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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Diazepam (Oral) - LiverTox - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]">
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<meta name="citation_title" content="Diazepam (Oral)">
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yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK547871_"><span class="title" itemprop="name">Diazepam (Oral)</span></h1><p class="fm-aai"><a href="#_NBK547871_pubdet_">Publication Details</a></p></div></div><div class="body-content whole_rhythm" itemprop="text"><div id="DiazepamOral.OVERVIEW"><h2 id="_DiazepamOral_OVERVIEW_">OVERVIEW</h2><div id="DiazepamOral.Introduction"><h3>Introduction</h3><p>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 epilepticus or severe recurrent seizures. Diazepam therapy has not been associated with serum aminotransferase elevations, and clinically apparent liver injury from diazepam has been reported but is exceedingly rare.</p></div><div id="DiazepamOral.Background"><h3>Background</h3><p>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. 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. 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. Diazepam was approved in the United States in 1963 and is still in wide use with more than 5 million prescriptions filled yearly. Diazepam is available in tablets of 2, 5 and 10 mg in generic forms and formerly under the brand name of Valium. Oral solutions and rectal gels are also available. Current indications for oral diazepam include treatment of anxiety disorders, acute alcohol withdrawal and as an adjunct to relief of skeletal muscle spasm. Among oral forms of benzodiazepines, diazepam is not as effective or well tolerated as a therapy for epilepsy as are clobazam, clonazepam and clorazepate. The typical dose of diazepam used for anxiety is 2 to 10 mg given two to four times daily. Diazepam is also available as a solution for injection, usually in vials or syringes of 5 mg/mL. 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. Common side effects of diazepam include somnolence, dizziness, confusion, dysarthria, and diplopia. Acute overdose of diazepam can cause coma, respiratory arrest and death. Diazepam like all oral benzodiazepines has a boxed warning in its product label stressing (<a class="bibr" href="#DiazepamOral.REF.1" rid="DiazepamOral.REF.1">1</a>) 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 physical and psychological dependence and severe potentially life-threatening withdrawal symptoms if discontinued suddenly. Benzodiazepines are all categorized as Schedule IV controlled substances, having potential for dependence, tolerance, and abuse.</p></div><div id="DiazepamOral.Hepatotoxicity"><h3>Hepatotoxicity</h3><p>Like other benzodiazepines, diazepam is rarely associated with serum ALT or alkaline phosphatase elevations during therapy. Furthermore, clinically apparent liver injury from diazepam is exceedingly rare. A small number of cases of hepatic injury have been described in patients on oral diazepam, but the clinical pattern has varied. The onset of injury has ranged from 1 to 6 months, and pattern of serum enzyme elevations has typically been cholestatic or mixed. Fever and rash are uncommon as is autoantibody formation. 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 and before the general available of tests for acute hepatitis A and C and advanced methods of hepatic and biliary imaging.</p><p>Likelihood score: D (Possible but rare cause of clinically apparent liver injury).</p></div><div id="DiazepamOral.Mechanism_of_Injury"><h3>Mechanism of Injury</h3><p>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.</p></div><div id="DiazepamOral.Outcome_and_Management"><h3>Outcome and Management</h3><p>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 (clobazam, clorazepate, lorazepam or alprazolam), but some degree of cross sensitivity may occur.</p><p>Drug Class: <a href="/books/n/livertox/BenzodiazepineDrugs/?report=reader">Benzodiazepines</a>; see also <a href="/books/n/livertox/DiazepamIV/?report=reader">Diazepam (Intravenous)</a></p></div></div><div id="DiazepamOral.CASE_REPORT"><h2 id="_DiazepamOral_CASE_REPORT_">CASE REPORT</h2><div id="DiazepamOral.Case_1_Cholestatic_hepatiti"><h3>Case 1. Cholestatic hepatitis due to oral diazepam.(<a class="bibr" href="#DiazepamOral.REF.1" rid="DiazepamOral.REF.1">1</a>)</h3><p>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.</p><div id="DiazepamOral.Key_Points"><h4>Key Points</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figDiazepamOralTc"><a href="/books/NBK547871/table/DiazepamOral.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figDiazepamOralTc" rid-ob="figobDiazepamOralTc"><img class="small-thumb" src="/books/NBK547871/table/DiazepamOral.Tc/?report=thumb" src-large="/books/NBK547871/table/DiazepamOral.Tc/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="DiazepamOral.Tc"><a href="/books/NBK547871/table/DiazepamOral.Tc/?report=objectonly" target="object" rid-ob="figobDiazepamOralTc">Table</a></h4></div></div></div><div id="DiazepamOral.Comment"><h4>Comment</h4><p>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. 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.</p></div></div></div><div id="DiazepamOral.PRODUCT_INFORMATION"><h2 id="_DiazepamOral_PRODUCT_INFORMATION_">PRODUCT INFORMATION</h2><p>
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<b>REPRESENTATIVE TRADE NAMES</b>
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</p><p>Diazepam – Generic, Valium® <i>(Trade name discontinued)</i></p><p>
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<b>DRUG CLASS</b>
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</p><p>Benzodiazepines, Antianxiety Agents</p><p>
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<a href="https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=Diazepam" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COMPLETE LABELING</a>
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</p><p>Product labeling at DailyMed, National Library of Medicine, NIH</p></div><div id="DiazepamOral.CHEMICAL_FORMULA_AND_STRUCT"><h2 id="_DiazepamOral_CHEMICAL_FORMULA_AND_STRUCT_">CHEMICAL FORMULA AND STRUCTURE</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figDiazepamOralTd"><a href="/books/NBK547871/table/DiazepamOral.Td/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figDiazepamOralTd" rid-ob="figobDiazepamOralTd"><img class="small-thumb" src="/books/NBK547871/table/DiazepamOral.Td/?report=thumb" src-large="/books/NBK547871/table/DiazepamOral.Td/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="DiazepamOral.Td"><a href="/books/NBK547871/table/DiazepamOral.Td/?report=objectonly" target="object" rid-ob="figobDiazepamOralTd">Table</a></h4></div></div></div><div id="DiazepamOral.CITED_REFERENCES"><h2 id="_DiazepamOral_CITED_REFERENCES_">CITED REFERENCES</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="DiazepamOral.REF.1">Fors B, Nilsson F. <span><span class="ref-journal">Lakartidningen. </span>1968;<span class="ref-vol">65</span>:4528–31.</span> [Hepatitis probably induced by diazepam medication] Swedish. [<a href="https://pubmed.ncbi.nlm.nih.gov/5745628" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5745628</span></a>]</div></dd></dl></dl></div><div id="DiazepamOral.ANNOTATED_BIBLIOGRAPHY"><h2 id="_DiazepamOral_ANNOTATED_BIBLIOGRAPHY_">ANNOTATED BIBLIOGRAPHY</h2><p>References updated: 22 June 2023</p><ul class="first-line-outdent"><li><div class="bk_ref" id="DiazepamOral.REF.zimmerman.1999">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.<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.larrey.2013">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.<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.mihic.2018">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.<div><i>(Textbook of pharmacology and therapeutics).</i></div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.cook.1965.175">Cook GC, Sherlock S. Jaundice and its relation to therapeutic agents. <span><span class="ref-journal">Lancet. </span>1965;<span class="ref-vol">1</span>:175–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14238042" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14238042</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.cunningham.1965.1107">Cunningham ML. Acute hepatic necrosis following treatment with amitriptyline and diazepam. <span><span class="ref-journal">Brit J Psychiat. </span>1965;<span class="ref-vol">111</span>:1107–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/5841222" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5841222</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.buchanan.1978.768">Buchanan N, Cane RD. Liver function tests and the prolonged use of high-dose diazepam with special reference to tetanus. <span><span class="ref-journal">S Afr Med J. </span>1978;<span class="ref-vol">54</span>:768.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/741305" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 741305</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.stacher.1973.401">Stacher G. Intrahepatic cholostasis following combined diazepam-barbiturate therapy in patients with tetanus]. <span><span class="ref-journal">Wien Klin Wochenschr. </span>1973;<span class="ref-vol">85</span>:401–6.</span> German. [<a href="https://pubmed.ncbi.nlm.nih.gov/4705881" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 4705881</span></a>]</div></li><li><div class="bk_ref" id="DiazepamOral.REF.franks.1975.605">Franks E, Jacobs WH. Cholestatic jaundice possibly due to benzodiazepine-type drugs. <span><span class="ref-journal">Mo Med. </span>1975;<span class="ref-vol">72</span>:605–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1181510" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1181510</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.fors.1968.4528">Fors B, Nilsson F. <span><span class="ref-journal">Lakartidningen. </span>1968;<span class="ref-vol">65</span>:4528–31.</span> [Hepatitis probably induced by diazepam medication] Swedish. [<a href="https://pubmed.ncbi.nlm.nih.gov/5745628" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5745628</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.tedesco.1982.470">Tedesco FJ, Mills LR. Diazepam (Valium) hepatitis. <span><span class="ref-journal">Dig Dis Sci. </span>1982;<span class="ref-vol">27</span>:470–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7075434" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7075434</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.d_ssing.1982.205">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. <span><span class="ref-journal">Scand J Gastroenterol. </span>1982;<span class="ref-vol">17</span>:205–11.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6982502" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6982502</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.davion.1985.117">Davion T, Capron-Chivrac D, Andrejak M, Capron JP. <span><span class="ref-journal">Gastroenterol Clin Biol. </span>1985;<span class="ref-vol">9</span>:117–26.</span> [Hepatitis due to antiepileptic agents] [<a href="https://pubmed.ncbi.nlm.nih.gov/3920108" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3920108</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.judd.1986.388">Judd FK, Norman TR, Marriott PF, Burrows GD. A case of alprazolam-related hepatitis. <span><span class="ref-journal">Am J Psychiatry. </span>1986;<span class="ref-vol">143</span>:388–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/2869702" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2869702</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.nahata.1990.335">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. <span><span class="ref-journal">J Pediatr Gastroenterol Nutr. </span>1990;<span class="ref-vol">10</span>:335–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/2324894" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2324894</span></a>]<div>
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<i>(Prospective study of safety of intravenous diazepam in 30 children undergoing endoscopy; no mention of ALT abnormalities or liver injury).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.wallace.1996.378">Wallace SJ. A comparative review of the adverse effects of anticonvulsants in children with epilepsy. <span><span class="ref-journal">Drug Saf. </span>1996;<span class="ref-vol">15</span>:378–93.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8968693" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8968693</span></a>]<div>
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<i>(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,”).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.lewis.1999.433">Lewis JH, Zimmerman HJ. Drug- and chemical-induced cholestasis. <span><span class="ref-journal">Clin Liver Dis. </span>1999;<span class="ref-vol">3</span>:433–64.</span> vii. Erratum in: Clin Liver Dis 1999; 3: 917. [<a href="https://pubmed.ncbi.nlm.nih.gov/11291233" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11291233</span></a>]<div>
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<i>(Review of drug induced cholestatic syndromes, listing many causes including chlordiazepoxide and flurazepam; “Benzodiazepines may cause cholestatic injury, although this is rare”).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.selim.1999.1347">Selim K, Kaplowitz N. Hepatotoxicity of psychotropic drugs. <span><span class="ref-journal">Hepatology. </span>1999;<span class="ref-vol">29</span>:1347–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10216114" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10216114</span></a>]<div>
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<i>(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”).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.sabat_.2007.1401">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. <span><span class="ref-journal">Aliment Pharmacol Ther. </span>2007;<span class="ref-vol">25</span>:1401–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17539979" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17539979</span></a>]<div>
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<i>(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]).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.chalasani.2008.1924">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. <span><span class="ref-journal">Gastroenterology. </span>2008;<span class="ref-vol">135</span>:1924–34.</span> [<a href="/pmc/articles/PMC3654244/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3654244</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18955056" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18955056</span></a>]<div>
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<i>(Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, none were attributed to a benzodiazepine).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.bj_rnsson.2008.281">Björnsson E. Hepatotoxicity associated with antiepileptic drugs. <span><span class="ref-journal">Acta Neurol Scand. </span>2008;<span class="ref-vol">118</span>:281–90.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18341684" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18341684</span></a>]<div>
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<i>(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”).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.reuben.2010.2065">Reuben A, Koch DG, Lee WM., Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. <span><span class="ref-journal">Hepatology. </span>2010;<span class="ref-vol">52</span>:2065–76.</span> [<a href="/pmc/articles/PMC3992250/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3992250</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20949552" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20949552</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.bj_rnsson.2013.1419">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. <span><span class="ref-journal">Gastroenterology. </span>2013;<span class="ref-vol">144</span>:1419–25.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23419359" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23419359</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.hern_ndez.2014.231">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. <span><span class="ref-journal">Ann Hepatol. </span>2014;<span class="ref-vol">13</span>:231–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24552865" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24552865</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.chalasani.2015.1340">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. <span><span class="ref-journal">Gastroenterology. </span>2015;<span class="ref-vol">148</span>:1340–1352.e7.</span> [<a href="/pmc/articles/PMC4446235/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4446235</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25754159" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25754159</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.carvalhana.2017.40">Carvalhana S, Oliveira A, Ferreira P, Resende M, Perdigoto R, Barroso E. Acute liver failure due to trazodone and diazepam. <span><span class="ref-journal">GE Port J Gastroenterol. </span>2017;<span class="ref-vol">24</span>:40–42.</span> [<a href="/pmc/articles/PMC5553376/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5553376</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28848778" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28848778</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.lugoboni.2018.451">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. <span><span class="ref-journal">Expert Opin Drug Saf. </span>2018;<span class="ref-vol">17</span>:451–456.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/29621907" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29621907</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF28">Drugs for anxiety disorders. <span><span class="ref-journal">Med Lett Drugs Ther. </span>2019;<span class="ref-vol">61</span>:121–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31386647" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31386647</span></a>]<div>
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<i>(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).</i>
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</div></div></li><li><div class="bk_ref" id="DiazepamOral.REF.kamitaki.2021.107832">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). <span><span class="ref-journal">Epilepsy Behav. </span>2021;<span class="ref-vol">117</span>:107832. </span> [<a href="https://pubmed.ncbi.nlm.nih.gov/33626490" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33626490</span></a>]<div>
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<i>(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).</i>
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</div></div></li></ul></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK547871_pubdet_">Publication Details</h2><h3>Publication History</h3><p class="small">Last Update: <span itemprop="dateModified">June 22, 2023</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p><a href="https://www.niddk.nih.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Institute of Diabetes and Digestive and Kidney Diseases</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Diazepam (Oral) [Updated 2023 Jun 22].<span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/livertox/DiazepamIV/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/livertox/Diclofenac/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobDiazepamOralTc"><div id="DiazepamOral.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547871/table/DiazepamOral.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__DiazepamOral.Tc_lrgtbl__"><table><tbody><tr><th id="hd_b_DiazepamOral.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Medication:</th><td headers="hd_b_DiazepamOral.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Diazepam (2 mg three times daily orally)</td></tr><tr><th id="hd_b_DiazepamOral.Tc_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pattern:</th><td headers="hd_b_DiazepamOral.Tc_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Mixed (R=~4)</td></tr><tr><th id="hd_b_DiazepamOral.Tc_1_1_3_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Severity:</th><td headers="hd_b_DiazepamOral.Tc_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3+ (jaundice, hospitalization)</td></tr><tr><th id="hd_b_DiazepamOral.Tc_1_1_4_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Latency:</th><td headers="hd_b_DiazepamOral.Tc_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4 months</td></tr><tr><th id="hd_b_DiazepamOral.Tc_1_1_5_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Recovery:</th><td headers="hd_b_DiazepamOral.Tc_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Complete recovery within a month of stopping</td></tr><tr><th id="hd_b_DiazepamOral.Tc_1_1_6_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Other medications:</th><td headers="hd_b_DiazepamOral.Tc_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Birth control pills</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobDiazepamOralTd"><div id="DiazepamOral.Td" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547871/table/DiazepamOral.Td/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__DiazepamOral.Td_lrgtbl__"><table><thead><tr><th id="hd_h_DiazepamOral.Td_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRUG</th><th id="hd_h_DiazepamOral.Td_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CAS REGISTRY NUMBER</th><th id="hd_h_DiazepamOral.Td_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MOLECULAR FORMULA</th><th id="hd_h_DiazepamOral.Td_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">STRUCTURE</th></tr></thead><tbody><tr><td headers="hd_h_DiazepamOral.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Diazepam</td><td headers="hd_h_DiazepamOral.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134974836" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">439-14-5</a>
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</td><td headers="hd_h_DiazepamOral.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">C16-H13-Cl-N2-O</td><td headers="hd_h_DiazepamOral.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134974836" title="View this structure in PubChem" class="img_link" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem"><img src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&sid=134974836" alt="image 134974836 in the ncbi pubchem database" /></a>
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