HYDROCODONE BITARTRATE AND IBUPROFEN
Clinical safety rating: avoid
ACE inhibitors and ARBs may have diminished antihypertensive effect Increases risk of serious cardiovascular thrombotic events and GI bleeding.
Hydrocodone is a semisynthetic opioid agonist with selectivity for mu-opioid receptors, producing analgesia and sedation. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX-1 and COX-2), reducing prostaglandin synthesis, thereby providing anti-inflammatory, analgesic, and antipyretic effects.
| Metabolism | Hydrocodone is primarily metabolized by CYP3A4 and CYP2D6 enzymes to hydromorphone (active) and norhydrocodone (inactive). Ibuprofen is metabolized by CYP2C9 to inactive metabolites (hydroxyibuprofen and carboxyibuprofen). |
| Excretion | Hydrocodone: primarily renal (60-70% as metabolites, <12% unchanged); Ibuprofen: primarily renal (90% as metabolites and conjugates, <1% unchanged), minor biliary/fecal. |
| Half-life | Hydrocodone: 3.8-4.5 hours (immediate release); Ibuprofen: 1.8-2.5 hours (racemic, S-enantiomer slightly shorter). Clinical context: dosing every 4-6 hours due to hydrocodone half-life. |
| Protein binding | Hydrocodone: ~19% bound to plasma proteins; Ibuprofen: >99% bound to albumin. |
| Volume of Distribution | Hydrocodone: 3.3-4.7 L/kg; Ibuprofen: 0.1-0.2 L/kg. High Vd for hydrocodone indicates extensive tissue distribution; low Vd for ibuprofen indicates plasma and interstitial fluid confinement. |
| Bioavailability | Hydrocodone: mean absolute bioavailability ~70-80% (oral); Ibuprofen: ~80-100% (oral, rapid absorption). |
| Onset of Action | Oral: 20-30 minutes (analgesic effect). |
| Duration of Action | 4-6 hours (analgesic); for pain relief, 4-6 hours following oral administration. |
| Molecular Weight | Hydrocodone bitartrate: 494.5 Da; Ibuprofen: 206.28 Da. Combination product: not applicable as a single entity. |
One tablet (hydrocodone bitartrate 5 mg/ibuprofen 200 mg) orally every 4 to 6 hours as needed for pain; maximum 5 tablets per day.
| Dosage form | TABLET |
| Renal impairment | GFR 30-60 mL/min: Use with caution, consider reducing dose or increasing interval. GFR <30 mL/min: Not recommended due to accumulation of ibuprofen and hydrocodone metabolites. |
| Liver impairment | Child-Pugh Class B: Start with lowest possible dose, monitor closely. Child-Pugh Class C: Contraindicated due to risk of toxicity. |
| Pediatric use | Not recommended for use in pediatric patients; safety and efficacy not established. |
| Geriatric use | Initiate with lowest effective dose (e.g., half tablet) and monitor for CNS and respiratory depression; reduce maximum daily dose to 4 tablets due to increased sensitivity and renal impairment. |
| 1st trimester | Avoid; associated with increased risk of congenital malformations (cardiac, gastroschisis) with NSAIDs; risk of opioid withdrawal in neonate if prolonged use. |
| 2nd trimester | Avoid; NSAIDs risk premature closure of ductus arteriosus after 20 weeks and oligohydramnios; maternal and fetal opioid dependence. |
| 3rd trimester | Avoid; NSAIDs increase risk of premature closure of ductus arteriosus, oligohydramnios, necrotizing enterocolitis; opioids cause neonatal withdrawal syndrome. |
Clinical note
ACE inhibitors and ARBs may have diminished antihypertensive effect Increases risk of serious cardiovascular thrombotic events and GI bleeding.
| FDA category | Positive |
| Placental transfer | Both components cross the placenta; hydrocodone is metabolized to hydromorphone and morphine, which readily cross; ibuprofen crosses but in limited amounts. |
■ FDA Black Box Warning
Risk of addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion (especially in children) can be fatal; neonatal opioid withdrawal syndrome with prolonged use during pregnancy; risks from concomitant use with benzodiazepines or other CNS depressants; hepatotoxicity from ibuprofen (NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation, which can be fatal).
| Common Effects | fever |
| Serious Effects |
Hypersensitivity to hydrocodone, ibuprofen, or any componentHistory of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDsUse during perioperative pain in setting of coronary artery bypass graft (CABG) surgerySignificant respiratory depressionAcute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipmentParalytic ileusGastrointestinal bleeding or perforationAdvanced renal diseaseSevere hepatic impairment
| Precautions | Addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; risks from concomitant use with CNS depressants; severe hypotension; adrenal insufficiency; hepatotoxicity; gastrointestinal bleeding, ulceration, and perforation; cardiovascular thrombotic events; hypertension; renal toxicity; anaphylactoid reactions; serious skin reactions; use in pregnancy; use in breastfeeding; use in hepatic impairment; use in renal impairment; use in elderly; use in patients with bleeding disorders. |
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| Breastfeeding | Hydrocodone is excreted into breast milk in low levels; ibuprofen is minimal. However, monitor infant for sedation, respiratory depression, and poor feeding. Avoid in breastfeeding mothers with poor metabolizer CYP2D6 phenotype due to increased morphine levels. Short-term use with caution. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Pregnancy Category C: No adequate studies in pregnant women. Ibuprofen (NSAID) is associated with increased risk of premature closure of ductus arteriosus and oligohydramnios in third trimester; avoid after 30 weeks gestation. Hydrocodone may cause respiratory depression in neonate if used near term; chronic use may lead to neonatal opioid withdrawal syndrome. First trimester: limited data, but NSAIDs may increase risk of miscarriage; hydrocodone not associated with major malformations. Second trimester: generally considered safer, but risks remain. Third trimester: avoid NSAIDs; hydrocodone use only if benefit outweighs risk. |
| Fetal Monitoring | Monitor for signs of maternal sedation, respiratory depression, constipation. Ibuprofen: monitor renal function, gastrointestinal bleeding, blood pressure. Fetal: ultrasound for oligohydramnios if NSAID used >48 hours after 20 weeks; Doppler assessment of ductus arteriosus after 30 weeks. Neonatal: observe for opioid withdrawal (irritability, high-pitched cry, poor feeding) and respiratory depression. |
| Fertility Effects | Ibuprofen may impair female fertility by inhibiting prostaglandin synthesis, leading to reversible luteinized unruptured follicle syndrome. Hydrocodone may increase prolactin levels, potentially causing menstrual irregularities and anovulation. Both drugs may reduce sperm motility and viability in males, but effects are reversible upon discontinuation. |
| Food/Dietary | Grapefruit and grapefruit juice may increase hydrocodone levels and risk of adverse effects; avoid concurrent use. Alcohol potentiates CNS depression and increases GI bleeding risk; avoid altogether. High-fat meals may delay absorption of hydrocodone, but clinical impact is minimal; take consistently with or without food. |
| Clinical Pearls | Hydrocodone/ibuprofen combines an opioid agonist with an NSAID. Be aware of additive risks: respiratory depression, sedation, GI bleeding, renal impairment, and cardiovascular thrombotic events. Avoid in patients with severe asthma, GI obstruction, or after recent bariatric surgery. Use lowest effective dose for shortest duration. Monitor for serotonin syndrome if used with other serotonergic drugs. Abrupt discontinuation after prolonged use may cause withdrawal. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · Hydrocodone can cause drowsiness; avoid driving or operating heavy machinery until you know how it affects you. · Do not consume alcohol or other CNS depressants (e.g., benzodiazepines, other opioids) while taking this medication. · Ibuprofen may increase risk of stomach bleeding; report black/tarry stools, coffee-ground vomit, or abdominal pain. · Avoid other NSAIDs (e.g., aspirin, naproxen) or COX-2 inhibitors to prevent additive GI and renal toxicity. · Store securely away from children and others; dispose of unused medication via take-back programs. · Do not abruptly stop after long-term use; withdrawal symptoms may occur (anxiety, sweating, nausea). |