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BENZHYDROCODONE

Benzhydrocodone is a hydrocodone prodrug providing mu-opioid receptor agonism combined with acetaminophen's central analgesic activity.

Benzhydrocodone is a marketed opioid analgesic prodrug combining hydrocodone with acetaminophen for acute severe pain management in patients who cannot tolerate or have failed alternative treatments. As a full mu-opioid receptor agonist, it provides potent analgesia without a ceiling effect, with dosing titrated to balance efficacy against adverse effects including respiratory depression. The combination formulation leverages hydrocodone's central opioid activity with acetaminophen's non-opioid analgesic properties. With 12 publications supporting its clinical use but no active trials, benzhydrocodone represents a mature marketed product in the competitive acute pain management space. Commercial significance is limited by the opioid class's regulatory scrutiny and market contraction, though it serves patients with documented inadequate response to non-opioid alternatives.

At a glance

Mechanism of action

Benzhydrocodone functions as a prodrug that is metabolized to hydrocodone, a full opioid agonist with relative selectivity for mu-opioid receptors in the central nervous system. Hydrocodone binds to opioid receptors distributed throughout the brain and spinal cord, modulating pain perception through endogenous opioid-like mechanisms. The combination with acetaminophen provides complementary analgesia through distinct central mechanisms, allowing lower opioid doses while maintaining therapeutic efficacy. Unlike partial agonists or antagonists, full agonists like hydrocodone demonstrate no ceiling effect for analgesia, meaning pain relief can be achieved at higher doses, though clinical dosing is limited by adverse effects including respiratory depression and CNS effects.

Approved indications

• Short-term management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate
• Use in patients for whom alternative treatment options have not been tolerated or are not expected to be tolerated
• Use in patients for whom alternative treatment options have not provided adequate analgesia or are not expected to provide adequate analgesia

Boxed warnings

• WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF APADAZ Addiction, Abuse, and Misuse Because the use of APADAZ exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 )] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of APADAZ, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of APADAZ are essential [see Warnings and Precautions ( 5.2 )] . Accidental Ingestion Accidental ingestion of even one dose of APADAZ, especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions ( 5.2 )] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of APADAZ and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )] . Neonatal Opioid Withdrawal Syndrome (NOWS) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions ( 5.4 )] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions ( 5.5 )] . Cytochrome P450 3A4 Interaction The concomitant use of APADAZ with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Regularly evaluate patients receiving APADAZ and any CYP3A4 inhibitor or inducer [see Warnings and Precautions ( 5.5 ), Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )] . Hepatotoxicity APADAZ contains acetaminophen. Acetaminophen 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 4000 milligrams per day, and often involve more than one acetaminophen-containing product [see Warnings and Precautions ( 5.6 )] . WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF APADAZ See full prescribing information for complete boxed warning. APADAZ exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and reassess regularly for these behaviors and conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of APADAZ are essential. ( 5.3 ) Accidental ingestion of APADAZ, especially by children, can result in a fatal overdose of hydrocodone. ( 5.3 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. ( 5.7 , 7 ) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. ( 5.4 ) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. ( 5.2 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone from APADAZ. ( 5.5 , 7 , 12.3 ) APADAZ contains acetaminophen. Acetaminophen 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 4000 milligrams per day, and often involve more than one acetaminophen-containing product. ( 5.6 )

Common side effects

• nausea
• somnolence
• vomiting
• constipation
• pruritus
• dizziness
• headache
• abdominal distension
• abdominal pain
• flatulence
• asthenia
• presyncope

Drug interactions

• CYP3A4 and 2D6 Inhibitors
• CYP3A4 Inducers
• Benzodiazepines and Other CNS Depressants
• Serotonergic Drugs
• Monoamine Oxidase Inhibitors (MAOIs)
• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Primary sources

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Competitive intelligence

For the full competitive landscape — auto-detected comparators, recent regulatory actions across the set, upcoming PDUFA, patent timeline, sponsor landscape:

• BENZHYDROCODONE CI brief — competitive landscape report
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