OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Midazolam – Generic, Versed® (Trade name discontinued)

DRUG CLASS

Benzodiazepines

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
Midazolam	59467-70-8	C18-H13-Cl-F-N3

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 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).
• 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; but “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. [PubMed: 11291233]

  (Review of drug induced cholestatic syndromes, listing many causes including chlordiazepoxide and flurazepam; “benzodiazepines may cause cholestatic injury, although this is rare”).
• 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, 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 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”).
• 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 midazolam or any other benzodiazepine, despite the fact millions of prescriptions for them 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 midazolam 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 midazolam or any other benzodiazepine).
• Rex DK, Bhandari R, Desta T, DeMicco MP, Schaeffer C, Etzkorn K, Barish CF, et al. A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy. Gastrointest Endosc. 2018;88:427–437.e6. [PubMed: 29723512]

  (Among 461 adults undergoing colonoscopy who received remimazolam, midazolam, or placebo as a procedural sedative after a single dose of fentanyl, adequate sedation was achieved more frequently with remimazolam and onset after starting and recovery of full alertness after stopping was more rapid with remimazolam, with similar rates of adverse events and no serious adverse event).
• Pastis NJ, Yarmus LB, Schippers F, Ostroff R, Chen A, Akulian J, Wahidi M, et al. PAION Investigators. Safety and efficacy of remimazolam compared with placebo and midazolam for moderate sedation during bronchoscopy. Chest. 2019;155:137–146. [PubMed: 30292760]

  (Among 446 patients undergoing bronchoscopy who received procedural sedation with remimazolam, midazolam or placebo, the onset of adequate sedation was faster with remimazolam than midazolam and time to being fully alert was more rapid after stopping while total and severe adverse event rates were similar in the three groups and success rates in completing the procedure were similar; no mention of ALT elevations or hepatotoxicity).