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DRUG RECORD

 

DIAZEPAM (Intravenous)

OVERVIEW
Diazepam

 

Introduction
Diazepam is a benzodiazepine used predominantly as an anxiolytic agent but also as anticonvulsant intravenously for therapy of status epilepticus.  Intravenous therapy with diazepam is not associated with serum aminotransferase elevations, and clinically apparent liver injury from diazepam is rare and has not been reported to be associated with short term intravenous therapy.

Background
Diazepam is a benzodiazepine with particularly potent activity against spread of seizure activity in several animal models.  The antiseizure activity of the benzodiazepines is mediated by their ability to enhance gamma-aminobutryic acid (GABA) mediated inhibition of synaptic transmission through binding to the GABAA receptor.  The use of diazepam as an anticonvulsant is limited largely to intravenous therapy of status epilepticus.  Among benzodiazepines, oral diazepam is not as effective or well tolerated as a therapy for epilepsy as are clonazepam and clorazepate.  Oral formulations of diazepam are widely used for therapy of anxiety, nervousness and insomnia.  Diazepam was approved in the United States in 1963 and it is currently widely used to treat acute seizures and status epilepticus.  Several generic forms of parenteral diazepam are available in ampules of 5 mg/mL.  The typical recommended dose is 5 to 10 mg given intravenously, which can be repeated at 10 to 15 minute intervals until control of seizure activity or to a maximum of 30 mg.  Common effects of the use of intravenous diazepam include somnolence, confusion, dysarthria, diplopia and coma. Acute overdose of diazepam can cause respiratory arrest and death.

Hepatotoxicity
Diazepam as with other benzodiazepines is rarely associated with serum ALT elevations, and clinically apparent liver injury from diazepam is extremely rare.  In particular, intravenous diazepam is not associated with elevations in serum ALT levels, even with prolonged use as with therapy of tetanus.  There have been no convincing case reports of acute liver injury from intravenous diazepam, although there are several case reports of acute liver injury from oral formulations.  The onset of injury has ranged from 4 to 12 weeks and the typical pattern of serum enzyme elevations has been hepatocellular or mixed.  Fever and rash have not been described nor has autoantibody formation.

Mechanism of Injury
The liver injury from benzodiazepines is probably due to a rarely produced intermediate metabolite.

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

 

Drug Class:  Anticonvulsants

 

Other drugs in the Class:  Carbamazepine, Clonazepam, Clorazepate, Ethosuximide, Felbamate, Fosphenytoin, Gabapentin, Lamotrigine, Levetiracetam, Oxcarbazepine, Phenobarbital, Phenytoin, Pregabalin, Primidone, Tiagabine, Topiramate, Valproate, Zonisamide

 

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CASE REPORT
Diazepam

 

Case 1.  Cholestatic hepatitis due to oral diazepam.
[Modified from:  Fors B, Nilsson F. [Hepatitis probably induced by diazepam medication] Lakartidningen 1968; 65: 4528-31. Swedish. PubMed Citation]

 

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.  Serum ALT was 306 U/L, alkaline phosphatase was twice elevated and bilirubin was 4.2 mg/dL.  A cholecystectomy was done for suspected cholelithiasis, but the gallbladder and biliary tree were normal.  A liver biopsy showed acute hepatocellular injury and cholestasis compatible with drug induced liver disease.  Diazepam was stopped and she recovered rapidly and had normal liver tests one month later.  Tests for hepatitis A, B and C were not available.

 

Key Points

Medication:Diazepam (2 mg orally three times daily)
Pattern: Mixed (R=~4)
Severity: 3+ (jaundice and hospitalization)
Latency: 4 months
Recovery:Complete recovery within a month after stopping
Other medications:Birth control pills

Comment

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 “probable” case of diazepam induced liver injury.  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.

 

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PRODUCT INFORMATION
Diazepam

 

REPRESENTATIVE TRADE NAMES
Diazepam – Valium®

 

DRUG CLASS
Anticonvulsants

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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

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REFERENCES
Benzodiazepines/Diazepam

 

References Last Updated: 21 August 2011

  1. Zimmerman HJ. Anticonvulsants. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott,1999: pp. 498-516  (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, prazepam, oxazepam and temazepam).

  2. Pirmohamed M, Leeder SJ. Anticonvulsant agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd ed. New York: Informa Healthcare USA, 2007: pp 485-506  (Review of anticonvulsant induced liver injury published in 2007, the benzodiazepines are not discussed).

  3. McNamara JO. Pharmacology of the epilepsies. In, Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill, 2006, pp. 501-525.  (Textbook of pharmacology and therapeutics).

  4. Cacioppo J, Merlis S. Chlordiazepoxide hydrochloride(Librium) and jaundice: report of a case. Am J Psychiatry 1961; 117: 1040-1. PubMed Citation  (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).

  5. Cook GC, Sherlock S.  Jaundice and its relation to therapeutic agents.  Lancet 1965; 1: 175-9.  PubMed Citation  (11 cases of druginduced liver disease, all due to agents no longer in use; 2 patients were receiving diazepam, but other agents were more likely the cause).

  6. Abbruzzese A, Swanson J. Jaundice after therapy with chlordiazepoxide hydrochloride. N Engl J Med 1965; 273; 321-2. PubMed Citation  (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).

  7. Cunningham ML. Acute hepatic necrosis following treatment with amitriptyline and diazepam. Brit J Psychiat 1965; 111: 1107-9. PubMed Citation  (54 year old woman with dementia-depression placed on amitriptyline and diazepam developed progressive confusion 5 months later 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).

  8. Pickering D. Hepatic necrosis after chlordiazepoxide therapy. N Engl J Med 1966; 274: 1449. Not in PubMed.  (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).

  9. 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 Citation  (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).

  10. 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 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 therapy).

  11. Kratzsch KH, Buttner W, Reinhardt G. [Intrahepatic cholestasis following chlordiazepoxide-contribution to the differential diagnosis of drug jaundice] Z Gesamte Inn Med 1972; 27: 408-11. German. PubMed Citation  (3 cases of cholestatic hepatitis during chlordiazepoxide use, after 4 weeks, 6 years and 2 days [bilirubin 6.0, 1.0 and 6.4 mg/dL, ALT 245, 18 and 25 U/L, Alk P 1.6 1.0 and 20 times ULN], with rapid recovery in 1-2 months: all 3 had biopsies showing intrahepatic cholestasis).

  12. Stacher G. Intrahepatic cholostasis following combined diazepam-barbiturate therapy in patients with tetanus]. Wien Klin Wochenschr. 1973; 85: 401-6. German. PubMed Citation

  13. Franks E, Jacobs WH. Cholestatic jaundice possibly due to benzodiazepine-type drugs. Mo Med 1975; 72: 605-6. 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, resolving rapidly when they were stopped, but attribution to benzodiazepines difficult).

  14. Fors B, Nilsson F. [Hepatitis probably induced by diazepam medication] Lakartidningen 1968; 65: 4528-31. Swedish. 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).

  15. Fang MH, Ginsberg AL, Dobbins WO 3rd. Cholestatic jaundice associated with flurazepam hydrochloride. Ann Intern Med 1978; 89: 363-4. PubMed Citation  (70 year old man developed fatigue followed by pruritis 3 months after starting flurazepam [bilirubin 6.6 mg/dL, ALT 179 U/L, Alk P 232 U/L, no eosinophilia], improving only when drug withdrawn).

  16. Parker JLW. Potassium clorazepate(Tranxene)-induced jaundice. Postgrad Med J 1979; 55: 908-910. PubMed Citation  (27 year old man developed jaundice, pruritus and fever, 2 months after starting clorazepate [bilirubin 7.6 mg/dL, ALT 880 U/L, Alk P 2.3 times ULN] and had 3 liver biopsies done over 5 months, showing intrahepatic cholestasis with thin portal-portal fibrosis septae that persisted as cholestasis and inflammation resolved).

  17. Bonkovsky HL, Sinclair PR, Emery S, Sinclair JF. Seizure management in acute hepatic porphyria: risks of valproate and clonazepam. Neurology 1980; 30: 588-92. PubMed Citation  (38 year old man with acute intermittent porphyria and seizures did not respond to clonazepam, and testing in chicken embryos showed that it increased hepatic prophyrins and ALA synthase activity).

  18. Cobden I, Record CO, White RWB. Fatal intrahepatic cholestasis associated with triazolam. Postgrad Med J 1981; 57: 730-1. PubMed Citation  (44 year old man developed jaundice after 5 months of intermittent triazolam therapy for insomnia [bilirubin 10.6 mg/dL, AST 97 U/L and Alk P 104 U/L], jaundice deepened and patient died, autopsy showing intrahepatic cholestasis without obstruction or cirrhosis).

  19. Reynolds R, Lloyd DA, Slinger RP. Cholestatic jaundice induced by flurazepam hydrochloride. Can Med Assoc J 1981; 124: 893-4. PubMed Citation  (44 year old woman taking flurazepam intermittently for 6 months developed abdominal pain [bilirubin 8.2 mg/dL, AST 106 U/L, Alk P 209 U/L], resolving rapidly upon stopping, biopsy showed intrahepatic cholestasis).

  20. Tedesco FJ, Mills LR. Diazepam (Valium) hepatitis. Dig Dis Sci 1982; 27: 470-2. PubMed Citation  (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).

  21. 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 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).

  22. Roy-Byrne P, Vittone BJ, Uhde TW. Alprazolam-related hepatotoxicity. Lancet 1983; 2: 786-7. PubMed Citation  (30 year old woman was found to have elevated ALT [96 U/L] 2 weeks after starting alprazolam which promptly resolved when drug was stopped; rechallenge led to asymptomatic ALT rise within 9 days [28 to 70 U/L]).

  23. Keränen T, Sivenius J. Side effects of carbamazepine, valproate and clonazepam during long-term treatment of epilepsy. Acta Neurol Scand Suppl 1983; 97: 69-80. PubMed Citation  (Clonazepam has many dose related sedative side effects but, compared to carbamazepine and valproate, few serious or long term side effects; no mention of hepatic side effects of clonazepam).

  24. Davion T, Capron-Chivrac D, Andrejak M, Capron JP. [Hepatitis due to antiepileptic agents] Gastroenterol Clin Biol 1985; 9: 117-26. 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 rare).

  25. Judd FK, Norman TR, Marriott PF, Burrows GD. A case of alprazolam-related hepatitis. Am J Psychiatry 1986; 143: 388-9. 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).

  26. Olsson R, Zettergren L. Anticonvulsant-induced liver damage. Am J Gastroenterol 1988; 83: 576-7. PubMed Citation  (30 year old man developed fever, rash and jaundice 6 weeks after starting phenytoin; he was switched to carbamazepine and clonazepine but redeveloped jaundice 3 months later; resolved with stopping but recurred with restarting clonazepine alone [bilirubin 1.8 mg/dL, ALT 1380 U/L, Alk P 176 U/L] without rash, fever or eosinophilia, resolving in 6 weeks of stopping clonazepine).

  27. Habersetzer F, Larrey D, Babany G, Degott C, Corbic M, Pessayre D, Benhamou J-P. Clotiazepam-induced acute hepatitis. J Hepatol 1989; 9: 256-9. PubMed Citation  (65 year old woman developed jaundice 6 months after starting clotiazepam [bilirubin 5.1 mg/dL, ALT 1028 U/L, GGT 143 U/L] with no rash or fever, resolving on stopping clotiazepam and no recurrence after taking triazolam and temazepam).

  28. 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 Citation  (Safety of use of intravenous diazepam in children undergoing endoscopy; no mention of ALT abnormalities or liver injury).

  29. Kleier RS, Breneman DL, Boiko S. Generalized pustulation as a manifestation of the anticonvulsant hypersensitivity syndrome. Arch Dermatol 1991; 127: 1361-4. PubMed Citation  (2 men, ages 21 and 49 years, developed rash after 3-4 weeks of phenytoin evolving into sterile pustules [bilirubin normal, ALT 57 and 660 U/L, Alk P 85 and 117 U/L], worsening on switching to carbamazepine and phenobarbital, resolving after switching to clonazepam).

  30. Suzuki A, Aso K, Ariyoshi C, Ishimaru M. Acute intermittent porphyria and epilepsy: safety of clonazepam. Epilepsia 1992; 33: 108-11. PubMed Citation  (13 year old girl with acute intermittent porphyria worsened on valproate and on phenytoin therapy, but clonazepam led to control of seizures and no worsening of porphyria).

  31. Hindmarch I, Fairweather DB, Rombaut N. Adverse events after triazolam substitution. Lancet 1993; 341: 55. PubMed Citation  (Survey of UK physicians, one year after withdrawal of triazolam in the UK, found higher rate of adverse reactions [largely CNS] with replacements such as temazepam, loprazolam, nitrazepam and lormetazepam, but no mention of hepatotoxicity).

  32. Andrade RJ, Lucena MI, Alcantara R, Fraile JM. Bentazepam-associated chronic liver disease. Lancet 1994; 343: 860. PubMed Citation  (65 year old man developed fatigue and weight loss 4 months after starting bentazepam [normal bilirubin, ALT 142 U/L, GGT 109 U/L, normal Alk P], biopsy showed chronic hepatitis, piecemeal necrosis and bridging fibrosis and abnormalities, resolved upon stopping). 

  33. Moulin CH, Rolachon A, Cohard M, et al. [Fulminant hepatitis secondary to alprazolam] Therapie 1994; 49: 362-3. French. PubMed Citation  (64 year old man developed jaundice and confusion 3 weeks after starting alprazolam [bilirubin 4.1 mg/dL, ALT 100 times ULN, Alk P 3.4 times ULN and prothrombin index of 19%], resolution starting within one week and all tests returning to normal by 3 months).

  34. Wallace SJ. A comparative review of the adverse effects of anticonvulsants in children with epilepsy. Drug Saf 1996; 15: 378-93. 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,”).

  35. de la Serna, Gil-Grande LA, Sanroman AL, Gonzalez M, Ruiz-del-Arbol L, Garcia Plaza A. Bentazepam-induced hepatic bridging necrosis. J Clin Gastroenterol 1997; 25: 710-1. PubMed Citation  (Bentazepam is a benzodiazepine used in Europe since 1981; 49 year old woman developed liver test abnormalities without symptoms 2 months after starting bentazepam [normal bilirubin, ALT 136 U/L,GGT 61 U/L], which persisted for 10 months and resolved rapidly when drug was stopped; biopsy showed chronic hepatitis with bridging necrosis).

  36. 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 Citation  (Review of drug induced cholestatic syndromes, listing many causes including chlordiazepoxide and flurazepam: “Benzodiazepines may cause cholestatic injury, although this is rare.”).

  37. Selim K, Kaplowitz N. Hepatotoxicity of psychotropic drugs. Hepatology 1999; 29: 1347-51. 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”).

  38. Andrade RJ, Lucena MI, Aguilar J, Lazo MD, Camargo R, Moreno P, Garcia-Escano MDP, et al. Chronic liver injury related to use of bentazepam: an unusual instance of benzodiazepine hepatotoxicity. Dig Dis Sci 2000; 45: 1400-4. PubMed Citation  (3 cases of liver injury after taking bentazepam for 1, 3 and 5 months with elevated bilirubin in one [4.6 mg/dL]; variable ALT [117-1050 U/L] and Alk P elevations [154-346 U/L] rapid resolution; some patients tolerated other benzodiazepines).

  39. Kanda T, Yokosuka O, Fujiwara K, Saisho H, Shiga H, Oda S, Okuda K, et al. Fulminant hepatic failure associated with triazolam. Dig Dis Sci 2002; 47: 1111-4. PubMed Citation  (64 year old woman developed acute liver failure after taking triazolam intermittently for a year [bilirubin 6.1 mg/dL, ALT 1272 U/L], with ascites and encephalopathy; successful living donor liver transplantation done 1 month after initial presentation).

  40. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States.  Liver Transpl 2004; 10: 1018-23. PubMed Citation  (Among ~50,000 liver transplants done in the United States between 1990 and 2002, 137 [0.2%] were done for idiosyncratic drug induced acute liver failure, of which 10 were attributed to phenytoin, 10 to valproate and 1 to carbamazepine, but none to benzodiazepines or other anticonvulsants).

  41. Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-101. PubMed Citation  (36 years of reporting to Swedish registry identified 103 cases of acute liver failure due to drugs, of which 1 was attributed to phenytoin, 1 to valproate and 1 to carbamazepine, but none to benzodiazepines or other anticonvulsants).

  42. Gil-Martin A, Saez-Royuela F, Arias L, Angulo ML, Nogal B. [Hepatic fibrosis after antidepressant treatment] Rev Esp Enferm Dig 2005; 97: 461-2. Spanish. PubMed Citation  (32 year old woman developed pruritis and jaundice 1-2 months after starting sertraline, aprazolam and clorazepate, resolving with stopping sertraline but had persistent minor ALT elevations and biopsy showing mild bridging fibrosis 4 months later).

  43. Andrade RJ, Lucena MI, Kaplowitz N, Garcia-Munoz B, Borraz Y, Pachkoria K, Garcia-Cortes M, et al. Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry. Hepatology 2006; 44: 1581-8. PubMed Citation  (28 of 493 [5.7%] cases of drug-induced liver disease had evidence of chronicity, including 3 cases due to bentazepam and one with clorazepate, the latter with recovery at 25 months).

  44. 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 Citation  (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]).

  45. Björnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scan 2008; 118: 281-90. PubMed Citation  (Review of hepatotoxicity of all anticonvulsants focusing upon phenytoin, valproate, carbamazepine; “Furthermore, hepatotoxicity has not been convincingly shown to be associated with the use of benzodiazepines”).

  46. 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.  PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, none were attributed to benzodiazepines).

  47. Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. PubMed Citation  (World wide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, benzodiazepines were not among the top 40 agents implicated).

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OTHER REFERENCE LINKS
Diazepam

 

  1. PubMed logoRecent References on Diazepam

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