Brand names: Hysingla ER, Zohydro ER
Drug class: Opiate Agonists
ATC class: R05DA03
VA class: RE301
CAS number: 34195-34-1

Medically reviewed by Drugs.com on Mar 20, 2023. Written by ASHP.

Introduction

Opiate agonist; phenanthrene derivative.

Uses for HYDROcodone

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. Not indicated for as-needed (“prn”) use.

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

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.

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

In symptomatic treatment of acute pain, reserve opiate analgesics for pain resulting from severe injuries, severe medical conditions, or surgical procedures, or when nonopiate alternatives for relieving pain and restoring function are expected to be ineffective or are contraindicated. Use smallest effective dosage for shortest possible duration since long-term opiate use often begins with treatment of acute pain. Optimize concomitant use of other appropriate therapies. (See Managing Opiate Therapy for Acute Pain under Dosage and Administration.)

Generally use opiates for management of chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing ) that is not associated with active cancer treatment, palliative care, or end-of-life care only if other appropriate nonpharmacologic and nonopiate pharmacologic strategies have been ineffective and expected benefits for both pain relief and functional improvement are anticipated to outweigh risks.

If used for chronic pain, opiate analgesics should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive-behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies (e.g., nonopiate analgesics, analgesic adjuncts such as selected anticonvulsants and antidepressants for certain neuropathic pain conditions).

Available evidence insufficient to determine whether long-term opiate therapy for chronic pain results in sustained pain relief or improvements in function and quality of life or is superior to other pharmacologic or nonpharmacologic treatments. Use is associated with serious risks (e.g., opiate use disorder [OUD], overdose). (See Managing Opiate Therapy for Chronic Noncancer Pain under Dosage and Administration.)

Cough

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

Not indicated for management of cough in patients <18 years of age. (See Pediatric Use under Cautions.)

HYDROcodone Dosage and Administration

General

Managing Opiate Therapy for Acute Pain

• Optimize concomitant use of other appropriate therapies.

• When opiate analgesia required, use conventional (immediate-release) opiates in smallest effective dosage and for shortest possible duration, since long-term opiate use often begins with treatment of acute pain.

• Consider prescribing naloxone concomitantly for patients who are at increased risk of opiate overdosage or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. (See Respiratory Depression under Cautions.)

• When sufficient for pain management, use lower-potency opiate analgesics given in conjunction with acetaminophen or an NSAIA on as-needed (“prn”) basis.

• For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days). Do not prescribe larger quantities for use in case pain continues longer than expected; instead, reevaluate patient if severe acute pain does not remit.

• For moderate to severe postoperative pain, provide opiate analgesic as part of a multimodal regimen that also includes acetaminophen and/or NSAIAs and other pharmacologic (e.g., certain anticonvulsants, regional local anesthetic techniques) and nonpharmacologic therapy as appropriate.

• Oral administration of conventional opiate analgesics generally preferred over IV administration in postoperative patients who can tolerate oral therapy.

• Scheduled (around-the-clock) dosing frequently is required during immediate postoperative period or following major surgery. When repeated parenteral administration is required, IV patient-controlled analgesia (PCA) generally is recommended.

Managing Opiate Therapy for Chronic Noncancer Pain

• Although specific recommendations may vary, common elements in clinical guideline recommendations include risk mitigation strategies, upper dosage thresholds, careful dosage titration, and consideration of risks associated with particular opiates and formulations, coexisting diseases, and concomitant drug therapy.

• Prior to initiating therapy, thoroughly evaluate patient; assess risk factors for misuse, abuse, and addiction; establish treatment goals (including realistic goals for pain and function); and consider how therapy will be discontinued if benefits do not outweigh risks.

• Regard initial opiate therapy for chronic noncancer pain as a therapeutic trial that will be continued only if there are clinically meaningful improvements in pain and function that outweigh treatment risks.

• Prior to and periodically during therapy, discuss with patients known risks and realistic benefits and patient and clinician responsibilities for managing therapy.

• Some experts recommend initiating opiate therapy for chronic noncancer pain with conventional (immediate-release) opiate analgesics prescribed at lowest effective dosage. Individualize opiate selection, initial dosage, and dosage titration based on patient’s health status, prior opiate use, attainment of therapeutic goals, and predicted or observed harms.

• Evaluate benefits and harms within 1–4 weeks following initiation of therapy or dosage increase and reevaluate on ongoing basis (e.g., at least every 3 months ) throughout therapy. Document pain intensity and level of functioning and assess progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies. Anticipate and manage common adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment). If benefits do not outweigh harms, optimize other therapies and taper opiate to lower dosage or taper and discontinue opiate.

• When repeated dosage increases required, evaluate potential causes and reassess relative benefits and risks. Although evidence is limited, some experts state that opiate rotation may be considered in patients with intolerable adverse effects or inadequate benefit despite dosage increases.

• Higher dosages require particular caution, including more frequent and intensive monitoring or referral to specialist. Greater benefits of high-dose opiates for chronic pain not established in controlled clinical studies; higher dosages associated with increased risks (motor vehicle accidents, overdosage, OUD).

• CDC states that primary care clinicians should carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily (approximately ≥50 mg of hydrocodone bitartrate daily) for chronic pain and should avoid dosages equivalent to ≥90 mg of morphine sulfate daily (approximately ≥90 mg of hydrocodone bitartrate daily) or carefully justify decision to prescribe such dosages. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily. Some states have established opiate dosage thresholds (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with specialist is mandated or recommended) or have mandated risk-management strategies (e.g., review of state prescription drug monitoring program [PDMP] data prior to prescribing).

• Recommended strategies for managing risks include written treatment agreements or plans (e.g., “contracts”), urine drug testing, review of state PDMP data, and risk assessment and monitoring tools.

• Taper and discontinue opiate therapy if patient engages in serious or repeated aberrant drug-related behaviors or drug abuse or diversion. Offer or arrange treatment for patients with OUD.

• Consider prescribing naloxone concomitantly for patients who are at increased risk of opiate overdosage or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. (See Respiratory Depression under Cautions.)

Administration

Oral Administration

Administer orally.

Hydrocodone Extended-release Capsules (Zohydro ER)

Administer every 12 hours.

Must be swallowed whole. Breaking, cutting, crushing, chewing, or dissolving the capsules will result in uncontrolled delivery of hydrocodone and can result in overdosage and death.

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.

Hydrocodone Extended-release Tablets (Hysingla ER)

Administer every 24 hours without regard to meals.

Must be swallowed whole. Crushing, chewing, or dissolving the tablets will result in uncontrolled delivery of hydrocodone and can result in overdosage and death.

Administer tablets one at a time with enough water to ensure that each tablet is completely swallowed immediately after it is placed in the mouth. Do not wet the tablets (e.g., by soaking or licking) before placing in mouth for swallowing. (See GI Complications with Extended-release Tablets under Cautions.)

Multiple tablets of lower-dose strengths that provide the desired total daily dosage can be taken as a once-daily dose.

Extended-release Suspension containing Hydrocodone Polistirex and Chlorpheniramine Polistirex (e.g., Tussionex Pennkinetic)

Use a calibrated dosing device when measuring doses of the suspension. Use of a household teaspoon could result in overdosage.

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

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

Dosage

Available as hydrocodone bitartrate and hydrocodone polistirex; dosage expressed in terms of hydrocodone bitartrate.

Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.

When used concomitantly with other CNS depressants, use lowest effective dosages and shortest possible duration of concomitant therapy. (See Specific Drugs under Interactions.)

Adults

Cough

Hydrocodone Bitartrate

Oral

Usual dosage is 5 mg every 4–6 hours as needed. Other drugs in combination preparations may limit daily hydrocodone dosage.

Extended-release Suspension Containing Hydrocodone Polistirex and Chlorpheniramine Polistirex (e.g., Tussionex Pennkinetic)

Oral

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

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

Oral

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

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.

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.

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

Oral

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

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

Oral

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

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

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

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 capsules; divide the calculated daily dosage in half for administration every 12 hours.

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 capsules; divide the calculated total daily dosage in half for administration every 12 hours.

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

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

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

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.

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

Oral

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

Monitor closely; experience with this dosage conversion is limited.

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.

Discontinuance of Therapy

Oral

Gradually taper dosage every 2–4 days to avoid manifestations of abrupt withdrawal. Monitor closely for withdrawal manifestations that may indicate need for slower tapering.

The tapering schedule in Table 2 was used in a phase 3 clinical trial; dosages >100 mg twice daily were not used in this trial.

Pain (Hydrocodone Bitartrate Extended-release Tablets [Hysingla ER])

Oral

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

Use dosages ≥80 mg daily only in opiate-tolerant patients.

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.

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

Oral

Initially, 20 mg every 24 hours. Higher initial dosages in patients who are not opiate tolerant may result in fatal respiratory depression.

Initial Dosage Selection in Patients Being Switched from Other Oral Hydrocodone-containing Formulations

Oral

Administer same total daily dosage once daily.

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

Oral

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

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

Use conversion factors in Table 3 as a guide for selecting initial dosage of extended-release hydrocodone tablets for patients being transferred from therapy with an oral opiate listed in the table. The doses in Table 3 are not equianalgesic, and the table cannot be used to transfer patients from extended-release hydrocodone tablets to another opiate, as this will overestimate the dosage and may result in fatal overdosage.

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 oral hydrocodone. Reduce this calculated dosage by 25% to account for interpatient variability in the relative potency of different opiates.

For patients receiving >1 opiate analgesic, calculate the approximate daily dosage of oral hydrocodone for each opiate and then add those totals to obtain the approximate total daily dosage of oral hydrocodone. Reduce this calculated dosage by 25% to account for interpatient variability in the relative potency of different opiates.

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

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

If calculated dose is <20 mg, use initial dosage of 20 mg once daily.

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

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.

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

Oral

Wait 18 hours after removal of the transdermal fentanyl system to initiate therapy with extended-release hydrocodone tablets; use an initial conservative dosage of approximately 20 mg every 24 hours for each 25 mcg/hr of transdermal fentanyl.

Monitor closely; experience with this dosage conversion is limited.

Initial Dosage Selection in Patients Being Switched from Transdermal Buprenorphine to Extended-release Hydrocodone Tablets

Oral

Initially, 20 mg every 24 hours in patients who previously received transdermal buprenorphine ≤20 mg/hour.

Monitor closely; experience with this dosage conversion is limited.

Dosage Adjustment to Achieve Adequate Analgesia

Oral

Adjust dosage gradually, every 3–5 days in increments of 10–20 mg every 24 hours, to provide adequate analgesia and to minimize adverse effects.

Discontinuance of Therapy

Oral

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

Each new dose in the taper should be ≥50% of the prior dose; decrease dosage to 20 mg daily for 2–4 days, then discontinue therapy.

Pain (Immediate-release Fixed Combinations)

Oral

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

2.5–10 mg (in fixed combination with ibuprofen) every 4–6 hours as needed, generally for <10 days. 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).

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

Nonopiate-containing analgesic fixed combinations: Nonopiate component may limit dosage of opiate component. 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.

Prescribing Limits

Adults

Cough

Hydrocodone Bitartrate

Oral

Maximum 30 mg daily. However, other drugs in combination preparations may further limit daily hydrocodone dosage.

Extended-release Suspension Containing Hydrocodone Polistirex and Chlorpheniramine Polistirex (e.g., Tussionex Pennkinetic)

Oral

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

Pain

Oral

For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for the expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days).

CDC recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily (approximately ≥50 mg of hydrocodone bitartrate daily) for chronic pain and avoid dosages equivalent to ≥90 mg of morphine sulfate daily (approximately ≥90 mg of hydrocodone bitartrate daily) or carefully justify their decision to prescribe such dosages. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.

Some states have set prescribing limits (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with a specialist is mandated or recommended).

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: No initial dosage adjustment required.

Severe hepatic impairment (extended-release capsules [Zohydro ER]): Initially, 10 mg every 12 hours.

Severe hepatic impairment (extended-release tablets [Hysingla ER]): Reduce initial dosage by 50%.

Monitor closely for adverse effects.

Renal Impairment

Manufacturer of extended-release capsules recommends use of low initial dosage in patients with renal impairment.

Manufacturer of extended-release tablets states that no initial dosage adjustment required in mild renal impairment; reduce initial dosage by 50% in patients with moderate or severe renal impairment, including end-stage renal disease.

Monitor closely for adverse effects.

Geriatric Patients

Use low initial dosage in older patients. Monitor closely for adverse effects.

Cautions for HYDROcodone

Contraindications

• Known hypersensitivity to hydrocodone or any ingredient in the formulation.

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

• Extended-release hydrocodone: Substantial respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment, known or suspected paralytic ileus and GI obstruction.

• Hydrocodone antitussives: Children <6 years of age.

Warnings/Precautions

Warnings

Respiratory Depression

Possible dose-related respiratory depression.

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. Monitor closely, particularly when initiating therapy or titrating dosage. Use nonopiate analgesics if possible.

Geriatric, cachectic, and debilitated patients are at increased risk of life-threatening respiratory depression. 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.

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

Serious, life-threatening, or fatal respiratory depression reported with use of 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. Monitor for respiratory depression, especially during the first 24–72 hours of therapy and following any dosage increase.

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

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

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

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.

Patients should seek immediate medical assistance if they experience respiratory depression. (See Advice to Patients.)

Routinely discuss availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for opiate analgesics, including hydrocodone.

Consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose) or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. Even if patients are not receiving an opiate analgesic, consider prescribing naloxone if the patient is at increased risk of opiate overdosage (e.g., those with current or past diagnosis of OUD, those who have experienced a prior opiate overdose).

Addiction, Abuse, and Misuse

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

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

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.

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.

Abuse or misuse of extended-release hydrocodone formulations by crushing or chewing the capsules or tablets, snorting the contents, or injecting the dissolved contents will result in uncontrolled delivery of hydrocodone and can result in a fatal overdose.

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 (up to 50 mg ).

Physical and chemical properties of Hysingla ER extended-release tablets (containing up to 120 mg of the drug) are intended to hinder manipulation for IV or intranasal abuse and misuse; some extended-release characteristics are retained if the tablet is physically compromised. However, potential for IV, intranasal, and oral abuse still exists.

Potential for abuse of hydrocodone-containing combinations is similar to that of schedule II (C-II) oxycodone-containing combinations. Because of increasing concerns about misuse, abuse, and diversion, hydrocodone-containing fixed-combination analgesic and antitussive preparations previously subject to control as C-III drugs were rescheduled as C-II drugs effective October 6, 2014. (See Preparations.)

Interactions with Drugs that Affect CYP3A4

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

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

Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opiates, including hydrocodone, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death. Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.

Avoid concomitant use of CNS depressants with hydrocodone antitussives; reserve concomitant use with hydrocodone-containing analgesics for patients in whom alternative treatment options are inadequate. (See Specific Drugs under Interactions.)

Other Warnings/Precautions

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

CNS Depression

Performance of activities requiring mental alertness and physical coordination may be impaired.

Concurrent use with other CNS depressants may result in profound sedation, respiratory depression, coma, or death. (See Specific Drugs under Interactions.)

Adrenal Insufficiency

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists. Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function. If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued. In some patients, switching to a different opiate improved symptoms.

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.

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.

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

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). (See Specific Drugs under Interactions.)

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

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

Seizure Disorders

May aggravate preexisting seizure disorder. Monitor for worsened seizure control.

May induce seizures in some clinical settings.

GI Complications with Extended-release Tablets

Some patients report difficulty in swallowing the extended-release tablets. The tablets form a gelatinous mass when wet. (See Hydrocodone Extended-release Tablets [Hysingla ER] under Dosage and Administration.)

Choking, dysphagia, and esophageal obstruction (at least 1 case requiring medical intervention to remove the tablet) reported. Increased risk in patients with underlying GI disorders (e.g., esophageal or colon cancer) associated with narrow GI lumen.

Consider using an alternative analgesic in patients who have difficulty swallowing and in those at risk for underlying GI disorders associated with narrow GI lumen.

Acute Abdominal Conditions

May obscure diagnosis or clinical course of patients with acute abdominal conditions.

Obstructive Bowel Disease

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

Monitor postoperative patients for decreased bowel motility.

Extended-release hydrocodone is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.

Postoperative Patients

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

Biliary Disease

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

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.

Tolerance and Dependence

Possible tolerance and physical dependence following prolonged administration. When discontinuing therapy, gradually taper dosage to avoid symptoms of withdrawal.

QT Interval Prolongation

Prolongation of corrected QT (QT_c) interval observed in healthy individuals receiving 160 mg daily (as extended-release tablets).

Consider this observation when making decisions regarding monitoring (e.g., periodic monitoring of ECGs and electrolyte concentrations) of patients with CHF, bradyarrhythmias, or electrolyte abnormalities and those receiving drugs that prolong the QT_c interval.

Manufacturer recommends avoiding use of extended-release tablets in patients with congenital long QT syndrome.

If QT_c interval prolongation occurs, consider reducing dosage by 33–50% or using an alternative analgesic.

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy; causality not established. Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility. Perform appropriate laboratory testing in patients with manifestations of hypogonadism.

Fixed-Combination Preparations

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

Specific Populations

Pregnancy

Category C.

Analysis of data from the National Birth Defects Prevention Study (large population-based, case-control study) suggests therapeutic use of opiates in pregnant women during organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis.

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. Syndrome presents with irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity vary depending on the specific opiate used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.

Use of opiates during late pregnancy can result in neonatal respiratory depression.

Extended-release opiates not recommended immediately before or during labor; shorter-acting analgesics or other analgesic techniques may be more appropriate.

Lactation

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

Monitor infants exposed to hydrocodone through breast milk for excessive sedation, respiratory depression, GI effects, and altered feeding patterns. Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped.

Pediatric Use

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

Pediatric patients may be at increased risk of esophageal obstruction, dysphagia, and choking (because of their smaller GI lumen) if they ingest the extended-release tablets, which form a gelatinous mass when exposed to fluids.

Do not use antitussive agents containing opiates, including hydrocodone, in pediatric patients <18 years of age; FDA states that risks of respiratory depression, misuse, abuse, addiction, overdosage, and death outweigh the potential benefit.

Hydrocodone antitussives contraindicated in children <6 years of age.

Geriatric Use

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

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

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.

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

Hepatic Impairment

Exposure to the drug and the risk of adverse effects may be increased. Monitor closely. (See Hepatic Impairment under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Exposure to the drug and the risk of adverse effects may be increased. Monitor closely. (See Renal Impairment under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

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

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.

With extended-release tablets for chronic pain: Nausea, constipation, vomiting, dizziness, headache, somnolence, fatigue, pruritus, tinnitus, insomnia, decreased appetite, influenza.

Interactions for HYDROcodone

Metabolized by CYP3A4 and to a lesser extent by CYP2D6. Also may be metabolized to a small extent by CYP2B6 and CYP2C19.

Drugs Affecting Hepatic Microsomal Enzymes

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

CYP3A4 inducers: Possible increased clearance and decreased plasma concentrations of hydrocodone; may result in lack of efficacy or withdrawal manifestations. If concomitant use is necessary, monitor for opiate withdrawal; consider dosage adjustments until stable drug effects are achieved. If CYP3A4 inducer is discontinued, plasma hydrocodone concentrations may increase, possibly increasing or prolonging therapeutic and adverse effects of the drug and increasing risk of fatal overdosage.

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs. May occur at usual dosages. Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases. (See Advice to Patients.)

If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.

If serotonin syndrome is suspected, discontinue hydrocodone, other opiate therapy, and/or any concurrently administered serotonergic agents.

Specific Drugs

HYDROcodone Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract following oral administration.

Extended-release capsules or tablets: Overall systemic exposure or bioavailability similar to that observed with immediate-release fixed-combination preparations containing the same or similar hydrocodone dose; however, peak plasma concentrations are lower with the extended-release formulations.

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

Extended-release tablets: Peak concentrations occur 6–30 hours (median: 14–16 hours) after administration. Peak concentrations and AUC increase linearly and in a slightly more than dose-proportional manner over the dose range of 20–120 mg. With once-daily dosing, peak plasma concentrations and AUC are about 1.1- and 1.3-fold higher at steady state. Higher doses (80 or 120 mg versus 30 mg) produce larger fluctuations in peak-to-trough concentrations.

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

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

Duration

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

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

Food

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

Extended-release tablets: At 120-mg dose, high-fat meal increased peak plasma concentrations by 54% and AUC by 20%.

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.

Hepatic impairment: Peak plasma concentrations and AUC of hydrocodone (administered as extended-release tablets) decreased by 6 and 14%, respectively, in patients with mild hepatic impairment; increased by 5 and 13%, respectively, in patients with moderate hepatic impairment; and increased by 5 and 4%, respectively, in patients with severe hepatic impairment.

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.

Renal impairment: Peak plasma concentrations of hydrocodone (administered as extended-release tablets) increased by 14, 23, or 11% and AUC increased by 13, 61, or 57% in patients with mild, moderate, or severe renal impairment, respectively; peak plasma concentrations decreased by 13% and AUC increased by 4% in patients with end-stage renal disease requiring dialysis.

Distribution

Extent

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

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

Readily crosses the placenta.

Plasma Protein Binding

About 36%.

Special Populations

Hepatic impairment does not substantially alter plasma protein binding.

Elimination

Metabolism

Metabolized by N-demethylation, O-demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. Metabolized principally by CYP3A4 to norhydrocodone (N-demethylation) and to lesser extent by CYP2D6 to hydromorphone (O-demethylation). May be metabolized to small extent by CYP2B6 and CYP2C19.

Hydromorphone is <3% of the circulating parent drug, but may contribute to hydrocodone’s analgesic effects.

Elimination Route

Excreted mainly in urine as unchanged drug (about 6.5%) and metabolites. About 99% of administered dose is eliminated within 72 hours.

Half-life

Extended-release preparations: Approximately 7–9 hours.

Immediate-release preparations: 3.8–4.5 hours.

Special Populations

Gender and age ≥65 years do not appear to substantially affect pharmacokinetics.

Stability

Storage

Oral

Extended-release Capsules

25ºC (may be exposed to 15–30°C).

Extended-release Tablets

25ºC (may be exposed to 15–30°C).

Tablets

20–25ºC (may be exposed to 15–30°C).

Solution

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

Extended-release Suspension

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

Actions

• Shares the actions of the opiate agonists.

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

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

• 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).

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

• 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.

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

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

• 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.

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

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

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

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

Advice to Patients

• Importance of not exceeding the recommended dosage.

• Consequences of overdosage may include potentially fatal respiratory depression.

• 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. Advise patients of the benefits of naloxone following opiate overdose and of their options for obtaining the drug.

• Accidental ingestion, especially by a child, may result in respiratory depression or death. Keep out of reach of children and do not share the drug with others. Importance of not giving hydrocodone to pediatric patients <18 years of age for cough and cold.

• Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.

• Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with benzodiazepines or other CNS depressants, including alcohol and other opiates, either therapeutically or illicitly. Avoid concomitant use of CNS depressants with hydrocodone antitussives; also avoid concomitant use with hydrocodone analgesics unless use is supervised by clinician. Importance of informing patients that hydrocodone should not be combined with alcohol.

• 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.

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

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

• Potential risk of serotonin syndrome with concurrent use of hydrocodone and other serotonergic agents. Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.

• Potential risk of adrenal insufficiency. Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.

• Potential for severe constipation to occur.

• Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use. Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.

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

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed. Importance of informing women that chronic use during pregnancy may result in neonatal opiate withdrawal syndrome, which can be life-threatening if not recognized and treated.

• Importance of advising patients of other important precautionary information. (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).

Hydrocodone Bitartrate Extended-release Capsules and Tablets

• Respiratory depression is most likely to occur following initiation of therapy or an increase in dosage; may occur at recommended dosages.

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

• Importance of swallowing capsules whole. Crushing, chewing, or dissolving the capsules can result in overdosage and death.

• Importance of swallowing tablets whole, one at a time, with enough water to ensure complete swallowing of the tablet immediately after it is placed in the mouth. Do not wet the tablet (e.g., by soaking, licking) before placing it in the mouth; wetting can lead to difficulty in swallowing the tablet. Crushing, chewing, or dissolving the tablets can result in overdosage and death.

• Importance of not consuming alcoholic beverages or taking prescription or nonprescription preparations that contain alcohol. Respiratory and CNS depressant effects of alcohol and hydrocodone are additive; ingestion of alcohol with extended-release capsules may increase hydrocodone absorption and result in fatal overdosage.

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

• Prolongation of QT interval observed with use of extended-release tablets; depending on coexisting medical conditions and concurrent drug therapy, periodic ECGs and electrolyte monitoring may be needed.

• Importance of seeking medical attention if symptoms of severe hypersensitivity (e.g., anaphylaxis) occur.

• When assessing own ability to perform hazardous tasks, consider that hydrocodone concentrations may still be high 24 hours after taking the extended-release tablets.

• Importance of monitoring analgesic response to hydrocodone extended-release tablets following the use of strong laxatives; inform clinician of any changes in response.

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Single-entity hydrocodone preparations: Subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drug.

Fixed-combination preparations containing hydrocodone in a concentration of ≤15 mg per dosage unit or 5 mL combined with a therapeutic amount of one or more non-opiate drugs or with a fourfold or greater quantity of isoquinolone opium alkaloid: Previously subject to control as schedule III (C-III) drug; however, rescheduled as C-II drug effective October 6, 2014. (See Addiction, Abuse, and Misuse under Cautions.)

Preparations containing hydrocodone in combination with >325 mg of acetaminophen per dosage unit have been discontinued to minimize the risk of inadvertent acetaminophen overdosage; some of these preparations may have been reformulated to limit the amount of acetaminophen to ≤325 mg per dosage unit.

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

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

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