Drug information of Acetaminophen and benzhydrocodone

Acetaminophen and benzhydrocodone

Drug group:

Benzhydrocodone is an opioid pain medication. Acetaminophen is a less potent pain reliever that increases the effects of hydrocodone.

Acetaminophen and benzhydrocodone is a combination medicine for short-term use to relieve moderate to severe pain.

Mechanism of effect

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


Benzhydrocodone is rapidly metabolized to hydrocodone which acts on the central nervous system to produce analgesia. The action of hydrocodone in the brain can also produce euphoria, leading to addiction. 

acetaminophen has both antipyretic and analgesic effects. 



Steady-state reached: 24-36 hr


  • 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


  • 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



  • 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


  • 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



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


  • 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



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

Initial dosage

  • Use as first opioid analgesic (ie, opioid-naïve): 1-2 tablets PO q4-6hr prn pain
  • Not to exceed 12 tablets/24 hr

Titration and maintenance

  • Titrate dose to provide adequate analgesia and minimizes adverse reactions


  • 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


<18 years: Safety and efficacy not established

Drug contraindications

Hypersensitivity to this drug


  • Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases 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 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
  • Adrenal insufficiency reported with opioid use, more often following use >1 month
  • 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
  • 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

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

  • 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

Cytochrome P450 3A4 interactions

  • Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone


  • 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
  • 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 benefits of opioid analgesics outweigh 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

Points of recommendation

Follow the directions on your prescription label and read all medication guides. Never use acetaminophen and benzhydrocodone in larger amounts, or for longer than 14 days. An overdose can damage your liver or cause death. Tell your doctor if you feel an increased urge to take more of this medicine.

Never share this medicine with another person, especially someone with a history of drug abuse or addiction. MISUSE CAN CAUSE ADDICTION, OVERDOSE, OR DEATH. Keep the medicine in a place where others cannot get to it.

Do not stop using acetaminophen and benzhydrocodone suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to safely stop using this medicine.

Store at room temperature away from moisture and heat.

Avoid driving or operating machinery until you know how this medicine will affect you. Dizziness or drowsiness can cause falls, accidents, or severe injuries.

Ask a doctor or pharmacist before using any other medicine that may contain acetaminophen (sometimes abbreviated as APAP). Taking certain medications together can lead to a fatal overdose.

Avoid drinking alcohol. It may increase your risk of liver damage.

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