benzhydrocodone/acetaminophen (Rx)

Brand and Other Names:Apadaz
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

benzhydrocodone/acetaminophen

tablet, immediate-release: Schedule II

  • 6.12mg/325mg

Acute Severe Pain

Indicated for short-term (ie, 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

Total dosage of benzhydrocodone/acetaminophen and any concomitant acetaminophen-containing products should not exceed 4000 mg/day of acetaminophen

Initiate 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 dose: 1-2 tablets q4-6hr PO prn; not to exceed 12 tablets/24-hr period

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 dose
  • Adjust dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions

Discontinuation of benzhydrocodone/acetaminophen

  • Patients taking benzhydrocodone/acetaminophen regularly and may be physically dependent no longer requires therapy: Taper dose gradually, by 25-50% q2-4days; carefully monitor signs and symptoms of withdrawal
  • If patient develops these signs or symptoms, raise dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing 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 (eg, respiratory depression and hepatotoxicity)
  • Renal impairment: Use a low initial dose; monitor closely for adverse events (eg, respiratory depression)

Dosing Considerations

Monitor patients closely for respiratory depression, especially within the first 24-72 hr of initiating therapy and following dosage increases; adjust dosage accordingly

Conversion from other opioids to benzhydrocodone/acetaminophen

  • 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

Conversion from hydrocodone bitartrate/acetaminophen to benzhydrocodone/acetaminophen

  • Hydrocodone content in 6.12 mg benzhydrocodone is 4.54 mg hydrocodone or is equivalent to 7.5 mg hydrocodone bitartrate
  • Switching from immediate-release hydrocodone bitartrate/acetaminophen, substitute 6.12 mg/325 mg hydrocodone bitartrate/acetaminophen for 7.5 mg/325 mg hydrocodone bitartrate/acetaminophen

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 (eg, 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

<18 years: Safety and efficacy not established

Patients aged ≥65 yr 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

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Interactions

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            Adverse Effects

            >10%

            Nausea (21.5%)

            Somnolence (18.5%)

            Vomiting (13%)

            Constipation (12%)

            Pruritus (11.5%)

            1-10%

            Dizziness (7.5%)

            Headache (6%)

            1-5%

            • Gastrointestinal disorder: Abdominal distension, abdominal pain, flatulence
            • General disorders and administration site conditions: Asthenia
            • Nervous system disorders: Presyncope, tremor
            • Respiratory, thoracic and mediastinal disorders: Dyspnea
            • Vascular disorders: Hot flush, hypotension

            <1%

            Eye disorders: Eye pruritus

            Gastrointestinal disorders: Diarrhea, gastroesophageal reflux disease, hematemesis

            General disorders and administration site conditions: Chest discomfort

            Infections and infestations: Rhinitis

            Nervous system disorders: Hypoesthesia, syncope

            Psychiatric disorders: Agitation, euphoric mood, nightmare

            Postmarketing Reports

            Serotonin syndrome, a potentially life-threatening condition, reported when opioids coadministered with serotonergic drugs

            Adrenal insufficiency reported with opioid use, more often following >1 month of use

            Anaphylaxis reported with hydrocodone and acetaminophen

            Androgen deficiency with chronic opioid use

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            Warnings

            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 coadministered 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 >1 acetaminophen-containing product

            Risks from concomitant use with benzodiazepines or other CNS depressants

            • Coadministration of opioids with benzodiazepines or other 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

            Contraindications

            Significant respiratory depression

            Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment

            Known or suspected gastrointestinal obstruction, including paralytic ileus

            Hypersensitivity to hydrocodone or acetaminophen

            Cautions

            Contains benzhydrocodone, a Schedule II controlled substance; as an opioid, benzhydrocodone exposes users to the risks of addiction, abuse, and misuse (see Black Box Warnings)

            Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended (see Black Box Warnings)

            Use in patients with acute or severe bronchial asthma in an unmonitored setting or in 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

            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 (see Black Box Warnings)

            Contains acetaminophen; acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death (see Black Box Warnings)

            Adrenal insufficiency reported with opioid use, more often following use >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 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 (eg, 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 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 (see Contraindications)

            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 (see Adult Dosing)

            May impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery

            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 result in an increase in hydrocodone plasma concentration
              • Monitor if coadministered with any CYP3A4 inhibitor or inducer
            • Coadministration with benzodiazepines or other CNS depressants
              • Also see Black Box Warnings
              • Profound sedation, respiratory depression, coma, and death may result from the concomitant use with 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
            • MAOIs
              • Opioid use not recommended concurrently with MAOIs or within 14 days of stopping MAOI
              • MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (eg, 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 (eg, nalbuphine, butorphanol) or partial agonist (eg, 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 risk of urinary retention and/or severe constipation
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            Pregnancy

            Pregnancy

            Prolonged use of opioid analgesics during pregnancy can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth (see Black Box Warnings)

            Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight

            Onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing, amount of last maternal use, and rate of elimination of the drug by the newborn

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

            Labor and delivery

            • Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates
            • An opioid antagonist (eg, naloxone) must be available for reversal of opioid-induced respiratory depression in the neonate

            Infertility

            • Chronic opioid use may cause reduced fertility in females and males of reproductive potential
            • Unknown whether these effects on fertility are reversible

            Lactation

            Hydrocodone

            • Present in human milk
            • Variable concentrations of hydrocodone and hydromorphone (active metabolite) reported in breast milk when administered to nursing mothers in the early postpartum period
            • Potential for sedation and respiratory depression in the breastfed infant

            Acetaminophen

            • Present in human milk in small quantities after PO administration
            • Based on data from >15 breastfeeding women, the calculated infant daily dose of acetaminophen is ~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

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Benzhydrocodone: Prodrug of hydrocodone, which is an opioid analgesic agonist; blocks pain perception in the cerebral cortex; decreases synaptic chemical transmission throughout the CNS, which in turn inhibits pain sensation into higher centers; when ingested, enzymes in the GI tract cleave the ligand from the prodrug (benzhydrocodone) and release the parent drug (hydrocodone)

            Acetaminophen: Acts on the hypothalamus to produce antipyresis; inhibits prostaglandin synthetase

            Absorption

            Steady-state reached: 24-36 hr

            Hydrocodone

            • Peak plasma time: 2.5 hr (fed); 1.25 hr (fasting)
            • Peak plasma concentration: 16.04 ng/mL (fed); 19.18 ng/mL (fasting)
            • AUC: 130.91 h·ng/mL (fed); 125.73 h·ng/mL (fasting)
            • Multiple doses: Accumulation ratios for hydrocodone Cmax and AUC values were 1.85-fold and 2.03-fold, respectively

            Acetaminophen

            • Peak plasma time: 1.5 hr (fed); 1 hr (fasting)
            • Peak plasma concentration: 3.34 mcg/mL (fed); 4.05 mcg/mL (Fasting)
            • AUC: 15 h·mcg/mL (fed); 14.7 h·mcg/mL (fasting)
            • Multiple doses: Accumulation ratios for acetaminophen Cmax and AUC values were 1.38-fold and 1.80-fold, respectively

            Metabolism

            Benzhydrocodone

            • Prodrug of hydrocodone and is converted to active hydrocodone by enzymes in the intestinal tract
            • Hydrocodone exhibits a complex pattern of metabolism, including O-demethylation, N-demethylation, and 6-keto reduction to the corresponding 6-alpha-and 6-beta-hydroxy metabolites
            • Hydromorphone, a potent opioid, is formed from the O-demethylation of hydrocodone and contributes to the total analgesic effect of hydrocodone
            • The O- and N- demethylation processes are mediated by separate P-450 isoenzymes: CYP2D6 and CYP3A4, respectively

            Acetaminophen

            • Principal metabolic pathways
              • Primarily metabolized in the liver by first-order kinetics and involves 3 principal separate pathways
              • Conjugation with glucuronide
              • Conjugation with sulfate
              • Oxidation via the CYP450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates; the principal CYP450 isoenzymes involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways
              • In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate; these glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity

            Elimination

            Hydrocodone

            • Half-life: 4.5 hr
            • Excretion: Primarily by kidneys (hydrocodone and metabolites)

            Acetaminophen

            • Half-life: 2-3 hr
            • Excretion: Primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner; <9% excreted unchanged in the urine
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            Administration

            Oral Administration

            Oral use only

            Take with or without food

            Do not take >4,000 mg/day of acetaminophen per day

            Do not discontinue treatment abruptly (see Adult Dosing)

            Flush expired or unused tablets down the toilet when benzhydrocodone/acetaminophen is no longer needed or contact Drug Enforcement Agency (DEA) to find location of an authorized collector

            Storage

            Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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