Benzhydrocodone Acetaminophen

Benzhydrocodone/acetaminophen is used for short-term (i.e., not to exceed 14 days) management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Benzhydrocodone/acetaminophen is available under the following different brand names: Apadaz.

Tablet, Immediate-Release (IR): Schedule II

• 4.08mg/325mg
• 6.12mg/325mg
• 8.16mg/325mg

Acute Severe Pain

• Indicated for short-term (i.e., not to exceed 14 days) management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate
• Use lowest effective dosage for the shortest duration consistent with individual patient treatment goals
• The total dosage of benzhydrocodone/acetaminophen and any concomitant acetaminophen-containing products should not exceed 4000 mg/day of acetaminophen
• Initiate the dosing regimen for each patient individually, taking into account the severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse

Initial dosage

• Use as a first opioid analgesic (i.e., opioid-naïve): 1-2 tablets orally every 4-6 hours p.r.n.
• Not to exceed 12 tablets/24 hours
• Children under 18 years: Safety and efficacy not established

Conversion from immediate-release hydrocodone bitartrate and to benzhydrocodone

• There is interpatient variability in the potency of opioid drugs and opioid formulations; a conservative approach is advised when determining the total daily dosage (TDD) of benzhydrocodone/acetaminophen
• Switch from hydrocodone bitartrate IR 5 mg: Substitute 4.08 mg benzhydrocodone
• Switch from hydrocodone bitartrate IR 7.5 mg: Substitute 6.12 mg benzhydrocodone
• Switch from hydrocodone bitartrate IR 10 mg: Substitute 8.16 mg benzhydrocodone

Titration and maintenance

• Titrate dose to provide adequate analgesia and minimizes adverse reactions
• Continually reevaluate patients taking benzhydrocodone/acetaminophen to assess maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse
• Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration
• If pain level increases after dosage stabilization, attempt to identify the source of increased pain before increasing the dose
• If unacceptable opioid-related adverse reactions are observed, consider reducing the dose
• Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions

Discontinuation

• Patients taking benzhydrocodone/acetaminophen regularly and may be physically dependent no longer requires therapy: Taper dose gradually, by 25-50% every 2-4 days; carefully monitor signs and symptoms of withdrawal
• If a patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both
• Do not abruptly discontinue treatment in a physically dependent patient

Dosage Modifications

Renal or hepatic impairment

• Patients with hepatic or renal impairment may have higher plasma concentrations than those with normal function
• Hepatic impairment or active liver disease: Use a low initial dose; monitor closely for adverse events (e.g., respiratory depression and hepatotoxicity)
• Renal impairment: Use a low initial dose; monitor closely for adverse events (e.g., respiratory depression)

Dosing Considerations

• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases; adjust dosage accordingly
• Patients aged 65 years and older may have increased sensitivity to hydrocodone
• In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function

Limitations of use

• Owing to the risks of addiction, abuse, and misuse with opioids, even at recommended, reserve benzhydrocodone/acetaminophen for use in patients for whom alternative treatment options (e.g., non-opioid analgesics): Have not been tolerated, or are not expected to be tolerated, have not provided adequate analgesia, or are not expected to provide adequate analgesia

Common side effects of benzhydrocodone/acetaminophen include:

• Nausea
• Drowsiness
• Vomiting
• Constipation
• Itching
• Dizziness
• Headache
• Gastrointestinal disorder: Abdominal distension, abdominal pain, gas (flatulence)
• General disorders and administration site conditions: Weakness/lethargy
• Nervous system disorders: Lightheadedness, tremor
• Respiratory, thoracic and mediastinal disorders: Shortness of breath
• Vascular disorders: Hot flush, low blood pressure (hypotension)

Less common side effects of benzhydrocodone/acetaminophen include:

• Eye disorders: Eye itching
• Gastrointestinal disorders: Diarrhea, gastroesophageal reflux disease (GERD), hematemesis
• General disorders and administration site conditions: Chest discomfort
• Infections and infestations: Runny nose
• Nervous system disorders: Numbness, fainting
• Psychiatric disorders: Agitation, euphoric mood, nightmare

Postmarketing side effects of benzhydrocodone/acetaminophen reported include:

• Serotonin syndrome, a potentially life-threatening condition, reported when opioids co-administered with serotonergic drugs
• Adrenal insufficiency reported with opioid use, more often following more than 1 month of use
• Anaphylaxis was reported with hydrocodone and acetaminophen
• Androgen deficiency with chronic opioid use

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first.

Severe interactions of benzhydrocodone/acetaminophen include:

• alvimopan

Benzhydrocodone/acetaminophen has serious interactions with at least 121 different drugs.

Benzhydrocodone/acetaminophen has moderate interactions with at least 124 different drugs.

Benzhydrocodone/acetaminophen has no listed mild interactions with other drugs.

Warnings

This medication contains benzhydrocodone/acetaminophen. Do not take Apadaz if you are allergic to benzhydrocodone/acetaminophen or any ingredients contained in this drug.

Black Box Warnings

Addiction, abuse, and misuse

• Exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death
• Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions

Life-threatening respiratory depression

• Serious, life-threatening, or fatal respiratory depression may occur
• Monitor closely for respiratory depression, especially during initiation or following a dose increase

Accidental ingestion

• Accidental ingestion of even 1 dose, especially by children, can result in a fatal overdose of hydrocodone

Neonatal opioid withdrawal syndrome

• Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated
• If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

Cytochrome P450 3A4 interactions

• Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone
• Monitor if co-administered with any CYP3A4 inhibitor or inducer

Hepatotoxicity

• Contains acetaminophen, which has been associated with cases of acute liver failure, at times resulting in liver transplant and death
• Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4 g/day and often involve more than 1 acetaminophen-containing product

Risks from concomitant use with benzodiazepines or other CNS depressants

• Coadministration of opioids with benzodiazepines or another central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death
• Reserve concomitant prescribing of benzhydrocodone/acetaminophen and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate
• Limit dosages and durations to the minimum required
• Monitor for signs and symptoms of respiratory depression and sedation

Opioid analgesic risk evaluation and mitigation strategy (REMS)

• To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products; under requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers;
• Healthcare providers are strongly encouraged to:
  • Complete a REMS-compliant education program
  • Counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products
  • Emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist,
  • Consider other tools to improve patient, household, and community safety

Contraindications

• Significant respiratory depression
• Acute or severe bronchial asthma in an unmonitored setting or absence of resuscitative equipment
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Hypersensitivity to hydrocodone or acetaminophen

Effects of Drug Abuse

Addiction, abuse, and misuse

• Exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death
• Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions
• Do not abruptly discontinue buprenorphine in a patient physically dependent on opioids; when discontinuing therapy, in a physically dependent patient, gradually taper the dosage; rapid tapering in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

Short-Term Effects

• See "What Are Side Effects Associated with Using Benzhydrocodone/Acetaminophen?"

Long-Term Effects

• See "What Are Side Effects Associated with Using Benzhydrocodone/Acetaminophen?"

Cautions

• Contains benzhydrocodone, a Schedule II controlled substance; as an opioid, benzhydrocodone exposes users to the risks of addiction, abuse, and misuse
• Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended
• Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases the risk of CSA in a dose-dependent fashion; in patients who present with CSA, consider decreasing opioid dosage using best practices for opioid taper
• Use in patients with acute or severe bronchial asthma in an unmonitored setting or the absence of resuscitative equipment is contraindicated; life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance
• Do not abruptly discontinue buprenorphine in a patient physically dependent on opioids; when discontinuing therapy, in a physically dependent patient, gradually taper the dosage; rapid tapering in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain
• Prolonged use during pregnancy can result in withdrawal in the neonate; neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts
• Contains acetaminophen; acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death
• Adrenal insufficiency was reported with opioid use, more often the following use more than 1 month
• Risk for severe hypotension, including orthostatic hypotension and syncope in ambulatory patients; risk increased in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs
• Severe hypotension, including orthostatic hypotension and syncope reported in ambulatory patients; risk increased if the ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs
• In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure [ICP] or brain tumors), hydrocodone may reduce respiratory drive, and the resultant CO2 retention can further increase ICP; avoid with impaired consciousness or coma
• Acetaminophen is associated with risk for rare, but serious skin reactions that can be fatal; these reactions include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP); symptoms may include skin redness, blisters and rash
• Acetaminophen associated with reports of hypersensitivity and anaphylaxis; clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting
• May cause spasm of the sphincter of Oddi; opioids may increase serum amylase; monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms; contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus
• Hydrocodone may increase the frequency of seizures in patients with seizure disorders, monitor patients with a history of seizure disorders for worsened seizure control
• Do not discontinue abruptly; gradually taper dose to avoid withdrawal symptoms
• May impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

• To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed; Use the following link to obtain the Patient Counseling Guide (PCG): www.fda.gov/OpioidAnalgesicREMSPCG
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities
• To obtain further information on opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com; the FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint

Drug interaction overview

• CYP inhibitors or inducers
  • Also, see Black Box Warnings
  • CYP3A4 or CYP2D6 inhibitors: Coadministration with CYP3A4 or CYP2D6 inhibitors may increase hydrocodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression
  • CYP3A4 inducers: Discontinuation of a concomitantly used CYP3A4 inducer may increase hydrocodone plasma concentration
  • Monitor if coadministered with any CYP3A4 inhibitor or inducer

• Coadministration with benzodiazepines or other CNS depressants
  • Profound sedation, respiratory depression, coma, and death may result from the concomitant use of benzodiazepines or other CNS depressants
  • Examples include nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, or alcohol
  • If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use

• Serotonergic drugs
  • Coadministration of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome
  • If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment
  • Discontinue if serotonin syndrome is suspected

• Monoamine Oxidase Inhibitors (MAOIs)
  • Opioid use is not recommended concurrently with MAOIs or within 14 days of stopping MAOI
  • MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma)
  • If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression

• Mixed or partial opioid agonists
  • Avoid coadministration with mixed agonist/antagonist (e.g., nalbuphine, butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist owing to reduced analgesic effect and/or precipitation of withdrawal

• Muscle relaxants
  • Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression
  • Monitor for signs of respiratory depression that may be greater than expected and decrease dose or benzhydrocodone or muscle relaxant as needed

• Diuretics
  • Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone

• Anticholinergic drugs
  • Coadministration with anticholinergic drugs may increase the risk of urinary retention and/or severe constipation

Pregnancy and Lactation

Prolonged use of opioid analgesics such as benzhydrocodone during pregnancy can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. Opioids such as benzhydrocodone cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist (e.g., naloxone) must be available for reversal of opioid-induced respiratory depression in the neonate.

Published studies with oral acetaminophen use during pregnancy have not reported an association with major congenital malformations.

Hydrocodone is present in human milk. Variable concentrations of hydrocodone and hydromorphone (active metabolite) have been reported in breast milk when administered to nursing mothers in the early postpartum period. There is the potential for sedation and respiratory depression in the breastfed infant.

Acetaminophen is present in human milk in small quantities after oral administration. Based on data from more than 15 breastfeeding women, the calculated infant daily dose of acetaminophen is approximately 1-2% of the maternal dose. There is 1 well-documented report of a rash in a breastfed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use. Consult your doctor before breastfeeding.