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. |
| 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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ULTRACET (ULTRACET).
| Breastfeeding | Tramadol: Present in breast milk; M/P ratio not established; monitor infant for sedation and respiratory depression. Acetaminophen: Excreted in low amounts; M/P ratio ~1.0; considered compatible at therapeutic doses. |
| 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. |
■ 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, acetaminophen, or any component; significant respiratory depression; acute or severe bronchial asthma; gastrointestinal obstruction; suspected surgical abdomen; monoamine oxidase inhibitor (MAOI) use within 14 days; acute alcoholism; severe hepatic impairment; concurrent use of alcohol or other CNS depressants; children under 12 years of age; children under 18 years after tonsillectomy/adenoidectomy; women who are breastfeeding; patients receiving or recently used MAOIs.
| 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. |
Loading safety data…
| 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. |