Hydrocodone Bitartrate

Pronunciation

Class: Opiate Agonists
ATC Class: R05DA03
VA Class: RE301
CAS Number: 34195-34-1
Brands: Anaplex-HD Cough, Codal-DH, Codiclear DH, Codimal DH, Cyndal HD, Cytuss HC, Detussin, Donatussin DC, Duratuss HD, Endal HD, Entuss, Entuss-D, Entuss Expectorant, G-Tuss, Histinex HC, Histinex-D, Histussin HC, Histussin-D, Hycomine Compound, Hycosin Expectorant, Hydromet, Hydromide, Hydrophene DH, Hydro-Tussin HD, Hyphed, KG-Dal HD, KG-Dal HD Plus, KG-Tuss HD, KG-Tussin, Kwelcof, Lortab, Nalex DH, Norco, Pneumotussin, Protuss, Protuss-D, P-V-Tussin, Reprexain, Su-Tuss-HD, Tussafed-HC, Tuss-DS, Tussend, Tuss-HC, Tussigon, Tussionex Pennkinetic, Tuss-PD, Tuss-S Expectorant, Vanex HD, Vicodin, Vicodin Tuss Expectorant, Vicoprofen, Vitussin Expectorant, Zydone, Zohydro

Warning(s)

  • Extended-release Hydrocodone Bitartrate
  • Risk of addiction, abuse, and misuse, which can lead to overdose and death, in patients and other users.122 Assess each patient’s risk for addiction, abuse, and misuse before prescribing the drug; monitor all patients regularly for development of these behaviors or conditions.122 (See Addiction, Abuse, and Misuse under Cautions.)

  • Serious, life-threatening, or fatal respiratory depression may occur.122 Monitor for respiratory depression, especially during initiation of therapy and following any dosage increase.122 (See Respiratory Depression under Cautions.)

  • Patients must swallow extended-release capsules whole; crushing, chewing, or dissolving the capsules can cause rapid release of the drug and absorption of a potentially fatal dose.122

  • Accidental ingestion of even 1 dose, especially by a child, can result in a fatal overdose.122

  • Prolonged maternal use of opiates during pregnancy can result in neonatal withdrawal syndrome, which may be life-threatening.122 (See Pregnancy under Cautions.)

  • Patients must not consume alcoholic beverages or take prescription or nonprescription preparations containing alcohol; use of alcohol with the extended-release capsules may result in increased plasma concentrations of hydrocodone and a potentially fatal overdose.122

REMS:

FDA approved a REMS for hydrocodone to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of hydrocodone and consists of the following: medication guide and elements to assure safe use. See the FDA REMS page () or the ASHP REMS Resource Center (). (Also see Risk Evaluation and Mitigation Strategy under Dosage and Administration.)

Introduction

Opiate agonist; phenanthrene derivative.a b c

Uses for Hydrocodone Bitartrate

Pain

Extended-release hydrocodone: Relief of pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic and for which alternative treatment options (e.g., nonopiate analgesics or immediate-release opiates) are inadequate or not tolerated.122 Not indicated for as-needed (“prn”) use.122

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Hydrocodone/acetaminophen fixed combinations: Symptomatic relief of moderate to moderately severe pain.123 a

Hydrocodone/ibuprofen fixed combinations: Short-term (generally <10 days) use for the relief of acute pain; not indicated for management of pain associated with such chronic conditions as osteoarthritis or rheumatoid arthritis.124

Combinations of hydrocodone and NSAIAs or acetaminophen may produce additive analgesic effects because of differing mechanisms of action.c

Cough

Symptomatic relief of nonproductive cough, alone or in combination with other antitussives or expectorants.b

Hydrocodone Bitartrate Dosage and Administration

General

Risk Evaluation and Mitigation Strategy

  • FDA has approved a REMS for hydrocodone extended-release capsules.125 (See REMS.) The REMS consists of a medication guide that must be dispensed with every prescription for the extended-release capsules and training materials that must be made available to clinicians who prescribe the extended-release preparation.125 The goal is to inform patients and clinicians about the potential for overdosage, misuse and abuse, and addiction to the drug and to ensure safe use of the drug.125

Administration

Oral Administration

Administer orally.a b 109 122 123 124

Hydrocodone Extended-release Capsules

Administer every 12 hours.122

Must be swallowed whole, one capsule at a time, with enough water to ensure complete swallowing of the capsule immediately after it is placed in the mouth.122

Crushing, chewing, or dissolving the capsules will result in uncontrolled delivery of hydrocodone and can result in overdosage and death.122

Patients must not consume alcoholic beverages or take prescription or nonprescription preparations containing alcohol during therapy; concomitant ingestion of alcohol may result in increased plasma concentrations of the drug and a potentially fatal overdose.122

Extended-release Suspension containing Hydrocodone Polistirex and Chlorpheniramine Polistirex (Tussionex Pennkinetic)

Use a calibrated dosing device when measuring doses of the suspension.109 112 Use of a household teaspoon could result in overdosage, especially when pediatric doses (2.5 mL of suspension) are measured.109 112

Do not give more frequently than every 12 hours; if cough is not controlled, contact clinician.112

Do not dilute with fluids or mix with other drugs; shake well prior to administration.109

Dosage

Available as hydrocodone bitartrate and hydrocodone polistirex; dosage expressed in terms of hydrocodone bitartrate.a b c 109

Pediatric Patients

Cough
Hydrocodone Bitartrate
Oral

Children 6–12 years of age: 2.5 mg every 4–6 hours as needed.108

Extended-release Suspension containing Hydrocodone Polistirex and Chlorpheniramine Polistirex (Tussionex Pennkinetic)
Oral

Children 6–11 years of age: 2.5 mL (5 mg when expressed in terms of hydrocodone bitartrate) every 12 hours.109

Children ≥12 years of age: 5 mL (10 mg when expressed in terms of hydrocodone bitartrate) every 12 hours.109

Adults

Cough
Hydrocodone Bitartrate
Oral

Usual dosage is 5 mg every 4–6 hours as needed.108

Extended-release Suspension Containing Hydrocodone Polistirex and Chlorpheniramine Polistirex (Tussionex Pennkinetic)
Oral

5 mL (10 mg when expressed in terms of hydrocodone bitartrate) every 12 hours.109

Pain (Hydrocodone Bitartrate Extended-release Capsules [Zohydro ER])

Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression.122 (See Respiratory Depression under Cautions.) Individualize initial dosage based on patient's prior analgesic use and risk factors for addiction, abuse, and misuse.122

Use single doses >40 mg, the 50-mg extended-release capsules, and total daily dosages >80 mg only in patients in whom tolerance to an opiate of comparable potency has been established.122

Patients are considered opiate tolerant if they have been receiving at least 60 mg of oral morphine sulfate daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone hydrochloride daily, 8 mg of oral hydromorphone hydrochloride daily, 25 mg of oral oxymorphone hydrochloride daily, or an equianalgesic dose of another opiate daily for at least 1 week.122

Initiation of Extended-release Hydrocodone Therapy in Opiate-naive or Nontolerant Patients
Oral

Initially, 10 mg every 12 hours.122 Higher initial dosages in patients who are not opiate tolerant may result in fatal respiratory depression.122

Initial Dosage Selection in Patients Being Switched from Other Chronic Oral Opiate Therapy to Extended-release Hydrocodone
Oral

Discontinue all other around-the-clock opiates when therapy with extended-release hydrocodone is initiated.122

Carefully individualize dosage; overestimation of initial dosage in opiate-tolerant patients can result in fatal overdosage.122

Use conversion factors in Table 1 as a guide for selecting initial extended-release hydrocodone dosage for patients being transferred from therapy with an oral opiate listed in the table.122 The doses in Table 1 are not equianalgesic, and the table cannot be used to transfer patients from extended-release hydrocodone to another opiate, as this will overestimate the dosage and may result in fatal overdosage.122

For patients receiving a single opiate analgesic, multiply the current total daily dosage of the opiate by the conversion factor to calculate the approximate daily dosage of extended-release hydrocodone; divide the calculated daily dosage in half for administration every 12 hours.122

For patients receiving >1 opiate analgesic, calculate the approximate daily dosage of extended-release hydrocodone for each opiate and then add those totals to obtain the approximate total daily dosage of extended-release hydrocodone; divide the calculated total daily dosage in half for administration every 12 hours.122

For patients receiving analgesics containing opiates and nonopiates in a fixed ratio, consider only the opiate component in the conversion.122

If calculated doses do not correspond to an available tablet strength, always round dosage down to the nearest whole capsule.122

Monitor for opiate withdrawal and for oversedation or toxicity following transfer to extended-release hydrocodone.122

Particularly close monitoring required following switch from methadone, since conversion ratios between methadone and other opiates vary widely depending on extent of prior methadone exposure and because methadone has a long half-life and tends to accumulate in plasma.122

Table 1. Conversion Factors for Transfer from Other Oral Opiates to Extended-release Hydrocodone Bitartrate (Zohydro ER)122

Prior Oral Opiate

Oral Dose (mg)

Approximate Oral Conversion Factor

Hydrocodone

10

1

Oxycodone

10

1

Methadone

10

1

Oxymorphone

5

2

Hydromorphone

3.75

2.67

Morphine

15

0.67

Codeine

100

0.1

Initial Dosage Selection in Patients Being Switched from Transdermal Fentanyl to Extended-release Hydrocodone
Oral

Wait 18 hours after removal of the transdermal fentanyl system to initiate therapy with extended-release hydrocodone; use an initial conservative dosage of approximately 10 mg every 12 hours for each 25 mcg/hr of transdermal fentanyl.122

Monitor closely; experience with this dosage conversion is limited.122

Dosage Adjustment to Achieve Adequate Analgesia
Oral

Adjust dosage gradually, every 3–7 days in increments of 10 mg every 12 hours, to provide adequate analgesia and to minimize adverse effects.122

Discontinuance of Therapy
Oral

Gradually taper dosage every 2–4 days to avoid manifestations of abrupt withdrawal.122

Pain (Immediate-release Fixed Combinations)
Oral

5–10 mg (in fixed combination with acetaminophen) every 4–6 hours as needed.123 a

2.5–10 mg (in fixed combination with ibuprofen) every 4–6 hours as needed, generally for <10 days.124 132 Manufacturers state total daily dosage should not exceed 5 tablets (each providing from 2.5–10 mg of hydrocodone bitartrate and 200 mg of ibuprofen).124 132

Adjust dosage according to severity of pain and response and tolerance of the patient.123 124 a

Nonopiate-containing analgesic fixed combinations: Nonopiate component may limit dosage of opiate component.117 119 120 121 Nonopiate analgesics are available in various fixed ratios with hydrocodone and also are available in many other prescription and OTC preparations; ensure that therapy is not duplicated and that nonopiate dosage does not exceed maximum recommended dosages.117 118 119 121

Prescribing Limits

Pediatric Patients

Cough
Hydrocodone Bitartrate
Oral

Children 6–12 years of age: Maximum is 15 mg daily.108

Extended-release Suspension Containing Hydrocodone Polistirex and Chlorpheniramine Polistirex (Tussionex Pennkinetic)
Oral

Children 6–11 years of age: Maximum 5 mL (10 mg when expressed in terms of hydrocodone bitartrate) daily.109

Children ≥12 years of age: Maximum 10 mL (20 mg when expressed in terms of hydrocodone bitartrate) daily.109

Adults

Cough
Hydrocodone Bitartrate
Oral

Maximum 30 mg daily.108

Extended-release Suspension Containing Hydrocodone Polistirex and Chlorpheniramine Polistirex (Tussionex Pennkinetic)
Oral

Maximum 10 mL (20 mg when expressed in terms of hydrocodone bitartrate) daily.109

Special Populations

Hepatic Impairment

Extended-release hydrocodone: Initial dose of 10 mg in patients with severe hepatic impairment.122 No adjustment of initial dosage required in patients with mild or moderate hepatic impairment.122 Monitor closely for adverse effects.122

Renal Impairment

Extended-release hydrocodone: Use low initial dosage in patients with renal impairment.122 Monitor closely for adverse effects.122

Geriatric Patients

Use low initial dosage in older patients.a b 109 122 123 Monitor closely for adverse effects.122

Cautions for Hydrocodone Bitartrate

Contraindications

  • Known hypersensitivity to hydrocodone or any ingredient in the formulation.b 109 122 123 124

  • Possible cross-sensitivity to hydrocodone if hypersensitive to other opiates.123 124

  • Extended-release hydrocodone: Substantial respiratory depression, acute or severe bronchial asthma or hypercarbia, known or suspected paralytic ileus.122

  • Extended-release oral suspension containing hydrocodone polistirex and chlorpheniramine polistirex (Tussionex Pennkinetic): Children <6 years of age.109

Warnings/Precautions

Warnings

Respiratory Depression

Possible dose-related respiratory depression.b c e 109 112 123 124

Even therapeutic doses of hydrocodone may decrease respiratory drive to the point of apnea in patients with COPD, cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.122 Monitor closely, particularly when initiating therapy or titrating dosage.122 Use nonopiate analgesics if possible.122

Geriatric, cachectic, and debilitated patients are at increased risk of life-threatening respiratory depression.122 Close monitoring of therapy with extended-release hydrocodone is required, particularly following initiation of therapy, during dosage titration, and during concomitant therapy with other respiratory depressants.122

Carbon dioxide retention from opiate-induced respiratory depression can exacerbate the drug's sedative effects.122

Serious, life-threatening, or fatal respiratory depression reported with use of modified-release (e.g., extended-release) opiates, even when used as recommended; can occur at any time during therapy, but risk is greatest during initiation of therapy and following dosage increases.122 Monitor for respiratory depression, especially during the first 24–72 hours of therapy and following any dosage increase.122

Only clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain should prescribe extended-release hydrocodone.122

Appropriate dosage selection and titration of extended-release hydrocodone are essential to reduce the risk of respiratory depression; overestimation of the dosage when transferring patients from another opiate can result in fatal overdosage with the first dose.122

Accidental ingestion of even 1 dose of extended-release hydrocodone, especially by a child, can result in respiratory depression and a fatal overdose.122

Potential for increased viscosity of bronchial secretions and suppression of cough reflex, with subsequent respiratory insufficiency, in patients with asthma or pulmonary emphysema who indiscriminately use antitussives.b

Overdosage and toxicity (including fatal respiratory depression) reported in adults and children receiving the extended-release oral suspension containing hydrocodone polistirex and chlorpheniramine polistirex (Tussionex Pennkinetic).109 112 Patients should seek immediate medical assistance if they experience respiratory depression.109 112 (See Advice to Patients.)

Addiction, Abuse, and Misuse

Addiction can occur with appropriately prescribed or illicitly obtained opiates, and at recommended dosages or with misuse or abuse.122

Assess each patient’s risk for addiction, abuse, and misuse prior to prescribing; monitor all patients for development of these behaviors or conditions.122 Personal or family history of substance abuse (drug or alcohol addiction or abuse) or mental illness (e.g., major depression) increases risk.122

The potential for addiction, abuse, and misuse should not prevent opiate prescribing for appropriate pain management, but does necessitate intensive counseling about risks and proper use and intensive monitoring for these behaviors and conditions.122

Modified-release (e.g., extended-release) opiates are associated with a greater risk of overdose and death because of the larger amount of drug contained in each dosage unit.122

Abuse or misuse of extended-release hydrocodone (Zohydro ER) by crushing or chewing the capsules, snorting the capsule contents, or injecting the dissolved capsule contents will result in uncontrolled delivery of hydrocodone and can result in a fatal overdose.122

Because of the challenges associated with providing access to an adequate array of options for management of chronic pain while simultaneously preventing prescription opiate abuse and misuse, FDA's decision to approve hydrocodone bitartrate extended-release capsules (Zohydro ER) was controversial, as the formulation lacks tamper-resistant features that might deter abuse and, like other extended-release opiates, some strengths contain substantial amounts of the drug.126 127 128 129 130

Sensitivity Reactions

Sulfite Sensitivity

Some formulations contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.b

Tartrazine Sensitivity

Some formulations may contain the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals.b Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin.100 101 102 103 104

Other Warnings/Precautions

Shares the toxic potentials of the opiate agonists; observe the usual precautions of opiate agonist therapy.a

CNS Depression

Performance of activities requiring mental alertness and physical coordination may be impaired.b c e 109 122 123 124

Concurrent use of other CNS depressants may potentiate CNS depression.b e 109 123 124 Concurrent use of other CNS depressants with extended-release hydrocodone may result in profound CNS depression.122 (See Specific Drugs under Interactions.)

When considering the use of extended-release hydrocodone in a patient receiving a CNS depressant, assess duration of use of the CNS depressant; patient’s response, including degree of tolerance to CNS depression; and patient’s use of alcohol or illicit drugs that cause CNS depression.122

Increased Intracranial Pressure or Head Trauma

Respiratory depressant effects and ability of opiates to increase CSF pressure may be markedly exaggerated in patients with head injury, other intracranial lesions, or preexisting elevation in intracranial pressure.b c e 109 122 123 124

Hydrocodone produces effects (e.g., pupillary changes, altered consciousness) that may obscure clinical course and neurologic signs of further increase in CSF pressure in patients with head injuries.b c e 109 122 123 124

Closely monitor patients with increased intracranial pressure or impaired consciousness.122 Avoid use of extended-release hydrocodone in patients with impaired consciousness or coma.122

Hypotension

Possible severe hypotension in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant drugs that compromise vascular tone (e.g., phenothiazines, general anesthetics).122 (See Specific Drugs under Interactions.)

May cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients.122

Avoid use of extended-release hydrocodone in patients with circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and BP.122

Acute Abdominal Conditions

May obscure diagnosis or clinical course of patients with acute abdominal conditions.e 109 122 123 124

Obstructive Bowel Disease

May diminish propulsive peristaltic waves in GI tract and decrease bowel motility.122 Use may result in obstructive bowel disease, especially in patients with underlying intestinal motility disorder.109

Monitor postoperative patients for decreased bowel motility.122

Extended-release hydrocodone is contraindicated in patients with known or suspected paralytic ileus.122

Postoperative Patients

Suppression of cough reflex following thoracotomy or laparotomy may lead to postoperative retention of secretions; cautious use recommended.b 109

Biliary Disease

Monitor patients with biliary disease, including acute pancreatitis; may cause spasm of the sphincter of Oddi and decrease biliary and pancreatic secretions.122

Debilitated and Special Risk Patients

Use with caution in debilitated patients and in those with hypothyroidism, Addison’s disease, prostatic hypertrophy, urethral stricture, or pulmonary disease.b c e 109 123 124

Tolerance and Dependence

Possible tolerance and physical dependence following prolonged administration.b c e 109 122 123 124 When discontinuing therapy, gradually taper dosage to avoid symptoms of withdrawal.122

Interactions with Drugs that Affect CYP3A4

Concomitant use of CYP3A4 inhibitors may increase plasma hydrocodone concentrations, increasing or prolonging opiate effects.122

Concomitant use of CYP3A4 inducers may result in decreased plasma hydrocodone concentrations, lack of efficacy, or manifestations of withdrawal,122 (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Fixed-Combination Preparations

When used in fixed combination with other drugs, consider the cautions, precautions, and contraindications associated with the other drug(s).a 123 124

Specific Populations

Pregnancy

Category C.e 109 122 123 124

Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome; in contrast to adults, withdrawal syndrome in neonates may be life-threatening and requires management according to protocols developed by neonatology experts.122 Syndrome presents with irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.122

Lactation

Low concentrations of hydrocodone and metabolite (hydromorphone) reported in breast milk of women receiving hydrocodone for postpartum pain.122 Discontinue nursing or the drug.109 123 124

Pediatric Use

Safety and efficacy as an analgesic not established in pediatric patients.122 123 124

Safety and efficacy as an antitussive not established in children <6 years of age.105 106 107 108 109 112

Extended-release oral suspension containing hydrocodone polistirex and chlorpheniramine polistirex (Tussionex Pennkinetic): Contraindicated in children <6 years of age; use with caution in children ≥6 years of age due to the risk of respiratory depression.109 112 Risk of potentially fatal respiratory depression is increased with overdosage or concomitant use of other respiratory depressants.109 (See Warnings/Precautions and see Dosage and Administration.)

Benefit-to-risk ratio should be carefully considered, especially in children with respiratory embarrassment (e.g., croup).109

Risk of overdosage and toxicity (including death) in children <2 years of age receiving preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.110 111 Clinicians should ask caregivers about use of OTC cough/cold preparations to avoid overdosage.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.109 122 123

May cause confusion and oversedation in geriatric patients.122 123 Increased risk of life-threatening respiratory depression in geriatric, cachectic, or debilitated patients.122 124

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, use with caution and select dosage at the lower end of the dosage range.109 122 123 124

Monitor closely for adverse effects, especially during initiation of therapy and dosage titration and when used concomitantly with other respiratory depressants.122

Hepatic Impairment

Exposure to the drug and the risk of adverse effects may be increased.122 Monitor closely.122 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Exposure to the drug and the risk of adverse effects may be increased.122 Monitor closely.122 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Lightheadedness, dizziness, sedation, nausea, vomiting, constipation.b 109 123 124 Adverse effects occur infrequently with usual oral antitussive dosages.b

With extended-release capsules for chronic pain: Constipation, nausea, somnolence, fatigue, headache, dizziness, dry mouth, vomiting, pruritus, abdominal pain, peripheral edema, upper respiratory tract infection, muscle spasms, urinary tract infection, back pain, tremor.122

Interactions for Hydrocodone Bitartrate

Metabolized by CYP3A4 and to a lesser extent by CYP2D6.122 124

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Possible decreased clearance and increased plasma concentrations of hydrocodone; may result in increased or prolonged opiate effects.122 If concomitant use is necessary, monitor for respiratory depression and sedation at frequent intervals; consider dosage adjustments until stable drug effects are achieved.122

CYP3A4 inducers: Possible increased clearance and decreased plasma concentrations of hydrocodone; may result in lack of efficacy or withdrawal manifestations.122 If concomitant use is necessary, monitor for opiate withdrawal; consider dosage adjustments until stable drug effects are achieved.122

Specific Drugs

Drug

Interaction

Comments

Anticholinergic agents

Possible increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileuse 109 122 124

Monitor for urinary retention and constipation122

Antidepressants, tricyclics

Potentiation of antidepressant adverse effecte 109 123

Use with caution; reduce dosage of hydrocodonee

CNS depressants (e.g., alcohol, antihistamines, general anesthetics, opiate agonists, phenothiazines, sedatives/hypnotics, anxiolytics)

Additive CNS effects;109 123 124 increased risk of respiratory depression, hypotension, profound sedation, coma, or death122

Hydrocodone extended-release capsules; Alcohol increases peak plasma hydrocodone concentrations, may result in fatal overdose122

Reduce dosage of one or both agents;e 109 122 123 124 reduce initial dosage of extended-release hydrocodone by 20–30% and use lower dosage of the concomitant agent122

Avoid alcohol use122 124

Monitor for respiratory depression, sedation, and hypotension122

MAO inhibitors

Severe, unpredictable potentiation of opiates reported122 124

Potentiation of antidepressant adverse effect123 124

Caution advised; allow at least 14 days to elapse between discontinuance of MAO inhibitor and initiation of hydrocodone122 124

Opiate partial agonists (butorphanol, buprenorphine, nalbuphine, pentazocine)

Possible reduced analgesic effect and/or withdrawal symptoms122 124

Caution advised;124 some manufacturers state that combined use is not recommended122

Skeletal muscle relaxants

May enhance the neuromuscular blocking action of skeletal muscle relaxants and increase respiratory depressant effects124

Hydrocodone Bitartrate Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract following oral administration.b

When administered at similar daily dosages, extended-release capsules and immediate-release preparations produce similar overall systemic exposure to hydrocodone, but peak plasma concentrations are lower with the extended-release formulation.122

Extended-release capsules: Peak serum concentrations occur 5 hours after administration.122 AUC and peak concentration are approximately twofold higher on day 7 than on day 1 of therapy.122 At doses up to 50 mg, pharmacokinetics are independent of dose.122

Immediate-release preparations: Peak serum concentrations of hydrocodone occur after 1.3–1.7 hours.123 124 b e

Extended-release oral suspension containing hydrocodone polistirex and chlorpheniramine polistirex (Tussionex Pennkinetic): Peak plasma concentrations of hydrocodone occur after 3.4 hours.109

Duration

Immediate-release preparations: Antitussive action is maintained for 4–6 hours.b

Extended-release oral suspension containing hydrocodone polistirex and chlorpheniramine polistirex (Tussionex Pennkinetic): Symptom control maintained for up to 12 hours.109

Food

Extended-release capsules: Food does not substantially affect extent of absorption, although high-fat meal increased peak plasma concentrations by 27%.122

Special Populations

Hepatic impairment: Peak plasma concentrations of hydrocodone (administered as extended-release capsules) increased by 8–10% and AUC increased by 10 or 26% in patients with mild or moderate hepatic impairment, respectively; pharmacokinetics not evaluated in patients with severe hepatic impairment.122

Renal impairment: Peak plasma concentrations of hydrocodone (administered as extended-release capsules) increased by 15, 48, or 41% and AUC increased by 15, 57, or 44% in patients with mild, moderate, or severe renal impairment, respectively.122

Distribution

Extent

Distributed into skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen, and brain.c

Low concentrations of hydrocodone and metabolite (hydromorphone) reported in breast milk of women receiving hydrocodone for postpartum pain.122

Readily crosses the placenta.c

Plasma Protein Binding

Structural similarities to related opiates suggest binding to plasma proteins is not extensive.122 124

Elimination

Metabolism

Metabolized by N-demethylation, O-demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites.122 123 124 Metabolized principally by CYP3A4 to norhydrocodone (N-demethylation) and to lesser extent by CYP2D6 to hydromorphone (O-demethylation); an unknown low-affinity CYP isoenzyme also may contribute to O-demethylation.122 124 Hydromorphone may contribute to hydrocodone's analgesic effects.122 124

Elimination Route

Excreted mainly in urine.122 b

Half-life

Extended-release capsules: Approximately 8 hours.122

Immediate-release preparations: 3.8–4.5 hours.e 109 123 124

Special Populations

Population analyses suggest gender and age ≥65 years do not substantially affect pharmacokinetics.122 124

Stability

Storage

Oral

Extended-release Capsules

25ºC (may be exposed to 15–30°C).122

Tablets

20–25ºC (may be exposed to 15–30°C).123 124

Solution

Tight, light resistant containers at 15–30°C.e

Extended-release Suspension

Tussionex Pennkinetic: Tight containers at 20–25ºC (may be exposed to 15–30°C).109 Shake well before use.109

Actions

  • Shares the actions of the opiate agonists.122 123 124 c

  • Opiate agonists alter perception of and emotional response to pain.c

  • Precise mechanism of action has not been fully elucidated; opiate agonists act at several CNS sites, involving several neurotransmitter systems to produce analgesia.c

  • Pain perception is altered in the spinal cord and higher CNS levels (e.g., substantia gelatinosa, spinal trigeminal nucleus, periaqueductal gray, periventricular gray, medullary raphe nuclei, hypothalamus).c

  • Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli, nor peripheral nerve impulse conduction.c

  • Opiate agonists act at specific receptor binding sites in the CNS and other tissues; opiate receptors are concentrated in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord.c

  • Agonist activity at the opiate μ- or κ-receptor can result in analgesia, miosis, and/or decreased body temperature.c

  • Agonist activity at the μ-receptor can also result in suppression of opiate withdrawal (and antagonist activity can result in precipitation of withdrawal).c

  • Respiratory depression may be mediated by μ-receptors, possibly μ2-receptors (which may be distinct from μ1-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression.c

  • Suppresses cough reflex by direct effect on cough center in medulla of brain.b 109 122

  • Exerts drying effect on respiratory tract mucosa and increases viscosity of bronchial secretions.b

  • Antitussive activity is slightly greater than that of codeine (on a weight basis).b

  • Hydrocodone may release histamine with or without associated peripheral vasodilation.122

Advice to Patients

  • Importance of not exceeding the recommended dosage.109 122 123 124

  • Consequences of overdosage may include potentially fatal respiratory depression.109 122

  • Importance of seeking medical attention if signs or symptoms of overdosage (trouble breathing, slow heartbeat, severe sleepiness, muscle flaccidity, dizziness, confusion, or cold, clammy skin) develop.109 112 122 123 124

  • Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.b c e 109 122 123 124

  • Importance of informing clinician if pain control is inadequate or adverse effects (e.g., constipation) occur, so that therapy may be adjusted based on individual requirements.122

  • Importance of informing patients that hydrocodone is a drug of potential abuse and should be protected from theft or misuse.122 124 Importance of properly disposing of the drug when no longer needed.122

  • Importance of not abruptly discontinuing hydrocodone following prolonged opiate therapy.122

  • Potential for severe constipation to occur.122

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and alcohol consumption.122 123 124 e Importance of avoiding alcohol-containing beverages or products.122 123 124

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.e 109 122 123 124 Importance of informing women that chronic use during pregnancy may result in neonatal opiate withdrawal syndrome, which can be life-threatening.122

  • Importance of advising patients of other important precautionary information.e 109 122 123 124 (See Cautions.)

  • Extended-release Oral Suspension Containing Hydrocodone Polistirex and Chlorpheniramine Polistirex
  • Importance of ensuring that the correct amount of medication required for the intended dose is administered (e.g., importance of using a calibrated dosing device).109

  • Hydrocodone Bitartrate Extended-release Capsules
  • Medication guide must be dispensed with each prescription.125 Importance of patients reading the medication guide before initiating therapy and each time the extended-release capsules are dispensed.125

  • Respiratory depression is most likely to occur following initiation of therapy or an increase in dosage; may occur at recommended dosages of the extended-release capsules.122

  • Extended-release hydrocodone, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdosage or death.122

  • Accidental ingestion of extended-release hydrocodone, especially by a child, may result in respiratory depression or death.122 Keep out of reach of children and do not share the drug with others.122

  • Importance of swallowing capsules whole, one at a time, with enough water to ensure complete swallowing of the capsule immediately after it is placed in the mouth.122 Crushing, chewing, or dissolving the capsules can result in overdosage and death.122

  • Importance of not consuming alcoholic beverages or taking prescription or nonprescription preparations that contain alcohol; potential for increased hydrocodone absorption from the extended-release capsules and fatal overdosage.122 Do not use other CNS depressants concomitantly unless use is supervised by clinician.122

  • Risk of orthostatic hypotension and syncope.122 Importance of rising slowly from a seated or supine position and of sitting or lying down if symptoms occur.122

  • Importance of seeking medical attention if symptoms of severe hypersensitivity occur.122

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drugs when available as a single entity or as schedule III (C-III) drugs when available as a fixed-combination preparation in a concentration of ≤15 mg per dosage unit or 5 mL combined with a therapeutic amount of one or more nonopiate drugs or with a fourfold or greater quantity of isoquinolone opium alkaloid.

Hydrocodone Bitartrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, extended-release

10 mg

Zohydro ER (C-II)

Zogenix

15 mg

Zohydro ER (C-II)

Zogenix

20 mg

Zohydro ER (C-II)

Zogenix

30 mg

Zohydro ER (C-II)

Zogenix

40 mg

Zohydro ER (C-II)

Zogenix

50 mg

Zohydro ER (C-II)

Zogenix

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Hydrocodone Bitartrate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

1.67 mg/5 mL with Chlorpheniramine Maleate 2 mg/5 mL and Phenylephrine Hydrochloride 5 mg/5 mL

Cyndal HD Syrup ( C-III)

Cypress

Hydrocodone Bitartrate Chlorpheniramine Maleate and Phenylephrine Hydrochloride Liquid ( C-III)

Hydrocodone HD Syrup ( C-III)

Morton Grove

KG-Dal HD Syrup ( C-III)

King

Tuss-PD ( C-III)

Seatrace

Vanex HD ( C-III)

Jones Pharma

1.67 mg/5 mL with Phenylephrine Hydrochloride 5 mg/5 mL

Nalex DH ( C-III)

Blansett

1.67 mg/5 mL with Phenylephrine Hydrochloride 5 mg/5 mL and Pyrilamine Maleate 8.33 mg/5 mL

Codal-DH Syrup ( C-III)

Cypress

Codimal DH Syrup ( C-III)

Schwarz

Hydrophene DH Syrup ( C-III)

Morton Grove

1.7 mg/5 mL with Brompheniramine Maleate 2 mg/5 mL and Pseudoephedrine Hydrochloride 30 mg/5 mL

Anaplex-HD Cough Syrup ( C-III)

ECR

2 mg/5 mL with Chlorpheniramine Maleate 2 mg/5 mL and Phenylephrine Hydrochloride 5 mg/5 mL

Endal HD Syrup ( C-III)

Propst

2.5 mg/5 mL with Acetaminophen 108 mg/5 mL*

Hydrocodone Bitartrate and Acetaminophen Oral Solution ( C-III)

2.5 mg/5 mL with Chlorpheniramine Maleate 2 mg/5 mL and Phenylephrine Hydrochloride 5 mg/5 mL

Cytuss HC Syrup ( C-III)

Cypress

Histinex HC ( C-III)

Ethex

Histussin HC Syrup ( C-III)

Sanofi-Synthelabo

Hydrocodone CP Syrup ( C-III)

KG-Dal HD Plus Syrup ( C-III)

King

Tuss-HC ( C-III)

Seatrace

2.5 mg/5 mL with Chlorpheniramine Maleate 2 mg/5 mL and Pseudoephedrine Hydrochloride 30 mg/5 mL

Hyphed Syrup ( C-III)

Cypress

KG-Tussin Syrup ( C-III)

King

P-V-Tussin Syrup ( C-III)

Numark

Tussend Syrup ( C-III)

Monarch

2.5 mg/5 mL with Guaifenesin 50 mg/5 mL and Phenylephrine Hydrochloride 7.5 mg/5 mL

Donatussin DC Syrup ( C-III)

Laser

Tussafed-HC ( C-III)

Everett

2.5 mg/5 mL with Guaifenesin 100 mg/5 mL and Pseudoephedrine Hydrochloride 30 mg/5 mL

Duratuss HD Elixir ( C-III)

UCB

Hydro-Tussin HD Elixir ( C-III)

Ethex

KG-Tuss HD Elixir ( C-III)

King

Su-Tuss-HD Elixir ( C-III)

Cypress

Tussend Expectorant ( C-III)

Monarch

2.5 mg/5 mL with Guaifenesin 200 mg/5 mL

Pneumotussin 2.5 Cough Syrup ( C-III)

ECR

3.5 mg/5 mL with Chlorpheniramine Maleate 2 mg/5 mL and Phenylephrine Hydrochloride 5 mg/5 mL

Endal HD Plus Syrup ( C-III)

Propst

5 mg/5 mL with Chlorpheniramine Maleate 2 mg/5 mL and Phenylephrine Hydrochloride 5 mg/5 mL

Tuss-DS ( C-III)

Seatrace

5 mg/5 mL with Guaifenesin 100 mg/5 mL

Codiclear DH Syrup ( C-III)

Schwarz

G-Tuss Syrup ( C-III)

Seatrace

Hycosin Expectorant ( C-III)

Alpharma

Hydrocodone Bitartrate and Guaifenesin Expectorant ( C-III)

Hydrocodone GF Syrup ( C-III)

Morton Grove

Kwelcof Liquid ( C-III)

Ascher

Vicodin Tuss Expectorant Syrup ( C-III)

Abbott

Vitussin Expectorant ( C-III)

Cypress

5 mg/5 mL with Homatropine Methylbromide 1.5 mg/5 mL

Hydrocodone Bitartrate and Homatropine Methylbromide Syrup ( C-III)

Hydromet Syrup ( C-III)

Alpharma

Hydromide Syrup ( C-III)

Major

5 mg/5 mL with Potassium Guaiacolsulfonate 300 mg/5 mL

Entuss Expectorant ( C-III)

Lee

Protuss ( C-III)

First Horizon

5 mg/5 mL with Potassium Guaiacolsulfonate 300 mg/5 mL and Pseudoephedrine Hydrochloride 30 mg/5 mL

Entuss-D Liquid ( C-III)

Lee

Protuss-D ( C-III)

First Horizon

5 mg/5 mL with Pseudoephedrine Hydrochloride 60 mg/5 mL

Detussin Liquid ( C-II)

Alpharma

Histinex-D ( C-III)

Ethex

Histussin-D ( C-III)

Sanofi-Synthelabo

Tuss-S Expectorant ( C-III)

Seatrace

10 mg/5 mL with Potassium Guaiacolsulfonate 400 mg/5 mL

Protuss ( C-III)

First Horizon

Tablets

2.5 mg with Acetaminophen 500 mg*

Hydrocodone Bitartrate and Acetaminophen Tablets ( C-III)

2.5 mg with Guaifenesin 300 mg

Pneumotussin ( C-III)

ECR

5 mg with Acetaminophen 250 mg, Caffeine Anhydrous 30 mg, Chlorpheniramine Maleate 2 mg, and Phenylephrine Hydrochloride 10 mg

Hycomine Compound ( C-III; scored)

Endo

5 mg with Acetaminophen 300 mg

Vicodin (C-III; scored)

AbbVie

5 mg with Acetaminophen 325 mg*

Hydrocodone Bitartrate and Acetaminophen Tablets (C-III)

Lortab 5/325 (C-III; scored)

UCB

Norco (C-III; scored)

Keltman

5 mg with Acetaminophen 400 mg

Zydone ( C-III)

Stat Rx

5 mg with Acetaminophen 500 mg*

Hydrocodone Bitartrate and Acetaminophen Tablets (C-III)

5 mg with Chlorpheniramine Maleate 4 mg and Pseudoephedrine Hydrochloride 60 mg

Tussend ( C-III)

Monarch

5 mg with Guaifenesin 300 mg

Entuss ( C-III)

Lee

5 mg with Homatropine Methylbromide 1.5 mg

Tussigon ( C-III; scored)

Jones Pharma

5 mg with Pseudoephedrine Hydrochloride 60 mg

P-V-Tussin ( C-III; scored)

Numark

7.5 mg with Acetaminophen 300 mg

Vicodin ES (C-III; scored)

AbbVie

7.5 mg with Acetaminophen 325 mg*

Hydrocodone Bitartrate and Acetaminophen Tablets (C-III)

Lortab 7.5/325 (C-III; scored)

UCB

Norco (C-III; scored)

Watson

7.5 mg with Acetaminophen 400 mg

Zydone ( C-III)

Stat Rx

7.5 mg with Acetaminophen 500 mg*

Hydrocodone Bitartrate and Acetaminophen Tablets (C-III)

7.5 mg with Acetaminophen 650 mg*

Hydrocodone Bitartrate and Acetaminophen Tablets (C-III)

7.5 mg with Acetaminophen 750 mg*

Hydrocodone Bitartrate and Acetaminophen Tablets (C-III)

10 mg with Acetaminophen 300 mg

Vicodin HP (C-III; scored)

AbbVie

10 mg with Acetaminophen 325 mg*

Hydrocodone Bitartrate and Acetaminophen Tablets ( C-III)

Lortab 10/325 (C-III; scored)

UCB

Norco ( C-III; scored)

Watson

10 mg with Acetaminophen 400 mg

Zydone ( C-III)

Stat Rx

10 mg with Acetaminophen 500 mg*

Hydrocodone Bitartrate and Acetaminophen Tablets (C-III)

10 mg with Acetaminophen 650 mg*

Hydrocodone Bitartrate and Acetaminophen Tablets (C-III)

10 mg with Acetaminophen 660 mg*

Hydrocodone Bitartrate and Acetaminophen Tablets (C-III)

10 mg with Acetaminophen 750 mg*

Hydrocodone Bitartrate and Acetaminophen Tablets (C-III)

Tablets, film-coated

2.5 mg with Ibuprofen 200 mg*

Hydrocodone Bitartrate and Ibuprofen Film-coated Tablets (C-III)

Reprexain ( C-III)

Hawthorn

5 mg with Ibuprofen 200 mg*

Hydrocodone Bitartrate and Ibuprofen Film-coated Tablets (C-III)

Reprexain ( C-III)

Hawthorn

7.5 mg with Ibuprofen 200 mg*

Hydrocodone Bitartrate and Ibuprofen Film-coated Tablets ( C-III)

Vicoprofen ( C-III)

AbbVie

10 mg with Ibuprofen 200 mg*

Hydrocodone Bitartrate and Ibuprofen Film-coated Tablets (C-III)

Reprexain ( C-III)

Hawthorn

Hydrocodone Polistirex Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension, extended-release

equivalent to Hydrocodone Bitartrate 10 mg/5 mL with Chlorpheniramine Polistirex equivalent to Chlorpheniramine Maleate 8 mg/5 mL

Tussionex Pennkinetic ( C-III)

UCB

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Hydrocod Polst-Chlorphen Polst 10-8MG/5ML Liquid (PAR): 60/$45.99 or 120/$80.98

Hydrocodone-Acetaminophen 10-325MG Tablets (WATSON LABS): 30/$17.99 or 90/$44.97

Hydrocodone-Acetaminophen 10-500MG Tablets (MALLINCKRODT PHARM): 30/$14.99 or 90/$39.97

Hydrocodone-Acetaminophen 10-650MG Tablets (MALLINCKRODT PHARM): 30/$14.99 or 90/$30.97

Hydrocodone-Acetaminophen 10-660MG Tablets (MALLINCKRODT PHARM): 30/$17.99 or 90/$37.97

Hydrocodone-Acetaminophen 10-750MG Tablets (MALLINCKRODT PHARM): 30/$32.99 or 90/$89.97

Hydrocodone-Acetaminophen 2.5-500MG Tablets (QUALITEST): 30/$12.99 or 90/$27.27

Hydrocodone-Acetaminophen 5-325MG Tablets (MALLINCKRODT PHARM): 30/$17.99 or 60/$29.98

Hydrocodone-Acetaminophen 5-500MG Tablets (WATSON LABS): 30/$12.99 or 60/$16.98

Hydrocodone-Acetaminophen 7.5-325MG Tablets (MALLINCKRODT PHARM): 30/$17.99 or 90/$51.97

Hydrocodone-Acetaminophen 7.5-500MG/15ML Solution (QUALITEST): 473/$60.98 or 1419/$182.95

Hydrocodone-Acetaminophen 7.5-500MG Tablets (WATSON LABS): 30/$13.99 or 60/$17.98

Hydrocodone-Acetaminophen 7.5-650MG Tablets (MALLINCKRODT PHARM): 100/$15.99 or 300/$35.97

Hydrocodone-Acetaminophen 7.5-750MG Tablets (MALLINCKRODT PHARM): 30/$12.99 or 90/$23.97

Hydrocodone-Ibuprofen 7.5-200MG Tablets (AMNEAL PHARMACEUTICALS): 30/$33.99 or 90/$82.97

Lorcet 10/650 10-650MG Tablets (FOREST): 30/$57.99 or 90/$159.97

Lorcet Plus 7.5-650MG Tablets (FOREST): 30/$48.49 or 90/$131.14

Lortab 5-500MG Tablets (UCB PHARMA): 30/$57.99 or 90/$155.98

Lortab 7.5-500MG/15ML Elixir (UCB PHARMA): 120/$47.99 or 360/$119.97

Lortab 10 10-500MG Tablets (UCB PHARMA): 30/$62.99 or 90/$165.97

Lortab 2.5 2.5-500MG Tablets (UCB PHARMA): 30/$30.99 or 90/$78.97

Lortab 7.5 7.5-500MG Tablets (UCB PHARMA): 30/$64.99 or 90/$173.97

Norco 10-325MG Tablets (WATSON LABS): 30/$69.95 or 90/$204.56

Norco 5-325MG Tablets (WATSON LABS): 30/$52.65 or 90/$132.76

Norco 7.5-325MG Tablets (WATSON LABS): 30/$57.23 or 90/$160.24

Reprexain 10-200MG Tablets (HAWTHORN PHARMACEUTICALS): 100/$110.85 or 300/$313.72

Reprexain 2.5-200MG Tablets (HAWTHORN PHARMACEUTICALS): 100/$75.81 or 300/$205.77

Reprexain 5-200MG Tablets (HAWTHORN PHARMACEUTICALS): 100/$79.44 or 300/$215.31

Stagesic 5-500MG Capsules (MAGNA PHARMACEUTICALS): 30/$24.99 or 90/$51.97

Tussionex Pennkinetic ER 10-8MG/5ML Liquid (UCB PHARMA): 115/$125.99 or 345/$349.97

Tussionex Pennkinetic ER 8-10MG/5ML Liquid (UCB PHARMA): 60/$50.99 or 120/$98.97

Vicodin 5-500MG Tablets (ABBOTT): 30/$50.99 or 90/$133.97

Vicodin ES 7.5-750MG Tablets (ABBOTT): 30/$54.99 or 90/$147.97

Vicodin HP 10-660MG Tablets (ABBOTT): 30/$53.99 or 90/$145.98

Vicoprofen 7.5-200MG Tablets (ABBOTT): 30/$91.99 or 90/$249.98

Xodol 10-300MG Tablets (SHIONOGI PHARMA): 100/$583.94 or 300/$1,646.45

Zamicet 10-325MG/15ML Solution (HAWTHORN PHARMACEUTICALS): 473/$164.88 or 1419/$468.25

Zydone 10-400MG Tablets (ENDO PHARMACEUTICALS): 30/$31.99 or 90/$83.97

Zydone 5-400MG Tablets (ENDO PHARMACEUTICALS): 30/$27.99 or 90/$65.97

Zydone 7.5-400MG Tablets (ENDO PHARMACEUTICALS): 30/$32.99 or 90/$72.58

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 27, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

Only references cited for selected revisions after 1984 are available electronically.

100. American Medical Association Council on Scientific Affairs. Aspartame: review of safety issues. JAMA. 1985; 254:400-2. [IDIS 202002] [PubMed 2861297]

101. Gossel TA. A review of aspartame: characteristics, safety and uses. US Pharm. 1984; 9:26,28-30.

102. Food and Drug Administration. Aspartame as an inactive ingredient in human drug products; labeling requirements. Proposed rule. [21 CFR Part 201] Fed Regist. 1983; 48:54993-5. (IDIS 178728)

103. Food and Drug Administration. Food additives permitted for direct addition to food for human consumption; aspartame. Final rule. [21 CFR Part 172] Fed Regist. 1983; 48:31376-82. (IDIS 172957)

104. Anon. Aspartame and other sweeteners. Med Lett Drugs Ther. 1982; 24:1-2. [PubMed 7054648]

105. Food and Drug Administration. FDA takes action to stop marketing of unapproved hydrocodone products. Rockville, MD; 2007 Sep 28. From FDA website.

106. Food and Drug Administration. Questions and answers about FDA’s enforcement action regarding unapproved hydrocodone drug products. Rockville, MD; 2007 Oct 1. From FDA website.

107. Food and Drug Administration. Drug products containing hydrocodone; enforcement action dates. Notice. [Docket No. 2007N-0353]. Fed Regist. 2007; 72:55780-4.

108. Endo Pharmaceuticals, Inc. Hycodan (hydrocodone bitartrate and homatropine methylbromide) tablets and suspension prescribing information. Chadds Ford, PA; 2001 Nov.

109. UCB, Inc. Tussionex Pennkinetic (hydrocodone polistirex and chlorpheniramine polistirex) extended-release suspension prescribing information. Smyrna, GA; 2008 Jan.

110. Srinivasan A, Budnitz D, Shehab N et al. Infant deaths associated with cough and cold medications—two states, 2005. MMWR Morb Mortal Wkly Rep. 2007; 56:1-4. [PubMed 17218934]

111. Food and Drug Administration. Cough and cold medications in children less than two years of age. Rockville, MD; 2007 Jan 12. From FDA website.

112. Food and Drug Administration. FDA public health advisory: Important information for the safe use of Tussionex Pennkinetic extended-release suspension. Rockville, MD; 2008 Mar 11. From FDA web site.

117. Jackson KC II, Lipman AG. Nonopioid analgesics. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004:43-58.

118. Cranmer KW, Mason M. Special considerations in geriatric pain management. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004:219-232.

119. Fakata KL, Miaskowski C, Lipman AG. Chronic malignant pain. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004:139-52.

120. McNicol E, Carr DB. Pharmacological treatment of pain. In: McCarberg B, Passik SD, eds. Expert guide to pain management. Philadelphia: American College of Physicians; 2005:145-78.

121. American Pain Society. Principles of analgesic use in the treatment of acute pain and cancer pain. 5th edition. Glenview, IL; 2003:3,9,13,14.

122. Zogenix, Inc. Zohydro ER (hydrocodone bitartrate) extended-release capsules prescribing information. San Diego, CA; 2013 Oct.

123. AbbVie Inc. Vicodin, Vicodin ES, and Vicodin HP (hydrocodone bitartrate and acetaminophen) tablets prescribing information. North Chicago, IL; 2013 Oct.

124. Hawthorne Pharmaceuticals, Inc. Reprexain (hydrocodone bitartrate and ibuprofen) tablets prescribing information. Madison, MS; 2008 Dec.

125. US Food and Drug Administration. Extended-release (ER) and long-acting (LA) opioid analgesics Risk Evaluation and Mitigation Strategy (REMS). Rockville, MD; 2013 Oct. From FDA website.

126. Olsen Y, Sharfstein JM. Chronic Pain, Addiction, and Zohydro. N Engl J Med. 2014; :. [PubMed 24758596]

127. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 202880Orig1s000: Summary review. From FDA website.

128. American Academy of Pain Management. Statement on extended-release hydrocodone (Zohydro ER). Sonora, CA: 2014 Apr 8. From American Academy of Pain Management website.

129. US Food and Drug Administration. FDA provides facts about Zohydro. Rockville, MD; 2014 Apr 30. From FDA website.

130. US Food and Drug Administration. FDA CDER Response to Center for Lawful Access and Abuse Deterrence - Partial Petition Approval and Denial. Silver Spring, MD; 2013 Oct 25. From FDA website.

131. Rauck RL, Nalamachu S, Wild JE et al. Single-Entity Hydrocodone Extended-Release Capsules in Opioid-Tolerant Subjects with Moderate-to-Severe Chronic Low Back Pain: A Randomized Double-Blind, Placebo-Controlled Study. Pain Med. 2014; :. [PubMed 24517082]

132. AbbVie Inc. Vicoprofen (hydrocodone bitartrate and ibuprofen) coated tablets prescribing information. North Chicago, IL; 2013 Apr.

a. AHFS Drug Information 2008. McEvoy GK, ed. Hydrocodone Bitartrate. Bethesda, MD: American Society of Health-System Pharmacists; 2008:2186-7.

b. AHFS Drug Information 2008. McEvoy GK, ed. Hydrocodone Bitartrate. Bethesda, MD; American Society of Health-System Pharmacists; 2008:2805-7.

c. AHFS drug information 2004. McEvoy GK, ed. Opiate agonists general statement. Bethesda, MD: American Society of Hospital Pharmacists; 2004:2030-5.

e. Monarch Pharmaceuticals. Tussend tablets and syrup prescribing information. Bristol, TN; 1998 Sep.

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