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Diazepam - LiverTox


10.15.2018 | Cameron Keat

Skip Navigation DRUG RECORD DIAZEPAM (Oral) Introduction.

Diazepam
Diazepam - LiverTox

Drug Class: Benzodiazepines, see also Diazepam (Intravenous).

COMPLETE LABELING Product labeling at DailyMed, National Library of Medicine, NIH Top of page CHEMICAL FORMULA AND STRUCTURE Diazepam DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE Diazepam C16-H13-Cl-N2-O Top of page REFERENCES Diazepam.

A liver biopsy showed acute hepatocellular injury and cholestasis compatible with drug induced liver disease. A 33 year old woman was started on diazepam (2 mg three times daily) for anxiety and four months later developed symptoms of abdominal pain and jaundice. Tests for hepatitis A, B and C were not available. Diazepam was stopped and she recovered rapidly and had normal liver tests one month later. Key Points Comment. A cholecystectomy was done for suspected cholelithiasis, but the gallbladder and biliary tree were normal. Serum ALT was 306 U/L, alkaline phosphatase was twice elevated and bilirubin was 4.2 mg/dL.

In view of the wide scale use of diazepam, instances of hepatic injury are very rare, and no cases of severe, prolonged, persistent or fatal liver injury from diazepam have been published. The patient developed an acute hepatitis-like illness four months after starting diazepam. A liver biopsy showed changes typical of drug induced liver disease and the pattern of enzyme elevations and biopsy did not suggest viral hepatitis, serological testing for which was not available at the time. Causality assessment can only rank this example as a “possible” case of diazepam induced liver injury.

Background. Diazepam therapy has not been associated with serum aminotransferase elevations, and clinically apparent liver injury from diazepam has been reported, but is exceedingly rare. Diazepam is a benzodiazepine that is widely used orally as an anxiolytic agent and muscle relaxant. Intravenous forms of diazepam are used for acute severe agitation, as a premediation for anesthesia, a sedative for minor surgery or invasive procedures, and for treatment of status epileptus or severe recurrent seizures.

Current indications for oral diazepam include treatment of anxiety disorders, acute alcohol withdrawal and as an adjunct to relief of skeletal muscle spasm. The sedative 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. Acute overdose of diazepam can cause coma, respiratory arrest and death. Diazepam is also available as a solution for injection, usually in vials or syringes of 5 mg/mL. Among oral forms of benzodiazepines, diazepam is not as effective or well tolerated as a therapy for epilepsy as are clobazam, clonazepam and clorazepate. Parenteral forms of diazepam are used for control of seizures and status epilepticus and as an adjunct to anesthesia or sedation for minor surgical procedures. Hepatotoxicity. Common side effects of diazepam include somnolence, dizziness, confusion, dysarthria, and diplopia. Diazepam was approved in the United States in 1963 and is still in wide use with more than 13 million prescriptions filled yearly. The typical dose of diazepam used for anxiety is 2 to 10 mg given two to four times daily. Diazepam (dye az' e pam) is a benzodiazepine that in oral formulations is used for the therapy of anxiety, alcohol withdrawal symptoms and muscle spasms. Current indications for intravenous diazepam include premedication for surgery, acute agitation due to alcohol withdrawal, as an adjunct to endoscopic and minimally invasive procedures and for treatment of status epilepticus and severe recurrent seizures. Diazepam is available in tablets of 2, 5 and 10 mg in generic forms and under the brand name of Valium. Oral solutions and rectal gels are also available.

No cases of acute liver failure or chronic liver injury due to diazepam have been described. The case reports of hepatic injury due to oral diazepam were followed by complete recovery, without evidence of residual or chronic injury. There is no information about cross reactivity with other benzodiazepines (clobazam, clorazepate, lorazepam or alprazolam), but some degree of cross sensitivity may occur.

The liver injury from benzodiazepines is probably due to a rarely produced intermediate metabolite. Diazepam is metabolized in the liver to its active metabolite which is excreted in the urine. Outcome and Management.

References updated: 24 January 2017.

The onset of injury has ranged from 1 to 6 months, and pattern of serum enzyme elevations has typically been cholestatic or mixed. In large surveys and case series of clinically apparent drug induced liver injury, diazepam and other benzodiazepines are usually not listed. There have been no case reports of hepatotoxicity from diazepam since the 1980s. Mechanism of Injury. Like other benzodiazepines, diazepam is rarely associated with serum ALT elevations during therapy. Furthermore, clinically apparent liver injury from diazepam is exceedingly rare. Likelihood score: D (Possible but rare cause of clinically apparent liver injury). A small number of cases of hepatic injury have been described in patients on oral diazepam, but the clinical pattern has varied. Fever and rash are uncommon as is autoantibody formation.

Swedish. Hepatotoxicity of psychotropic drugs and drugs of abuse. multicenter, prospective study. Psychotropic and anticonvulsant agents. Lancet 1965; 1: 175-9. Brit J Psychiat 1965; 111: 1107-9. Cunningham ML. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. e7. 2nd ed. PubMed Citation (45 year old man developed elevations of ALT while on isoniazid and diazepam, which resolved upon stopping and recurred upon rechallenge with diazepam, but not isoniazid which was tolerated long term). PubMed Citation (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], seemed to worsen on benzodiazepines including chlordiazepoxide, diazepam and flurazepam, improving rapidly when they were stopped, but attribution to benzodiazepines was difficult). In, Zimmerman HJ. (Textbook of pharmacology and therapeutics). Hepatology 1999; 29: 1347-51. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. A comparative review of the adverse effects of anticonvulsants in children with epilepsy. 455. J Pediatr Gastroenterol Nutr 1990; 10: 335-8. PubMed Citation (Review of hepatotoxicity of phenothiazines, butyrophenones, tricyclics, MAO inhibitors, acetylcholesterase 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”). PubMed Citation (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,”). Dig Dis Sci 1982; 27: 470-2. Davion T, Capron-Chivrac D, Andrejak M, Capron JP. PubMed Citation (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). Drug-induced liver disease in Denmark. Acute hepatic necrosis following treatment with amitriptyline and diazepam. Stacher G. Hepatotoxicity of psychotropic drugs. 3rd ed. PubMed Citation (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). (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). Philadelphia: Lippincott, 1999, pp. Hepatotoxicity associated with antiepileptic drugs. PubMed Citation (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). Lewis JH, Zimmerman HJ. Jaundice and its relation to therapeutic agents. PubMed Citation (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). An analysis of published reports. Gastroenterol Clin Biol 1985; 9: 117-26. Tedesco FJ, Mills LR. PubMed Citation (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”). Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). New York: McGraw-Hill, 2011, pp. Selim K, Kaplowitz N. Profile of idiosyncratic drug induced liver injury in Latin America. PubMed Citation (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). PubMed Citation (Review of drug induced cholestatic syndromes, listing many causes including chlordiazepoxide and flurazepam; “Benzodiazepines may cause cholestatic injury, although this is rare”). Acta Neurol Scand 2008; 118: 281-90. Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. In, Brunton LL, Chabner BA, Knollman BC, eds. [Hepatitis probably induced by diazepam medication] Lakartidningen 1968; 65: 4528-31. Scand J Gastroenterol 1982; 17: 205-11. PubMed Citation (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). German. An analysis of 572 cases of hepatotoxicity reported to the Danish Board of Adverse Reactions to Drugs. PubMed Citation (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). A case of alprazolam-related hepatitis. PubMed Citation (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). Benzodiazepines. 12th ed. Zimmerman HJ. Drug-induced acute liver failure: results of a U.S. Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. PubMed Citation (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). 491-3. Gastroenterology 2015; 148:. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. PubMed Citation (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, none were attributed to a benzodiazepine). Amsterdam: Elsevier, 2013, pp. Mihic SJ, Harris RA. Clin Liver Dis 1999; 3: 433-64, vii. Drug- and chemical-induced cholestasis. Buchanan N, Cane RD. PubMed Citation (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). Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Benzodiazepines. Aliment Pharmacol Ther 2007; 25: 1401-9. PubMed Citation (Prospective study of safety of intravenous diazepam in 30 children undergoing endoscopy; no mention of ALT abnormalities or liver injury). Fors B, Nilsson F. PubMed Citation (Among 126 cases of drug induced liver injury seen in Spain between, 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]). PubMed Citation Franks E, Jacobs WH. Wallace SJ. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Björnsson E. Drug-induced liver disease. Wien Klin Wochenschr. Gastroenterology 2008; 135: 1924-34. Drug Saf 1996; 15: 378-93. PubMed Citation (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). Cholestatic jaundice possibly due to benzodiazepine-type drugs. Liver function tests and the prolonged use of high-dose diazepam with special reference to tetanus. In, Kaplowitz N, DeLeve LD, eds. S Afr Med J 1978 54: 768. Hypnotics and sedatives. Døssing M, Andreasen PB. Larrey D, Ripault MP. Ann Hepatol 2014; 13: 231-9. 1973; 85: 401-6. Hepatology 2010; 52: 2065-76. 457-80. Mo Med 1975; 72: 605-6. Intrahepatic cholostasis following combined diazepam-barbiturate therapy in patients with tetanus]. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. Judd FK, Norman TR, Marriott PF, Burrows GD. Diazepam (Valium) hepatitis. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Nahata MC, Murray RD, Zingarelli J, Li BU, McClung HJ, Lininger B. Erratum in: Clin Liver Dis 1999; 3: 917. Am J Psychiatry 1986; 143: 388-9. Cook GC, Sherlock S. (Review of benzodiazepine induced liver injury mentions that increases in liver enzymes during therapy are rare and significant hepatotoxicity uncommon, only a few cases have been reported with alprazolam, chlordiazepoxide, diazepam, flurazepam and triazolam). Efficacy and safety of a diazepam and meperidine combination for pediatric gastrointestinal procedures. Gastroenterology 2013; 144: 1419-25. Goodman & Gilman’s the pharmacological basis of therapeutics.

DRUG CLASS Benzodiazepines, Antianxiety Agents.

Diazepam