TRANXENE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRANXENE (TRANXENE).
Benzodiazepine; enhances GABA-A receptor activity by binding to benzodiazepine site, increasing chloride ion influx and neuronal hyperpolarization.
| Metabolism | Hepatic via oxidative metabolism; primarily by CYP3A4 and CYP2C19 to active metabolite nordazepam, then to oxazepam and others. Also undergoes glucuronidation. |
| Excretion | Primarily renal (80-90% as conjugated metabolites, including oxazepam and desmethyldiazepam); biliary/fecal excretion accounts for <10%. |
| Half-life | Terminal elimination half-life of the active metabolite desmethyldiazepam is 30-200 hours (mean ~100 hours); parent drug clorazepate is rapidly hydrolyzed and has negligible half-life. Accumulation occurs with repeated dosing, leading to delayed peak effects and prolonged sedation. |
| Protein binding | Clorazepate and desmethyldiazepam: 95-98% bound to albumin. |
| Volume of Distribution | Clorazepate: 0.2-0.3 L/kg. Desmethyldiazepam: 0.5-1.5 L/kg (large Vd indicates extensive tissue distribution). |
| Bioavailability | Oral: nearly 100% (prodrug completely hydrolyzed in gastric acid to desmethyldiazepam). Intramuscular: erratic and incomplete (approximately 50-70% bioavailability due to variable absorption). |
| Onset of Action | Oral: 1-2 hours for anxiolytic effect (due to conversion to desmethyldiazepam). Peak plasma concentrations of desmethyldiazepam occur at 2-4 hours. Intramuscular: slower, with onset in 2-4 hours due to erratic absorption. |
| Duration of Action | Long duration (24-48 hours) for anxiolytic effect due to long half-life of desmethyldiazepam. Single dose effects may persist for several days. Accumulation with chronic use can lead to prolonged sedation. |
7.5 mg to 15 mg orally 2 to 4 times daily; maximum dose 90 mg/day.
| Dosage form | TABLET |
| Renal impairment | GFR 10-50 mL/min: reduce dose by 25%; GFR <10 mL/min: reduce dose by 50% and use with caution. |
| Liver impairment | Child-Pugh Class A: no adjustment; Child-Pugh Class B: reduce dose by 50%; Child-Pugh Class C: contraindicated. |
| Pediatric use | Children 9-12 years: 7.5 mg orally twice daily; increase to 7.5 mg three times daily if needed. Not recommended under 9 years. |
| Geriatric use | Initiate at 3.75 mg orally 1 to 2 times daily; titrate slowly to avoid sedation and falls. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TRANXENE (TRANXENE).
| Breastfeeding | Excreted in human milk. M/P ratio not established. Case reports indicate low milk levels (approx 4-10% of maternal weight-adjusted dose) but infant accumulation possible due to long half-life. Benefits of breastfeeding should be weighed against potential risks of sedation and poor feeding in the infant. Monitor infant for drowsiness, poor suckling, and weight loss. |
| Teratogenic Risk | FDA Pregnancy Category D. First trimester: Increased risk of congenital malformations, particularly cleft lip/palate, when used during the first trimester. Second and third trimesters: Chronic use may lead to physical dependence and withdrawal symptoms in the neonate, including floppy infant syndrome, respiratory depression, and feeding difficulties. Late pregnancy or near delivery: Risk of neonatal sedation, hypotonia, and withdrawal. |
■ FDA Black Box Warning
Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death. Reserve for patients with inadequate alternative treatment options.
| Serious Effects |
["Hypersensitivity to clorazepate or other benzodiazepines","Acute narrow-angle glaucoma","Severe hepatic impairment","Pregnancy (especially first trimester)","Breastfeeding","Concomitant use with opioids unless alternative treatments are inadequate"]
| Precautions | ["Risk of dependence and withdrawal seizures with abrupt discontinuation","CNS depressant effects may impair driving or operating machinery","Use caution in hepatic impairment","Avoid in pregnancy (risk of neonatal withdrawal and floppy infant syndrome)","Potential for anterograde amnesia","Elderly patients at increased risk for adverse effects"] |
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| Fetal Monitoring | Monitor maternal sedation, respiratory rate, and blood pressure. For fetus: assess fetal movements and consider nonstress test and biophysical profile if chronic use. Neonatal monitoring for withdrawal syndrome (e.g., hypertonia, hyperreflexia, irritability, feeding problems) for at least 48 hours post-delivery. Also monitor for respiratory depression in neonate. |
| Fertility Effects | No established adverse effects on human fertility. In animal studies, no significant reproductive impairment at therapeutic doses. However, high doses may cause menstrual irregularities and anovulation in some women. Effects on male fertility not reported. |