LIBRIUM
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LIBRIUM (LIBRIUM).
Binds to benzodiazepine site on GABA-A receptor, potentiating GABAergic inhibition and increasing chloride ion conductance.
| Metabolism | Hepatic via oxidative N-dealkylation (CYP3A4) to active metabolite (desmethyldiazepam) and subsequent hydroxylation. |
| Excretion | Renal excretion of unchanged drug and metabolites (primarily glucuronide conjugates of chlordiazepoxide and demoxepam, <2% unchanged); approximately 60-70% of a dose appears in urine as metabolites, with 4-9% in feces via biliary elimination. |
| Half-life | Terminal elimination half-life of chlordiazepoxide is 24-48 hours; active metabolite desmethyldiazepam has half-life of 36-200 hours; with repeated dosing, effective half-life extends due to accumulation of active metabolites. |
| Protein binding | 96-98% bound, primarily to albumin. |
| Volume of Distribution | 0.3-0.5 L/kg; distributes widely into tissues; crosses blood-brain barrier and placenta. |
| Bioavailability | Oral: 90-100% (well absorbed); IM: 80-100% but absorption slow and erratic; IV: 100%. |
| Onset of Action | Oral: 30-60 minutes (anxiolytic); IM: 15-30 minutes (peak plasma levels at 30-60 min); IV: 1-5 minutes (sedation); delayed onset in IM due to erratic absorption. |
| Duration of Action | Oral: 6-8 hours for single dose, but prolonged with repeated dosing due to long-acting metabolites; IV: 15-30 minutes for acute effects; clinical duration extends to 24-48 hours for anxiolytic/sedative effects. |
| Molecular Weight | 299.75 |
5-25 mg orally 3-4 times daily; or 50-100 mg intramuscularly or intravenously initially, then 25-50 mg 3-4 times daily as needed.
| Dosage form | CAPSULE |
| Renal impairment | CrCl <10 mL/min: administer at 50% of normal dose; CrCl ≥10 mL/min: no adjustment required. |
| Liver impairment | Child-Pugh Class A: no adjustment; Child-Pugh Class B: reduce dose by 50%; Child-Pugh Class C: not recommended. |
| Pediatric use | Children 6-12 years: 5 mg orally 2-4 times daily; 5-10 mg intramuscularly or intravenously every 6-8 hours. Children >12 years: adult dosing. |
| Geriatric use | Initiate at 5 mg orally once or twice daily; avoid doses >10 mg/day; reduce parenteral dose by 50%. |
| 1st trimester | Associated with increased risk of congenital malformations, particularly cleft lip and palate, when used during first trimester. Avoid use if possible. |
| 2nd trimester | May cause fetal CNS depression, hypotonia, and respiratory difficulties if used near term. Use only if clearly needed. |
| 3rd trimester | Chronic use during third trimester can lead to neonatal withdrawal and floppy infant syndrome. Avoid use, especially near delivery. |
Clinical note
Comprehensive clinical and safety monograph for LIBRIUM (LIBRIUM).
| Placental transfer | Chlordiazepoxide and its active metabolite (nordiazepam) cross the placenta; both are detected in fetal tissues and cord blood. Accumulation in fetus may occur due to slower elimination. |
| Breastfeeding | Chlordiazepoxide and its active metabolite are excreted into breast milk in low concentrations. However, reported effects include sedation, poor feeding, and weight loss in infants. Use caution and monitor infant for drowsiness. |
■ FDA Black Box Warning
Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for patients for whom alternative treatment options are inadequate.
| Serious Effects |
Hypersensitivity to chlordiazepoxide or any benzodiazepineSevere hepatic impairmentNarrow-angle glaucomaMyasthenia gravisAcute intoxication with alcohol, opioids, or other CNS depressants
| Precautions | Risk of respiratory depression, Dependence and withdrawal reactions, Abuse potential, CNS depressant effects (impaired cognition/motor function), Elderly/debilitated patients at increased risk of toxicity, Neonatal withdrawal syndrome during pregnancy |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may increase chlordiazepoxide levels. Take with food if GI upset occurs. Avoid excessive caffeine as it may reduce sedative effects. |
Loading safety data…
| Lactation Rating | L3 - Moderately safe. Use with caution. |
| Teratogenic Risk | First trimester: Increased risk of oral clefts (odds ratio ~2.0). Late third trimester or labor: Risk of neonatal withdrawal syndrome (irritability, hypertonia, feeding difficulties) and floppy infant syndrome (hypotonia, lethargy, respiratory depression). |
| Fetal Monitoring | Monitor maternal blood pressure, respiratory rate, and sedation level. In late pregnancy, assess fetal heart rate and consider ultrasound for growth if chronic use. For neonates, monitor for signs of withdrawal (e.g., poor feeding, irritability) and respiratory depression. |
| Fertility Effects | No well-documented adverse effects on fertility in humans. Animal studies high doses may affect reproductive organs, but clinical relevance unknown. |
| Clinical Pearls | Librium (chlordiazepoxide) is a long-acting benzodiazepine with active metabolites (desmethyldiazepam, oxazepam). Onset of action is slow (30-60 min) with peak effect at 2-4 hours. Useful for alcohol withdrawal due to long half-life and low abuse potential. Caution in elderly: lower doses recommended (5 mg BID) due to increased sensitivity and risk of falls. Hepatic impairment prolongs half-life; avoid in severe liver disease. |
| Patient Advice | Avoid alcohol consumption while taking Librium. · Do not drive or operate heavy machinery until you know how this drug affects you. · Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · Do not stop abruptly; withdrawal seizures may occur. Taper under medical supervision. · Inform your doctor if you are pregnant, planning to become pregnant, or breastfeeding. · Report any unusual changes in mood or behavior, especially suicidal thoughts. · Store at room temperature away from moisture and heat. |