HYDROCODONE BITARTRATE AND ACETAMINOPHEN
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur.
Hydrocodone is a mu-opioid receptor agonist that inhibits ascending pain pathways and alters pain perception. Acetaminophen inhibits cyclooxygenase (COX) enzymes, primarily in the CNS, reducing prostaglandin synthesis and providing analgesic and antipyretic effects.
| Metabolism | Hydrocodone: primarily CYP3A4 and CYP2D6 to hydromorphone (active). Acetaminophen: primarily glucuronidation (UGT1A1, UGT1A6, UGT1A9) and sulfation (SULT1A1, SULT1A3), with minor CYP2E1 oxidation to NAPQI (toxic). |
| Excretion | Renal excretion of metabolites (hydrocodone: ~60% as conjugates, <12% unchanged; acetaminophen: ~85-90% as glucuronide and sulfate conjugates, <5% unchanged). Biliary/fecal elimination of minor metabolites. |
| Half-life | Hydrocodone: 3.8-7.4 hours (terminal), prolonged in hepatic impairment. Acetaminophen: 1.5-2.5 hours (terminal). |
| Protein binding | Hydrocodone: ~20-50% bound to albumin and other proteins. Acetaminophen: 10-25% bound to albumin. |
| Volume of Distribution | Hydrocodone: 3.3-4.7 L/kg (extensive tissue distribution). Acetaminophen: 0.75-1.0 L/kg (primarily total body water). |
| Bioavailability | Oral: Hydrocodone ~70-80% (first-pass metabolism). Acetaminophen ~60-90% (product dependent). |
| Onset of Action | Oral: 30-60 minutes for analgesic effect. |
| Duration of Action | Oral: 4-6 hours (analgesic effect). Clinical note: Duration may vary with dose and patient factors; extended-release formulations not applicable. |
| Molecular Weight | Hydrocodone bitartrate: 494.49 Da; Acetaminophen: 151.16 Da |
Oral: 1-2 tablets (5-10 mg hydrocodone/325-650 mg acetaminophen) every 4-6 hours as needed for pain; maximum daily doses: hydrocodone 40 mg, acetaminophen 3000 mg.
| Dosage form | CAPSULE |
| Renal impairment | eGFR 30-89 mL/min: No adjustment. eGFR <30 mL/min: Avoid use or reduce dose and frequency. Hemodialysis: Not recommended. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce total daily dose by 50% or extend dosing interval. Child-Pugh C: Avoid use. |
| Pediatric use | Not recommended for children <18 years due to safety concerns. For postoperative tonsillectomy/adenoidectomy: contraindicated. |
| Geriatric use | Initiate at lowest effective dose (e.g., 2.5 mg hydrocodone/325 mg acetaminophen) and titrate slowly; monitor for CNS depression and constipation. Avoid in renal impairment. |
| 1st trimester | Hydrocodone/acetaminophen is not recommended in the first trimester due to risk of congenital malformations associated with opioid use, particularly neural tube defects and cardiac malformations. Acetaminophen is generally considered low risk at therapeutic doses, but data are limited for combination products. |
| 2nd trimester | Use with caution; avoid prolonged use due to risk of dependence and withdrawal in the neonate. Acetaminophen component is generally safe in short-term, low-dose use. |
| 3rd trimester | Avoid; use in third trimester may cause neonatal opioid withdrawal syndrome (NOWS) and respiratory depression. Acetaminophen is safe in standard doses but chronic high-dose use may be associated with adverse effects. |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur.
| FDA category | Positive |
| Placental transfer |
■ FDA Black Box Warning
Addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; risks from concomitant use with benzodiazepines or other CNS depressants; hepatotoxicity from acetaminophen overdose.
| Common Effects | Cough |
| Serious Effects |
Hypersensitivity to hydrocodone or acetaminophenSignificant respiratory depressionAcute or severe bronchial asthma in an unmonitored setting or without resuscitative equipmentParalytic ileusSevere hepatic impairment (Child-Pugh Class C) due to acetaminophen component
| Precautions | Respiratory depression, drug dependence, abuse potential, risks with CNS depressants, elderly/debilitated patients, hepatic impairment, renal impairment, severe hypotension, head injury, seizures, use in pregnancy, use in breastfeeding, adrenal insufficiency, anaphylaxis, withdrawal, and driving impairment. |
| Food/Dietary |
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| Both hydrocodone and acetaminophen cross the placenta. Hydrocodone is classified as a category C drug in pregnancy and its transfer is well-documented, with fetal plasma levels approximately 50-100% of maternal levels. Acetaminophen crosses readily and achieves comparable fetal and maternal concentrations. |
| Breastfeeding | Hydrocodone is excreted into breast milk in low concentrations, but there is potential for infant sedation and respiratory depression, especially in mothers with CYP2D6 ultra-rapid metabolizer phenotype. Acetaminophen is considered compatible with breastfeeding at recommended doses. Use lowest effective dose for shortest duration and monitor infant for drowsiness, feeding difficulties, or breathing problems. |
| Lactation Rating | L3 (Moderately Safe, but caution advised per American Academy of Pediatrics; consider risk of infant sedation and variability in maternal metabolism) |
| Teratogenic Risk | First trimester: Limited human data; animal studies show no consistent teratogenicity. Second and third trimesters: Chronic use may cause fetal opioid dependence, neonatal withdrawal syndrome, and reduced fetal growth. Acetaminophen component: no known teratogenic risk at therapeutic doses. |
| Fetal Monitoring | Maternal: respiratory rate, oxygen saturation, sedation level, signs of abuse/dependence. Fetal: ultrasound for growth restriction in chronic use; nonstress test or biophysical profile if prolonged therapy near term. Neonatal: observe for signs of neonatal opioid withdrawal syndrome for 48-72 hours after delivery. |
| Fertility Effects | Opioids may disrupt the hypothalamic-pituitary-gonadal axis, potentially causing decreased libido, erectile dysfunction, and menstrual irregularities. Acetaminophen: no known direct effect on fertility. Reversible upon discontinuation. |
| Avoid alcohol consumption due to increased risk of hepatotoxicity and additive CNS depression. Grapefruit juice may inhibit CYP3A4 and potentially increase hydrocodone levels; consider avoiding or limiting intake. No significant food restrictions otherwise; may take with or without food. Maintain adequate hydration to prevent constipation. |
| Clinical Pearls | Hydrocodone/acetaminophen carries a boxed warning for addiction, abuse, and misuse; respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; and hepatotoxicity (acetaminophen). Avoid in patients with severe respiratory depression, acute or severe bronchial asthma, GI obstruction, or known acetaminophen hypersensitivity. Maximum acetaminophen dose from all sources should not exceed 4 g/day (3 g/day in at-risk patients). Use with caution in elderly, cachectic, or debilitated patients due to increased risk of respiratory depression. CYP3A4 inducers (e.g., rifampin) may reduce hydrocodone efficacy; CYP3A4 inhibitors (e.g., ketoconazole) may increase toxicity. Do not combine with other CNS depressants without dose adjustment. Monitor for signs of opioid-induced constipation; prescribe a bowel regimen. Prescribe immediate-release formulations only for acute pain (generally ≤3 days). Avoid combining with MAOIs or within 14 days of MAOI use. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · Do not crush, chew, or dissolve extended-release tablets; swallow whole. · Avoid alcohol and any products containing acetaminophen (e.g., Tylenol, cold medicines) to prevent liver damage. · Do not drive or operate heavy machinery until you know how this medication affects you. · Store in a secure place away from children and pets; dispose of unused medication via a drug take-back program. · Contact your doctor immediately if you experience shallow breathing, difficulty waking, confusion, or signs of allergic reaction. · Do not stop abruptly; withdrawal symptoms include anxiety, sweating, diarrhea, and muscle aches. · Inform all healthcare providers that you are taking this medication. · Use exactly as directed; misuse can lead to addiction, overdose, or death. |