OVERVIEW

CASE REPORT

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Diazepam – Generic, Valium® (Trade name discontinued)

DRUG CLASS

Benzodiazepines, Antianxiety Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Diazepam	439-14-5	C16-H13-Cl-N2-O

CITED REFERENCES

1.

Fors B, Nilsson F. Lakartidningen. 1968;65:4528–31. [Hepatitis probably induced by diazepam medication] Swedish. [PubMed: 5745628]

ANNOTATED BIBLIOGRAPHY

References updated: 22 June 2023

• Zimmerman HJ. Benzodiazepines. Psychotropic and anticonvulsant agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 491-3.

  (Expert review of benzodiazepines and liver injury published in 1999 mentions that 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).
• Larrey D, Ripault MP. Benzodiazepines. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 455.

  (Review of benzodiazepine induced liver injury mentions that increases in liver enzymes during therapy are rare and significant hepatotoxicity uncommon, only a few cases [usually cholestatic] have been reported with alprazolam, chlordiazepoxide, diazepam, flurazepam and triazolam).
• Mihic SJ, Mayfield J, Harris RA. Hypnotics and sedatives. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 339-53.

  (Textbook of pharmacology and therapeutics).
• Cook GC, Sherlock S. Jaundice and its relation to therapeutic agents. Lancet. 1965;1:175–9. [PubMed: 14238042]

  (11 cases of drug induced liver disease, all due to agents no longer in use; 2 were receiving diazepam, but other agents were more likely the cause).
• Cunningham ML. Acute hepatic necrosis following treatment with amitriptyline and diazepam. Brit J Psychiat. 1965;111:1107–9. [PubMed: 5841222]

  (54 year old woman with dementia-depression developed progressive confusion 5 months after starting amitriptyline and diazepam, which was followed by jaundice, obtundation and death [bilirubin 5.2 mg/dL, ALT 200 U/L, Alk P 9.5 unknown units]; autopsy showed small liver, but no description of histology; role of diazepam unclear).
• Buchanan N, Cane RD. Liver function tests and the prolonged use of high-dose diazepam with special reference to tetanus. S Afr Med J. 1978;54:768. [PubMed: 741305]

  (After noting jaundice in a few patients receiving high doses of diazepam for tetanus, the authors prospectively tested 4 patients finding no consistent rises in serum ALT, Alk P or bilirubin on intravenous therapy).
• Stacher G. Intrahepatic cholostasis following combined diazepam-barbiturate therapy in patients with tetanus]. Wien Klin Wochenschr. 1973;85:401–6. German. [PubMed: 4705881]
• Franks E, Jacobs WH. Cholestatic jaundice possibly due to benzodiazepine-type drugs. Mo Med. 1975;72:605–6. [PubMed: 1181510]

  (40 year old woman on multiple drugs including chlorpromazine developed jaundice [bilirubin 2.0 rising to 9.7 mg/dL, ALT 280 U/L, Alk P 546 U/L, 16% eosinophils] and seemed to worsen on benzodiazepines including chlordiazepoxide, diazepam and flurazepam, improving rapidly when they were stopped, but attribution to benzodiazepines was difficult).
• Fors B, Nilsson F. Lakartidningen. 1968;65:4528–31. [Hepatitis probably induced by diazepam medication] Swedish. [PubMed: 5745628]

  (24- and 34 year old women developed mild hepatitis with jaundice 1 and 4 months after starting diazepam [bilirubin 11 and 4.2 mg/dL, ALT 434 U/L, Alk ~2 times ULN], rapid resolution with stopping: Case 1).
• Tedesco FJ, Mills LR. Diazepam (Valium) hepatitis. Dig Dis Sci. 1982;27:470–2. [PubMed: 7075434]

  (45 year old man developed elevations of ALT [130 U/L] while on isoniazid [for 1 day] and diazepam [3 days], which resolved upon stopping and recurred upon rechallenge with diazepam, but not isoniazid which was tolerated long term).
• Døssing M, Andreasen PB. Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to the Danish Board of Adverse Reactions to Drugs. Scand J Gastroenterol. 1982;17:205–11. [PubMed: 6982502]

  (Among 572 cases of hepatotoxicity reported to a Danish registry between 1968 and 1978, 97 were due to psychotropic agents, but only two attributed to benzodiazepines).
• Davion T, Capron-Chivrac D, Andrejak M, Capron JP. Gastroenterol Clin Biol. 1985;9:117–26. [Hepatitis due to antiepileptic agents] [PubMed: 3920108]

  (Review of hepatotoxicity of anticonvulsants; among benzodiazepines, cases of cholestatic hepatitis have been linked to chlordiazepoxide and diazepam, but liver injury from this class of drugs is exceptionally rare).
• Judd FK, Norman TR, Marriott PF, Burrows GD. A case of alprazolam-related hepatitis. Am J Psychiatry. 1986;143:388–9. [PubMed: 2869702]

  (59 year old woman developed lethargy 2 weeks after starting alprazolam followed by jaundice [bilirubin 2.6 mg/dL, AST 156 U/L, Alk P 241 U/L], resolving within 4 weeks of switching to diazepam).
• Nahata MC, Murray RD, Zingarelli J, Li BU, McClung HJ, Lininger B. Efficacy and safety of a diazepam and meperidine combination for pediatric gastrointestinal procedures. J Pediatr Gastroenterol Nutr. 1990;10:335–8. [PubMed: 2324894]

  (Prospective study of safety of intravenous diazepam in 30 children undergoing endoscopy; no mention of ALT abnormalities or liver injury).
• Wallace SJ. A comparative review of the adverse effects of anticonvulsants in children with epilepsy. Drug Saf. 1996;15:378–93. [PubMed: 8968693]

  (Systematic review; ALT elevations occur in 4% of children on phenytoin, 6% on valproate, 1% on carbamazepine; “No child taking… benzodiazepines had raised liver enzyme levels,”).
• Lewis JH, Zimmerman HJ. Drug- and chemical-induced cholestasis. Clin Liver Dis. 1999;3:433–64. vii. Erratum in: Clin Liver Dis 1999; 3: 917. [PubMed: 11291233]

  (Review of drug induced cholestatic syndromes, listing many causes including chlordiazepoxide and flurazepam; “Benzodiazepines may cause cholestatic injury, although this is rare”).
• Selim K, Kaplowitz N. Hepatotoxicity of psychotropic drugs. Hepatology. 1999;29:1347–51. [PubMed: 10216114]

  (Review of hepatotoxicity of phenothiazines, butyrophenones, tricyclics, MAO inhibitors, acetylcholinesterase inhibitors, and psychotropic drugs of abuse; “benzodiazepines…have a very low hepatotoxic potential, with only case reports in the literature, usually with a cholestatic pattern”).
• Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther. 2007;25:1401–9. [PubMed: 17539979]

  (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 compared to controls, the relative risk of injury was increased only for clorazepate [8.3: estimated frequency 3.4 per 100,000 person-year exposures]).
• 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).
• Björnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand. 2008;118:281–90. [PubMed: 18341684]

  (Review of hepatotoxicity of all anticonvulsants focusing upon phenytoin, valproate, carbamazepine; “Furthermore, hepatoxicity has not been convincingly shown to be associated with the use of benzodiazepines”).
• Reuben A, Koch DG, Lee WM., Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52:2065–76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (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 attributed to a benzodiazepine).
• 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 a benzodiazepine, despite the fact that millions of prescriptions are filled yearly).
• 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]

  (Systematic review of literature on drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, none of which were attributed to diazepam or any other benzodiazepine).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–1352.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, no cases were attributed to diazepam or any other benzodiazepine).
• Carvalhana S, Oliveira A, Ferreira P, Resende M, Perdigoto R, Barroso E. Acute liver failure due to trazodone and diazepam. GE Port J Gastroenterol. 2017;24:40–42. [PMC free article: PMC5553376] [PubMed: 28848778]

  (63 year old man developed acute liver failure 3 months after starting trazodone and diazepam [bilirubin 12.0 mg/dL, ALT 4638 U/L, Alk P 122 U/L, INR 1.84], with worsening liver failure and transplant two weeks later).
• Lugoboni F, Mirijello A, Morbioli L, Arzenton E, Leone R, Faccini M, Casari R, et al. Does high-dose benzodiazepine abuse really produce liver toxicity? Results from a series of 201 benzodiazepine monoabusers. Expert Opin Drug Saf. 2018;17:451–456. [PubMed: 29621907]

  (Among 201 patients see for benzodiazepine abuse, 10% had elevations in liver enzymes, but none were suggestive of drug induced liver injury, and most were associated with overweight or obesity).
• Drugs for anxiety disorders. Med Lett Drugs Ther. 2019;61:121–6. [PubMed: 31386647]

  (Concise review of drugs for anxiety including benzodiazepines summaries their mechanism of action, clinical efficacy, safety, and costs; mentions that benzodiazepines such as diazepam can provide immediate relief of anxiety symptoms, but long term therapy can cause tolerance and dependence, and sudden withdrawal can cause severe and even life-threatening symptoms; no mention of ALT elevations or hepatotoxicity).
• Kamitaki BK, Minacapelli CD, Zhang P, Wachuku C, Gupta K, Catalano C, Rustgi V. Drug-induced liver injury associated with antiseizure medications from the FDA Adverse Event Reporting System (FAERS). Epilepsy Behav. 2021;117:107832. [PubMed: 33626490]

  (Analysis of 112,901 spontaneous adverse event reports of antiseizure medications to the FDA, 2175 of which [4.8%] were for liver injury including 1232 hospitalizations and 262 deaths, the reporting odds ratio for liver injury being high [>2.0] for carbamazepine, phenobarbital, phenytoin, valproate, oxcarbazepine, and lamotrigine and modestly elevated [1.0-2.0] for clobazam, diazepam, and levetiracetam, but not elevated [<1.0] for gabapentin, topiramate, clonazepam and zonisamide).