Head-to-head clinical analysis & difference comparison: details on mechanism of action, dosing, half-life, interactions, and maternal-fetal safety.
APADAZ vs ACEPHEN
Clinician-reviewed, head-to-head comparison of mechanism, dosing, pharmacokinetics, and safety profiles.
Last clinically reviewed: July 2026 · OpiCalc Medical Review Team
APADAZ is a combination of benzhydrocodone, a prodrug of hydrocodone, and acetaminophen. Hydrocodone acts as a full mu-opioid receptor agonist, inhibiting ascending pain pathways and altering pain perception. Acetaminophen's mechanism involves inhibition of cyclooxygenase (COX) enzymes, particularly in the CNS, and modulation of serotonergic pathways, contributing to analgesia and antipyresis.
ACEPHEN (acetaminophen) is a para-aminophenol derivative with analgesic and antipyretic activity. Its mechanism involves inhibition of cyclooxygenase (COX) enzymes in the central nervous system, particularly COX-2, reducing prostaglandin synthesis. It has weak peripheral COX inhibition and minimal anti-inflammatory effect.
Management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate
Mild to moderate pain,Fever
Each tablet contains benzhydrocodone 4.08 mg (hydrocodone 3.33 mg) and acetaminophen 325 mg. One to 2 tablets every 4 to 6 hours as needed for pain; maximum 12 tablets per 24 hours.
325-650 mg orally every 4-6 hours as needed; maximum 4 g/day.
Terminal elimination half-life: 2-4 hours for benzhydrocodone; context: immediate-release, dosing every 4-6 hours.
Terminal elimination half-life: 1.0-1.5 hours in adults with normal renal function. Prolonged to 2-5 hours in hepatic impairment or elderly; requires dose adjustment in severe hepatic disease.
Benzhydrocodone is converted to hydrocodone by intestinal and hepatic enzymes (e.g., esterases). Hydrocodone is metabolized via CYP3A4 and CYP2D6 to norhydrocodone, hydromorphone, and other metabolites. Acetaminophen is primarily metabolized by glucuronidation (UGT1A1, UGT1A6, UGT1A9) and sulfation (SULT1A1, SULT1A3); a minor amount is oxidized by CYP2E1, CYP1A2, and CYP3A4 to the reactive metabolite NAPQI, which is conjugated with glutathione.
Acetaminophen is primarily metabolized in the liver via glucuronidation (UGT1A1, UGT1A6, UGT1A9) and sulfation (SULT1A1, SULT1A3). A minor fraction is oxidized by cytochrome P450 enzymes (CYP2E1, CYP1A2, CYP3A4) to a reactive toxic metabolite (NAPQI), which is normally detoxified by conjugation with glutathione.
Renal: ~90% as conjugates, ~10% unchanged; fecal: minimal; enterohepatic recirculation occurs.
Renal: 90-95% as unchanged drug; tubular secretion and glomerular filtration. Biliary/fecal: <5%.
Benzhydrocodone: ~20% bound to albumin; acetaminophen: 10-25% bound.
Approximately 10-20% bound to serum albumin; extensive tissue binding.
Benzhydrocodone: ~3-5 L/kg; context: extensive tissue distribution.
Apparent Vd: 0.5-0.7 L/kg (30-40 L in a 70 kg adult). Distributions into CSF and breast milk.
Oral: ~50% for benzhydrocodone (due to first-pass metabolism); acetaminophen: 60-90%.
Oral: 85-90% (first-pass metabolism minimal). Rectal: approximately 70-80% of oral bioavailability.
Contraindicated in severe renal impairment (e GFR <30 m L/min/1.73m²). For moderate impairment (e GFR 30-59 m L/min/1.73m²), initiate with lowest dose and monitor; do not exceed 6 tablets per day.
GFR 10-50 m L/min: 650 mg every 6 hours; GFR <10 m L/min: 650 mg every 8 hours.
Contraindicated in severe hepatic impairment (Child-Pugh C). For moderate impairment (Child-Pugh B), reduce dose by 50% and monitor; maximum 6 tablets per day. Mild impairment (Child-Pugh A): no adjustment but monitor.
Child-Pugh Class A: no adjustment; Child-Pugh Class B: maximum 2 g/day; Child-Pugh Class C: maximum 1 g/day.
Not recommended for pediatric patients under 18 years of age.
10-15 mg/kg/dose orally every 4-6 hours; maximum 75 mg/kg/day or 4 g/day, whichever is less.
Initiate with lowest dose (1 tablet every 6 hours as needed); do not exceed 6 tablets per day; monitor for respiratory depression, falls, and cognitive impairment.
Start at lowest effective dose (325 mg every 6 hours); avoid exceeding 3 g/day unless closely monitored.
Addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; risks from concomitant use with benzodiazepines or other CNS depressants; neonatal opioid withdrawal syndrome; and risks associated with use of acetaminophen (hepatotoxicity).
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 4,000 milligrams per day, and often involve more than one acetaminophen-containing product.
Life-threatening respiratory depression,Addiction, abuse, and misuse,Risks from concomitant use with benzodiazepines or other CNS depressants,Neonatal opioid withdrawal syndrome,Hepatotoxicity from acetaminophen,Severe hypotension,Gastrointestinal adverse reactions (e.g., constipation, ileus),Seizures in patients with seizure disorders,Adrenal insufficiency,Risks in patients with head injury or increased intracranial pressure
Risk of severe liver injury with doses >4000 mg/day; use caution with hepatic impairment, chronic alcoholism, malnutrition, or concomitant hepatotoxic drugs; avoid exceeding recommended dose; limit use to 10 days for pain or 3 days for fever unless directed by physician; serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) have occurred.
Significant respiratory depression,Acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment,Known or suspected gastrointestinal obstruction (e.g., paralytic ileus),Hypersensitivity to hydrocodone, acetaminophen, or any component of the formulation,Severe hepatic impairment (acetaminophen component)
Hypersensitivity to acetaminophen or any component of the formulation; severe hepatic impairment or active liver disease.
Avoid alcohol. Grapefruit juice may alter metabolism via CYP3A4 inhibition; consider limiting intake. High-fat meals can increase absorption of benzhydrocodone; take consistently with or without food to maintain effect.
Alcohol: increased risk of hepatotoxicity. Avoid concurrent use. Food: no significant interaction, but taking with food may reduce minor gastrointestinal irritation.
Apadaz (benzhydrocodone/acetaminophen) is a combination opioid/acetaminophen product. Opioid use during pregnancy may cause neonatal opioid withdrawal syndrome (NOWS) with prolonged use; risk is highest in third trimester. Acetaminophen is not teratogenic at therapeutic doses. FDA Pregnancy Category C (prior to 2019 labeling); current labeling advises use only if potential benefit justifies potential risk to fetus. First trimester: limited data; opioid use associated with neural tube defects in some studies, but confounding by maternal factors. Second trimester: no specific malformation risk. Third trimester: risk of NOWS, preterm labor, and intrauterine growth restriction with chronic use. Avoid prolonged use; acute use at standard doses is not associated with major teratogenic risk.
Pregnancy Category C. First trimester: potential risk of neural tube defects and orofacial clefts (limited human data, animal studies show embryotoxicity). Second and third trimesters: NSAID exposure associated with oligohydramnios, premature ductus arteriosus constriction, and fetal renal impairment. Avoid in third trimester.
Benzhydrocodone is a prodrug of hydrocodone; both hydrocodone and acetaminophen are excreted into breast milk. Hydrocodone M/P ratio is approximately 2.0 (milk:plasma concentration ratio). Acetaminophen M/P ratio is approximately 1.0. Low absolute infant dose; relative infant dose is about 2-4% of maternal weight-adjusted dose for hydrocodone and 10-20% for acetaminophen. AAP considers acetaminophen compatible with breastfeeding. Opioids should be used with caution; monitor infant for sedation, respiratory depression, and poor feeding. Avoid in mothers with CYP2D6 ultra-rapid metabolizer phenotype due to risk of increased morphine conversion.
Excreted into breast milk in low concentrations (M/P ratio approximately 0.10). Considered compatible with breastfeeding; however, use lowest effective dose for shortest duration given potential for neonatal adverse effects (e.g., thrombocytopenia, renal dysfunction).
Pharmacokinetic changes in pregnancy (increased plasma volume, hepatic enzyme induction, altered opioid clearance): For acute pain, use lowest effective dose for shortest duration. Consider dose reduction postpartum as metabolic changes resolve. No specific dose adjustment guidelines for Apadaz; clinical judgment for opioid dose titration needed. Monitor for inadequate analgesia or withdrawal due to increased clearance. For chronic pain, consider tapering or alternative non-opioid therapy.
No standard dose adjustments recommended; however, due to increased plasma volume and metabolism in pregnancy, higher doses may be required to achieve therapeutic effect. Avoid near term.
Contains benzhydrocodone, a prodrug of hydrocodone, and acetaminophen. Abuse-deterrent properties due to enzymatic activation required in GI tract; consider in patients with risk of opioid misuse. Monitor for acetaminophen hepatotoxicity; max daily acetaminophen dose from all sources should not exceed 4 g. Avoid in severe hepatic impairment. Onset of analgesia is slower than immediate-release hydrocodone due to prodrug conversion.
ACEPHEN (acetaminophen) is commonly used for mild to moderate pain and fever. Avoid exceeding 4 g/day in adults to prevent hepatotoxicity. In patients with hepatic impairment, reduce maximum daily dose to 2 g. Consider acetylcysteine for overdose. Onset of action is 15-30 minutes orally.
Take exactly as prescribed; do not crush, chew, or dissolve tablets as this can cause rapid release and overdose.,Avoid alcohol and other CNS depressants; may cause severe drowsiness, respiratory depression, or coma.,Do not take other acetaminophen-containing products; check labels for acetaminophen (APAP) to prevent liver damage.,Store securely and dispose of unused medication via take-back programs; prevent misuse by others.,Common side effects include nausea, constipation, dizziness, and drowsiness; contact prescriber if severe or persistent.
Do not exceed 4000 mg (4 grams) in 24 hours.,Avoid drinking alcohol while taking this medication.,Do not combine with other products containing acetaminophen.,Take with food if stomach upset occurs.,Seek immediate medical help if you experience symptoms of liver damage: yellowing of skin/eyes, dark urine, severe abdominal pain.
No interactions on record
No interactions on record
Explore head-to-head clinical comparisons of other medications in the same therapeutic classes.
Common clinical questions about APADAZ vs ACEPHEN, answered by our medical review team.
APADAZ is a Opioid Analgesic that works by APADAZ is a combination of benzhydrocodone, a prodrug of hydrocodone, and acetaminophen. Hydrocodone acts as a full mu-opioid receptor agonist, inhibiting ascending pain pathways and altering pain perception. Acetaminophen's mechanism involves inhibition of cyclooxygenase (COX) enzymes, particularly in the CNS, and modulation of serotonergic pathways, contributing to analgesia and antipyresis.. ACEPHEN is a Non-Opioid Analgesic that works by ACEPHEN (acetaminophen) is a para-aminophenol derivative with analgesic and antipyretic activity. Its mechanism involves inhibition of cyclooxygenase (COX) enzymes in the central nervous system, particularly COX-2, reducing prostaglandin synthesis. It has weak peripheral COX inhibition and minimal anti-inflammatory effect.. They differ in pharmacokinetic profiles, FDA-approved indications, and side effect profiles.
Potency comparisons between APADAZ and ACEPHEN depend on the specific clinical indication. These are agents from distinct pharmacological classes and are not directly interchangeable by dose. A physician or clinical pharmacist should guide any therapeutic switching decisions.
The standard adult dose of APADAZ is: Each tablet contains benzhydrocodone 4.08 mg (hydrocodone 3.33 mg) and acetaminophen 325 mg. One to 2 tablets every 4 to 6 hours as needed for pain; maximum 12 tablets per 24 hours.. The standard adult dose of ACEPHEN is: 325-650 mg orally every 4-6 hours as needed; maximum 4 g/day.. Dosing should always be individualized based on indication, renal and hepatic function, age, and other patient factors.
No direct drug-drug interaction has been formally documented between APADAZ and ACEPHEN in current clinical databases. However, individual patient risk factors including other medications, organ function, and comorbidities should always be evaluated by a qualified healthcare provider.
The maternal-fetal safety profiles differ. APADAZ is classified as Category C. Apadaz (benzhydrocodone/acetaminophen) is a combination opioid/acetaminophen product. Opioid use during pregnancy may cause neonatal opioid withdrawal syndrome (NOWS) with prolonge. ACEPHEN is classified as Category C. Pregnancy Category C. First trimester: potential risk of neural tube defects and orofacial clefts (limited human data, animal studies show embryotoxicity). Second and third trimest. Always consult a maternal-fetal medicine specialist before taking either drug during pregnancy or lactation.