Hydrocodone Bitartrate/Hydrocodone Polistirex

Last Updated

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

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

1. Dosage

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

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

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

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

1.1. Adults

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

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

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

Table 1: Recommended Adult Hydrocodone Dosages: Monotherapy

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

Table 2: Recommended Adult Hydrocodone Dosages: Combination Therapy

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

Legend:

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

1.2. Pediatrics

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

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

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

Table 3: Recommended Pediatric Hydrocodone Dosages: Combination Therapy

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

Legend:

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

1.3. Opioid Reversal Agents

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

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

2. Duration of Therapy

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

3. Drug-Drug Interactions

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

Table 4: Hydrocodone Drug-Drug Interactions

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

Legend:

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

4. References

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