COMBUNOX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for COMBUNOX (COMBUNOX).
COMBUNOX is a fixed-dose combination of oxycodone, a full mu-opioid receptor agonist, and ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX-1 and COX-2), thereby reducing prostaglandin synthesis.
| Metabolism | Oxycodone: Primarily hepatic via CYP3A4 and CYP2D6 to active and inactive metabolites. Ibuprofen: Hepatic via CYP2C9 to inactive metabolites; also undergoes glucuronidation. |
| Excretion | Oxycodone is primarily metabolized in the liver; metabolites are excreted mainly in urine. Approximately 87% of an oral dose is eliminated within 24 hours: 60-70% as oxycodone metabolites (mostly noroxycodone and oxymorphone conjugates) and 10-15% as unchanged oxycodone. Ibuprofen is rapidly metabolized and excreted; about 90% of a dose is eliminated in urine as metabolites (primarily hydroxylated and carboxylated forms) and <1% as unchanged drug. Biliary/fecal elimination accounts for <10% of each component. |
| Half-life | Oxycodone terminal half-life is 3.5-5.5 hours (mean ~3.8 hours) in immediate-release form; controlled-release formulations have a prolonged absorption phase with an effective half-life of 4.5-8 hours. Ibuprofen terminal half-life is 1.8-2.5 hours (mean ~2 hours). Clinical context: Oxycodone's half-life supports dosing every 4-6 hours (IR) or 12 hours (CR); ibuprofen's short half-life requires frequent dosing for sustained anti-inflammatory effect. In elderly or hepatic impairment, oxycodone half-life may increase to 6-8 hours; ibuprofen half-life may be slightly prolonged. |
| Protein binding | Oxycodone: ~45% bound primarily to albumin. Ibuprofen: >99% bound to albumin. No displacement interactions likely at therapeutic concentrations. |
| Volume of Distribution | Oxycodone: Vd of 2.0-3.0 L/kg (mean ~2.6 L/kg), indicating extensive tissue distribution. Ibuprofen: Vd of 0.1-0.2 L/kg (mean ~0.15 L/kg), confined to plasma and extracellular fluid. Combined formulation Vd not significantly altered. |
| Bioavailability | Oral bioavailability of oxycodone: 60-87% (mean ~75%) with first-pass metabolism accounting for ~25% loss. Ibuprofen: >80% (mean ~95%) with minimal first-pass effect. Food reduces rate but not extent of absorption; taking with food may delay peak concentrations by 1-2 hours. |
| Onset of Action | Oral: Oxycodone onset is 15-30 minutes; ibuprofen onset is 30-60 minutes. Peak analgesic effect occurs at 1-2 hours (oxycodone) and 2-4 hours (ibuprofen). There is no parenteral or rectal formulation of Combunox (combination tablet). |
| Duration of Action | Oxycodone analgesic duration is 4-6 hours (IR). Ibuprofen analgesic and anti-inflammatory duration is 4-6 hours. The combination provides overlapping coverage; clinical duration of analgesia from Combunox is typically 4-6 hours, with potential for longer effect due to synergy. Note: The manufacturer's recommended dosing interval is every 6 hours as needed. |
1 tablet (ibuprofen 400 mg/oxycodone HCl 10 mg) orally every 4 to 6 hours as needed for pain; maximum 4 tablets per day.
| Dosage form | TABLET |
| Renal impairment | GFR 30-89 mL/min: No adjustment needed. GFR <30 mL/min: Avoid use due to ibuprofen component. Hemodialysis: Not recommended. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce oxycodone dose by 50% (e.g., consider alternative). Child-Pugh C: Avoid use (contraindicated). |
| Pediatric use | Not approved for pediatric use; safety and efficacy not established in patients <18 years. |
| Geriatric use | Initiate at lower dose (e.g., 1 tablet of ibuprofen 200 mg/oxycodone HCl 5 mg) every 6 hours as needed; monitor for CNS depression and renal function. Maximum 4 tablets per day. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for COMBUNOX (COMBUNOX).
| Breastfeeding | Oxycodone excreted in breast milk; M/P ratio approximately 3.6:1. Ibuprofen minimal transfer (M/P ~0.01). Relative infant dose (RID) for oxycodone ~3.5% of maternal weight-adjusted dose; ibuprofen <0.1%. Potential for infant sedation, respiratory depression, and withdrawal. Use caution; avoid if mother is a CYP2D6 ultra-rapid metabolizer. American Academy of Pediatrics recommends use with monitoring. |
| Teratogenic Risk | COMBUNOX (oxycodone/ibuprofen) is pregnancy category C prior to 30 weeks and category D after 30 weeks. First trimester: limited data, potential neural tube defects with NSAIDs; second trimester: NSAID use associated with fetal renal dysfunction and oligohydramnios; third trimester: NSAIDs may cause premature closure of ductus arteriosus, pulmonary hypertension, and oligohydramnios; oxycodone may lead to neonatal opioid withdrawal syndrome (NOWS) with chronic use. |
■ 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; risk of serious cardiovascular and gastrointestinal events with NSAIDs.
| Serious Effects |
Significant respiratory depression; acute or severe bronchial asthma; paralytic ileus; known hypersensitivity to oxycodone, ibuprofen, or any component; patients with gastrointestinal bleeding or perforation; advanced renal disease; coronary artery bypass graft (CABG) surgery perioperative pain; use of MAO inhibitors within 14 days.
| Precautions | Respiratory depression; addiction potential; CNS depression; hepatotoxicity; renal toxicity; gastrointestinal bleeding; cardiovascular thrombotic events; anaphylactic reactions; drug interactions with CYP3A4 inhibitors/inducers; avoid in severe hepatic impairment. |
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| Fetal Monitoring | Monitor maternal renal function, blood pressure, and signs of bleeding (NSAID effect). Assess fetal growth and amniotic fluid volume via ultrasound. In third trimester, monitor ductus arteriosus patency and fetal pulmonary artery pressure. For prolonged oxycodone, monitor neonatal withdrawal signs (e.g., Finnegan score) after delivery. |
| Fertility Effects | NSAIDs (ibuprofen) may impair female fertility by inhibiting prostaglandin synthesis, affecting ovulation and implantation. Effect is reversible upon discontinuation. Oxycodone may disrupt hypothalamic-pituitary-gonadal axis, causing amenorrhea or oligomenorrhea. Data on male fertility limited but opiates may reduce testosterone and sperm parameters. |