Publication Details



Chlordiazepoxide is an orally available benzodiazepine used for therapy of anxiety disorders and alcohol withdrawal syndromes. As with other benzodiazepines, chlordiazepoxide is not associated with serum aminotransferase or alkaline phosphatase elevations during therapy, and clinically apparent liver injury from chlordiazepoxide has been reported but is rare.


Chlordiazepoxide (klor" dye az" e pox' ide) is the prototype of benzodiazepines used in the therapy of anxiety and acute alcohol withdrawal. The antianxiety (anxiolytic) activity of the benzodiazepines is mediated by their ability to enhance gamma-aminobutyric acid (GABA) mediated inhibition of synaptic transmission through binding to the GABA A receptor. Chlordiazepoxide was approved in the United States in 1960 and for many years was one of the most prescribed medications. Currently, it no longer commonly used, having been replaced by benzodiazepines with more favorable pharmacokinetics, half-life and tolerance. Indications include anxiety disorders and alcohol withdrawal syndrome. Chlordiazepoxide is available in multiple generic forms and formerly under the brand name of Librium in capsules of 5, 10 and 25 mg. The recommended initial dose for adults is 5 to 10 mg three to four times per day, but higher doses are used for severe anxiety disorders. Chlordiazepoxide is also available for parenteral administration (100 mg/ampule) for use in acute anxiety, preoperative sedation and acute alcohol withdrawal syndromes. In addition, combinations of chlordiazepoxide with clidinium bromide or amitriptyline have been marketed under generic as well as brand names (Librax and Limbitrol). The most common side effects of chlordiazepoxide are dose related and include drowsiness, lethargy, ataxia, dysarthria and dizziness. Tolerance develops to these side effects, but tolerance may also develop to the anxiolytic effects. Chlordiazepoxide like all oral benzodiazepines has a boxed warning in its product label stressing (1) the risks of severe sedation and potentially fatal respiratory depression when combined with opiates, (2) with prolonged use, the risks of abuse, misuse, and addiction which can lead to overdose and death, and (3) with continued use, the risks of dependence and severe, potentially life-threatening withdrawal symptoms if discontinued suddenly. Benzodiazepines are all categorized as Schedule IV controlled substances, having potential for abuse, addiction, and dependence.


Chlordiazepoxide, as with other benzodiazepines, is rarely associated with serum ALT elevations, and clinically apparent liver injury from its use is rare. There have been at least ten case reports of acute liver injury from chlordiazepoxide, published largely before 1980. The latency to onset of acute liver injury was 1 to 4 months, and the pattern of liver enzyme elevations varied from hepatocellular to cholestatic and mixed. The injury was usually mild-to-moderate in severity and self-limited. Fever and rash were uncommon, as was autoantibody formation.

Likelihood score: C (probable rare cause of clinically apparent liver injury).

Mechanism of Injury

Chlordiazepoxide is metabolized extensively in the liver and has a prolonged half-life. The liver injury from benzodiazepines is probably due to a rarely produced metabolic intermediate metabolite.

Outcome and Management

The case reports of hepatic injury due to benzodiazepines were marked by prompt and complete recovery upon stopping the medication, without evidence of residual or chronic injury. No cases of acute liver failure or chronic liver injury due to chlordiazepoxide have been described. There is little information about cross reactivity with other benzodiazepines, but some degree of cross sensitivity should be assumed.

Drug Class: Benzodiazepines, Antianxiety Agents


Case 1. Mild acute liver injury due to chlordiazepoxide.(1)

A 26 year old woman developed nausea, anorexia and fatigue 2 days after starting chlordiazepoxide (30 mg per day). She was given an injection of penicillin followed by several days of oral penicillin. Ten days later she developed jaundice and pruritus and chlordiazepoxide was stopped. She had no previous history of liver disease or known exposures to viral hepatitis. She had delivered a healthy, full-term baby shortly before starting the chlordiazepoxide. She had no known drug allergies. Physical examination showed jaundice and a tender liver, without fever or skin rash. Laboratory tests showed elevated serum bilirubin (5.0 mg/dL) and elevations in both serum alkaline phosphatase and aminotransferase levels (Table). She had severe pruritus that persisted for several weeks, even while her laboratory test results improved. A liver biopsy showed intra-hepatic cholestasis. Two months later her symptoms had resolved and all blood tests had returned to normal.

Key Points

Laboratory Values


An acute cholestatic hepatitis arose within two weeks of starting chlordiazepoxide in a patient whose only other medical exposure was to a few days or penicillin. While both benzodiazepines and the penicillins can cause cholestatic hepatitis, penicillin induced liver injury is usually accompanied by other signs of hypersensitivity such as fever and rash. Cholestatic drug induced liver injury tends to be slower to resolve that hepatocellular injury.



Chlordiazepoxide – Generic, Librium® (Trade name discontinued)




Product labeling at DailyMed, National Library of Medicine, NIH



Lo KJ, Eastwood IR, Eidelman S. Cholestatic jaundice associated with chlordiazepoxide hydrochloride (Librium) therapy. Report of a case and review of the literature. Am J Dig Dis. 1967;12:845–9. [PubMed: 4952749]


References updated: 22 June 2023

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    (Expert review of benzodiazepines and liver injury published in 1999; mentions rare instances of cholestatic hepatitis have been reported due to alprazolam, chlordiazepoxide, diazepam, flurazepam, and triazolam, and hepatocellular injury with clorazepate and clotiazepam, but no reports of hepatic injury with lorazepam, oxazepam, or temazepam).
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    (Review of drug induced liver injury mentions that isolated instances of acute liver injury [usually cholestatic] have been reported with alprazolam, chlordiazepoxide, diazepam, flurazepam, and triazolam; a hepatitis-like pattern has been reported with clonazepam and clorazepate).
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    (Textbook of pharmacology and therapeutics).
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    (39 year old man with schizophrenia and seizures on phenytoin developed jaundice 5 days after starting chlordiazepoxide [50 mg/day] [icterus index 49.6, Alk P 3 times ULN], resolving within 3 months of stopping).
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    (51 year old man developed jaundice and pruritus 4-5 weeks after starting chlordiazepoxide [bilirubin ~4.0 mg/dL, AST 300 U/L, Alk P 2.5 times ULN], biopsy showed inflammation and cholestasis, recovery not mentioned).
  • Pickering D. Hepatic necrosis after chlordiazepoxide therapy. N Engl J Med. 1966;274:1449.
    (64 year old woman developed jaundice 3 weeks after 12 day course of chlordiazepoxide [bilirubin ~32 mg/dL, ALT 225 U/L, Alk P 38 U/L], prolonged course, transient ascites, prednisone therapy).
  • Lo KJ, Eastwood IR, Eidelman S. Cholestatic jaundice associated with chlordiazepoxide hydrochloride (Librium) therapy. Report of a case and review of the literature. Am J Dig Dis. 1967;12:845–9. [PubMed: 4952749]
    (26 year old woman developed nausea after 2 and jaundice after 11 days of chlordiazepoxide therapy [bilirubin 5.0 mg/dL, AST 51 U/L, Alk K 69 KA ~5 times ULN], recovery over 8 weeks, marked pruritis: Case 1).
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    (Among 126 cases of drug induced liver injury seen in Spain between 1993-2000, 20 were attributed to benzodiazepines including 5 for clorazepate, 5 alprazolam, 6 lorazepam and 4 diazepam, but none attributed to chlordiazepoxide).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, none were attributed to a benzodiazepine).
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    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were linked benzodiazepines).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144:1419–25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to chlordiazepoxide or other benzodiazepines).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol. 2014;13:231–9. [PubMed: 24552865]
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  • Drugs for chronic insomnia. Med Lett Drugs Ther. 2023;65:1–6. [PubMed: 36630579]
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