APADAZ
Clinical safety rating
cautionComprehensive clinical and safety monograph for APADAZ (APADAZ).
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.
| Metabolism | 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. |
| Excretion | Renal: ~90% as conjugates, ~10% unchanged; fecal: minimal; enterohepatic recirculation occurs. |
| Half-life | Terminal elimination half-life: 2-4 hours for benzhydrocodone; context: immediate-release, dosing every 4-6 hours. |
| Protein binding | Benzhydrocodone: ~20% bound to albumin; acetaminophen: 10-25% bound. |
| Volume of Distribution | Benzhydrocodone: ~3-5 L/kg; context: extensive tissue distribution. |
| Bioavailability | Oral: ~50% for benzhydrocodone (due to first-pass metabolism); acetaminophen: 60-90%. |
| Onset of Action | Oral: 30-60 minutes. |
| Duration of Action | Analgesic: 4-6 hours; clinical notes: duration may be dose-dependent. |
| Molecular Weight | 425.5 |
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.
| Dosage form | TABLET |
| Renal impairment | Contraindicated in severe renal impairment (eGFR <30 mL/min/1.73m²). For moderate impairment (eGFR 30-59 mL/min/1.73m²), initiate with lowest dose and monitor; do not exceed 6 tablets per day. |
| Liver impairment | 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. |
| Pediatric use | Not recommended for pediatric patients under 18 years of age. |
| Geriatric use | 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. |
| 1st trimester | APADAZ (benzhydrocodone/acetaminophen) is not recommended in the first trimester due to limited safety data and potential for acetaminophen-associated risks; however, no major teratogenic effects are established. Use only if benefit outweighs risk. |
| 2nd trimester | Second trimester use may be considered if clearly needed, but prolonged or high-dose use may increase risk of neonatal withdrawal. Acetaminophen is generally considered safe; benzhydrocodone's effects are similar to other opioids. |
| 3rd trimester | Third trimester use is associated with risk of neonatal opioid withdrawal syndrome (NOWS) and respiratory depression at delivery. Avoid prolonged use; if used near term, monitor neonate for withdrawal. |
Clinical note
Comprehensive clinical and safety monograph for APADAZ (APADAZ).
| Placental transfer | Benzhydrocodone is a prodrug of hydrocodone, which crosses the placenta. Acetaminophen also crosses the placenta. Degree of transfer is similar to other opioids and acetaminophen; hydrocodone has been detected in cord blood at maternal serum levels. |
| Breastfeeding | APADAZ is not recommended during breastfeeding due to potential for infant sedation and respiratory depression from the opioid component. Acetaminophen is excreted in low amounts and generally considered compatible, but benzhydrocodone's active metabolite (hydrocodone) may accumulate in breastfeeding infants, particularly with maternal doses exceeding 30 mg/day. Use only if clearly needed and monitor infant for drowsiness and feeding difficulties. |
| Lactation Rating | L4 (Possibly Hazardous) - Opioid component may cause infant sedation or respiratory depression; avoid if possible. |
| Teratogenic Risk | 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. |
| Fetal Monitoring | Maternal: monitor for respiratory depression, sedation, constipation, and signs of opioid misuse or withdrawal. Fetal/neonatal: monitor for neonatal opioid withdrawal syndrome (NOWs) if maternal use >1 week; assess using Finnegan or Eat, Sleep, Console tool. Growth ultrasound if chronic use (potential for intrauterine growth restriction). Nonstress test or biophysical profile if third-trimester chronic use. Acetaminophen: monitor liver function tests if high doses or overdose suspected. |
| Fertility Effects | Opioid use may suppress gonadotropin-releasing hormone (GnRH) leading to hypothalamic hypogonadism, causing oligomenorrhea, amenorrhea, and reduced fertility. Acetaminophen: limited evidence suggests potential reduction in ovulation with chronic use, but data inconclusive. Return to normal fertility upon discontinuation is possible. Use during pregnancy does not impact subsequent fertility. |
■ FDA Black Box Warning
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).
| Serious Effects |
Hypersensitivity to benzhydrocodone, hydrocodone, acetaminophen, or any componentSignificant respiratory depressionAcute or severe bronchial asthma in an unmonitored setting or without resuscitation equipmentKnown or suspected gastrointestinal obstruction (e.g., paralytic ileus)Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of such therapy
| Precautions | 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 |
| Food/Dietary | 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. |
| Clinical Pearls | 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. |
| Patient Advice | 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. |
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