ACETAMINOPHEN AND HYDROCODONE BITARTRATE
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur.
Acetaminophen: analgesic and antipyretic effects via inhibition of cyclooxygenase (COX) and activation of descending serotonergic pathways; central action. Hydrocodone: mu-opioid receptor agonist; activates G-protein coupled receptors to modulate pain perception and emotional response.
| Metabolism | Acetaminophen: primarily via glucuronidation (UGT1A1, UGT1A6, UGT1A9) and sulfation; minor CYP2E1 oxidation to NAPQI (toxic metabolite). Hydrocodone: CYP3A4 and CYP2D6; N-demethylation to norhydrocodone; O-demethylation to hydromorphone (CYP2D6). |
| Excretion | Acetaminophen: primarily renal excretion of conjugated metabolites (glucuronide and sulfate) with approximately 5% excreted unchanged. Hydrocodone: renal excretion as unchanged drug and metabolites (O-demethylated and N-demethylated); total renal excretion accounts for about 60-70% of dose (parent and metabolites). Biliary/fecal elimination is minimal. |
| Half-life | Acetaminophen: 2-3 hours in adults; prolonged in hepatic impairment (up to 5 hours). Hydrocodone: 3.8-4.5 hours (range 3-5 hours) in healthy adults; prolonged in elderly or hepatic/renal impairment. Clinical context: repeated dosing may require extended intervals in renal impairment. |
| Protein binding | Acetaminophen: 10-25% bound, nonspecific binding to albumin. Hydrocodone: 25-50% bound, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Acetaminophen: 0.8-1.0 L/kg, indicating distribution into total body water; clinically relevant for loading dose calculations. Hydrocodone: 3.0-4.0 L/kg, suggesting extensive tissue distribution; higher Vd may require higher loading doses but has no clinical target. |
| Bioavailability | Acetaminophen: oral bioavailability 85-95% (first-pass metabolism minimal). Hydrocodone: oral bioavailability about 25-45% due to first-pass hepatic metabolism; significant interindividual variability. |
| Onset of Action | Oral: 10-30 minutes for analgesic effect; peak effect at 30-60 minutes. |
| Duration of Action | Oral: 4-6 hours for analgesia. Clinical notes: duration may be shorter with repeated use due to tolerance; extended-release formulations available but immediate-release product typically lasts 4-6 hours. |
1-2 tablets (containing 5-10 mg hydrocodone and 300-325 mg acetaminophen) orally every 4-6 hours as needed for pain; maximum 8 tablets per day.
| Dosage form | CAPSULE |
| Renal impairment | GFR 10-50 mL/min: administer every 6 hours; GFR <10 mL/min: administer every 8 hours; avoid in severe impairment due to acetaminophen metabolite accumulation. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50% or extend interval; Child-Pugh C: use with caution, avoid if possible, consider alternative therapy. |
| Pediatric use | Dosing based on hydrocodone component: 0.1-0.2 mg/kg/dose every 4-6 hours; maximum daily acetaminophen limit: 75 mg/kg/day; not recommended for children <2 years. |
| Geriatric use | Initiate at lowest effective dose, typically 1 tablet (2.5-5 mg hydrocodone) every 6 hours; monitor for respiratory depression and acetaminophen toxicity; avoid in frail elderly with hepatic impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur.
| FDA category | Positive |
| Breastfeeding | Acetaminophen excretion in breast milk is low (M/P ratio ~0.9). Hydrocodone is excreted in small amounts (M/P ratio ~2.1). The relative infant dose is estimated to be 2.5-3.5% of maternal weight-adjusted dose for hydrocodone. Monitor infant for sedation and respiratory depression. Consider benefit to mother and potential neonatal opioid withdrawal if used chronically. |
| Teratogenic Risk |
■ FDA Black Box Warning
Addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion of acetaminophen; neonatal opioid withdrawal syndrome; interaction with alcohol; risk of medication errors.
| Common Effects | Cough |
| Serious Effects |
Hypersensitivity to acetaminophen or hydrocodone; significant respiratory depression; acute or severe bronchial asthma; upper airway obstruction; known or suspected gastrointestinal obstruction; paralytic ileus; concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days; severe hepatic impairment (acetaminophen toxicity risk); acute alcoholism.
| Precautions | Hepatotoxicity from acetaminophen overdose; respiratory depression; increased intracranial pressure; CNS depression; elderly/debilitated patients; renal impairment; opioid-induced hyperalgesia; serotonin syndrome; interaction with CNS depressants; risk of adrenal insufficiency; severe hypotension; use in patients with gastrointestinal obstruction; convulsion risk; severe hepatic impairment; urinary retention; acute abdominal conditions; hypothyroidism; prostatic hypertrophy; adrenocortical insufficiency; pregnancy/lactation; pediatric use; geriatric use; renal impairment; hepatic impairment. |
Loading safety data…
| First trimester: Acetaminophen considered low risk; hydrocodone is a pregnancy category C drug. Data from retrospective studies suggest a small increased risk of certain congenital malformations (e.g., neural tube defects, cleft palate) with first trimester opioid use, but absolute risk is low. Second trimester: Low risk as above. Third trimester: Prolonged use of hydrocodone can cause neonatal opioid withdrawal syndrome (NOWS); acetaminophen is safe. Use only if benefit outweighs risk. |
| Fetal Monitoring | Monitor maternal vital signs, respiratory rate, pain control, and signs of opioid misuse. Fetal monitoring: In third trimester, assess fetal movement and consider nonstress test or biophysical profile if prolonged opioid exposure. Neonatal monitoring: Observe for signs of NOWS (irritability, poor feeding, respiratory distress) for at least 48 hours after birth if maternal use near term. |
| Fertility Effects | Acetaminophen: No known significant effect on fertility. Hydrocodone: Chronic opioid use can cause hypothalamic-pituitary-gonadal axis suppression, leading to menstrual cycle irregularities, anovulation, and reduced fertility. Effects are reversible after discontinuation. |
| Food/Dietary | Avoid alcohol consumption during therapy; ethanol increases acetaminophen hepatotoxicity risk and enhances CNS depression. Grapefruit juice may inhibit CYP2D6 (minor effect) but no significant clinical interaction. No other specific food restrictions. |
| Clinical Pearls | Acetaminophen-hydrocodone is contraindicated in severe respiratory depression, acute or severe bronchial asthma, and known hypersensitivity. Monitor for respiratory depression, especially in elderly or debilitated patients. Avoid use with other acetaminophen-containing products to prevent hepatotoxicity. Hydrocodone is a prodrug metabolized by CYP2D6 to hydromorphone; CYP2D6 ultrarapid metabolizers may experience toxicity. Use with caution in patients with head injury, increased intracranial pressure, or severe hepatic impairment. Naloxone is the reversal agent for opioid effects; acetylcysteine for acetaminophen overdose. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · Avoid alcohol and other CNS depressants (e.g., benzodiazepines, sedatives) as they increase risk of severe drowsiness and respiratory depression. · Do not exceed 4000 mg of acetaminophen per day from all sources; check labels of other medications. · This medication may cause dizziness or drowsiness; avoid driving or operating heavy machinery until you know how it affects you. · Store securely out of reach of others, especially children, as misuse can cause overdose and death. · Do not stop abruptly; withdrawal may occur. Taper under medical supervision. · Contact emergency if you experience trouble breathing, extreme drowsiness, or signs of allergic reaction. · Report any history of substance abuse, as this medication has abuse potential. |