ULTRACET
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ULTRACET (ULTRACET).
ULTRACET is a combination of tramadol (a centrally acting opioid agonist) and acetaminophen (a centrally acting analgesic with antipyretic effects). Tramadol binds to mu-opioid receptors and inhibits norepinephrine and serotonin reuptake. Acetaminophen's mechanism is not fully understood but involves inhibition of cyclooxygenase (COX) enzymes in the central nervous system.
| Metabolism | Tramadol is metabolized via CYP2D6 and CYP3A4 to active O-desmethyltramadol (M1) and inactive metabolites. Acetaminophen is metabolized primarily via glucuronidation and sulfation, with minor CYP-mediated (CYP2E1, CYP1A2, CYP3A4) oxidation to toxic N-acetyl-p-benzoquinone imine (NAPQI). |
| Excretion | Tramadol and its metabolites are primarily excreted via the kidneys (approximately 90% of the dose), with about 30% excreted as unchanged drug and 60% as metabolites. Approximately 10% is excreted in feces. Acetaminophen is primarily conjugated in the liver and excreted renally as glucuronide (60-80%) and sulfate (20-30%) conjugates, with about 5% excreted unchanged. |
| Half-life | Tramadol: 5.1 ± 0.9 hours (range 4-6 hours) for the parent drug; the active M1 metabolite has a half-life of 6.7 ± 1.7 hours. In hepatic impairment, tramadol half-life increases ~2-3 fold. Acetaminophen: 2-3 hours (range 1.25-3 hours); prolonged in overdose. |
| Protein binding | Tramadol: ~20% bound to plasma proteins. Acetaminophen: 10-25% bound (minimal). No significant displacement interactions. |
| Volume of Distribution | Tramadol: Vd approximately 2.6-3.0 L/kg, indicating extensive tissue distribution. Acetaminophen: Vd approximately 0.9-1.0 L/kg, distributed relatively evenly throughout body water. |
| Bioavailability | Tramadol: Oral bioavailability ~75% (first-pass metabolism yields a higher ratio to M1). Acetaminophen: Oral bioavailability ~60-90% (first-pass metabolism reduces bioavailability slightly). Commercially, ULTRACET tablets have similar bioavailability to reference formulations. |
| Onset of Action | Oral: Tramadol onset within 1 hour, peak analgesic effect at 2-3 hours. Acetaminophen onset within 30 minutes, peak at 1 hour. Combined product onset approximately 30-60 minutes. |
| Duration of Action | Analgesic effects last 4-6 hours for tramadol (extended-release forms provide up to 12 hours) and 4-6 hours for acetaminophen. Immediate-release ULTRACET is dosed every 4-6 hours. Duration may be prolonged in elderly or hepatically impaired. |
| Molecular Weight | 263.4 |
| Brand Substitutes | Tolydol Tablet, PT 325mg/37.5mg Tablet, Calpol T Tablet, Dolonat Tablet, Ultramol 325 mg/37.5 mg Tablet, Tranzat Plus 500 mg/50 mg Tablet, Tramacad Plus 500 mg/50 mg Tablet, Mortadol 500 mg/50 mg Tablet, Tromanil Extra 500 mg/50 mg Tablet, Troma P 500 mg/50 mg Tablet |
1-2 tablets (37.5 mg tramadol/325 mg acetaminophen per tablet) orally every 4-6 hours as needed for pain, not to exceed 8 tablets per day.
| Dosage form | TABLET |
| Renal impairment | For CrCl 30-60 mL/min: increase dosing interval to every 12 hours, maximum 4 tablets per day. For CrCl <30 mL/min: not recommended. |
| Liver impairment | For Child-Pugh Class A: no adjustment needed. For Child-Pugh Class B: reduce dose by 50% or extend interval to every 12 hours, maximum 4 tablets per day. For Child-Pugh Class C: contraindicated. |
| Pediatric use | Not recommended for pediatric use due to tramadol risk of respiratory depression in children <12 years, and contraindicated in children <12 years for postoperative tonsillectomy/adenoidectomy. For adolescents ≥12 years: same as adult, but limited data; use lowest effective dose. |
| Geriatric use | For patients >65 years: consider reduced dose (e.g., 1 tablet) due to increased sensitivity; maximum 4 tablets per day. For patients >75 years: increase dosing interval to every 6 hours as needed; avoid use if possible. |
| 1st trimester | Avoid due to risk of neural tube defects from valproate component. Use only if benefits outweigh risks. |
| 2nd trimester | Avoid; valproate associated with decreased IQ and neurodevelopmental disorders. |
| 3rd trimester | Avoid; risk of neonatal hemorrhage and withdrawal symptoms from tramadol; valproate can cause hepatic toxicity. |
Clinical note
Comprehensive clinical and safety monograph for ULTRACET (ULTRACET).
| Placental transfer | Both components cross placenta: tramadol (passive diffusion) and valproate (active transport). |
| Breastfeeding | Tramadol and its active metabolite M1 are excreted into breast milk; may cause neonatal respiratory depression. Valproate is excreted, risk of hepatotoxicity. Not recommended. |
| Lactation Rating |
■ FDA Black Box Warning
Risk of medication errors: confusion between immediate-release and extended-release formulations; Addiction, abuse, and misuse; Life-threatening respiratory depression; Accidental ingestion; Neonatal opioid withdrawal syndrome; Cytochrome P450 2D6 genetic variability; Concomitant use with benzodiazepines or CNS depressants; Hepatotoxicity with acetaminophen overdose.
| Serious Effects |
Hypersensitivity to tramadol or valproateAcute asthma or respiratory depressionMAOI use within 14 daysSevere hepatic impairment (Child-Pugh C)Urea cycle disordersKnown pregnancy (especially 3rd trimester) unless absolutely necessary
| Precautions | Respiratory depression; serotonin syndrome; seizure risk; anaphylactoid reactions; hepatotoxicity (acetaminophen overdose); renal impairment; adrenal insufficiency; hypotension; severe hypotension in hypovolemic patients; use in patients with head injury or increased intracranial pressure; gastrointestinal effects; severe skin reactions; accidental ingestion and overdose; interaction with CNS depressants; CYP2D6 poor metabolizers; pregnancy and breastfeeding; elderly and debilitated patients; withdrawal syndrome. |
| Food/Dietary |
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| Avoid |
| Teratogenic Risk | ULTRACET contains tramadol and acetaminophen. Tramadol: Avoid in first trimester due to possible neural tube defects; third trimester use may cause neonatal respiratory depression and withdrawal. Acetaminophen: Generally considered low risk at therapeutic doses; prolonged high doses may increase risk of fetal hepatotoxicity. |
| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, and pain control. Fetal: ultrasound for growth and anatomy if first trimester exposure; neonatal monitoring for respiratory depression and withdrawal if used near delivery. |
| Fertility Effects | Tramadol may impair male and female fertility by affecting hormonal regulation and sperm parameters; acetaminophen has been associated with reduced fertility in some studies. Effects are generally reversible upon discontinuation. |
| Avoid alcohol consumption due to increased hepatotoxicity risk from acetaminophen. No significant food interactions with tramadol; however, high-fat meals may delay tramadol absorption but do not affect overall exposure. Grapefruit juice does not interact significantly. |
| Clinical Pearls | ULTRACET (tramadol/acetaminophen) combines a weak opioid agonist with SNRI properties and a non-opioid analgesic. Avoid in patients with MAOI use within 14 days, severe asthma, or opioid dependence. Seizure risk increased with tramadol, especially in epilepsy, head injury, or concomitant serotonergic drugs. Monitor for serotonin syndrome (agitation, hyperthermia, clonus). Max acetaminophen dose ≤3 g/day from all sources to prevent hepatotoxicity. Do not exceed 8 tablets/day (37.5 mg tramadol/325 mg acetaminophen per tablet). Use lowest effective dose for shortest duration. |
| Patient Advice | Take exactly as prescribed; do not exceed 8 tablets per day due to seizure and liver risks. · Do not drink alcohol while taking this medication; may cause severe liver damage. · Avoid driving or operating heavy machinery until you know how ULTRACET affects you; may cause drowsiness or dizziness. · Report symptoms of serotonin syndrome (confusion, fast heart rate, fever, muscle stiffness) or seizures immediately. · Do not use with other acetaminophen-containing products (e.g., Tylenol, cold medicines) without doctor approval. · Discontinue slowly under medical guidance to prevent withdrawal symptoms (anxiety, sweating, nausea). · Keep out of reach of children; accidental overdose of acetaminophen can be fatal. |