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<!-- Definition and medical uses -->
<!-- Definition and medical uses -->
'''Nefazodone''', sold formerly under the brand names '''Serzone''', '''Dutonin''', and '''Nefadar''' among others, is an [[atypical antidepressant]] medication which is used in the treatment of [[depression (mood)|depression]] and for other uses.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" /><ref name=WHOPN2004>{{cite journal|title=Drugs of Current Interest: Nefazodone|journal=WHO Pharmaceuticals Newsletter|date=2003|issue=1|url=http://apps.who.int/medicinedocs/en/d/Js4944e/3.html|archive-url=https://web.archive.org/web/20150403165029/http://apps.who.int/medicinedocs/en/d/Js4944e/3.html|url-status=dead|archive-date=April 3, 2015}}</ref> Nefazodone is still available in the United States,<ref name="Teva Nefazodone Statement" /> but was withdrawn from other countries due to rare liver toxicity. The medication is taken [[oral administration|by mouth]].<ref name="USlabel2005" />
'''Nefazodone''', sold formerly under the brand names '''Serzone''', '''Dutonin''', and '''Nefadar''' among others, is a drug used in the treatment of [[depression (mood)|depression]] and for other uses.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" /><ref name=WHOPN2004>{{cite journal|title=Drugs of Current Interest: Nefazodone|journal=WHO Pharmaceuticals Newsletter|date=2003|issue=1|url=http://apps.who.int/medicinedocs/en/d/Js4944e/3.html|archive-url=https://web.archive.org/web/20150403165029/http://apps.who.int/medicinedocs/en/d/Js4944e/3.html|url-status=dead|archive-date=April 3, 2015}}</ref>


== Background ==
<!-- Side effects and mechanism of action -->
[[Side effect]]s of nefazodone include [[dry mouth]], [[sleepiness]], [[nausea]], [[dizziness]], [[blurred vision]], [[weakness]], [[lightheadedness]], [[confusion]], and [[orthostatic hypotension|postural low blood pressure]], among others.<ref name="USlabel2005" /> Rarely, nefazodone can cause serious [[liver damage]], with an incidence of death or [[liver transplantation]] of about 1 in every 250,000 to 300,000 patient years.<ref name=USlabel2005>{{cite web|title=Serzone (Nefazodone): Side Effects, Interactions, Warning, Dosage & Uses|url=http://www.rxlist.com/serzone-drug.htm|publisher=RxList|access-date=3 June 2017|language=en|date=January 2005}}</ref> Nefazodone is a [[phenylpiperazine]] [[chemical compound|compound]] and is related to [[trazodone]]. It has been described as a [[serotonin antagonist and reuptake inhibitor]] (SARI) due to its combined actions as a [[potency (pharmacology)|potent]] [[receptor antagonist|antagonist]] of the [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub>]] and [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]]s and weak [[serotonin–norepinephrine–dopamine reuptake inhibitor]] (SNDRI).
Nefazodone is a [[phenylpiperazine]] [[chemical compound|compound]] and is related to [[trazodone]]. It has been described as a [[serotonin antagonist and reuptake inhibitor]] (SARI) due to its combined actions as a [[potency (pharmacology)|potent]] [[receptor antagonist|antagonist]] of the [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub>]] and [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]]s and weak [[serotonin–norepinephrine–dopamine reuptake inhibitor]] (SNDRI).<!-- History, society, and culture -->
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Nefazodone was introduced for medical use in 1994.<ref name="WHOPN2004" /><ref name="pmid8748566" /><ref name="pmid29609830">{{cite journal |vauthors=Babai S, Auclert L, Le-Louët H |date=2021 |title=Safety data and withdrawal of hepatotoxic drugs |url= |journal=Therapie |volume=76 |issue=6 |pages=715–723 |doi=10.1016/j.therap.2018.02.004 |pmid=29609830}}</ref> [[Generic drug|Generic versions]] were introduced in 2003.<ref name="DPW">{{cite web |title=Nefazodone |url=https://www.drugpatentwatch.com/p/generic-api/nefazodone+hydrochloride |access-date=3 June 2017 |publisher=Drug Patent Watch |language=en}}</ref> Nefazodone is available as 50{{nbsp}}mg, 100{{nbsp}}mg, 150{{nbsp}}mg, 200{{nbsp}}mg, and 250{{nbsp}}mg [[tablet (pharmacy)|tablet]]s for [[oral administration|oral]] ingestion.<ref name="Drugs.com-2">{{Cite web |title=Nefazodone Package insert / prescribing information |url=https://www.drugs.com/pro/nefazodone.html |work=Drugs.com}}</ref>


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The drug has been associated with serious hepatotoxicity. The first reports of serious liver toxicity in connection with nefazodone were published in 1998 and 1999.<ref name="pmid10068386">{{cite journal |vauthors=Aranda-Michel J, Koehler A, Bejarano PA, Poulos JE, Luxon BA, Khan CM, Ee LC, Balistreri WF, Weber FL |date=February 1999 |title=Nefazodone-induced liver failure: report of three cases |url= |journal=Ann Intern Med |volume=130 |issue=4 Pt 1 |pages=285–8 |doi=10.7326/0003-4819-130-4-199902160-00013 |pmid=10068386}}</ref><ref name="pmid10341782">{{cite journal |vauthors=Schrader GD, Roberts-Thompson IC |date=May 1999 |title=Adverse effect of nefazodone: hepatitis |url= |journal=Med J Aust |volume=170 |issue=9 |pages=452 |doi=10.5694/j.1326-5377.1999.tb127827.x |pmid=10341782 |s2cid=1907139}}</ref> These instances were quickly followed by many additional cases.<ref name="pmid17609231">{{cite journal |vauthors=DeSanty KP, Amabile CM |date=July 2007 |title=Antidepressant-induced liver injury |url= |journal=Ann Pharmacother |volume=41 |issue=7 |pages=1201–11 |doi=10.1345/aph.1K114 |pmid=17609231 |s2cid=24974828}}</ref><ref name="pmid12699949">{{cite journal |vauthors=Edwards IR |date=April 2003 |title=Withdrawing drugs: nefazodone, the start of the latest saga |journal=Lancet |volume=361 |issue=9365 |pages=1240 |doi=10.1016/S0140-6736(03)13030-9 |pmid=12699949 |s2cid=39993080}}</ref><ref name="pmid14638657">{{cite journal |vauthors=Choi S |date=November 2003 |title=Nefazodone (Serzone) withdrawn because of hepatotoxicity |journal=CMAJ |volume=169 |issue=11 |pages=1187 |doi= |pmc=264962 |pmid=14638657}}</ref><ref name="pmid12025437">{{cite journal |vauthors=Stewart DE |date=May 2002 |title=Hepatic adverse reactions associated with nefazodone |journal=Canadian Journal of Psychiatry |volume=47 |issue=4 |pages=375–377 |doi=10.1177/070674370204700409 |pmid=12025437 |doi-access=free}}</ref>. It was withdrawn from most markets by 2004.<ref name="pmid29609830" /><ref name="CBS2004" /> However, as of 2023, it continues to be available in the United States as a generic.
<!-- History, society, and culture -->
⚫
Nefazodone was introduced for medical use in 1994.<ref name="WHOPN2004" /><ref name="pmid8748566" /><ref name="pmid29609830">{{cite journal | vauthors = Babai S, Auclert L, Le-Louët H | title = Safety data and withdrawal of hepatotoxic drugs | journal = Therapie | volume = 76 | issue = 6 | pages = 715–723 | date = 2021 | pmid = 29609830 | doi = 10.1016/j.therap.2018.02.004 | url = }}</ref> [[Generic drug|Generic versions]] were introduced in 2003.<ref name="DPW">{{cite web |title=Nefazodone |url=https://www.drugpatentwatch.com/p/generic-api/nefazodone+hydrochloride |access-date=3 June 2017 |publisher=Drug Patent Watch |language=en}}</ref> Serious liver toxicity was first reported with nefazodone in 1998, and it was withdrawn from most markets by 2004.<ref name="pmid29609830" /><ref name="CBS2004" /> However, as of 2023, it continues to be available in the United States in generic from one manufacturer, [[Teva Pharmaceuticals]]<ref name="Drugs@FDA">{{cite web | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process | title=Drugs@FDA: FDA-Approved Drugs }}</ref> and is manufactured in Israel.<ref>{{Cite web |title=DailyMed - NEFAZODONE HYDROCHLORIDE tablet |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51ff7db5-aaf9-4c3c-86e6-958ebf16b60f |access-date=2023-10-29 |website=dailymed.nlm.nih.gov}}</ref>


The FDA identified nefazodone as a drug of "most concern for drug induced liver injury" and has a black boxed warning for this.<ref>{{Cite journal |last=Research |first=National Center for Toxicological |date=2023-02-09 |title=Drug Induced Liver Injury Rank (DILIrank) Dataset |url=https://www.fda.gov/science-research/liver-toxicity-knowledge-base-ltkb/drug-induced-liver-injury-rank-dilirank-dataset |journal=FDA |language=en}}</ref> Furthermore, the FDA identified the severity of the drug induced liver injury with the highest score given to any drug in the evaluation.<ref>Id.</ref>
==Medical uses==
Nefazodone is used to treat [[major depressive disorder]], [[aggression|aggressive behavior]], [[anxiety]],<ref>{{Cite web|title=List of 54 Anxiety Medications Compared|url=https://www.drugs.com/condition/anxiety.html|access-date=2022-01-23|website=Drugs.com|language=en}}</ref> and [[panic disorder]].<ref name=LiverTox>{{cite book|title=Nefazodone|url=https://livertox.nih.gov/Nefazodone.htm|publisher=LiverTox (NIDDK)|date=2 June 2017}}</ref>


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== Side Effects ==
===Available forms===
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Common and mild [[side effect]]s of nefazodone reported in [[clinical trial]]s more often than [[placebo]] include [[dry mouth]] (25%), sleepiness (25%), nausea (22%), dizziness (17%), blurred vision (16%), [[weakness]] (11%), lightheadedness (10%), confusion (7%), and [[orthostatic hypotension]] (5%). Rare and serious adverse reactions may include allergic reactions, fainting, [[priapism|painful/prolonged erection]], and [[jaundice]].<ref name="USlabel2005">{{cite web |date=January 2005 |title=Serzone (Nefazodone): Side Effects, Interactions, Warning, Dosage & Uses |url=http://www.rxlist.com/serzone-drug.htm |access-date=3 June 2017 |publisher=RxList |language=en}}</ref> Nefazodone is not especially associated with increased appetite and weight gain.<ref name="pmid11379839">{{cite journal |vauthors=Sussman N, Ginsberg DL, Bikoff J |date=April 2001 |title=Effects of nefazodone on body weight: a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials |journal=The Journal of Clinical Psychiatry |volume=62 |issue=4 |pages=256–260 |doi=10.4088/JCP.v62n0407 |pmid=11379839}}</ref> It is also known for having low levels of sexual side effects in comparisons to SSRIs.<ref>{{cite journal |display-authors=6 |vauthors=Ferguson JM, Shrivastava RK, Stahl SM, Hartford JT, Borian F, Ieni J, McQuade RD, Jody D |date=January 2001 |title=Reemergence of sexual dysfunction in patients with major depressive disorder: double-blind comparison of nefazodone and sertraline |journal=The Journal of Clinical Psychiatry |volume=62 |issue=1 |pages=24–29 |doi=10.4088/jcp.v62n0106 |pmid=11235924}}</ref><ref>{{cite journal |vauthors=Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F |date=2001 |title=Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction |url=https://pubmed.ncbi.nlm.nih.gov/11229449/ |journal=The Journal of Clinical Psychiatry |volume=62 |issue=Suppl 3 |pages=10–21 |pmid=11229449}}</ref>
Nefazodone is available as 50{{nbsp}}mg, 100{{nbsp}}mg, 150{{nbsp}}mg, 200{{nbsp}}mg, and 250{{nbsp}}mg [[tablet (pharmacy)|tablet]]s for [[oral administration|oral]] ingestion.<ref name="Drugs.com-2">{{Cite web|url=https://www.drugs.com/pro/nefazodone.html|title = Nefazodone Package insert / prescribing information | work = Drugs.com }}</ref>


==Contraindications==
==Contraindications==
[[Contraindication]]s include the coadministration of [[terfenadine]], [[astemizole]], [[cisapride]], [[pimozide]], or [[carbamazepine]]. Nefazodone is contraindicated in patients who were withdrawn from nefazodone because of evident liver injury as well as those that have shown hypersensitivity to the drug, its inactive ingredients, or other [[phenylpiperazine]] antidepressants. Furthermore, the coadministration of [[triazolam]] and nefazodone should be avoided for all patients, including the elderly, since it causes a significant increase in the plasma level of triazolam and not all commercially available dosage forms of triazolam permit a sufficient dosage reduction. If coadministrated, a 75% reduction in the initial dosage of triazolam is recommended.<ref name="Drugs.com-2" />
[[Contraindication]]s include the coadministration of [[terfenadine]], [[astemizole]], [[cisapride]], [[pimozide]], or [[carbamazepine]]. Nefazodone is contraindicated in patients who were withdrawn from nefazodone because of evident liver injury as well as those that have shown hypersensitivity to the drug, its inactive ingredients, or other [[phenylpiperazine]] antidepressants. Furthermore, the coadministration of [[triazolam]] and nefazodone should be avoided for all patients, including the elderly, since it causes a significant increase in the plasma level of triazolam and not all commercially available dosage forms of triazolam permit a sufficient dosage reduction. If coadministrated, a 75% reduction in the initial dosage of triazolam is recommended.<ref name="Drugs.com-2" />
== Mechanisms of Hepatotoxicity and Health Complications ==
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Nefazodone is both a substrate for, and a potent [[enzyme inhibitor|inhibitor]] of, [[CYP3A4]], and will interact adversely with [[CYP3A4#Ligands|many commonly used medications]] that are metabolized by CYP3A4<ref name="Lexi-Comp">{{cite web |author=Lexi-Comp |date=September 2008 |title=Nefazodone |url=http://www.merck.com/mmpe/lexicomp/nefazodone.html |work=[[Merck Manual of Diagnosis and Therapy|The Merck Manual Professional]]}} Retrieved on November 29, 2008.</ref><ref>{{cite journal |vauthors=Spina E, Santoro V, D'Arrigo C |date=July 2008 |title=Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update |journal=Clinical Therapeutics |volume=30 |issue=7 |pages=1206–1227 |doi=10.1016/S0149-2918(08)80047-1 |pmid=18691982}}</ref><ref>{{cite journal |vauthors=Richelson E |date=September 1997 |title=Pharmacokinetic drug interactions of new antidepressants: a review of the effects on the metabolism of other drugs |journal=Mayo Clinic Proceedings |volume=72 |issue=9 |pages=835–847 |doi=10.4065/72.9.835 |pmid=9294531 |doi-access=free}}</ref>, thereby causing hepatotoxicity.


Furthermore, hepatotoxicity is likely caused in part by the drug's pronounced bile salt export inhibition<ref>Weaver, Richard J., et al. "Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models." ''Nature Reviews Drug Discovery'' 19.2 (2020): 131-148 ''citing'' Kostrubsky, Seva E., et al. "Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone." ''Toxicological Sciences'' 90.2 (2006): 451-459.</ref> and cytotoxicity.<ref>Wang, Zenan, et al. "HepaRG culture in tethered spheroids as an in vitro three‐dimensional model for drug safety screening." ''Journal of Applied Toxicology'' 35.8 (2015): 909-917 ''citing'' Capezzone de Joannon, A., et al. "Inhibitory Activity on The Human Cytochrome P450 and in vitro Cytotoxic Effects on Human Hepatocytes of Nefazodone. Triazoledione, M-Chlorophenylpiperazine and Trazodone." ''Pharmacologyonline'' 3 (2002): 77-87.</ref><ref>Todorović Vukotić, Nevena, et al. "Antidepressants-and antipsychotics-induced hepatotoxicity." ''Archives of Toxicology'' 95 (2021): 767-789 ''citing'' Dykens, James A., et al. "In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone." Toxicological Sciences 103.2 (2008): 335-345. </ref>
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==Side effects==
⚫
Common and mild [[side effect]]s of nefazodone reported in [[clinical trial]]s more often than [[placebo]] include [[dry mouth]] (25%), sleepiness (25%), nausea (22%), dizziness (17%), blurred vision (16%), [[weakness]] (11%), lightheadedness (10%), confusion (7%), and [[orthostatic hypotension]] (5%). Rare and serious adverse reactions may include allergic reactions, fainting, [[priapism|painful/prolonged erection]], and [[jaundice]].<ref name="USlabel2005" /> Nefazodone is not especially associated with increased appetite and weight gain.<ref name="pmid11379839">{{cite journal | vauthors = Sussman N, Ginsberg DL, Bikoff J | title = Effects of nefazodone on body weight: a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials | journal = The Journal of Clinical Psychiatry | volume = 62 | issue = 4 | pages = 256–260 | date = April 2001 | pmid = 11379839 | doi = 10.4088/JCP.v62n0407 }}</ref> It is also known for having low levels of sexual side effects in comparisons to SSRIs.<ref>{{cite journal | vauthors = Ferguson JM, Shrivastava RK, Stahl SM, Hartford JT, Borian F, Ieni J, McQuade RD, Jody D | display-authors = 6 | title = Reemergence of sexual dysfunction in patients with major depressive disorder: double-blind comparison of nefazodone and sertraline | journal = The Journal of Clinical Psychiatry | volume = 62 | issue = 1 | pages = 24–29 | date = January 2001 | pmid = 11235924 | doi = 10.4088/jcp.v62n0106 }}</ref><ref>{{cite journal | vauthors = Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F | title = Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction | journal = The Journal of Clinical Psychiatry | volume = 62 | issue = Suppl 3 | pages = 10–21 | date = 2001 | pmid = 11229449 | url = https://pubmed.ncbi.nlm.nih.gov/11229449/ }}</ref>


The metabolism of nefazodone into toxic metabolites has been implicated as well. Two quinone-imines, benzoquinone and several iminium ions have been identified as oxidative metabolites of nefazodone through the trapping of reactive metabolites following hydroxylation para to nitrogen on the chlorophenylpiperazine ring system.<ref>Kalgutkar, Amit S., and Mary T. Didiuk. "Structural alerts, reactive metabolites, and protein covalent binding: how reliable are these attributes as predictors of drug toxicity?." ''Chemistry & biodiversity'' 6.11 (2009): 2115-2137 ''citing'' Bauman, J.N., Frederick, K.S., Sawant, A., Walsky, R.L., Cox, L.M., Obach, R.S. & Kalgutkar, A.S. 2008a, "Comparison of the bioactivation potential of the antidepressant and hepatotoxin nefazodone with aripiprazole, a structural analog and marketed drug", Drug Metabolism and Disposition, vol. 36, no. 6, pp. 1016- 1029.</ref> Additionally, hepatic metabolism also creates para-hydroxynefazodone, which in turn produces a para-hydroxyaniline analog, a toxicophore. This undergoes P4503A4-mediated bioactivation to electrophilic quinonoid intermediates in human liver microsomes.<ref>Comparison of the Bioactivation Potential of the Antidepressant and Hepatotoxin Nefazodone with Aripiprazole, a Structural Analog and Marketed Drug ''citing'' Mayol, R. F., et al. "Characterization of the metabolites of the antidepressant drug nefazodone in human urine and plasma." ''Drug metabolism and disposition'' 22.2 (1994): 304-311.</ref>
Nefazodone can cause severe [[hepatotoxicity|liver damage]]; the damage may lead to the need for liver transplantation or death. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 [[Incidence (epidemiology)|patient-years]].<ref name=WHOPN2004/><ref name=USlabel2005/> By the time it started to be withdrawn from the market in 2003, nefazodone had been associated with at least 53 cases of liver injury (of which 11 death led to death) in the [[United States]],<ref name="pmid12699949">{{cite journal | vauthors = Edwards IR | title = Withdrawing drugs: nefazodone, the start of the latest saga | journal = Lancet | volume = 361 | issue = 9365 | pages = 1240 | date = April 2003 | pmid = 12699949 | doi = 10.1016/S0140-6736(03)13030-9 | s2cid = 39993080 }}</ref> and 51 cases of liver toxicity (of which two led to transplantation) in [[Canada]].<ref name="pmid14638657">{{cite journal | vauthors = Choi S | title = Nefazodone (Serzone) withdrawn because of hepatotoxicity | journal = CMAJ | volume = 169 | issue = 11 | pages = 1187 | date = November 2003 | pmid = 14638657 | pmc = 264962 | doi = }}</ref><ref name="pmid12025437">{{cite journal | vauthors = Stewart DE | title = Hepatic adverse reactions associated with nefazodone | journal = Canadian Journal of Psychiatry | volume = 47 | issue = 4 | pages = 375–377 | date = May 2002 | pmid = 12025437 | doi = 10.1177/070674370204700409 | doi-access = free }}</ref> In a 2002 Canadian study of 32 cases, it was noted that databases like those used in the study tended to include only a small proportion of suspected drug reactions.<ref name="pmid12025437" />


Liver biopsy following nefazodone administration has revealed cholestasis, cirrhosis, centrilobular necrosis, and fibrosis,<ref>Silva, Ana Marta, et al. "Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity." ''Food and Chemical Toxicology'' 94 (2016): 148-158 ''citing'' Lucena, M.I., Andrade, R.J., Gomez-Outes, A., Rubio, M. & Cabello, M.R. 1999, "Acute liver failure after treatment with nefazodone", Digestive diseases and sciences, vol. 44, no. 12, pp. 2577-2579</ref> likely as a cumulative effect of the above-identified toxic mechanisms. Hepatic fibrosis caused by hepatotoxic drugs exerts deleterious affects on the brain, including reduced cognitive ability and brain volume.<ref>{{cite web |date=23 June 2023 |title=Liver fibrosis linked to reduced cognitive ability and brain volume |url=https://news.yale.edu/2023/06/23/liver-fibrosis-linked-reduced-cognitive-ability-and-brain-volume}}</ref> Raised liver enzymes has also been correlated with neurodegenerative disorders.<ref>Jiang, Rongtao, et al. "Elevated C-reactive protein mediates the liver-brain axis: a preliminary study." ''EBioMedicine'' 93 (2023) ''citing'' Nho, Kwangsik, et al. "Association of altered liver enzymes with Alzheimer disease diagnosis, cognition, neuroimaging measures, and cerebrospinal fluid biomarkers." ''JAMA network open'' 2.7 (2019): e197978-e197978.</ref>
Treatment protocols suggest screening for pre-existing liver disease before initiating nefazodone, and those with known liver disease should not be prescribed nefazodone. If serum AST or serum ALT levels are more than 3 times the upper limit of normal (ULN), treatment should be permanently withdrawn. Regular enzyme labs should be done every six months, and nefazodone should not be a first-line treatment.<ref>{{Cite web |title=Nefazodone hydrochloride - Drug Summary | work = PDR.net |url=https://www.pdr.net/drug-summary/Nefazodone-nefazodone-hydrochloride-661 |access-date=2022-10-12 }}</ref>

==Interactions==
⚫
Nefazodone is a potent [[enzyme inhibitor|inhibitor]] of [[CYP3A4]], and may interact adversely with [[CYP3A4#Ligands|many commonly used medications]] that are metabolized by CYP3A4.<ref name=Lexi-Comp>{{cite web |url=http://www.merck.com/mmpe/lexicomp/nefazodone.html |title=Nefazodone |date=September 2008 |author=Lexi-Comp |work=[[Merck Manual of Diagnosis and Therapy|The Merck Manual Professional]]}} Retrieved on November 29, 2008.</ref><ref>{{cite journal | vauthors = Spina E, Santoro V, D'Arrigo C | title = Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update | journal = Clinical Therapeutics | volume = 30 | issue = 7 | pages = 1206–1227 | date = July 2008 | pmid = 18691982 | doi = 10.1016/S0149-2918(08)80047-1 }}</ref><ref>{{cite journal | vauthors = Richelson E | title = Pharmacokinetic drug interactions of new antidepressants: a review of the effects on the metabolism of other drugs | journal = Mayo Clinic Proceedings | volume = 72 | issue = 9 | pages = 835–847 | date = September 1997 | pmid = 9294531 | doi = 10.4065/72.9.835 | doi-access = free }}</ref>


==Pharmacology==
==Pharmacology==
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Nefazodone is a [[phenylpiperazine]];<ref>{{cite journal | vauthors = Davis R, Whittington R, Bryson HM | title = Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression | journal = Drugs | volume = 53 | issue = 4 | pages = 608–636 | date = April 1997 | pmid = 9098663 | doi = 10.2165/00003495-199753040-00006 | s2cid = 239077479 }}</ref> it is an alpha-phenoxyl derivative of [[etoperidone]] which in turn was a derivative of [[trazodone]].<ref name=DD>{{cite book| vauthors = Eison MS, Taylor DB, Riblet LA | veditors = Williams M, Malick JB |title=Drug Discovery and Development|date=1987|publisher=Springer Science & Business Media|isbn=9781461248286|page=390|chapter-url=https://books.google.com/books?id=O0LuBwAAQBAJ&pg=PA390|language=en|chapter=Atypical Psychotropic Agents}}</ref>
Nefazodone is a [[phenylpiperazine]];<ref>{{cite journal | vauthors = Davis R, Whittington R, Bryson HM | title = Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression | journal = Drugs | volume = 53 | issue = 4 | pages = 608–636 | date = April 1997 | pmid = 9098663 | doi = 10.2165/00003495-199753040-00006 | s2cid = 239077479 }}</ref> it is an alpha-phenoxyl derivative of [[etoperidone]] which in turn was a derivative of [[trazodone]].<ref name=DD>{{cite book| vauthors = Eison MS, Taylor DB, Riblet LA | veditors = Williams M, Malick JB |title=Drug Discovery and Development|date=1987|publisher=Springer Science & Business Media|isbn=9781461248286|page=390|chapter-url=https://books.google.com/books?id=O0LuBwAAQBAJ&pg=PA390|language=en|chapter=Atypical Psychotropic Agents}}</ref>


==History and Withdrawal from Markets due to Safety Concerns==
==History==
Nefazodone was discovered by scientists at [[Bristol-Myers Squibb]] (BMS) who were seeking to improve on trazodone by reducing its sedating qualities.<ref name=DD/>
Nefazodone was discovered by scientists at [[Bristol-Myers Squibb]] (BMS) who were seeking to improve on trazodone by reducing its sedating qualities.<ref name=DD/>


BMS obtained marketing approvals for nefazodone worldwide, including in the United States and Europe, in 1994.<ref name=WHOPN2004/><ref name="pmid8748566">{{cite journal | vauthors = Ellingrod VL, Perry PJ | title = Nefazodone: a new antidepressant | journal = Am J Health Syst Pharm | volume = 52 | issue = 24 | pages = 2799–812 | date = December 1995 | pmid = 8748566 | doi = 10.1093/ajhp/52.24.2799 | url = }}</ref><ref name="pmid29609830" /> It was marketed in the United States under the brand name Serzone<ref>{{cite news|last1=Associated Press|title=Consumer group seeks ban on antidepressant|url=http://www.nbcnews.com/id/4536220/ns/health-mental_health/t/consumer-group-seeks-ban-antidepressant/|work=NBC News|date=16 March 2004|language=en}}</ref> and in Europe under the brand name Dutonin.<ref name=FirstWord>{{cite news| vauthors = Hoffmann C |title=Bristol-Myers to withdraw Dutonin in Europe |url= http://www.firstwordpharma.com/node/213988#axzz4iz3Sls6H |work=First Word Pharma|date=January 8, 2003|language=en}}</ref>
BMS obtained marketing approvals for nefazodone worldwide, including in the United States and Europe, in 1994.<ref name=WHOPN2004/><ref name="pmid8748566">{{cite journal | vauthors = Ellingrod VL, Perry PJ | title = Nefazodone: a new antidepressant | journal = Am J Health Syst Pharm | volume = 52 | issue = 24 | pages = 2799–812 | date = December 1995 | pmid = 8748566 | doi = 10.1093/ajhp/52.24.2799 | url = }}</ref><ref name="pmid29609830" /> It was marketed in the United States under the brand name Serzone<ref>{{cite news|last1=Associated Press|title=Consumer group seeks ban on antidepressant|url=http://www.nbcnews.com/id/4536220/ns/health-mental_health/t/consumer-group-seeks-ban-antidepressant/|work=NBC News|date=16 March 2004|language=en}}</ref> and in Europe under the brand name Dutonin.<ref name=FirstWord>{{cite news| vauthors = Hoffmann C |title=Bristol-Myers to withdraw Dutonin in Europe |url= http://www.firstwordpharma.com/node/213988#axzz4iz3Sls6H |work=First Word Pharma|date=January 8, 2003|language=en}}</ref>


⚫
In 2002 the FDA obligated BMS to add a black box warning about potential fatal liver toxicity to the drug label.<ref name="PL2004">{{cite news|title=Public Citizen to sue FDA over Serzone - Pharmaceutical industry news|url=https://www.thepharmaletter.com/article/public-citizen-to-sue-fda-over-serzone|work=The Pharma Letter|date=22 March 2004|language=en}}</ref><ref name="CBS2004" /> Worldwide sales in 2002 were $409 million.<ref name="FirstWord" />
⚫
The first reports of serious liver toxicity with nefazodone were published in 1998 and 1999.<ref name="pmid10068386">{{cite journal | vauthors = Aranda-Michel J, Koehler A, Bejarano PA, Poulos JE, Luxon BA, Khan CM, Ee LC, Balistreri WF, Weber FL | title = Nefazodone-induced liver failure: report of three cases | journal = Ann Intern Med | volume = 130 | issue = 4 Pt 1 | pages = 285–8 | date = February 1999 | pmid = 10068386 | doi = 10.7326/0003-4819-130-4-199902160-00013 | url = }}</ref><ref name="pmid10341782">{{cite journal | vauthors = Schrader GD, Roberts-Thompson IC | title = Adverse effect of nefazodone: hepatitis | journal = Med J Aust | volume = 170 | issue = 9 | pages = 452 | date = May 1999 | pmid = 10341782 | doi = 10.5694/j.1326-5377.1999.tb127827.x | s2cid = 1907139 | url = }}</ref> These instances were quickly followed by many additional cases.<ref name="pmid17609231">{{cite journal | vauthors = DeSanty KP, Amabile CM | title = Antidepressant-induced liver injury | journal = Ann Pharmacother | volume = 41 | issue = 7 | pages = 1201–11 | date = July 2007 | pmid = 17609231 | doi = 10.1345/aph.1K114 | s2cid = 24974828 | url = }}</ref><ref name="pmid12699949" /><ref name="pmid14638657" /><ref name="pmid12025437" />

⚫
In 2002 the FDA obligated BMS to add a black box warning about potential fatal liver toxicity to the drug label.<ref name=PL2004>{{cite news|title=Public Citizen to sue FDA over Serzone - Pharmaceutical industry news|url=https://www.thepharmaletter.com/article/public-citizen-to-sue-fda-over-serzone|work=The Pharma Letter|date=22 March 2004|language=en}}</ref><ref name=CBS2004/> Worldwide sales in 2002 were $409 million.<ref name=FirstWord/>


In 2003 [[Public Citizen]] filed a [[citizen petition]] asking the FDA to withdraw the marketing authorization in the United States, and in early 2004 the organization sued the FDA to attempt to force withdrawal of the drug.<ref name=PL2004/><ref name=FDAcourt>{{cite web|title=Court Decisions and Updates|url=https://www.fda.gov/downloads/ICECI/EnforcementActions/EnforcementStory/EnforcementStoryArchive/UCM091483.pdf|publisher=FDA|access-date=3 June 2017}}</ref> The FDA issued a response to the petition in June 2004 and filed a motion to dismiss, and Public Citizen withdrew the suit.<ref name=FDAcourt/>
In 2003 [[Public Citizen]] filed a [[citizen petition]] asking the FDA to withdraw the marketing authorization in the United States, and in early 2004 the organization sued the FDA to attempt to force withdrawal of the drug.<ref name=PL2004/><ref name=FDAcourt>{{cite web|title=Court Decisions and Updates|url=https://www.fda.gov/downloads/ICECI/EnforcementActions/EnforcementStory/EnforcementStoryArchive/UCM091483.pdf|publisher=FDA|access-date=3 June 2017}}</ref> The FDA issued a response to the petition in June 2004 and filed a motion to dismiss. Unfortunately, Public Citizen withdrew the suit.<ref name=FDAcourt/>


Sales of nefazodone were about $100 million in 2003.<ref name="WebMD">{{cite news| vauthors = DeNoon DJ |title=Company Pulls Antidepressant Off Market|url=http://www.webmd.com/depression/news/20040520/company-pulls-antidepressant-off-market|work=WebMD|date=May 4, 2004}}</ref> By that time, it was also being marketed under the additional brand names Serzonil, Nefadar, and Rulivan.<ref name="WHOPN2004" />
Sales of nefazodone were about $100 million in 2003.<ref name="WebMD">{{cite news| vauthors = DeNoon DJ |title=Company Pulls Antidepressant Off Market|url=http://www.webmd.com/depression/news/20040520/company-pulls-antidepressant-off-market|work=WebMD|date=May 4, 2004}}</ref> By that time, it was also being marketed under the additional brand names Serzonil, Nefadar, and Rulivan.<ref name="WHOPN2004" />


Generic versions were introduced in the United States in 2003<ref name=DPW /> and [[Health Canada]] withdrew the marketing authorization that same year.<ref name="pmid15767610">{{cite journal | vauthors = Lexchin J | title = Drug withdrawals from the Canadian market for safety reasons, 1963-2004 | journal = CMAJ | volume = 172 | issue = 6 | pages = 765–767 | date = March 2005 | pmid = 15767610 | pmc = 552890 | doi = 10.1503/cmaj.045021 }}</ref>
Generic versions were introduced in the United States in 2003.<ref name=DPW /> [[Health Canada]] withdrew the marketing authorization that same year.<ref name="pmid15767610">{{cite journal | vauthors = Lexchin J | title = Drug withdrawals from the Canadian market for safety reasons, 1963-2004 | journal = CMAJ | volume = 172 | issue = 6 | pages = 765–767 | date = March 2005 | pmid = 15767610 | pmc = 552890 | doi = 10.1503/cmaj.045021 }}</ref>


In April 2004, BMS announced that it was going to discontinue the sale of Serzone in the United States in June 2004 and said that this was due to declining sales and generic versions were available in the United States.<ref name="DPW" /><ref name="CBS2004" /><ref name="WebMD" /> By that time, BMS had already withdrawn the drug from the market in Europe, Australia, New Zealand, and Canada.<ref name="CBS2004">{{cite news| vauthors = Cosgrove-Mather B |title=Anti-Depressant Taken Off Market|url=http://www.cbsnews.com/news/anti-depressant-taken-off-market/|work=CBS News|date=April 15, 2004|language=en}}</ref>
In April 2004, BMS announced that it was going to discontinue the sale of Serzone in the United States in June 2004 and said that this was due to declining sales and generic versions were available in the United States.<ref name="DPW" /><ref name="CBS2004" /><ref name="WebMD" /> By that time, BMS had already withdrawn the drug from the market in Europe, Australia, New Zealand, and Canada.<ref name="CBS2004">{{cite news| vauthors = Cosgrove-Mather B |title=Anti-Depressant Taken Off Market|url=http://www.cbsnews.com/news/anti-depressant-taken-off-market/|work=CBS News|date=April 15, 2004|language=en}}</ref>


In August 2020, Teva Pharmaceuticals placed nefazodone in shortage due to a shortage of a raw ingredient. On December 20, 2021, nefazodone was again made available in all strengths.<ref name="Teva Nefazodone Statement">{{Cite web|title=Teva Nefazodone Statement|url=https://www.tevausa.com/news-and-media/press-releases/teva-nefazodone-statement/|access-date=2022-01-23|website=www.tevausa.com|language=en}}</ref><ref>{{Cite web|title=FDA Drug Shortages|url=https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Nefazodone%20Hydrochloride%20Tablets|access-date=2022-01-23|website=www.accessdata.fda.gov}}</ref>
In August 2020, Teva Pharmaceuticals placed nefazodone in shortage due to a shortage of a raw ingredient. On December 20, 2021, nefazodone was again made available in all strengths.<ref name="Teva Nefazodone Statement">{{Cite web|title=Teva Nefazodone Statement|url=https://www.tevausa.com/news-and-media/press-releases/teva-nefazodone-statement/|access-date=2022-01-23|website=www.tevausa.com|date=20 December 2021 |language=en}}</ref><ref>{{Cite web|title=FDA Drug Shortages|url=https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Nefazodone%20Hydrochloride%20Tablets|access-date=2022-01-23|website=www.accessdata.fda.gov}}</ref>


==Society and culture==
==Society and culture==

Revision as of 04:10, 17 January 2024

Nefazodone
Clinical data
Trade namesSerzone, Dutonin, Nefadar, others
Other namesBMY-13754-1; MJ-13754-1; MJ-13754; MS-13754
AHFS/Drugs.comMonograph
MedlinePlusa695005
Pregnancy
category
  • C
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • BR: Class C1 (Other controlled substances)[1]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability20% (variable)[2]
Protein binding99% (loosely)[2]
MetabolismLiver (CYP3A4, CYP2D6)[3]
Metabolites• Hydroxynefazodone[2]
• mCPPTooltip meta-Chlorophenylpiperazine[2]
• p-Hydroxynefazodone[3]
• Triazoledione[2]
Elimination half-life• Nefazodone: 2–4 hours[2]
• Hydroxynefazodone: 1.5–4 hours[2]
• Triazoledione: 18 hours[2]
• mCPPTooltip meta-Chlorophenylpiperazine: 4–8 hours[2]
ExcretionUrine: 55%
Feces: 20–30%
Identifiers
  • 1-(3-[4-(3-chlorophenyl)piperazin-1-yl]propyl)-3-ethyl-4-(2-phenoxyethyl)-1H-1,2,4-triazol-5(4H)-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC25H32ClN5O2
Molar mass470.01 g·mol−1
3D model (JSmol)
  • Clc4cccc(N3CCN(CCCN1/N=C(\N(C1=O)CCOc2ccccc2)CC)CC3)c4
  • InChI=1S/C25H32ClN5O2/c1-2-24-27-31(25(32)30(24)18-19-33-23-10-4-3-5-11-23)13-7-12-28-14-16-29(17-15-28)22-9-6-8-21(26)20-22/h3-6,8-11,20H,2,7,12-19H2,1H3 checkY
  • Key:VRBKIVRKKCLPHA-UHFFFAOYSA-N checkY
  (verify)

Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is a drug used in the treatment of depression and for other uses.[4][5][6][7]

Background

Nefazodone is a phenylpiperazine compound and is related to trazodone. It has been described as a serotonin antagonist and reuptake inhibitor (SARI) due to its combined actions as a potent antagonist of the serotonin 5-HT2A and 5-HT2C receptors and weak serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI). Nefazodone was introduced for medical use in 1994.[7][8][9] Generic versions were introduced in 2003.[10] Nefazodone is available as 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg tablets for oral ingestion.[11]

The drug has been associated with serious hepatotoxicity. The first reports of serious liver toxicity in connection with nefazodone were published in 1998 and 1999.[12][13] These instances were quickly followed by many additional cases.[14][15][16][17]. It was withdrawn from most markets by 2004.[9][18] However, as of 2023, it continues to be available in the United States as a generic.

The FDA identified nefazodone as a drug of "most concern for drug induced liver injury" and has a black boxed warning for this.[19] Furthermore, the FDA identified the severity of the drug induced liver injury with the highest score given to any drug in the evaluation.[20]

Side Effects

Common and mild side effects of nefazodone reported in clinical trials more often than placebo include dry mouth (25%), sleepiness (25%), nausea (22%), dizziness (17%), blurred vision (16%), weakness (11%), lightheadedness (10%), confusion (7%), and orthostatic hypotension (5%). Rare and serious adverse reactions may include allergic reactions, fainting, painful/prolonged erection, and jaundice.[21] Nefazodone is not especially associated with increased appetite and weight gain.[22] It is also known for having low levels of sexual side effects in comparisons to SSRIs.[23][24]

Contraindications

Contraindications include the coadministration of terfenadine, astemizole, cisapride, pimozide, or carbamazepine. Nefazodone is contraindicated in patients who were withdrawn from nefazodone because of evident liver injury as well as those that have shown hypersensitivity to the drug, its inactive ingredients, or other phenylpiperazine antidepressants. Furthermore, the coadministration of triazolam and nefazodone should be avoided for all patients, including the elderly, since it causes a significant increase in the plasma level of triazolam and not all commercially available dosage forms of triazolam permit a sufficient dosage reduction. If coadministrated, a 75% reduction in the initial dosage of triazolam is recommended.[11]

Mechanisms of Hepatotoxicity and Health Complications

Nefazodone is both a substrate for, and a potent inhibitor of, CYP3A4, and will interact adversely with many commonly used medications that are metabolized by CYP3A4[25][26][27], thereby causing hepatotoxicity.

Furthermore, hepatotoxicity is likely caused in part by the drug's pronounced bile salt export inhibition[28] and cytotoxicity.[29][30]

The metabolism of nefazodone into toxic metabolites has been implicated as well. Two quinone-imines, benzoquinone and several iminium ions have been identified as oxidative metabolites of nefazodone through the trapping of reactive metabolites following hydroxylation para to nitrogen on the chlorophenylpiperazine ring system.[31] Additionally, hepatic metabolism also creates para-hydroxynefazodone, which in turn produces a para-hydroxyaniline analog, a toxicophore. This undergoes P4503A4-mediated bioactivation to electrophilic quinonoid intermediates in human liver microsomes.[32]

Liver biopsy following nefazodone administration has revealed cholestasis, cirrhosis, centrilobular necrosis, and fibrosis,[33] likely as a cumulative effect of the above-identified toxic mechanisms. Hepatic fibrosis caused by hepatotoxic drugs exerts deleterious affects on the brain, including reduced cognitive ability and brain volume.[34] Raised liver enzymes has also been correlated with neurodegenerative disorders.[35]

Pharmacology

Pharmacodynamics

Nefazodone[36]
Site Ki (nM) Species Ref
SERTTooltip Serotonin transporter 200–459 Human [37][38]
NETTooltip Norepinephrine transporter 360–618 Human [37][38]
DATTooltip Dopamine transporter 360 Human [37]
5-HT1A 80 Human [39]
5-HT2A 26 Human [39]
5-HT2C 72 Human [40]
α1 5.5–48 Human [39][38]
α1A 48 Human [40]
α2 84–640 Human [39][38]
β >10,000 Rat [41]
D2 910 Human [39]
H1 ≥370 Human [39][40]
mAChTooltip Muscarinic acetylcholine receptor >10,000 Human [39]
Notes: Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Nefazodone acts primarily as a potent antagonist of the serotonin 5-HT2A receptor and to a lesser extent of the serotonin 5-HT2C receptor.[39] It also has high affinity for the α1-adrenergic receptor and serotonin 5-HT1A receptor, and relatively lower affinity for the α2-adrenergic receptor and dopamine D2 receptor.[39] Nefazodone has low but significant affinity for the serotonin, norepinephrine, and dopamine transporters as well, and therefore acts as a weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).[37] It has low but potentially significant affinity for the histamine H1 receptor, where it is an antagonist, and hence may have some antihistamine activity.[39][40] Nefazodone has negligible activity at muscarinic acetylcholine receptors, and accordingly, has no anticholinergic effects.[37]

Pharmacokinetics

The bioavailability of nefazodone is low and variable, about 20%.[2] Its plasma protein binding is approximately 99%, but it is bound loosely.[2]

Nefazodone is metabolized in the liver, with the main enzyme involved thought to be CYP3A4.[3] The drug has at least four active metabolites, which include hydroxynefazodone, para-hydroxynefazodone, triazoledione, and meta-chlorophenylpiperazine.[2] Nefazodone has a short elimination half-life of about 2 to 4 hours.[2] Its metabolite hydroxynefazodone similarly has an elimination half-life of about 1.5 to 4 hours, whereas the elimination half-lives of triazoledione and mCPP are longer at around 18 hours and 4 to 8 hours, respectively.[2] Due to its long elimination half-life, triazoledione is the major metabolite and predominates in the circulation during nefazodone treatment, with plasma levels that are 4 to 10 times higher than those of nefazodone itself.[2][42] Conversely, hydroxynefazodone levels are about 40% of those of nefazodone at steady state.[2] Plasma levels of mCPP are very low at about 7% of those of nefazodone; hence, mCPP is only a minor metabolite.[2][42] mCPP is thought to be formed from nefazodone specifically by CYP2D6.[3][42]

The ratios of brain-to-plasma concentrations of mCPP to nefazodone are 47:1 in mice and 10:1 in rats, suggesting that brain exposure to mCPP may be much higher than plasma exposure.[2] Conversely, hydroxynefazodone levels in the brain are 10% of those in plasma in rats.[2] As such, in spite of its relatively low plasma concentrations, brain exposure to mCPP may be substantial, whereas that of hydroxynefazodone may be minimal.[2]

Chemistry

Nefazodone is a phenylpiperazine;[43] it is an alpha-phenoxyl derivative of etoperidone which in turn was a derivative of trazodone.[44]

History and Withdrawal from Markets due to Safety Concerns

Nefazodone was discovered by scientists at Bristol-Myers Squibb (BMS) who were seeking to improve on trazodone by reducing its sedating qualities.[44]

BMS obtained marketing approvals for nefazodone worldwide, including in the United States and Europe, in 1994.[7][8][9] It was marketed in the United States under the brand name Serzone[45] and in Europe under the brand name Dutonin.[46]

In 2002 the FDA obligated BMS to add a black box warning about potential fatal liver toxicity to the drug label.[47][18] Worldwide sales in 2002 were $409 million.[46]

In 2003 Public Citizen filed a citizen petition asking the FDA to withdraw the marketing authorization in the United States, and in early 2004 the organization sued the FDA to attempt to force withdrawal of the drug.[47][48] The FDA issued a response to the petition in June 2004 and filed a motion to dismiss. Unfortunately, Public Citizen withdrew the suit.[48]

Sales of nefazodone were about $100 million in 2003.[49] By that time, it was also being marketed under the additional brand names Serzonil, Nefadar, and Rulivan.[7]

Generic versions were introduced in the United States in 2003.[10] Health Canada withdrew the marketing authorization that same year.[50]

In April 2004, BMS announced that it was going to discontinue the sale of Serzone in the United States in June 2004 and said that this was due to declining sales and generic versions were available in the United States.[10][18][49] By that time, BMS had already withdrawn the drug from the market in Europe, Australia, New Zealand, and Canada.[18]

In August 2020, Teva Pharmaceuticals placed nefazodone in shortage due to a shortage of a raw ingredient. On December 20, 2021, nefazodone was again made available in all strengths.[51][52]

Society and culture

Generic names

Nefazodone is the generic name of the drug and its INNTooltip International Nonproprietary Name and BANTooltip British Approved Name, while néfazodone is its DCFTooltip Dénomination Commune Française and nefazodone hydrochloride is its USANTooltip United States Adopted Name and USPTooltip United States Pharmacopeia.[4][5][53][6]

Brand names

Nefazodone has been marketed under a number of brand names including Dutonin (ATTooltip Austria, ESTooltip Spain, IETooltip Ireland, UKTooltip United Kingdom), Menfazona (ESTooltip Spain), Nefadar (CHTooltip Switzerland, DETooltip Germany, NOTooltip Norway, SETooltip Sweden), Nefazodone BMS (ATTooltip Austria), Nefazodone Hydrochloride Teva (USTooltip United States), Reseril (ITTooltip Italy), Rulivan (ESTooltip Spain), and Serzone (AUTooltip Australia, CATooltip Canada, USTooltip United States).[5][6]

Research

Nefazodone was under development for the treatment of panic disorder, and reached phase 3 clinical trials for this indication, but development was discontinued in 2004.[54]

The use of nefazodone to prevent migraine has been studied, due to its antagonism of the serotonin 5-HT2A and 5-HT2C receptors.[55][56][57]

References

  1. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ^ a b c d e f g h i j k l m n o p q r s t Schatzberg AF, Nemeroff CB (2017). The American Psychiatric Association Publishing Textbook of Psychopharmacology, Fifth Edition. American Psychiatric Pub. pp. 460–. ISBN 978-1-58562-523-9.
  3. ^ a b c d Pacifici GM, Pelkonen O (24 May 2001). Interindividual Variability in Human Drug Metabolism. CRC Press. pp. 103–. ISBN 978-0-7484-0864-1.
  4. ^ a b Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 857–. ISBN 978-1-4757-2085-3.
  5. ^ a b c Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 722–. ISBN 978-3-88763-075-1.
  6. ^ a b c "Nefazodone International Brands". Drugs.com. Retrieved 1 June 2017.
  7. ^ a b c d "Drugs of Current Interest: Nefazodone". WHO Pharmaceuticals Newsletter (1). 2003. Archived from the original on April 3, 2015.
  8. ^ a b Ellingrod VL, Perry PJ (December 1995). "Nefazodone: a new antidepressant". Am J Health Syst Pharm. 52 (24): 2799–812. doi:10.1093/ajhp/52.24.2799. PMID 8748566.
  9. ^ a b c Babai S, Auclert L, Le-Louët H (2021). "Safety data and withdrawal of hepatotoxic drugs". Therapie. 76 (6): 715–723. doi:10.1016/j.therap.2018.02.004. PMID 29609830.
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  11. ^ a b "Nefazodone Package insert / prescribing information". Drugs.com.
  12. ^ Aranda-Michel J, Koehler A, Bejarano PA, Poulos JE, Luxon BA, Khan CM, Ee LC, Balistreri WF, Weber FL (February 1999). "Nefazodone-induced liver failure: report of three cases". Ann Intern Med. 130 (4 Pt 1): 285–8. doi:10.7326/0003-4819-130-4-199902160-00013. PMID 10068386.
  13. ^ Schrader GD, Roberts-Thompson IC (May 1999). "Adverse effect of nefazodone: hepatitis". Med J Aust. 170 (9): 452. doi:10.5694/j.1326-5377.1999.tb127827.x. PMID 10341782. S2CID 1907139.
  14. ^ DeSanty KP, Amabile CM (July 2007). "Antidepressant-induced liver injury". Ann Pharmacother. 41 (7): 1201–11. doi:10.1345/aph.1K114. PMID 17609231. S2CID 24974828.
  15. ^ Edwards IR (April 2003). "Withdrawing drugs: nefazodone, the start of the latest saga". Lancet. 361 (9365): 1240. doi:10.1016/S0140-6736(03)13030-9. PMID 12699949. S2CID 39993080.
  16. ^ Choi S (November 2003). "Nefazodone (Serzone) withdrawn because of hepatotoxicity". CMAJ. 169 (11): 1187. PMC 264962. PMID 14638657.
  17. ^ Stewart DE (May 2002). "Hepatic adverse reactions associated with nefazodone". Canadian Journal of Psychiatry. 47 (4): 375–377. doi:10.1177/070674370204700409. PMID 12025437.
  18. ^ a b c d Cosgrove-Mather B (April 15, 2004). "Anti-Depressant Taken Off Market". CBS News.
  19. ^ Research, National Center for Toxicological (2023-02-09). "Drug Induced Liver Injury Rank (DILIrank) Dataset". FDA.
  20. ^ Id.
  21. ^ "Serzone (Nefazodone): Side Effects, Interactions, Warning, Dosage & Uses". RxList. January 2005. Retrieved 3 June 2017.
  22. ^ Sussman N, Ginsberg DL, Bikoff J (April 2001). "Effects of nefazodone on body weight: a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials". The Journal of Clinical Psychiatry. 62 (4): 256–260. doi:10.4088/JCP.v62n0407. PMID 11379839.
  23. ^ Ferguson JM, Shrivastava RK, Stahl SM, Hartford JT, Borian F, Ieni J, et al. (January 2001). "Reemergence of sexual dysfunction in patients with major depressive disorder: double-blind comparison of nefazodone and sertraline". The Journal of Clinical Psychiatry. 62 (1): 24–29. doi:10.4088/jcp.v62n0106. PMID 11235924.
  24. ^ Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F (2001). "Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction". The Journal of Clinical Psychiatry. 62 (Suppl 3): 10–21. PMID 11229449.
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