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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="_NBK548298_"><span class="title" itemprop="name">Benzodiazepines</span></h1><p class="fm-aai"><a href="#_NBK548298_pubdet_">Publication Details</a></p></div></div><div class="body-content whole_rhythm" itemprop="text"><div id="BenzodiazepineDrugs.OVERVIEW"><h2 id="_BenzodiazepineDrugs_OVERVIEW_">OVERVIEW</h2><p>The benzodiazepines are a large class of medications that have multiple clinical uses including therapy of anxiety, insomnia, muscle spasm, alcohol withdrawal and seizures. As a class, the benzodiazepines do not cause significant serum enzyme elevations and have been linked to only very rare instances of acute, symptomatic liver disease.</p><p>The pharmacological effects of the benzodiazepines are a result of their interaction with the central nervous system, their effects being sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia and anticonvulsant activity. At high doses, when given intravenously, the benzodiazepines may also cause coronary vasodilation and neuromuscular blockade. The CNS effects of benzodiazepines are believed to be mediated by activation of GABA A receptors and modulation of their inhibition of neurotransmission.</p><p>Benzodiazepines in current use, with their initial brand name and year of approval, include alprazolam (Xanax, 1981), chlordiazepoxide (Librium, 1960), clonazepam (Klonopin, 1997), clorazepate (Tranxene, 1972), diazepam (Valium, 1963), estazolam (ProSom, 1990), flurazepam (Dalmane, 1970), lorazepam (Ativan, 1977), midazolam (Versed, 1985), oxazepam (Serax, 1965), quazepam (Doral, 1985), temazepam (Restoril, 1981), triazolam (Halcion, 1982), and most recently clobazam (2011). They are variously indicated for treatment of anxiety, alcohol withdrawal symptoms, insomnia, muscle relaxation, panic disorders and seizure disorders. The benzodiazepines all share similar activity and clinical effects, but variability in dosing, pharmacokinetics, rapidity of uptake and half-life make them more suited for one or another of these indications. Thus, estazolam, flurazepam, quazepam, temazepam and triazolam are generally used as sleeping pills, whereas alprazolam, chlordiazepoxide, diazepam, and lorazepam are used largely in therapy of anxiety. Clobazam, clonazepam, and clorazepate are used as anticonvulsants, and high dose, parenteral diazepam and lorazepam are used for status epilepticus. Parenteral midazolam, diazepam and lorazepam are also used as anesthetics or anesthetic premedications.</p><p>Benzodiazepine therapy is uncommonly associated with serum enzyme elevations, and clinically apparent liver injury from the benzodiazepines is quite rare. Alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam and triazolam have been linked to rare instances of cholestatic liver injury but the other benzodiazepines have not. The absence of reports of this rare adverse event, however, may be due to the fact that these other benzodiazepines are not as commonly or continuously used. Alternatively, the use of the sleeping aids in intermittent and low doses may favor their lack of hepatic injury.</p><p>References for drug induced liver injury for all of the benzodiazepines follow this introduction, and specific references are appended to the text for the specific agents. The individual agents discussed include the following:</p><ul><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Alprazolam/?report=reader">Alprazolam</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Chlordiazepoxide/?report=reader">Chlordiazepoxide</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/DiazepamOral/?report=reader">Diazepam (Oral)</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Estazolam/?report=reader">Estazolam</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Flurazepam/?report=reader">Flurazepam</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Lorazepam/?report=reader">Lorazepam</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Midazolam/?report=reader">Midazolam</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Oxazepam/?report=reader">Oxazepam</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Quazepam/?report=reader">Quazepam</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Remimazolam/?report=reader">Remimazolam</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Temazepam/?report=reader">Temazepam</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Triazolam/?report=reader">Triazolam</a>
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</div></li></ul><p>The following benzodiazepine drugs are discussed in the record for Anticonvulsants Drugs:</p><ul><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Clobazam/?report=reader">Clobazam</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Clonazepam/?report=reader">Clonazepam</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/Clorazepate/?report=reader">Clorazepate</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/livertox/DiazepamIV/?report=reader">Diazepam (Intravenous)</a>
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</div></li></ul><p>Drug Class: <a href="/books/n/livertox/Anticonvulsants/?report=reader">Anticonvulsants</a>, <a href="/books/NBK548298/?report=reader">Benzodiazepines</a></p></div><div id="BenzodiazepineDrugs.CHEMICAL_FORMULAS_AN"><h2 id="_BenzodiazepineDrugs_CHEMICAL_FORMULAS_AN_">CHEMICAL FORMULAS AND STRUCTURES</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figBenzodiazepineDrugsTc"><a href="/books/NBK548298/table/BenzodiazepineDrugs.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figBenzodiazepineDrugsTc" rid-ob="figobBenzodiazepineDrugsTc"><img class="small-thumb" src="/books/NBK548298/table/BenzodiazepineDrugs.Tc/?report=thumb" src-large="/books/NBK548298/table/BenzodiazepineDrugs.Tc/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="BenzodiazepineDrugs.Tc"><a href="/books/NBK548298/table/BenzodiazepineDrugs.Tc/?report=objectonly" target="object" rid-ob="figobBenzodiazepineDrugsTc">Table</a></h4></div></div></div><div id="BenzodiazepineDrugs.ANNOTATED_BIBLIOGRAP"><h2 id="_BenzodiazepineDrugs_ANNOTATED_BIBLIOGRAP_">ANNOTATED BIBLIOGRAPHY</h2><p>References updated: 24 January 2017</p><ul class="first-line-outdent"><li><div class="bk_ref" id="BenzodiazepineDrugs.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 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="BenzodiazepineDrugs.REF.larrey.2013">Larrey D, Ripault M-P. Benzodiazepines. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 455.<div><i>(Review of drug induced liver injury mentions that there have been rare instances of acute liver injury [usually cholestatic] reported with alprazolam, chlordiazepoxide, clonazepam, clorazepate, clotiazepam, diazepam, flurazepam, triazolam and more recently bentazepam [which is not available in the US]; a hepatitis-like pattern was reported with alprazolam and diazepam).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.mihic.2011">Mihic SJ, Harris RA. Hypnotics and sedatives. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 457-80.<div><i>(Textbook of pharmacology and therapeutics).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.cacioppo.1961.1040">Cacioppo
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J, Merlis
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S.
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Chlordiazepoxide hydrochloride(Librium) and jaundice: report of a case.
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Am J Psychiatry
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1961; 117: 1040-1. [<a href="https://pubmed.ncbi.nlm.nih.gov/13689710" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 13689710</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.cook.1965.175">Cook
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GC, Sherlock
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S. Jaundice and its relation to therapeutic agents.
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Lancet
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1965; 1: 175-9. [<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><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 in both cases).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.abbruzzese.1965.321">Abbruzzese
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A, Swanson
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J. Jaundice after therapy with chlordiazepoxide hydrochloride.
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N Engl J Med
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1965; 273; 321-2. Not in PubMed [<a href="https://pubmed.ncbi.nlm.nih.gov/21417069" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21417069</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.cunningham.1965.1107">Cunningham
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ML. Acute hepatic necrosis following treatment with amitriptyline and diazepam.
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Brit J Psychiat
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1965; 111: 1107-9. [<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><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.pickering.1966.1449">Pickering
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D.
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Hepatic necrosis after chlordiazepoxide therapy.
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N Engl J Med
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1966; 274: 1449. Not in PubMed<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.lo.1967.845">Lo
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KJ, Eastwood
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IR, Eidelman
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S. Cholestatic jaundice associated with chlordiazepoxide hydrochloride (Librium) therapy. Report of a case and review of the literature.
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Am J Dig Dis
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1967; 12: 845-9. [<a href="https://pubmed.ncbi.nlm.nih.gov/4952749" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 4952749</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.buchanan.1978.768">Buchanan
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N, Cane
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RD. Liver function tests and the prolonged use of high-dose diazepam with special reference to tetanus.
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S Afr Med J
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1978
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54: 768. [<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><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 therapy).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.kratzsch.1972.408">Kratzsch
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KH, Buttner
|
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W, Reinhardt
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G. [Intrahepatic cholestasis following chlordiazepoxide-contribution to the differential diagnosis of drug jaundice]. Z Gesamte
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Inn Med
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1972; 27: 408-11. German. [<a href="https://pubmed.ncbi.nlm.nih.gov/5055057" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5055057</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.stacher.1973.401">Stacher
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G.
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Intrahepatic cholostasis following combined diazepam-barbiturate therapy in patients with tetanus].
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Wien Klin Wochenschr.
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1973; 85: 401-6. 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="BenzodiazepineDrugs.REF.franks.1975.605">Franks
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E, Jacobs
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WH. Cholestatic jaundice possibly due to benzodiazepine-type drugs.
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Mo Med
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1975; 72: 605-6. [<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><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], seemed to worsen on benzodiazepines including chlordiazepoxide, diazepam and flurazepam, resolving rapidly when they were stopped, but attribution to benzodiazepines difficult).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.fors.1968.4528">Fors
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B, Nilsson
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F.
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[Hepatitis probably induced by diazepam medication]
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Lakartidningen
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1968; 65: 4528-31. 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><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], with rapid resolution with stopping).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.fang.1978.363">Fang
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MH, Ginsberg
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AL, Dobbins
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WO
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3rd. Cholestatic jaundice associated with flurazepam hydrochloride.
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Ann Intern Med
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1978; 89: 363-4. [<a href="https://pubmed.ncbi.nlm.nih.gov/28685" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28685</span></a>]<div><i>(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 the drug was withdrawn).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.parker.1979.908">Parker
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JLW. Potassium clorazepate(Tranxene)-induced jaundice.
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Postgrad Med J
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1979; 55: 908-10. [<a href="/pmc/articles/PMC2425684/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2425684</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/44913" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 44913</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.bonkowsky.1980.588">Bonkowsky
|
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HL, Sinclair
|
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PR, Emery
|
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S, Sinclair
|
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JF. Seizure management in acute hepatic porphyria: risks of valproate and clonazepam.
|
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Neurology
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1980; 30: 588-92. [<a href="https://pubmed.ncbi.nlm.nih.gov/6770287" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6770287</span></a>]<div><i>(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 porphyrins and ALA synthase activity).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.cobden.1981.730">Cobden
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I, Record
|
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CO, White
|
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RWB. Fatal intrahepatic cholestasis associated with triazolam.
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Postgrad Med J
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1981; 57: 730-1. [<a href="/pmc/articles/PMC2426204/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2426204</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/6122205" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6122205</span></a>]<div><i>(44 year old man developed jaundice after 5 months of intermittent triazolam therapy for insomnia [bilirubin 10.6 mg/dL, AST 97 U/L, Alk P 104 U/L]; jaundice deepened and patient died, autopsy showing intrahepatic cholestasis without obstruction or cirrhosis).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.reynolds.1981.893">Reynolds
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R, Lloyd
|
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DA, Slinger
|
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RP. Cholestatic jaundice induced by flurazepam hydrochloride.
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Can Med Assoc J
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1981; 124: 893-4. [<a href="/pmc/articles/PMC1705357/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1705357</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7214289" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7214289</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.tedesco.1982.470">Tedesco
|
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FJ, Mills
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LR. Diazepam(Valium) hepatitis.
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Dig Dis Sci
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1982; 27: 470-2. [<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><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></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.d_ssing.1982.205">Døssing
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M, Andreasen
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PB. Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to the Danish Board of Adverse Reactions to Drugs.
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Scand J Gastroenterol
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1982; 17: 205-11. [<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><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></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.jacobson.1983.296">Jacobson
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AF, Goldstein
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BJ, Dominguez
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RA, Steinbook
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RM. A placebo-controlled, double-blind comparison of clobazam and diazepam in the treatment of anxiety.
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J Clin Psychiatry
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1983; 44: 296-300. [<a href="https://pubmed.ncbi.nlm.nih.gov/6135690" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6135690</span></a>]<div><i>(Controlled trial of 4 weeks of diazepam vs clobazam vs placebo in 114 patients with anxiety found sedation similar with either drug, but dizziness more frequent with diazepam; no mention of ALT elevations or hepatotoxicity, although ALT was measured at the start and end of therapy).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.roybyrne.1983.786">Roy-Byrne
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P, Vittone
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BJ, Uhde
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TW. Alprazolam-related hepatotoxicity.
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Lancet.
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1983; 2: 786-7. [<a href="https://pubmed.ncbi.nlm.nih.gov/6137615" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6137615</span></a>]<div><i>(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]).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.ker_nen.1983.69">Keränen
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T, Sivenius
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J. Side effects of carbamazepine, valproate and clonazepam during long-term treatment of epilepsy.
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Acta Neurol Scand Suppl
|
|
1983; 97: 69-80. [<a href="https://pubmed.ncbi.nlm.nih.gov/6424398" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6424398</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.davion.1985.117">Davion
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T, Capron-Chivrac
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D, Andrejak
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M, Capron
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JP. [Hepatitis due to antiepileptic agents]
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Gastroenterol Clin Biol
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1985; 9: 117-26. [<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><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 rare).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.judd.1986.388">Judd
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FK, Norman
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TR, Marriott
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PF, Burrows
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GD. A case of alprazolam-related hepatitis.
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Am J Psychiatry
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1986; 143: 388-9. [<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><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></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.noyes.1988.423">Noyes
|
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R, DuPont
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RL, Pecknold
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JC, Rifkin
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A, Rubin
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RT, Swinson
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RP, Ballenger
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JC, et al.
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Alprazolam in panic disorder and agoraphobia: results from a multicenter trial.
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Arch Gen Psychiatry
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1988; 45: 423-8. [<a href="https://pubmed.ncbi.nlm.nih.gov/3358644" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3358644</span></a>]<div><i>(Controlled trial of alprazolam vs placebo in 525 patients with panic disorder; side effects were sedation, ataxia, fatigue, slurred speech, amnesia and increased appetite; 2 patients on alprazolam developed liver disease, one with jaundice at 4 weeks, resolving quickly on stopping and a second with abnormal laboratory values that returned to normal with lowering the dose; details not given).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.olsson.1988.576">Olsson
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R, Zettergren
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L.
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Anticonvulsant-induced liver damage.
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Am J Gastroenterol
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1988; 83: 576-7. [<a href="https://pubmed.ncbi.nlm.nih.gov/3364416" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3364416</span></a>]<div><i>(30 year old man developed fever, rash and jaundice 6 weeks after starting phenytoin; he was switched to carbamazepine and clonazepam, but redeveloped jaundice 3 months later; resolved with stopping, but recurred with restarting clonazepam 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 clonazepam).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.habersetzer.1989.256">Habersetzer
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F, Larrey
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D, Babany
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G, Degott
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C, Corbic
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M, Pessayre
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D, Benhamou
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JP. Clotiazepam-induced acute hepatitis.
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J Hepatol
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1989; 9: 256-9. [<a href="https://pubmed.ncbi.nlm.nih.gov/2572625" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2572625</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.nahata.1990.335">Nahata
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MC, Murray
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RD, Zingarelli
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J, Li
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BU, McClung
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HJ, Lininger
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B. Efficacy and safety of a diazepam and meperidine combination for pediatric gastrointestinal procedures.
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J Pediatr Gastroenterol Nutr
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1990; 10: 335-8. [<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><i>(Safety of use of intravenous diazepam in children undergoing endoscopy; no mention of ALT abnormalities or liver injury).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF31">Clobazam in treatment of refractory epilepsy: the Canadian experience. A retrospective study. Canadian Clobazam Cooperative Group.
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Epilepsia
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1991; 32: 407-16. [<a href="https://pubmed.ncbi.nlm.nih.gov/2044502" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2044502</span></a>]<div><i>(Retrospective survey of Canadian neurologists with experience using clobazam in refractory epilepsy in a total of 877 patients; 32% had adverse events, most commonly somnolence, dizziness, ataxia, mood changes, hostility, blurred vision and weight gain; no mention of ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.suzuki.1992.108">Suzuki
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A, Aso
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K, Ariyoshi
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C, Ishimaru
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M. Acute intermittent porphyria and epilepsy: safety of clonazepam.
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Epilepsia
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1992; 33: 108-11. [<a href="https://pubmed.ncbi.nlm.nih.gov/1733741" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1733741</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.hindmarch.1993.55">Hindmarch
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I, Fairweather
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DB, Rombaut
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N. Adverse events after triazolam substitution.
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Lancet
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1993; 341: 55. [<a href="https://pubmed.ncbi.nlm.nih.gov/8093301" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8093301</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.andrade.1994.860">Andrade
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RJ, Lucena
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MI, Alcantara
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R, Fraile
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JM. Bentazepam-associated chronic liver disease.
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Lancet
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1994; 343: 860. [<a href="https://pubmed.ncbi.nlm.nih.gov/7908109" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7908109</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.andrade.2000.1400">Andrade
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RJ, Lucena
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MI, Aguilar
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J, Lazo
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MD, Camargo
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R, Moreno
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P, García-Escaño
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MD, et al.
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Chronic liver injury related to use of bentazepam: an unusual instance of benzodiazepine hepatotoxicity.
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Dig Dis Sci
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2000; 45: 1400-4. [<a href="https://pubmed.ncbi.nlm.nih.gov/10961721" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10961721</span></a>]<div><i>(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 switched to other benzodiazepines without difficulty).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.moulin.1994.362">Moulin
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CH, Rolachon
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A, Cohard
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M, Girard
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M, Bichard
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P, Pasquier
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D, Mallaret
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M, et al.
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[Fulminant hepatitis secondary to alprazolam]
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Therapie
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1994; 49: 362-3. French. [<a href="https://pubmed.ncbi.nlm.nih.gov/7878609" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7878609</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.wallace.1996.378">Wallace
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SJ. A comparative review of the adverse effects of anticonvulsants in children with epilepsy.
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Drug Saf
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1996; 15: 378-93. [<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><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></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.lewis.1999.433">Lewis
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JH, Zimmerman
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HJ. Drug- and chemical-induced cholestasis.
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Clin Liver Dis
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1999; 3: 433-64, vii. [<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><i>(Review of drug induced cholestatic syndromes, listing many causes including chlordiazepoxide and flurazepam; “Benzodiazepines may cause cholestatic injury, although this is rare”).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.selim.1999.1347">Selim
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K, Kaplowitz
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N. Hepatotoxicity of psychotropic drugs.
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Hepatology
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1999; 29: 1347-51. [<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><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></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.delaserna.1997.710">de-la-Serna
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C, Gil-Grande
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LA, Sanromán
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AL, Gonzalez
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M, Ruiz-del-Arbol
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L, Garcia Plaza
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A. Bentazepam-induced hepatic bridging necrosis.
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J Clin Gastroenterol.
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1997;25:710-1. [<a href="https://pubmed.ncbi.nlm.nih.gov/9451703" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9451703</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.kanda.2002.1111">Kanda
|
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T, Yokosuka
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O, Fujiwara
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K, Saisho
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H, Shiga
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H, Oda
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S, Okuda
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K, et al.
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Fulminant hepatic failure associated with triazolam.
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Dig Dis Sci
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2002; 47: 1111-4. [<a href="https://pubmed.ncbi.nlm.nih.gov/12018909" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12018909</span></a>]<div><i>(64 year old woman developed acute liver failure after taking triazolam intermittently for a year [bilirubin 6.1 rising to 18.6 mg/dL, ALT 1272 U/L] with progressive ascites and encephalopathy; successful living donor liver transplant 1 month after onset).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.andrade.2003.678">Andrade
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RJ, López-Torres
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E, Lucena
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MI, Fernández Mdel
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C. [Acute hepatitis due to bentazepam]. Med Clin (Barc)
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2003; 120: 678-9. Spanish. [<a href="https://pubmed.ncbi.nlm.nih.gov/12747823" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12747823</span></a>]<div><i>(Bentazepam is an oral benzodiazepine that was approved for use in anxiety in 1981 in Spain [but never in the US]; 55 year old woman developed fatigue within 2 weeks and jaundice with 4-5 months of starting bentazepam therapy [bilirubin 9.3 mg/dL, ALT 1932 U/L, Alk P 160 U/L], improving after stopping).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.russo.2004.1018">Russo
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MW, Galanko
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JA, Shrestha
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R, Fried
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MW, Watkins
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P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States.
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Liver Transpl
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2004; 10: 1018-23. [<a href="https://pubmed.ncbi.nlm.nih.gov/15390328" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15390328</span></a>]<div><i>(Among ~50,000 liver transplants done in the US 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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.bj_rnsson.2005.1095">Björnsson
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E, Jerlstad
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P, Bergqvist
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A, Olsson
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R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden.
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Scand J Gastroenterol
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2005; 40: 1095-101. [<a href="https://pubmed.ncbi.nlm.nih.gov/16165719" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16165719</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.gilmart_n.2005.461">Gil-Martín
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A, Sáez-Royuela
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F, Arias
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L, Angulo
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ML, Nogal
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B. [Hepatic fibrosis after antidepressant treatment]. Rev Esp Enferm Dig.
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2005;97:461-2. Spanish. [<a href="https://pubmed.ncbi.nlm.nih.gov/16048430" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16048430</span></a>]<div><i>(32 year old woman developed pruritis and jaundice 1-2 months after starting sertraline, alprazolam and clorazepate, resolving with stopping sertraline, but had persistent minor ALT elevations and biopsy showing mild bridging fibrosis 4 months later).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.andrade.2006.1581">Andrade
|
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RJ, Lucena
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MI, Kaplowitz
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N, García-Muņoz
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B, Borraz
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Y, Pachkoria
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K, García-Cortés
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Hepatology.
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2006; 44: 1581-8. [<a href="https://pubmed.ncbi.nlm.nih.gov/17133470" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17133470</span></a>]<div><i>(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).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.sabat_.2007.1401">Sabaté
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M, Ibáñez
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L, Pérez
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E, Vidal
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X, Buti
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M, Xiol
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Aliment Pharmacol Ther
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2007; 25: 1401-9. [<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><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, relative risk of injury was increased only for clorazepate [8.3: estimated frequency 3.4 per 100,000 person-year exposures]).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.chalasani.2008.1924">Chalasani
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N, Fontana
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RJ, Bonkovsky
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HL, Watkins
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PB, Davern
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T, Serrano
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J, Yang
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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.
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Gastroenterology
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2008; 135: 1924-34. [<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><i>(Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, none were attributed to a benzodiazepine).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.bj_rnsson.2008.281">Björnsson
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E.
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Hepatotoxicity associated with antiepileptic drugs.
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Acta Neurol Scand
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2008; 118: 281-90. [<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><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></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.conry.2009.1158">Conry
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JA, Ng
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YT, Paolicchi
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JM, Kernitsky
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L, Mitchell
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WG, Ritter
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FJ, Collins
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SD, Tracy
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K, et al.
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Clobazam in the treatment of Lennox-Gastaut syndrome.
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Epilepsia
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2009; 50: 1158-66. [<a href="https://pubmed.ncbi.nlm.nih.gov/19170737" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19170737</span></a>]<div><i>(Among 68 children with Lennox-Gastaut syndrome who were treated with either low or high dose clobazam for 7 weeks, seizure reduction was more frequent with the higher dose as were side effects, which included somnolence, sedation, constipation, salivation, insomnia, irritability and lability; no mention of ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.ferrajolo.2010.721">Ferrajolo
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C, Capuano
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A, Verhamme
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KM, Schuemie
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M, Rossi
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F, Stricker
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MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase.
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Br J Clin Pharmacol
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2010; 70: 721-8. [<a href="/pmc/articles/PMC2997312/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2997312</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21039766" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21039766</span></a>]<div><i>(Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children; benzodiazepines were not among the top 40 agents implicated).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.reuben.2010.2065">Reuben
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A, Koch
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DG, Lee
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WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study.
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Hepatology
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2010; 52: 2065-76. [<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><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 linked to benzodiazepine use).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.ng.2011.1473">Ng
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YT, Conry
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JA, Drummond
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R, Stolle
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J, Weinberg
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MA; OV-1012 Study Investigators. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome.
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Neurology.
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2011; 77: 1473-81. [<a href="https://pubmed.ncbi.nlm.nih.gov/21956725" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21956725</span></a>]<div><i>(Among 238 patients with Lennox-Gastaut syndrome treated with one of 3 doses of clobazam or placebo for at least 18 weeks, no patient developed serious hepatic adverse events and there were no abnormal clinical laboratory results linked to clobazam therapy).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF54">Clobazam (Onfi) for Lennox-Gastaut syndrome.
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Med Lett Drugs Ther
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2012; 54 (1385): 18-9. [<a href="https://pubmed.ncbi.nlm.nih.gov/22382580" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22382580</span></a>]<div><i>(Concise review of the pharmacology, clinical efficacy, adverse events, drug interactions and costs of clobazam for Lennox-Gastaut syndrome shortly after its approval for this indication in the US; no mention of ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.yang.2012.983">Yang
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LP, Scott
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LJ. Clobazam : in patients with Lennox-Gastaut syndrome.
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CNS Drugs
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2012; 26: 983-91. [<a href="https://pubmed.ncbi.nlm.nih.gov/23034582" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23034582</span></a>]<div><i>(Summary of the structure, mechanism of action, pharmacology, clinical efficacy and safety of clobazam for Lennox Gastaut syndrome; no mention of hepatotoxicity or ALT elevations).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.ng.2012.687">Ng
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YT, Conry
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J, Paolicchi
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J, Kernitsky
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L, Mitchell
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W, Drummond
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R, Isojarvi
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J, Lee
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D, Owen
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R; OV-1004 study investigators. Long-term safety and efficacy of clobazam for Lennox-Gastaut syndrome: interim results of an open-label extension study.
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Epilepsy Behav
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2012; 25: 687-94. [<a href="https://pubmed.ncbi.nlm.nih.gov/23141144" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23141144</span></a>]<div><i>(Among 267 children and adults who participated in controlled trials of clobazam and were enrolled in a long term extension study, 13 discontinued therapy because of side effects and six died, but none were attributed to hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.wick.2013.538">Wick
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JY. The history of benzodiazepines.
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Consult Pharm
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2013; 28: 538-48. [<a href="https://pubmed.ncbi.nlm.nih.gov/24007886" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24007886</span></a>]<div><i>(History of the development, approval, widescale use and eventual restriction and decrease in use of the benzodiazepines).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.bj_rnsson.2013.1419">Björnsson
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ES, Bergmann
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OM, Björnsson
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HK, Kvaran
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RB, Olafsson
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S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.
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Gastroenterology
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2013; 144: 1419-25. [<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><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 linked to benzodiazepines).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.wheless.2013.219">Wheless
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JW, Phelps
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SJ. Clobazam: a newly approved but well-established drug for the treatment of intractable epilepsy syndromes.
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J Child Neurol
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2013; 28: 219-29. [<a href="https://pubmed.ncbi.nlm.nih.gov/23112237" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23112237</span></a>]<div><i>(Review of the pharmacology, safety and efficacy of clobazam in Lennox Gastaut syndrome; no mention of hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF60">Drugs for epilepsy.
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Treat Guidel Med Lett.
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2013; 11: 9-18. Erratum in: Treat Guidel Med Lett. 2013; 11: 112. [<a href="https://pubmed.ncbi.nlm.nih.gov/23348233" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23348233</span></a>]<div><i>(Concise review of indications and side effects of anticonvulsants; clobazam is approved only for treatment of severe seizures associated with Lennox-Gastaut syndrome; no mention of hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.bj_rnsson.2013.1419_1">Björnsson
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ES, Bergmann
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OM, Björnsson
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HK, Kvaran
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RB, Olafsson
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S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.
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Gastroenterology
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2013; 144: 1419-25. [<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><i>(In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none of the 96, none were attributed to clobazam or other benzodiazepines).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.klehm.2014.60">Klehm
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J, Thome-Souza
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S, Sánchez Fernández
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I, Bergin
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AM, Bolton
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J, Harini
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C, Kadish
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NE, et al.
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Clobazam: effect on frequency of seizures and safety profile in different subgroups of children with epilepsy.
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Pediatr Neurol
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2014; 51: 60-6. [<a href="https://pubmed.ncbi.nlm.nih.gov/24830765" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24830765</span></a>]<div><i>(Among 300 children with seizures treated with clobazam for more than 1 month at a single referral center, 28% became seizure free and the most common side effects were tiredness [15%] and mood or behavioral changes [8%]; no mention of ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.conry.2014.558">Conry
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JA, Ng
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YT, Kernitsky
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L, Mitchell
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WG, Veidemanis
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R, Drummond
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R, Isojarvi
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J, Lee
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D, et al.; OV-1004 Study Investigators. Stable dosages of clobazam for Lennox-Gastaut syndrome are associated with sustained drop-seizure and total-seizure improvements over 3 years.
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Epilepsia
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2014; 55: 558-67. [<a href="/pmc/articles/PMC4303987/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4303987</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24580023" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24580023</span></a>]<div><i>(Among 267 patients with Lennox-Gastaut syndrome enrolled in a long term, open label, observational study of clobazam, adverse events were similar to those in controlled trials and none of the serious adverse events or the 18 discontinuations because of side effects or the 10 deaths were attributed to liver injury).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.hern_ndez.2014.231">Hernández
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N, Bessone
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F, Sánchez
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A, di Pace
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M, Brahm
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J, Zapata
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R, A
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Chirino
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R, et al.
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Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports.
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Ann Hepatol
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2014; 13: 231-9. [<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><i>(Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, but none were attributed to a benzodiazepine).</i></div></div></li><li><div class="bk_ref" id="BenzodiazepineDrugs.REF.chalasani.2015.1340">Chalasani
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N, Bonkovsky
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HL, Fontana
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R, Lee
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W, Stolz
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A, Talwalkar
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J, Reddy
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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.
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Gastroenterology
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2015; 148: 1340-52.e7. [<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><i>(Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, no cases were attributed to a benzodiazepine).</i></div></div></li></ul></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK548298_pubdet_">Publication Details</h2><h3>Publication History</h3><p class="small">Last Update: <span itemprop="dateModified">January 24, 2017</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-. Benzodiazepines. [Updated 2017 Jan 24].<span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/livertox/Benznidazole/?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/Benztropine/?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="figobBenzodiazepineDrugsTc"><div id="BenzodiazepineDrugs.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK548298/table/BenzodiazepineDrugs.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__BenzodiazepineDrugs.Tc_lrgtbl__"><table><thead><tr><th id="hd_h_BenzodiazepineDrugs.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">DRUG</th><th id="hd_h_BenzodiazepineDrugs.Tc_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAS REGISTRY NUMBER</th><th id="hd_h_BenzodiazepineDrugs.Tc_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MOLECULAR FORMULA</th><th id="hd_h_BenzodiazepineDrugs.Tc_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">STRUCTURE</th></tr></thead><tbody><tr><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Alprazolam</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134997022" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">28981-97-7</a>
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</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C17-H13-Cl-N4</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134997022" 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=134997022" alt="image 134997022 in the ncbi pubchem database" /></a>
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</td></tr><tr><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Diazepam</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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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_BenzodiazepineDrugs.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C16-H13-Cl-N2-O</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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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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</td></tr><tr><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Flurazepam</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134979955" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1172-18-5</a>
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</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C21-H23-Cl-F-N3-O.2Cl-H</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134979955" 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=134979955" alt="image 134979955 in the ncbi pubchem database" /></a>
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</td></tr><tr><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Lorazepam</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134979720" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">846-49-1</a>
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</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C15-H10-Cl2-N2-O2</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134979720" 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=134979720" alt="image 134979720 in the ncbi pubchem database" /></a>
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</td></tr><tr><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Midazolam</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/135006020" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">59467-70-8</a>
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</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C18-H13-Cl-F-N3</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/135006020" 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=135006020" alt="image 135006020 in the ncbi pubchem database" /></a>
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</td></tr><tr><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Clobazam</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134994740" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">22316-47-8</a>
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</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C16-H13-Cl-N2-O2</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134994740" 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=134994740" alt="image 134994740 in the ncbi pubchem database" /></a>
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</td></tr><tr><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Clonazepam</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134979678" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1622-61-3</a>
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</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C15-H10-Cl-N3-O3</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134979678" 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=134979678" alt="image 134979678 in the ncbi pubchem database" /></a>
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</td></tr><tr><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Clorazepate</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/135004253" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57109-90-7</a>
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</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C16-H10-Cl-N4-O3.K.H-K-O</td><td headers="hd_h_BenzodiazepineDrugs.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/135004253" 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=135004253" alt="image 135004253 in the ncbi pubchem database" /></a>
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