pantoprazole (Protonix®, generics) 8 weeks#
    duodenal ulcer rabeprazole (Aciphex®, generics) 4 weeks+
    EE   8 weeks#
    GERD   4 weeks+

    Legend:

    • ^ may consider an additional 4- to 8-week treatment course in patients who do not heal with initial treatment
    • + may consider an additional 4-week treatment course in patients who do not heal with initial treatment 
    • # may consider an additional 8-week treatment course in patients with incomplete healing or EE recurrence after initial treatment
    • * PPI treatment duration should not exceed 14 days during a 4-month period, unless alternate instructions are provided by a physician
    • ~ treatment longer than 14 days has not been studied in critically ill patients

    C-3.40.3. Duplicative Therapy

    The combination of two or more PPIs is not supported by the current literature. Additional clinical benefit is not realized when multiple PPIs are prescribed adjunctively. Therefore, concurrent use of multiple PPIs will be reviewed.

    C-3.40.4. 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 PPIs are summarized in Table 13. Only those drug-drug interactions identified as clinical significance level 1 or contraindicated, or those considered life-threatening which have not yet been classified will be reviewed.

    C-3.40. Table 13. Major PPI Drug-Drug Interactions

    Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
    dexlansoprazole, esomeprazole, lansoprazole, omeprazole tacrolimus adjunctive administration may result in increased tacrolimus serum levels as tacrolimus is metabolized by CYP3A4, and select PPIs are substrates for CYP3A4 and CYP2C19 avoid combination, if possible; if concurrent therapy necessary, monitor serum tacrolimus levels and observe for adverse events; adjust doses as needed major, moderate (DrugReax) 3-moderate (CP)
    esomeprazole, omeprazole cilostazol (Pletal®) adjunctive use may increase cilostazol serum levels and enhance cilostazol pharmacologic/adverse effects as cilostazol is metabolized by CYP2C19 as esomeprazole and omeprazole are CYP2C19 inhibitors reduce cilostazol dose by 50% when given concurrently with omeprazole and monitor for enhanced cilostazol pharmacologic/ adverse effects moderate (DrugReax) 2-major (CP)
    esomeprazole, omeprazole citalopram (Celexa®) adjunctive use may increase citalopram serum levels and enhance citalopram, pharmacologic/adverse effects (including QT interval prolongation) as citalopram is metabolized by CYP2C19 and esomeprazole and omeprazole are CYP2C19 inhibitors citalopram dose should not exceed 20 mg/day if this drug combination is utilized; monitor for enhanced citalopram pharmacologic/ adverse effects major (DrugReax) 2-major (CP)
    esomeprazole, omeprazole, pantoprazole methotrexate (MTX) concurrent administration of select PPIs and MTX (primarily high-dose MTX) may result in elevated MTX parent and metabolite concentrations and the potential for enhanced pharmacologic and adverse effects; these PPIs reduce renal MTX elimination use combination cautiously; monitor MTX levels and observe patients for signs/symptoms of adverse events; may use alternative PPI or H2RA that does not interact; may not occur with lower MTX doses major (DrugReax) 2-major (CP)
    PPIs select azole antifungals (e.g., itraconazole, ketoconazole, posaconazole) combined administration may decrease antifungal absorption and effectiveness; itraconazole, ketoconazole, and posaconazole dependent on acidic environment for favorable absorption and PPIs increase gastric pH avoid concurrent administration, if possible; if PPI-antifungal combination necessary, may administer antifungal with acidic beverage (e.g., Coke) to increase absorption; monitor closely for continued antifungal efficacy moderate (DrugReax) 2-major (CP)
    PPIs clopidogrel (Plavix®) combined administration may attenuate clopidogrel effects on platelet aggregation, increase potential risk of secondary acute cardiovascular events following percutaneous coronary intervention or acute coronary syndrome; exact mechanism for interaction unknown, but PPIs may delay or minimize clopidogrel conversion to its active form by competitively inhibiting CYP2C19 avoid combined use, if possible; H2RAs# other than cimetidine or pantoprazole (has less CYP2C19 inhibitory activity) are suitable alternatives for acid suppressive therapy in patients requiring clopidogrel major (DrugReax) 2-major (CP)
    PPIs dasatinib (Sprycel®) adjunctive administration for extended duration may result in reduced dasatinib exposure and serum levels as dasatinib dependent on acidic gastric pH for solubility and absorption combined use not recommended; alternative acid suppressives (e.g., antacids) should be given 2 hours before or 2 hours after dasatinib dose for optimal efficacy major (DrugReax) 2-major (CP)
    PPIs delavirdine 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 PPIs affect gastric pH for prolonged time period 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)
    PPIs erlotinib (Tarceva®) adjunctive administration may decrease erlotinib absorption and reduce effectiveness as erlotinib solubility, which is pH dependent, is reduced with PPI therapy avoid combination, if possible; if adjunctive therapy necessary, use lowest effective PPI dose, monitor for reduced erlotinib efficacy, and adjust erlotinib dose as needed; may use alternate acid suppressive therapy (e.g., H2RAs, antacids); antacid and erlotinib doses should be separated by several hours major (DrugReax)
    PPIs mycophenolate combined administration may result in decreased mycophenolic acid serum levels and reduced therapeutic efficacy, most likely due to decreased mycophenolate absorption with increased gastric pH avoid combined use, if possible; if adjunctive therapy necessary, closely monitor mycophenolic acid serum levels and adjust mycophenolate doses as necessary major (DrugReax)
    PPIs select protease inhibitors (e.g., atazanavir, indinavir, nelfinavir) concurrent administration may result in reduced protease inhibitor serum levels and effectiveness and increased potential for resistance, as PPIs may interfere with protease inhibitor solubility and absorption by increasing gastric pH avoid PPI and atazanavir, indinavir, or nelfinavir combinations major (DrugReax) 1-severe: atazanavir, nelfinavir; 2-major: indinavir (CP)
    PPIs rilpivirine (Edurant®) adjunctive administration may promote rilpivirine treatment failure and potential for impaired virologic response and rilpivirine/NNRI† resistance as rilpivirine requires more acidic gastric pH for absorption combined administration contraindicated contraindicated (DrugReax) 1-severe (CP)
    PPIs other agents with solubility affected by changes in gastric pH (e.g., bosutinib, ponatinib, vismodegib) concomitant administration may result in reduced bioavailability and activity of agents requiring low gastric pH for solubility as PPIs increase gastric pH avoid combination, if possible; if adjunctive therapy necessary, use lowest effective PPI dose, monitor for reduced efficacy of agents requiring low gastric pH for solubility, and adjust dose as needed; may use alternate acid suppressive therapy (e.g., H2RAs, antacids); antacid and doses for agents with solubility issues should be separated by several hours major (DrugReax)
    PPIs vitamin K antagonists (e.g., warfarin) concurrent administration may result in elevated INR^ levels and prothrombin time and enhanced anticoagulant effects; warfarin is metabolized by CYP2C19 and omeprazole is a CYP2C19 inhibitor, but mechanism for other PPIs is not well known monitor INR levels and observe for bleeding issues/adverse effects; adjust warfarin doses as needed moderate (DrugReax) 3-moderate (CP)

    Legend:

    • CP = Clinical Pharmacology
    • # histamine (H2) receptor antagonists
    • † non-nucleoside reverse transcriptase inhibitor
    • ^ International Normalized Ratio

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    23. Shashidhar H, Peters J, Lin CH, et al.  A prospective trial of lansoprazole triple therapy for pediatric Helicobacter pylori infection. J Pediatr Gastroenterol Nutr. 2000;30:276-82.
    24. Behrens R, Lang T, Keller KM, et al. Dual versus triple therapy of Helicobacter pylori infection: results of a multicentre trial. Arch Dis Child. 1999;81:68-70.
    25. Zimmermann AE, Walters JK, Katona BG, et al. A review of omeprazole use in the treatment of acid-related disorders in children. Clin Ther. 2001;23:660-79.
    26. Marchetti F, Gerarduzzi T, Ventura A. Proton pump inhibitors in children: a review. Dig Liver Dis. 2003;35:738-46.
    27. Kahrilas PJ, Shaheen NJ, Vaezi MF, for the AGA Institute. American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology.  2008;135:1383-91.
    28. van der Pol RJ, Smits MJ, van Wijk MP, et al. Efficacy of proton-pump inhibitors in children with gastroesophageal reflux disease: a systematic review. Pediatrics. 2011;127(5):925-35. 
    29. Wolfe WM. Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on December 2, 2020.) 
    30. Crowe SE. Treatment regimens for Helicobacter pylori. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on March 13, 2019.) 
    31. Love BL, Mohorn PL. Peptic Ulcer Disease and Related Disorders. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill; Accessed December 02, 2020. https://accesspharmacy-mhmedical-com.ezproxy.lib.utexas.edu/content.aspx?bookid=2577&sectionid=219309460.
    32. Spechler SJ. Proton pump inhibitors: what the internist needs to know. Med Clin North Am. 2019;103(1):1-14.

    C-3.41. Quetiapine (low dose)

    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 Oct. 2021; September 2019; September 2017; December 2015; March 2014; May 2012; July 2010; May 2007; March 2007
    • Initially developed
      • Jan. 2007

    C-3.41.1. Dosage

    HHSC does not support low-dose quetiapine use as non-FDA-approved sleep aid monotherapy. Data included in these criteria address available studies evaluating low-dose quetiapine in insomnia, the limits of these studies, as well as risks associated with quetiapine use for this indication.  Additionally, evidence-based use of lower quetiapine doses for FDA-approved and pediatric purposes is also discussed.

    C-3.41.1.1. Adults

    Quetiapine, a dibenzothiazepine antipsychotic agent, is FDA-approved for acute manic and mixed episodes of bipolar disorder, acute depressive episodes associated with bipolar disorder, maintenance therapy of bipolar disorder when used adjunctively with lithium or divalproex, major depressive disorder when used as adjunctive therapy to antidepressants (extended-release formulation only), and schizophrenia.1-6 Recommended quetiapine dosages are summarized in Table 1 1-6.

    While not FDA-approved, quetiapine has been evaluated in adults with insomnia utilizing doses less than 150 mg/day in the literature. Measurements commonly used to assess insomnia treatment effectiveness include sleep period time (SPT; the duration of time from sleep onset to final awakening), total sleep time (TST; the difference of time between SPT and the time spent awake), and sleep efficiency (SE; the ratio of TST compared to the amount of time spent in bed).7 Patient-reported outcomes are also often assessed. The Spiegel Sleep Questionnaire (SSQ) is comprised of 7 items that are each scored from 1 to 5, with higher scores indicating positive outcomes.8 The Insomnia Severity Index scale (ISI) is a tool used to measure a patient’s perception of their insomnia. This instrument also consists of 7 items, but each item is scored from 0 to 4. Higher scores correlate with more severe insomnia.9 Clinical evidence of low-dose quetiapine use for insomnia is exhibited in Table 2.

    Based on available clinical evidence, low-dose quetiapine has shown some benefit for adult patients suffering from insomnia.7-19 Quetiapine not only improved the quantity of sleep, by increasing TST and SE, but also the quality of sleep, by increasing patient-reported outcomes. However, available results are based on data from case reports and uncontrolled trials and include few patients over 65 years of age or those in nursing homes. Too, the mechanism of action for low-dose quetiapine targets histamine H1 and alpha-1 adrenergic receptors rather than serotonergic and dopaminergic receptors, which may aid in promoting sleep but does not significantly impact mood or psychotic disorders. Additionally, quetiapine has been assigned black box warnings: increased mortality in elderly patients with dementia-related psychosis; and increased risk of suicidality in children, adolescents, and young adults taking antidepressants for major depressive and other psychiatric disorders. Other warnings include leukopenia, neutropenia, neuroleptic malignant syndrome, metabolic changes, and agranulocytosis.2, 3, 19-21 Commonly reported adverse events include xerostomia, morning sedation, and weight gain. Reports of weight gain despite the use of low quetiapine doses may predispose some patients to metabolic disturbances (e.g., diabetes, dyslipidemia) associated with second generation antipsychotic (SGA) use. 16, 19

    Long-term efficacy of low-dose quetiapine treatment for insomnia has yet to be demonstrated in larger, randomized, controlled trials. Additional safety data are also needed before quetiapine can be prescribed with confidence for insomnia patients. Until strong evidence is established, low-dose quetiapine should be used with caution for the off-label treatment of insomnia, especially when other FDA-approved agents for insomnia are available and more economically feasible.22 Patients with co-morbid conditions and insomnia, however, may find some benefit from low-dose quetiapine, with close monitoring for potential long-term adverse events. 14, 23

    A comparative effectiveness review published by the Agency for Healthcare Research and Quality (AHRQ) evaluated physician prescribing patterns for off-label uses of atypical antipsychotics. Researchers found one small trial (n = 13) in which physicians prescribed quetiapine to patients for insomnia and concluded that quetiapine may not be effective in managing insomnia; the strength of evidence used to determine the efficacy of quetiapine in insomnia was very low. 24

    Quetiapine doses less than 150 mg/day are not routinely recommended. However, elderly patients (defined as 65 years of age and older) and debilitated patients may not tolerate higher initial quetiapine doses due to decreased oral quetiapine clearance. Slower titration schedules using doses of 25-50 mg/day until clinical response is achieved are necessary to avoid adverse events.1-6 Some patients have been managed with doses as low as 25 mg to 50 mg/day for psychosis and bipolar disorder. 25-27 Quetiapine is not FDA-approved for use in doses lower than 150 mg/day, except in elderly and debilitated patients, and will be reviewed.

    C-3.41. Table 1: Quetiapine Approved Adult Dosage Recommendations

    Treatment Indication Dosage Form Usual Dosage Range Maximum Recommended Dosage
    BD treatment: depression IR, ER 300 mg/day 300 mg/day
    BD treatment: mania IR, ER 400-800 mg/day 800 mg/day
    BD: maintenance IR, ER 400-800 mg/day 800 mg/day
    Major depressive disorder, adjunctive therapy ER 150-300 mg/day 300 mg/day
    Major depressive disorder, adjunctive therapy ER 150-300 mg/day 300 mg/day
    Schizophrenia: acute IR 150-750 mg/day 750 mg/day
    Schizophrenia: maintenance IR, ER 00-800 mg/day 800 mg/day

    Legend:

    • BD = bipolar I disorder
    • ER = extended-release
    • IR = immediate-release

    C-3.41. Table 2: Quetiapine Studies/Case Reports for the Treatment of Insomnia

    Study Population Design Intervention Outcomes
    Cohrs et al. 7 (2004)

    14 patients:

    • healthy males
    • age: 18-65 years

    DB, PC, R, crossover, single-center study

    Duration: 3 consecutive nights, 4 days apart

    Quetiapine:

    • 25 mg one hour before bedtime
    • 100 mg one hour before bedtime Control: placebo
    Under standard sleep laboratory conditions:
    • 25 mg: significant differences for SPT, TST, and SE compared to placebo
    • 100 mg: significant difference for SPT compared to placebo

    Under Acoustic Stress:*

    • 25 mg: significant differences for SPT, TST, and SE compared to placebo
    • 100 mg: significant differences at SPT, TST and SE compared to placebo
    Juri et al. 10 (2005)

    14 patients:

    • male and female
    • Parkinson’s disease

    Open-label study

    Duration: 12 weeks

    Quetiapine:

    • initial dose: 12.5 mg at bedtime
    • dose adjusted according to response and tolerance
    • mean dose: 31.9 mg at bedtime at week 12

    Sleep Latency:

    • decrease of 82 ± 65.4 vs 28.6 ± 22.7 minutes from baseline (p less than 0.05)
    • no correlation between response and dose of levodopa or dopamine agonist

    Safety:

    • two patients withdrew due to restless leg symptoms that subsided after quetiapine discontinuation
    • two patients reported increased diurnal sleepiness
    • no reports of orthostatic symptoms or significant changes in blood pressure
    Fernando et al. 11 (2005)

    1 patient:

    • 34-year-old male
    • insomnia due to chronic back pain
    Case report Quetiapine: titrated up to 200 mg at bedtime

    Observations:

    • improved quality of sleep
    • improved sleep latency
    Sokolski et al. 12 (2006) 1 patient:
    • 42-year-old white male
    • 25-year history of major depression 
    • insomnia exacerbated by phenelzine use
    Case report Quetiapine:
    • initial dose: 6.25 mg at bedtime
    • dose increased by 6.25 mg every 3 - 4 days until reached 25 mg at bedtime
    • later increased to 37.5 mg at bedtime
    • max dose: 50 mg at bedtime
    Observations:
    • insomnia dramatically improved
    • patient slept 6 - 7 hours per night without interruption

    Safety:

    • only reported adverse event was morning sedation; patient gradually habituated
    • patient continued on phenelzine and quetiapine for more than 1 year with no report of adverse events
    Wiegand et al. 13 (2008)

    18 patients:

    • primary insomnia
    Open-label pilot study Duration: 6 weeks

    Quetiapine:

    • initial dose: 25 mg at bedtime
    • increased to 50 mg at bedtime (n = 7)
    • increased to 75 mg at bedtime (n = 1)

    Objective Sleep Parameters:

    • significant improvements in TST and SE
    • initial improvements observed at 2 weeks and continued throughout study period
    • sleep onset latency not significantly decreased no test variable showed a decline from baseline over the study period

    Safety:

    • reports of xerostomia and morning sedation (frequency not defined)
    • no reports of severe adverse events
    Terán et al. 14 (2008)

    52 patients:

    • drug abusers in   detoxification process
    • insomnia as primary 
    • withdrawal symptom
    • included both outpatients and inpatients
    Retrospective study Follow-up period of at least 60 days

    Quetiapine:

    • median dose: 50 mg at bedtime
    • mean dose: 62.35 mg at bedtime
    • range: 22 mg - 225 mg at bedtime

    Change in SSQ:

    • 75% improvement from baseline (p less than 0.001)
    • greatest improvement in mean score occurred in first week (p less than 0.001)
    • benzodiazepine use decreased from baseline (83% vs 22.6% of patients)

    Safety:

    • well tolerated
    • no patients dropped out due to adverse events
    • xerostomia most common adverse event (n=18; 34.5%)
    Pasquini et al. 15 (2009) 6 patients:
    • females
    • localized breast cancer receiving tamoxifen
    Case series Duration: 6 weeks

    Quetiapine:

    • initial dose: 25 mg one hour before bedtime
    • max dose: 100 mg one hour before bedtime

    Efficacy:

    • swift improvement in insomnia in 5/6 patients
    • patients moved from the moderate ISI category (score of 15 to 21) to absence of insomnia
    • effect maintained after 6 weeks

    Safety:

    • weight gain (n=2)
    • dizziness (n=1)
    Cates et al. 16 (2009)

    43 patients:

    • male and female psychiatric patients
    • 19 – 65 years old
    • receiving at least one other psychotropic medication
    • mean BMI = 31
    Retrospective study

    Quetiapine:

    • mean initial dose: 109.3 mg ± 47.3 per day
    • mean final dose: 120.3 mg plus or minus 58.6 per day
    • most common regimen: 100 mg at bedtime
    • mean duration: 11.1 months plus or minus 8.2

    Efficacy:

    • Primary Outcome:
      • changes in weight, BMI, and waist circumference compared to baseline
      • mean weight gain of 4.9 lb over approximately 11 months
      • statistically significant increase in weight (p = 0.037)
      • statistically significant increase in BMI (p = 0.048)
      • increase in waist circumference not statistically significant
      • male mean increase in weight: 10.5 lb plus or minus 15.6 (p = 0.009)
      • male mean increase in BMI: 1.3 points plus or minus 2.1 (p = 0.016)
    • Secondary Outcome: (compared to baseline)
      • correlation of metabolic changes with patient and treatment variables;
      • no significant differences were found
    Tassniyom et al. 17 (2010)

    13 patients:

    • primary insomnia
    • mean age: 45.95 years

    R, DB, PC
    Duration: 3 weeks

    Sleep diary kept for 1 week prior to treatment

    Quetiapine (Q):

    • 25 mg every night X 2 weeks

    Placebo (P):

    • every night x 2 weeks
       

    Efficacy:

    • Primary Outcome:
      • TST, sleep latency, daytime alertness/functioning, sleep satisfaction
      • TST:  increased 124.92 min (Q) vs 72.24 min (P) – NS
      • SL:  decreased 96.16 min (Q) vs 23.72 min (P) – NS
    • Safety:
      • dry lips, dry tongue, morning drowsiness in two Q patients

    Legend:

    • BMI = body mass index
    • DB = double-blind
    • ISI = Insomnia Severity Index scale
    • PC = placebo-controlled
    • R = randomized
    • SE = sleep efficiency
    • SL = sleep latency
    • SPT = sleep period time
    • SSQ = Spiegel Sleep Questionnaire
    • TST = total sleep time
    • *Acoustic Stress = staccato piano tones ranging in pitch and tone intensity played in short spurts during the 8 hour bedtime period (duration: 4-5 seconds; interval: 30 – 90 seconds)

    C-3.41.1.2. Pediatrics

    Quetiapine is FDA-approved for acute mania in bipolar disorder in pediatric patients 10-17 years of age, and acute management of schizophrenia in adolescents 13-17 years of age. Pediatric quetiapine 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 Table 3 1-6, 28.

    Currently there is no FDA-approved indication for low-dose quetiapine use (150 mg/day or less) in the pediatric population. Data have been published that address quetiapine safety and efficacy for the treatment of various conditions in the pediatric population, and some of the patients included were taking quetiapine doses of 150 mg/day or less. Summary details of these publications can be found in Table 4.

    Evidence suggests that quetiapine use in children for a variety of indications including conduct disorder, attention-deficit/hyperactivity disorder, bipolar disorder, and other psychoses may be beneficial as monotherapy in some situations and as combination therapy in others. Although most trials used a mean dose greater than 300 mg/day, all studies presented in Table 4 utilized quetiapine doses of 150 mg/day or less. Based on the trials collectively, using quetiapine in patients younger than 18 years of age resulted in significantly improved scores on many of the psychiatric evaluations. Although average doses in the trials exceeded 150 mg/day, efficacy did not seem to be limited to higher quetiapine doses.29-39 However, many of these trials had several limitations that are important to consider. All trials were open-label trials, included very small numbers of participants, and were relatively short in duration. Only one trial was randomized, and most did not have a comparator or control group. 35-38

    While efficacy results seem promising from these trials, there are important adverse effects associated with quetiapine use in children. Weight gain, other metabolic changes, and sedation/somnolence, well known adverse effects associated with quetiapine use, were frequently reported by trial participants 35-38. Moreno et al.40 published a trial examining the metabolic effects of quetiapine and other SGA medications on children being treated for bipolar disorder as well as other psychotic and nonpsychotic disorders. This study found that after three months of treatment with an SGA, over 70% of patients experienced abnormal weight gain. Due to the frequency of weight gain and sedation occurring with SGA use, Penzner et al.41 studied the effect of co-prescribing a stimulant, which can cause weight loss and insomnia, to neutralize the adverse effects of the antipsychotic. Investigators found no significant differences in body composition and metabolic profiles between SGA-treated patients managed concurrently with or without stimulants.

    Low-dose quetiapine treatment for children with various psychotic or behavioral disorders has been beneficial in some cases. However, possible adverse events that may negatively impact health and quality of life need to be considered before treatment initiation.

    C-3.41. Table 3: Quetiapine: Pediatric Dosage Recommendations

    Treatment Indication Dosage Form Usual Dosage Range Per Age Group Literature Based Maximum Dosage Maximum Recommended Dosage
    BD treatment: acute mania IR, ER 10-17 years of age: 400-600 mg/day
    • Age 5-9 years: 400 mg/ day
    • Age 10-17 years: 800 mg/ day
    600 mg/day
    Schizophrenia: acute IR, ER 13-17 years of age: 400-800 mg/day Age 10-17 years: 800 mg/day 800 mg/day

     

    C-3.41. Table 4: Quetiapine Dosages in Pediatric Patients

    Study Age Quetiapine Dosage Disease State
    Stathis et al. 29 15 to 17 years of age (mean age 16.7 yrs) dose range 50 mg -200 mg/day (mean dose: 133 mg) Posttraumatic stress disorder
    Findling et al. 30 (2006) 6-12 years of age (mean age 8.9 yrs) range 75mg -300 mg/day (median dose: 150 mg/day; mean dose: 4.4 mg/kg/day) Conduct disorder
    Marchand et al. 31 4-17 years of age (mean age 10.8 yrs) dose range 100 mg -1000 mg/day (mean dose: 407, plus or minus 230 mg/day) Bipolar disorder
    Findling et al. 32 (2004) 12-17 years of age (mean age 14.6, plus or minus 2.3 yrs) mean maximum total daily dose range 100 mg - 450 mg/day (overall mean dose: 291.7 mg/day) Autistic disorder
    Mukaddes et al. 33 8-16 years of age (mean age 11.4 plus or minus 2.4 yrs) dose range 50 mg - 100 mg/day (mean dose: 72.9 mg plus or minus 22.5 mg/day) Tourette’s disorder
    Tufan 34 17-year-old-female 100 mg/day in divided doses (plus sertraline 50 mg/day) Autism; pervasive developmental disorder with mental retardation and self-injurious behavior
    Arango et al. 35 12-18 years of age dose range 73.2 mg – 992.4 mg/day (mean dose:  532.8 mg/day) Schizophrenia; bipolar disorder
    Findling et al. 36 (2007) 6-12 years of age dose range 75 mg-350 mg/day (mean dose at study end: 158.3 mg/day) (methylphenidate administered adjunctively in majority of patients) Conduct disorder
    Duffy et al. 37 13-20 years of age
    • throughout study:
      • dose range 64.4 mg – 617.4 mg/day (mean dose:  340.9 mg/day)
    • at study end:
      • dose range 27.3 mg – 561.9 mg/day (mean dose: 294.6 mg/day)
    Bipolar disorder
    Kronenberger et al. 38 12-16 years of age dose range 120.2 mg – 538.2 mg/day (mean dose: 329.2 mg/day) (given in conjunction with methylphenidate) ADHD*-combined type and disruptive behavior disorder with conduct disorder
    Golubchik et al. 39 13-17 years of age dose range 50 mg-150 mg/day (mean dose:  122.7 plus or minus 39.5 mg/day) Autistic spectrum disorder

    C-3.41.2. Duration of Therapy

    Low-dose quetiapine (less than 150 mg/day) is only FDA-approved as part of a drug titration schedule to aid patients in getting to the target quetiapine dosage goal (see Table 1). Therefore, quetiapine dosages less than 150 mg/day should not be prescribed for more than 30 days, except in elderly and debilitated patients. Quetiapine dosages less than 150 mg/day prescribed for greater than 30 days, except in elderly and debilitated patients, are not recommended and will be reviewed.

    C-3.41.3. 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 quetiapine are summarized in Table 5 1, 2. 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:

    C-3.41. Table 5: Select Drug-Drug Interactions for Quetiapine

    Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
    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)
    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, 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)

    C-3.41.4. References

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    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 August 17, 2021. 
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    32. Findling RL, McNamara NK, Gracious BL, et al. Quetiapine in nine youths with autistic disorder. J Child Adolesc Psychopharmacol. 2004;14:287-94.
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    34. Tufan AE. Adjunctive quetiapine may help depression comorbid with pervasive developmental disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1570-1.
    35. Arango C, Robles O, Parellada M, et al. Olanzapine compared to quetiapine in adolescents with a first psychotic episode. Eur Child Adolesc Psychiatry. 2009;18:418-28.
    36. Findling RL, Reed MD, O’Riordan MA, et al. A 26-week open-label study of quetiapine in children with conduct disorder. J Child Adolesc Psychopharmacol. 2007;17(1):1-9.
    37. Duffy A, Milin R, Grog P. Maintenance treatment of adolescent bipolar disorder: open study of the effectiveness and tolerability of quetiapine. BMC Psychiatry. 2009;9(4).
    38. Kronenberger WG, Giauque AL, Lafata D, et al. Quetiapine addition in methylphenidate treatment-resistant adolescents with comorbid attention-deficit/hyperactivity disorder, conduct/oppositional-defiant disorder, and aggression: a prospective, open-label study. J Child Adolesc Psychopharmacol. 2007;17(3):334-7.
    39. Golubchik P, Sever J, Weizman A. Low-dose quetiapine for adolescents with autistic spectrum disorder and aggressive behavior: open-label trial.  Clin Neuropharmacol. 2011;34(6):216-9.
    40. Moreno C, Merchan-Naranjo J, Alvarez M, et al. Metabolic effects of second-generation antipsychotics in bipolar youth: comparison with other psychotic and nonpsychotic diagnoses. Bipolar Disord. 2010;12:172-84.
    41. Penzner JB, Dudas M, Saito E, et al. Lack of effect of stimulant combination with second-generation antipsychotics on weight gain, metabolic changes, prolactin levels, and sedation in youth with clinically relevant aggression or oppositionality. J Child Adolesc Psychopharmacol. 2009;19:563-73.
    42. Kamphuis J, Taxis K, Schuiling-Veninga CC, et al. Off-label prescriptions of low-dose quetiapine and mirtazapine for insomnia in The Netherlands.  J Clin Psychopharmacol. 2015;35(4):468-70.

    C-3.43. Sedative/Hypnotics

    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; May 2018; May 2016; March 2016; August 2014; May 2014; March 2014; March 2012; May 2010; November 2006; August 2006; July 2006; December 2003; October 2002; November 2001; October 2000; December 1999; November 1998; November 1997; November 1996
    • Initially developed
      • January 1995

    C-3.43.1. Dosage

    C-3.43.1.1. Adults

    Maximum recommended daily doses for sedative/hypnotics in adults, including the elderly population, are summarized in Table 1. Prescribed dosages exceeding these recommendations will be reviewed.

    In the elderly, short- and intermediate-acting benzodiazepines (e.g., temazepam, triazolam) are preferred, as long-acting benzodiazepines (e.g., flurazepam) are associated with increased sedation and an increased risk of falls and fractures in this patient population.

    The appropriate sedative/hypnotic dose for debilitated patients is the same as that prescribed in elderly patients for most sedative/hypnotic agents. However, estazolam 0.5 mg is used in small or debilitated geriatric patients, a dose lower than that recommended for elderly patients.

    Doxepin is FDA-approved for use in managing insomnia characterized by difficulty in maintaining sleep. Studies have documented efficacy for up to 3 months in duration.

    Patients with hepatic insufficiency have a reduced clearance of zolpidem. A 5 mg zolpidem immediate-release, sublingual (Edluar®), or oral spray (Zolpimist®) dose, a 1.75 mg sublingual tablet (Intermezzo®) dose, or a 6.25 mg extended-release dose is recommended in these patients.

    Eszopiclone should be used cautiously in patients with severe hepatic impairment with initial doses of 1 mg daily at bedtime, as eszopiclone is significantly hepatically metabolized and serum concentrations may increase substantially in this patient population.

    Suvorexant and lemborexant are newer sedative/hypnotics with a novel mechanism of action. Known as orexin receptor antagonists, suvorexant and lemborexant works by altering signaling of the orexin neurotransmitters in the brain. Orexins are responsible for regulating the sleep-wake cycle and helping to keep people awake. Suvorexant was FDA-approved in August 2014 as a schedule IV-controlled substance to manage insomnia associated with difficulties in sleep onset and/or sleep maintenance. Lemborexant was FDA-approved in December 2019 as a schedule IV-controlled substance for the treatment of insomnia characterized by difficulties with sleep onset and/ or sleep maintenance.

    C-3.43. Table 1: Maximum Recommended Daily Dosages for Sedative/Hypnotics in Adults: Benzodiazepines

    Drug Name Dosage Form/ Strength Maximum Recommended Dosage: Less than or equal to 65 years Maximum Recommended Dosage: Greater than 65 years
    estazolam (generics) 1 mg, 2 mg tablets 2 mg 2  mg*
    flurazepam (generics) 15 mg, 30 mg capsules 30 mg 15 mg*
    temazepam (Restoril®, generics) 7.5 mg, 15 mg, 22.5 mg, 30 mg capsules 30 mg 30 mg*
    triazolam (Halcion®, generics) 0.125 mg, 0.25 mg tablets 0.5 mg 0.25 mg*
    quazepam (Doral®) 15 mg tablets 15 mg 15 mg*

    Legend:

    • *In elderly patients (patients greater than 65 years of age), sedative/hypnotic dosages should be reduced if possible, as these patients are more sensitive to sedative/hypnotic pharmacologic/adverse effects.  

    C-3.43. Table 2: Maximum Recommended Daily Dosages for Sedative/Hypnotics in Adults: Barbiturates+

    Drug Name Dosage Form/ Strength Maximum Recommended Dosage: Less than or equal to 65 years Maximum Recommended Dosage: Greater than 65 years
    phenobarbital (generics) 15 mg, 16.2 mg, 30 mg, 32.4 mg, 60 mg, 64.8 mg, 97.2 mg, 100 mg tablets; 20 mg/5 mL elixir 320 mg 320 mg*
    secobarbital (Seconal®) 100 mg capsule 300 mg 300 mg*

    Legend:

    • +No longer considered acceptable drug class to manage insomnia as safer agents (i.e., benzodiazepines, nonbarbiturates) are available
    • *In elderly patients (patients greater than 65 years of age), sedative/hypnotic dosages should be reduced if possible, as these patients are more sensitive to sedative/hypnotic pharmacologic/adverse effects.

    C-3.43. Table 3: Maximum Recommended Daily Dosages for Sedative/Hypnotics in Adults: Non-Benzodiazepine, Benzodiazepine Receptor Agonists

    Drug Name Dosage Form/ Strength Maximum Recommended Dosage: Less than or equal to 65 years Maximum Recommended Dosage: Greater than 65 years
    eszopiclone (Lunesta®) 1 mg, 2 mg, 3 mg tablets 3 mg 2 mg
    zaleplon (generics) 5 mg, 10 mg capsules 20 mg 10 mg
    zolpidem immediate-release (IR) (Ambien®, generics) 5 mg, 10 mg IR tablets 10 mg 5 mg
    zolpidem extended-release (ER) (Ambien CR®, generics) 6.25 mg, 12.5 mg ER tablets 12.5 mg 6.25 mg
    zolpidem sublingual tablets (Edluar®) 5 mg, 10 mg sublingual tablets 10 mg 5 mg
    zolpidem sublingual tablets (Intermezzo®, generics) 1.75 mg, 3.5 mg sublingual tablets 1.75 mg  (women)
    3.5 mg  (men)
    1.75 mg
    zolpidem lingual spray (Zolpimist®) 5 mg/ actuation 10 mg 5 mg

    C-3.43. Table 4: Maximum Recommended Daily Dosages for Sedative/Hypnotics in Adults: Melatonin Receptor Agonists

    Drug Name Dosage Form/Strength Maximum Recommended Dosage: Less than or equal to 65 years Maximum Recommended Dosage: Greater than 65 years
    ramelteon (Rozerem®) 8 mg tablets 8 mg 8 mg

    C-3.43. Table 5: Maximum Recommended Daily Dosages for Sedative/Hypnotics in Adults: Orexin Receptor Antagonists

    Drug Name Dosage Form/Strength Maximum Recommended Dosage: Less than or equal to 65 years Maximum Recommended Dosage: Greater than 65 years
    suvorexant (Belsomra®) 5 mg, 10 mg 15 mg, 20 mg tablets 20 mg 20 mg
    lemborexant (Dayvigo®) 5 mg, 10 mg tablets 10 mg 10 mg

    C-3.43. Table 6: Maximum Recommended Daily Dosages for Sedative/Hypnotics in Adults: Miscellaneous Nonbarbiturates

    Drug Name Dosage Form/Strength Maximum Recommended Dosage: Less than or equal to 65 years Maximum Recommended Dosage: Greater than 65 years
    doxepin (Silenor®) 3 mg, 6 mg tablets 6 mg 6 mg

     

    C-3.43.1.2. Pediatrics

    Safety and efficacy of eszopiclone, ramelteon, zaleplon, zolpidem, lemborexant or suvorexant, as well as most sedative/hypnotic benzodiazepines, have not been established in pediatric patients. Flurazepam has been used to manage insomnia in adolescents 15 years of age and older. Although the oral barbiturates, phenobarbital and secobarbital are approved as sedatives and pre-anesthetics in pediatric patients, parenteral sedative/hypnotic agents are recommended due to shorter, more predictable onsets and quicker recovery times. Barbiturates are no longer recommended for use in pediatric insomnia as safer, more effective agents are available. Pediatric dosage recommendations for benzodiazepines are summarized in Table 7.

    C-3.43. Table 7: Recommended Sedative/Hypnotic Dosages for Pediatric Patients: Benzodiazepines

    Treatment Indication Drug Name Maximum Recommended Dosage 
    insomnia flurazepam adolescents 15 years and older: 30 mg orally at bedtime

     

    C-3.43.2. Duration of Therapy

    In adults, insomnia is classified based on symptom duration. Periods of sleep difficulty lasting from one to three nights are classified as transient insomnia, periods lasting three nights to one month are classified as    short-term insomnia, while chronic or long-term insomnia represents sleep difficulties exceeding one month.

    Acute, transient insomnia is due to minor situational, familial, or occupational stress and is managed primarily by teaching patients to re-establish normal sleep-wake patterns. Short-term insomnia is precipitated by events such as divorce, job loss, health concerns, or prescription medications and may be managed by behavioral techniques, lifestyle changes, and, if necessary, short-term pharmacologic therapy.

    Long-term insomnia may be associated with medical or psychiatric illness (e.g., mood and anxiety disorders, asthma, chronic pain, and gastroesophageal reflux) as well as a variety of prescribed medications, although approximately 50% of patients may develop chronic insomnia due to psychophysiological characteristics. Chronic insomnia with a psychophysiologic component is characterized by a marked over concern about the inability to fall asleep. A definitive diagnosis of the specific cause for long-term insomnia is necessary before a treatment plan can be delineated. Sedative/hypnotics are generally reserved for use in those patients with insomnia in whom secondary causes of insomnia have been evaluated and managed or in whom sleep hygiene practices have failed. Chronic insomnia without underlying medical or psychiatric disease can be managed most effectively with a benzodiazepine or nonbenzodiazepine hypnotic used concurrently for a finite period with daily behavioral therapy. Ideally, sedative/hypnotics are not routinely recommended for the management of chronic insomnia. However, in certain circumstances (e.g., severe, refractory insomnia, chronic comorbid illnesses), benzodiazepine and nonbenzodiazepine hypnotics may be administered in conjunction with non-pharmacologic behavioral therapy in the lowest effective dose several times per week for extended durations. Hypnotics should typically be dosed intermittently once every two to three nights to avoid tolerance and dependence. Recently, though, eszopiclone and ramelteon have been approved for use in the long-term management of sleep onset and/or sleep maintenance insomnia, while zolpidem extended-release has been approved for use in managing insomnia without a limit to treatment duration.

    Suvorexant and lemborexant, the most recently approved medications for insomnia, are prescribed to help patients with sleep onset and sleep maintenance. These drugs may be prescribed on a nightly basis if patients can remain in bed for at least 7 hours before the scheduled waking time.

    Zolpidem immediate-release prescribed quantities should not exceed a one-month supply.

    Barbiturates are indicated for short-term treatment of insomnia, as these agents appear to lose effectiveness in sleep induction and maintenance after 2 weeks.

    Sedative/hypnotic treatment regimens lasting longer than four months in adult patients will be reviewed.

    In pediatric patients, sedative/hypnotics are primarily used to alleviate anxiety and/or pain associated with painful or nonpainful but threatening procedures.

    C-3.43.3. Duplicative Therapy

    The concurrent use of two or more sedative/hypnotics is not recommended. Additional therapeutic benefit is not appreciated when several sedative/hypnotics are administered in combination. Patient profiles containing concurrent prescriptions for multiple sedative/hypnotics will be reviewed.

    C-3.43.4. Drug-Drug Interactions

    Patient profiles will be assessed to identify those drug regimens that may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for sedative/hypnotics 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 reviewed.

    C-3.43. Table 8: Sedative/Hypnotic Drug-Drug Interactions

    Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level#
    barbiturates (BARB) anticoagulants BARB induction of apixaban, rivaroxaban, and warfarin metabolic clearance (CYP3A4) with potential for decreased anticoagulant clinical effects avoid combination, if possible; closely monitor international normalized ratio (INR) when BARB therapy added, discontinued or changed to warfarin; addition of warfarin to chronic BARB regimen more tolerable moderate (DrugReax) 2-major (CP)
    barbiturates cyclosporine BARB induction of cyclosporine metabolic clearance (CYP3A4) with potential for reduced cyclosporine clinical effects avoid concurrent therapy, if possible; if combination necessary, monitor for cyclosporine immunosuppressive efficacy; monitor cyclosporine serum concentrations when BARB therapy added, discontinued, or changed 2-major (CP)
    barbiturates oral contraceptives (OC) BARB induction of estrogen/ progestin hepatic metabolic clearance with potential for decreased OC clinical effects and risk of contraceptive failure OCs with higher ethinyl estradiol dosages (e.g., 50 mcg) to increase contraceptive efficacy may be necessary; second contraceptive method recommended to prevent unwanted pregnancy 3-moderate (CP)
    barbiturates voriconazole BARB induction, especially long-acting BARBs (phenobarbital), of voriconazole metabolic clearance (CYP3A4) with potential for decreased voriconazole clinical effects voriconazole contraindicated for use with long-acting BARBs; use cautiously with short-acting BARBs and monitor clinical effects contraindicated (DrugReax) 1-severe (CP)
    doxepin drugs metabolized by CYP2D6 (e.g., phenothiazines, delavirdine) potential for increased doxepin serum levels and enhanced pharmacologic/ adverse effects due to competition for CYP2D6 metabolic pathway monitor patients for enhanced doxepin effects; adjust doses as necessary 2-major (CP)
    eszopiclone CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine) induction of eszopiclone metabolic clearance (CYP3A4) with potential for decreased eszopiclone clinical effects monitor patients for decreased eszopiclone efficacy; consider hypnotic agent not metabolized by CYP3A4 moderate (DrugReax) 3-moderate (CP)
    eszopiclone CYP3A4 inhibitors (e.g., ketoconazole, protease inhibitors, macrolides) potential for increased eszopiclone serum concentrations and enhanced pharmacologic/ adverse effects monitor patients for enhanced eszopiclone effects; adjust doses as necessary moderate (DrugReax) 3-moderate (CP)
    lemborexant CYP3A inducers potential for decreased lemborexant exposure and risk of reduced efficacy monitor patients for decreased efficacy. Consider alternate therapy if possible 2- major 
    oxidatively metabolized benzodiazepines (BZDs) (e.g., estazolam, triazolam) imidazole antifungals (e.g., itraconazole, ketoconazole) potential for increased serum concentrations and enhanced pharmacologic/ adverse effects in oxidatively metabolized BZDs  (metabolized by CYP3A4) as imidazole antifungals inhibit CYP3A4 adjunctive therapy with imidazole antifungals and oxidatively metabolized BZD contraindicated; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative contraindicated (DrugReax) 1-severe (CP)
    oxidatively metabolized BZDs (e.g., estazolam, triazolam) macrolides potential for increased serum concentrations and enhanced pharmacologic/ adverse effects in oxidatively metabolized BZDs (metabolized by CYP3A4) as macrolides inhibit CYP3A4 adjunctive therapy with macrolides and oxidatively metabolized BZD not recommended; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative; azithromycin may be macrolide alternative (not metabolized by CYP3A4) moderate (DrugReax) triazolam: 2-major
    estazolam: 3-moderate (CP)
    oxidatively metabolized BZDs (e.g., estazolam, triazolam) macrolides potential for increased serum concentrations and enhanced pharmacologic/ adverse effects in oxidatively metabolized BZDs (metabolized by CYP3A4) as macrolides inhibit CYP3A4 adjunctive therapy with macrolides and oxidatively metabolized BZD not recommended; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative; azithromycin may be macrolide alternative (not metabolized by CYP3A4) moderate (DrugReax) triazolam: 2-major; estazolam: 3-moderate (CP)
    oxidatively metabolized benzodiazepines (e.g., estazolam, triazolam) nefazodone potential for increased serum concentrations and enhanced pharmacologic/ adverse effects(e.g., prolonged sedation, excessive hypnotic effects) in oxidatively metabolized BZDs (metabolized by CYP3A4) as nefazodone potently inhibits CYP3A4 adjunctive therapy with nefazodone and oxidatively metabolized BZD contraindicated; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative contraindicated (DrugReax) 1-severe (CP)
    oxidatively metabolized BZDs (e.g., estazolam, triazolam) non-nucleotide reverse transcriptase (NNRT) inhibitors potential for altered serum concentrations and pharmacologic effects in oxidatively metabolized BZDs (metabolized by CYP3A4); delavirdine, efavirenz inhibit CYP3A4  and magnify oxidative BZD pharmacologic/ adverse effects, while nevirapine induces oxidative BZD metabolism and diminishes pharmacologic effects adjunctive therapy with NNRT inhibitors and oxidatively metabolized BZD contraindicated; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative contraindicated (DrugReax) 1-severe (CP)
    oxidatively metabolized BZDs (e.g., estazolam, triazolam) protease inhibitors potential for increased serum concentrations and enhanced pharmacologic/ adverse effects (e.g., severe sedation, respiratory depression) in oxidatively metabolized BZDs (metabolized by CYP3A4) as protease inhibitors inhibit CYP3A4 adjunctive therapy with protease inhibitors and oxidatively metabolized BZD contraindicated; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative contraindicated (DrugReax) 1-severe (CP)
    oxidatively metabolized BZDs (e.g., estazolam, triazolam) triazole antifungals (e.g., fluconazole, voriconazole) potential for increased serum concentrations and enhanced pharmacologic/ adverse effects in oxidatively metabolized BZDs (metabolized by CYP3A4) as triazole antifungals inhibit CYP3A4 adjunctive therapy with triazole antifungals and oxidatively metabolized BZD not recommended; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative major (DrugReax) 3-moderate (CP)
    ramelteon antifungal agents (triazoles or imidazoles) potential for increased ramelteon serum concentrations and increased clinical/adverse effects due to CYP2C9 inhibition by triazole antifungals (e.g., fluconazole, voriconazole) or CYP3A4 inhibition by imidazole antifungals (e.g., itraconazole, ketoconazole) cautiously administer therapy concurrently; monitor for enhanced ramelteon pharmacologic/ adverse effects moderate (DrugReax) 3-moderate (CP)
    ramelteon fluvoxamine fluvoxamine inhibition of ramelteon metabolism (CYP1A2) and potential for increased ramelteon serum concentrations and increased clinical/adverse effects avoid concurrent administration; other selective serotonin reuptake inhibitors (e.g., citalopram, fluoxetine) may be safer alternatives to fluvoxamine contraindicated (DrugReax) 1-severe (CP)
    ramelteon strong CYP1A2 inducers (e.g., rifampin, rifabutin) induction of ramelteon metabolic clearance (CYP1A2) with potential for decreased ramelteon clinical effects monitor for decreased ramelteon effectiveness minor (DrugReax) 3-moderate (CP)
    ramelteon strong CYP1A2 inducers (e.g., rifampin, rifabutin) induction of ramelteon metabolic clearance (CYP1A2) with potential for decreased ramelteon clinical effects monitor for decreased ramelteon effectiveness minor (DrugReax) 3-moderate (CP)
    sedative/hypnotics sodium oxybate (Xyrem®) adjunctive administration may result in additive central nervous system (CNS) depression concurrent administration contraindicated contraindicated (DrugReax) 1-severe (CP)
    sedative/hypnotics sodium oxybate (Xyrem®) adjunctive administration may result in additive central nervous system (CNS) depression concurrent administration contraindicated contraindicated (DrugReax) 1-severe (CP)
    suvorexant CNS depressants adjunctive administration may result in additive CNS depression, cognitive/ behavioral changes, and complex sleep behaviors combined administration not recommended; if necessary, monitor for residual CNS depressant effects major (DrugReax) 3-moderate (CP)
    suvorexant strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) potential for increased suvorexant serum levels and increased pharmacologic/ adverse effects and toxicity as suvorexant is CYP3A4 substrate combined administration not recommended contraindicated (DrugReax) 2-major (CP)
    suvorexant moderate CYP3A4 inhibitors (e.g., fluconazole, aprepitant, ciprofloxacin) potential for increased suvorexant serum levels and increased pharmacologic/ adverse effects as suvorexant is CYP3A4 substrate administer together cautiously, observing for increased adverse effects; suvorexant dose should be reduced to 5 mg/day, but may be increased to maximum of 10 mg/day to maintain efficacy moderate (DrugReax) 2-major (CP)
    suvorexant CYP3A4 inducers (e.g., carbamazepine, rifampin) combined administration may result in reduced suvorexant serum levels and decreased efficacy as suvorexant is CYP3A4 substrate monitor for decreased suvorexant efficacy and adjust dosages as needed moderate (DrugReax) 2-major (CP)
    TCAs (e.g., doxepin) monoamine oxidase inhibitors (MAOIs) increased risk of serotonin syndrome (e.g., mental status changes, hyperpyrexia, restless, shivering) 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)
    TCAs (e.g., doxepin) drugs other than MAOIs with serotonergic activity (e.g., tramadol, sumatriptan, nefazodone, trazodone) increased risk of serotonin syndrome (e.g., mental status changes, hyperpyrexia, restless, shivering, hypertonia, tremor) due to additive serotonergic effects  use cautiously together; if adjunctive administration necessary, monitor for  signs and symptoms of serotonin syndrome major (DrugReax) 2-major, 3-moderate (CP)
    TCAs (e.g., doxepin) drugs that prolong QT interval increased risk of somnolence, bradycardia and serious cardiotoxicity (QT prolongation, torsades de pointes) due to potential additive effects on QT interval avoid concurrent use; if adjunctive use necessary, monitor for increased pharmacologic/toxic effects; adjust dose as necessary contraindicated (DrugReax) 1-severe (CP)
    TCAs (e.g., doxepin) drugs that prolong QT interval increased risk of somnolence, bradycardia and serious cardiotoxicity (QT prolongation, torsades de pointes) due to potential additive effects on QT interval avoid concurrent use; if adjunctive use necessary, monitor for increased pharmacologic/toxic effects; adjust dose as necessary contraindicated (DrugReax) 1-severe (CP)
    zolpidem CYP3A4 inhibitors (e.g., ketoconazole, protease inhibitors) potential for increased zolpidem serum concentrations and enhanced pharmacologic/ adverse effects (e.g., severe sedation, respiratory depression) with concurrent administration of CYP3A4 inhibitors, as zolpidem is metabolized by CYP3A4 monitor patients for enhanced zolpidem effects; adjust doses as necessary moderate (DrugReax) 2-major, 3-moderate (CP)
    zolpidem CYP3A4 inducers (e.g., carbamazepine, rifampin) induction of zolpidem metabolic clearance (CYP3A4) with potential for decreased zolpidem clinical effects monitor for decreased zolpidem effectiveness moderate (DrugReax) 3-moderate (CP)

    Legend:

    • # Clinical Pharmacology

    C-3.43.5. References

    1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2020. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu. Accessed December 8, 2020.
    2. AHFS Drug Information 2020. Bethesda, MD: American Society of Health-System Pharmacists. 2020. Available at: https://online-statref-com.libproxy.uthscsa.edu. Accessed December 8, 2020. 
    3. IBM Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu/  (cited: December 8, 2020). 
    4. Quazepam (Doral®) oral tablets package insert. Galt Pharmaceuticals, LLC, October 2020. 
    5. Phenobarbital oral tablets package insert. Hikma Pharmaceuticals USA Inc., March 2020.  
    6. Butabarbital (Butisol®) sodium tablets package insert. Meda Pharmaceuticals Inc., December 2020.
    7. Zolpidem sublingual tablets (Edluar™) package insert  Meda Pharmaceuticals, August 2019.
    8. Zolpidem oral spray (Zolpimist®) package insert. Aytu BioScience, Inc., August 2019. 
    9. Eszopiclone (Lunesta®) package insert. Sunovion Pharmaceuticals Inc., June 2020.
    10. Ramelteon (Rozerem®) package insert. Takeda Pharmaceuticals America Inc., December 2018.
    11. Lemborexant (Dayvigo®) oral tablets package insert. Eisai Inc., April 2020.
    12. Zolpidem extended-release (Ambien CR®) package insert. Sanofi Aventis U.S., September 2020.
    13. Zolpidem sublingual tablets (Intermezzo®) package insert. Purdue Pharma, September 2019.
    14. Doxepin tablets (Silenor®) package insert. Currax Pharmaceuticals LLC, November 2020.
    15. Merck. FDA approves Belsomra® (suvorexant) for the treatment of insomnia. (August 13, 2014) Available at:  http://www.mrknewsroom.com/news-release/prescription-medicine-news/fda-approves-belsomra-suvorexant-treatment-insomnia.   Accessed December 8, 2020.
    16. Suvorexant tablets (Belsomra®) package insert. Merck & Co., Inc., March 2020.
    17. Dopp JM, Phillips BG. Chapter 89. Sleep-wake disorders (Chapter).  In: DiPiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: a pathophysiologic approach. 11th ed.  New York, McGraw-Hill, 2020.  Access Pharmacy Web site. Available at: https://accesspharmacy-mhmedical-com.ezproxy.lib.utexas.edu.   Accessed December 8, 2020.
    18. Patel KV, Aspesi AV, Evoy KE. Suvorexant: a dual orexin receptor antagonist for the treatment of sleep onset and sleep maintenance insomnia. Ann Pharmacother. 2015;49(4):477-83.
    19. Ramar K, Olson EJ. Management of common sleep disorders. Am Fam Physician. 2013;88(4):231-8.
    20. Roehrs T, Roth T. Insomnia pharmacotherapy. Neurotherapeutics. 2012;9:728-38.
    21. Sullivan SS.  Insomnia pharmacology. Med Clin North Am. 2010;94(3):563-80.
    22. EMSC Panel (Writing Committee) on critical issues in the sedation of pediatric patients in the emergency department. Clinical policy: critical issues in the sedation of pediatric patients in the emergency department.  Ann Emerg Med. 2008;51:378-399, 399e1-e57.
    23. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487-504.
    24. Ramelteon (Rozerem®) for insomnia. Med Lett Drugs Ther. 2005;47:89-91.
    25. Roth T, Walsh JK, Krystal A, Wessel T, Roehrs TA. An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia. Sleep Med. 2005;6:487-95.
    26. Fick DM, Cooper JW, Wade WE, Waller JL, Maclean JR, Beers MH.  Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts. Arch Intern Med.  2003;163(22):2716-24.
    27. Coté CJ, Karl HW, Notterman DA, et al. Adverse sedation events in pediatrics: analysis of medications used for sedation. Pediatrics. 2000;106;633-44.
    28. Cravero JP, Roback MG. Selection of medications for pediatric procedural sedation outside of the operating room. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on December 8, 2020.)
    29. Daud YN, Carlson DW. Pediatric sedation. Pediatr Clin N Am. 2014;61(4):703-17.

    C-3.44. Serotonin 5-HT1B/1D Receptor Agonists

    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; December 2014; March 2013; April 2011; October 2008; May 2007; December 2006; August 2003; July 2002; November 2001; September 2001; August 2000; October 1999
    • Initially developed
      • August 1998

    C-3.44.1. Dosage

    C-3.44.1.1. Adults

    Serotonin 5-HT1B/1D receptor agonists (SRAs) are FDA-approved to manage acute migraine headache attacks with or without aura. Injectable sumatriptan is also FDA-approved to manage cluster headache episodes. The maximum recommended adult doses for available SRAs are summarized in Tables 1 and 2. Dosages exceeding these recommendations will be reviewed.

    C-3.44. Table 1: Maximum Recommended Daily Adult Dosages for SRAs - Monotherapy

    Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
    almotriptan (generic) migraine with or without aura tablets (6.25 mg, 12.5 mg) 25 mg/day
    eletriptan (Relpax®, generic) migraine with or without aura tablets (20 mg, 40 mg) 80 mg/day
    frovatriptan (Frova®, generic) migraine with or without aura tablets (2.5 mg) 7.5 mg/day
    naratriptan (Amerge®, generic) migraine with or without aura tablets (1 mg, 2.5 mg) 5 mg/day
    rizatriptan (Maxalt®, generic) migraine with or without aura tablets (5 mg, 10 mg) 30 mg/day
    rizatriptan (Maxalt -MLT®, generic) migraine with or without aura orally-disintegrating tablets (5 mg, 10 mg) 30 mg/day
    rizatriptan propranolol patients migraine with or without aura   15 mg/day
    sumatriptan (Imitrex®, generic) migraine with or without aura intranasal spray (5mg/spray, 20 mg/spray - 6 per package) 40 mg/day
    sumatriptan (Onzetra Xsail®) migraine with or without aura intranasal powder (11 mg/actuation) 44 mg/day*
    sumatriptan (Imitrex®, generic) migraine with or without aura oral tablets (25 mg, 50 mg, 100 mg) 200 mg/day
    sumatriptan (Imitrex®, generic) migraine with or without aura subcutaneous injection (4 mg and 6 mg STATdose system, 6 mg/0.5 mL single dose vial) 12 mg/day
      cluster headache   12 mg/day
    sumatriptan (Tosymra®) migraine with or without aura Intranasal spray (10 mg/ spray - 6 per package) 30 mg/ day
    sumatriptan (Zembrace® SymTouch®) migraine with or without aura 3 mg/0.5 mL auto injector 12 mg/day
    zolmitriptan (Zomig®, generic) migraine with or without aura tablets (2.5 mg, 5 mg) 10 mg/day
    zolmitriptan (Zomig-ZMT®, generic) migraine with or without aura orally disintegrating tablets (2.5 mg, 5 mg) 10 mg/day
    zolmitriptan (Zomig®) migraine with or without aura intranasal (2.5 mg/ actuation, 5 mg/ actuation) 10 mg/day

    Legend:

    • *Alternatively, patients may receive a maximum Onzetra Xsail® dose of 22 mg plus one dose of another sumatriptan product at least 2 hours later

    C-3.44. Table 2: Maximum Recommended Daily Adult Dosages for SRAs – Combination Therapy

    Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
    sumatriptan/naproxen (Treximet®) migraine with or without aura tablets (85 mg/500 mg) 170 mg/1000 mg per day

     

    C-3.44.1.2. Pediatrics

    Rizatriptan is the only SRA FDA approved in children 6 to 17 years of age to treat acute migraine attacks in patients with a history of migraine with or without aura. Almotriptan, zolmitriptan, and sumatriptan/ naproxen are FDA approved for patients 12 years of age and older.4, 8, 16-22 Children/ adolescents 6 to 17 years of age prescribed propranolol weighing less than 40 kg should not receive rizatriptan concurrently. Maximum recommended pediatric doses for SRAs are summarized in Tables 3 and 4. Dosages exceeding these recommendations will be reviewed.

    The remaining SRAs are not FDA-approved for use in patients less than 18 years of age as safety and efficacy have not been established in this patient population. Additionally, patients less than 18 years of age have demonstrated a significant placebo response following SRA use as well as an adverse event profile, including serious adverse events, comparable to that seen in adults.

    No significant data are available evaluating SRA use in pediatric patients younger than 6 years of age. In limited randomized, controlled trials, sumatriptan nasal spray has demonstrated some efficacy in mitigating migraine attacks in adolescents; children as young as 6 years of age have achieved favorable responses with intranasal sumatriptan in a few small randomized and open-label studies.24-27 However, oral sumatriptan tablets used in children 8 to 16 years of age to treat acute migraine attacks were not significantly better than placebo.28 A few small studies with oral zolmitriptan have shown mixed outcomes.29,30 Although not FDA-approved, Table 5 summarizes SRA doses that have been utilized in the pediatric population. Due to lack of definitive efficacy, prescriptions for SRAs not FDA-approved for pediatric patients will be reviewed in patients 6 to 18 years of age.

    C-3.44. Table 3: Maximum Recommended Daily Pediatric Dosages for FDA-Approved SRAs to manage Acute Migraine With or Without Aura - Monotherapy

    Drug Patient Characteristics Maximum Daily Dosage
    almotriptan 12 to 17 years of age 25 mg
    rizatriptan 6 to 17 years of age:
    20 to 39 kg
    40 kg or greater
    5 mg
    10 mg
    rizatriptan
    propranolol patients
    6 to 17 years of age:
    40 kg or greater
    5 mg
    zolmitriptan nasal spray 12 to 17 years of age 10 mg

     

    C-3.44. Table 4: Maximum Recommended Daily Pediatric Dosages for FDA-Approved SRAs to manage Acute Migraine With or Without Aura – Combination Therapy

    Drug Patient Characteristics Maximum Daily Dosage
    sumatriptan/naproxen 12 to 17 years of age 85 mg/500 mg

     

    C-3.44. Table 5: Non FDA-Approved Pediatric Dosages for Select SRAs

    Drug Patient Characteristics Dose Utilized Per Headache
    sumatriptan intranasal spray 6 to 17 years of age 20 mg
    sumatriptan subcutaneous 6 to 18 years of age 0.06 mg/kg
    sumatriptan subcutaneous 6 to 16 years of age
    Less than 30 kg
    Greater than 30 kg
    3 mg
    6 mg
    zolmitriptan tablets 6 to 18 years of age 2.5 mg

    C-3.44.2. Duration of Therapy

    Migraine headache is a chronic, recurrent condition usually requiring long-term, intermittent therapy for pain relief. Serotonin 5-HT1B/1D receptor agonists are approved for acute treatment of migraine attacks and may be utilized indefinitely to manage migraine headaches provided that the maximum dosage recommendation is not exceeded in a 24-hour period.22, 31, 32 Additionally, the safety of treating more than 3 or 4 headaches during a 30-day time period has not been established. Children/adolescents 6 to 17 years of age are allowed only one rizatriptan dose per 24 hours, as safety and efficacy have not been determined for multiple rizatriptan doses in pediatric patients.8 Maximum quantities of serotonin 5-HT1B/1D receptor agonists to be dispensed in a 30-day time period, based on number of headaches to be treated, are summarized in Tables 6 and 7 for adults and Tables 8 and 9 for adolescents. Patient profiles documenting quantities of serotonin 5-HT1B/1D receptor agonists that exceed these recommendations will be reviewed.

    C-3.44. Table 6: Maximum Recommended SRA Adult Dosage Frequency - Monotherapy

    Drug Maximum Number of Headaches Treated per 30 Days Recommended Prescribed Tablet Number/Sprays or Dose per 30 Days
    almotriptan tablets 4 headaches 8 x 12.5 mg tablets or 100 mg
    eletriptan tablets 3 headaches 6 x 40 mg tablets or 240 mg
    frovatriptan tablets 4 headaches 12 x 2.5 mg tablets or 30 mg
    naratriptan tablets 4 headaches 8 x 2.5 mg tablets or 20 mg
    rizatriptan tablets 4 headaches 12 x 10 mg tablets or 120 mg
    rizatriptan orally disintegrating tablets (ODTs) 4 headaches 12 x 10 mg ODT or 120 mg
    rizatriptan propranolol patients (regular or ODT) 4 headaches 12 x 5 mg tablets/ODT or 60 mg
    sumatriptan intranasal spray 4 headaches 8 x 20 mg spray or 160 mg
    sumatriptan intranasal spray 4 headaches 12 x 10 mg spray or 120 mg
    sumatriptan intranasal powder 4 headaches 8 x 22 mg powder or 176 mg
    sumatriptan oral tablets 4 headaches 8 x 100 mg tablets or 800 mg*
    sumatriptan subcutaneous injection ----+ ----
    zolmitriptan intranasal 4 headaches 8 sprays or 40 mg
    zolmitriptan tablets 3 headaches 6 x 5 mg tablets or 30 mg*
    zolmitriptan orally-disintegrating tablets 3 headaches 6 x 5 mg tablets or 30 mg*

    Legend:

    • *After May 1, 2002, the HHSC extended dosage limits for oral sumatriptan to not exceed 900 mg/month (9 x 100 mg tablets) and oral zolmitriptan to not exceed 40 mg/month (8 x 5 mg tablets).
    • +Patients taking Imitrex® or Sumavel® DosePro® should not receive more than 2 subcutaneous injections in a 24-hour time period; patients taking Zembrace® should not receive more than 4 subcutaneous injections per day.

    C-3.44. Table 7: Maximum Recommended SRA Adult Dosage Frequency – Combination Therapy

    Drug Maximum Number of Headaches Treated per 30 Days Recommended Prescribed Tablet Number/Sprays or Dose per 30 Days
    sumatriptan/naproxen tablets 5 headaches 10 tablets or 850 mg/500 mg

     

    C-3.44. Table 8: Maximum Recommended SRA Pediatric Dosage Frequency – Monotherapy4, 8, 16, 17

    Drug Maximum Number of Headaches Treated per 30 Days Recommended Prescribed Tablet Number/Sprays or Dose per 30 Days
    almotriptan tablets 4 headaches 8 x 12.5 mg tablets or 100 mg
    rizatriptan tablets 20 to 39 kg: 4 headaches
    Greater than or equal to 40 kg: 4 headaches
    4 x 5 mg tablets or 20 mg
    4 x 10 mg tablets or 40 mg
    rizatriptan orally disintegrating tablets (ODTs) 20 to 39 kg: 4 headaches
    Greater than or equal to 40 kg: 4 headaches
    4 x 5 mg tablets or 20 mg
    4 x 10 mg tablets or 40 mg
    rizatriptan propranolol patients (regular or ODT) 4 headaches 4 x 5 mg tablets or 20 mg
    zolmitriptan nasal spray 4 headaches 8 x 5 mg/actuation or 40 mg

    C-3.44. Table 9: Maximum Recommended SRA Pediatric Dosage Frequency – Combination Therapy

    Drug Maximum Number of Headaches Treated per 30 Days Recommended Prescribed Tablet Number/Sprays or Dose per 30 Days
    sumatriptan/naproxen tablets 2 headaches 2 tablets or 170 mg/1000 mg

     

    C-3.44.3. Duplicative Therapy

    Using two or more serotonin 5-HT1B/1D receptor agonists concurrently is not justified due to lack of additional therapeutic benefit and the potential for additive vasospastic effects. Patient profiles documenting receipt of multiple serotonin 5-HT1B/1D receptor agonists will be reviewed. 

    C-3.44.4. Drug-Drug Interactions

    Patient profiles will be reviewed to identify drug regimens that may result in clinically significant drug-drug interactions. Clinically relevant drug-drug interactions for serotonin 5-HT1B/1D receptor agonists are summarized in Tables 10 and 11. 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.

    C-3.44. Table 10: Summary of Significant SRA Drug Interactions

    Triptan Amphetamines CYP3A4 inhibitors Ergots Linezolid MAOIs+ Propranolol SNRIs#/SSRIs*
    almotriptan ----
    eletriptan ----
    frovatriptan ---- ns
    naratriptan ---- ----
    rizatriptan ----
    sumatriptan ---- ----
    zolmitriptan ---- ns

    Legend:

    • ns = not significant
    • +MAOIs = monoamine oxidase inhibitors
    • #SNRIs = serotonin-norepinephrine reuptake inhibitors
    • *SSRIs = selective serotonin reuptake inhibitors

    C-3.44.5. References

    1. Clinical Pharmacology [database online].  Tampa, FL: Gold Standard, Inc.; 2020. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed December 18, 2020.
    2. IMB Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu. Accessed December 18, 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 December 18, 2020.
    4. Almotriptan (Axert®) package insert. Ajanta Pharma Limited, April 2020. 
    5. Eletriptan (Relpax®) package insert. Greenstone LLC. April 2020.
    6. Frovatriptan (Frova®) package insert. Glenmark Pharmceuticals Inc., USA. December 2019.
    7. Naratriptan (Amerge®) package insert. GlaxoSmithKline, October 2020.
    8. Rizatriptan (Maxalt® and Maxalt-MLT®) package insert. Breckenridge Pharmaceutical, Inc. June 2020.
    9. Sumatriptan tablets (Imitrex®) package insert. GlaxoSmithKline, September 2020.
    10. Sumatriptan injection (Imitrex®) package insert. GlaxoSmithKline, September 2020.
    11. Sumatriptan nasal spray (Imitrex®) package insert. Perrigo New York Inc., October 2020. 
    12. Sumatriptan nasal powder (Onzetra® Xsail®) package insert. Avanir Pharmaceuticals, Inc., January 2020.
    13. Food & Drug Administration. Current and Resolved Drug Shortages and Discontinuations Reported to FDA. Sumavel DosePro (sumatriptan injection) 6 mg/ 0.5 mL. February 27, 2018. Available at: https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Sumatriptan%20(Sumavel%20DosePro)%20Injection&st=d. Accessed December 18, 2020.
    14. Sumatriptan succinate injection (Zembrace® SymTouch®) package insert. Promius Pharma, LLC, June 2019.
    15. Zolmitriptan tablets and orally disintegrating tablets (Zomig® and Zomig-ZMT®) package insert. Amneal Pharmaceuticals, May 2019.
    16. Zolmitriptan nasal spray (Zomig®) package insert. Amneal Pharmaceuticals, May 2019.
    17. Sumatriptan/naproxen tablets (Treximet®) Package Insert. Pernix Therapeutics, January 2020.
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