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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="_NBK608428_"><span class="title" itemprop="name">Fezolinetant</span></h1><p class="fm-aai"><a href="#_NBK608428_pubdet_">Publication Details</a></p></div></div><div class="body-content whole_rhythm" itemprop="text"><div id="Fezolinetant.OVERVIEW"><h2 id="_Fezolinetant_OVERVIEW_">OVERVIEW</h2><div id="Fezolinetant.Introduction"><h3>Introduction</h3><p>Fezolinetant is an orally available neurokinin 3 receptor antagonist that is used to treat women with vasomotor symptoms (such as hot flashes) due to menopause. Fezolinetant is associated with a low rate of serum aminotransferase elevations during therapy and has been linked to rare instances of clinically apparent liver injury with jaundice.</p></div><div id="Fezolinetant.Background"><h3>Background</h3><p>Fezolinetant (fez oh’ lin eh tant) is a neurokinin 3 (NK3) receptor antagonist that is used to treat moderate-to-severe vasomotor symptoms due to menopause. The neurokinin 3 receptor is found on neurons in the thermoregulatory center of the brain, is activated by binding to neurokinin B, and is inhibited by circulating estrogen levels. During menopause, estrogen levels fall, and neurokinin B binding is unopposed, which leads to altered thermoregulation manifested by hot flashes, episodes of sensations of heat in the upper body lasting 1 to 5 minutes arising multiple times per day and which can be accompanied by flushing, chills, perspiration, clamminess and anxiety, symptoms that can interfere with activities of daily living and quality of life. Conventional therapy of menopausal vasomotor symptoms is estrogen replacement, which is effective but can be associated with adverse events including an increased risk of hormone-sensitive cancers. Fezolinetant is a small molecule, nonhormonal inhibitor of neurokinin binding and has been shown to decrease both the frequency and the severity of the vasomotor symptoms. Fezolinetant was approved for use in the United States in 2019 and is available in tablets of 45 mg under the brand name Veozah. The recommended dose is 45 mg daily. Current indications are for moderate-to-severe vasomotor symptoms due to menopause. Contraindications include cirrhosis, end-stage renal disease, and concurrent therapy with inhibitors of CYP 1A2, the cytochrome P450 enzyme primarily responsible for its metabolism. Fezolinetant is generally well tolerated. Side effects can include serum aminotransferase elevations, abdominal pain, diarrhea, insomnia, and back pain.</p></div><div id="Fezolinetant.Hepatotoxicity"><h3>Hepatotoxicity</h3><p>In preregistration clinical trials, serum ALT or AST elevations above 3 times the upper limit of normal (ULN) occurred in 2.3% of patients taking fezolinetant vs 0.9% of placebo recipients. The elevations were largely asymptomatic and transient, resolving promptly after stopping therapy and sometimes despite drug continuation. Nevertheless, the elevations appeared to be related to therapy and arose most frequently during the first few months of treatment. More striking elevations arose in early phase trials using higher doses of fezolinetant. Bilirubin elevations were rare and there were no instances of clinically apparent liver injury with jaundice in preregistration clinical studies even with high doses. However, within a year of its approval, a case of mixed-cholestatic hepatitis with symptoms and jaundice occurred in a patient taking fezolinetant. The episode arose within 54 days of starting fezolinetant and resolved once the drug was stopped. Because of this case, the warning about drug induced liver injury was strengthened, and more explicit recommendations were made regarding prescreening and monitoring patients in the product label of fezolinetant.</p><p>Likelihood score: D (possible rare cause of clinically apparent liver injury).</p></div><div id="Fezolinetant.Mechanism_of_Liver_Injury"><h3>Mechanism of Liver Injury</h3><p>The mechanism by which fezolinetant might cause liver injury is unclear, but it may be dose related and direct hepatotoxicity. Fezolinetant is metabolized in the liver primarily by CYP 1A2 and inhibitors of this isoenzyme (such as cimetidine and ciprofloxacin) can result in higher drug levels and possibly increased rate of adverse events.</p></div><div id="Fezolinetant.Outcome_and_Management"><h3>Outcome and Management</h3><p>The product label for fezolinetant has a warning about drug induced liver injury and recommends assessing symptoms and laboratory features of liver disease before starting therapy and monitoring routine liver tests thereafter monthly for 3 months, again at 6 and 9 months, thereafter if signs of symptoms of liver injury arise. Fezolinetant should be discontinued if ALT or AST levels rise to above 5 times ULN or above 3 times ULN if symptoms or jaundice are present. Patients found to have serum aminotransferase elevations should be followed more carefully until they resolve. Fezolinetant is contraindicated in women with cirrhosis or renal failure and should be used with caution in those with liver test abnormalities at baseline.</p><p>Drug Class: Obstetrical and Gynecological Agents</p><p>Other Menopausal Symptom Agents: <a href="/books/n/livertox/Estrogens/?report=reader">Estrogens</a></p></div></div><div id="Fezolinetant.PRODUCT_INFORMATION"><h2 id="_Fezolinetant_PRODUCT_INFORMATION_">PRODUCT INFORMATION</h2><p>
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<b>REPRESENTATIVE TRADE NAMES</b>
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</p><p>Fezolinetant – Veozah®</p><p>
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<b>DRUG CLASS</b>
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</p><p>Obstetrical and Gynecological Agents</p><p>
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<a href="https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=Fezolinetant" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COMPLETE LABELING</a>
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</p><p>Product labeling at DailyMed, National Library of Medicine, NIH</p></div><div id="Fezolinetant.CHEMICAL_FORMULA_AND_STRUCT"><h2 id="_Fezolinetant_CHEMICAL_FORMULA_AND_STRUCT_">CHEMICAL FORMULA AND STRUCTURE</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figFezolinetantTc"><a href="/books/NBK608428/table/Fezolinetant.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobFezolinetantTc"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="Fezolinetant.Tc"><a href="/books/NBK608428/table/Fezolinetant.Tc/?report=objectonly" target="object" rid-ob="figobFezolinetantTc">Table</a></h4></div></div></div><div id="Fezolinetant.ANNOTATED_BIBLIOGRAPHY"><h2 id="_Fezolinetant_ANNOTATED_BIBLIOGRAPHY_">ANNOTATED BIBLIOGRAPHY</h2><p>References updated: 10 October 2024</p><p>Abbreviations: NK3, neurokinin 3.</p><ul class="first-line-outdent"><li><div class="bk_ref" id="Fezolinetant.REF.zimmerman.1999">Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.<div><i>(Review of hepatotoxicity published in 1999 before the availability of NK3 receptor antagonists).</i></div></div></li><li><div class="bk_ref" id="Fezolinetant.REF2">FDA. Clinical Review. <a href="https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000MedR.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.accessdata<wbr style="display:inline-block"></wbr>​.fda.gov/drugsatfda_docs<wbr style="display:inline-block"></wbr>​/nda/2023/216578Orig1s000MedR.pdf</a><div><i>(FDA website with product label and integrated clinical review of data on fezolinetant provided by the sponsor in support of its approval as therapy of the vasomotor symptoms of menopause, mentions that in a pooled analysis of 3 randomized, placebo controlled trials, serum aminotransferase elevations above 3 times the upper limit of normal [ULN] occurred in 2.3% of fezolinetant- [n=1100] vs 0.9% of placebo-recipients [n=952], but that no patient developed liver injury with jaundice, and the abnormalities resolved with dose interruption or discontinuation. Nevertheless, the FDA recommended a warning about drug induced liver injury and monitoring of liver tests during therapy).</i></div></div></li><li><div class="bk_ref" id="Fezolinetant.REF.depypere.2019.5893">Depypere
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H, Timmerman
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D, Donders
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G, Sieprath
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P, Ramael
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S, Combalbert
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J, Hoveyda
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HR, et al.
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Treatment of menopausal vasomotor symptoms with fezolinetant, a neurokinin 3 receptor antagonist: a phase 2a trial.
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J Clin Endocrinol Metab.
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2019;104:5893-5905.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/31415087" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31415087</span></a>]<div><i>(Among 87 women with vasomotor symptoms due to menopause treated with fezolinetant [90 mg] or placebo twice daily for 12 weeks, the frequency and severity of vasomotor symptoms decreased with fezolinetant treatment within 1-2 weeks and relapsed at a similar rate upon stopping, while adverse event rates were similar in the two groups except for gastrointestinal complaints [14% vs none] and ALT elevations [11% vs 2%], all of the latter being transient, less than 3 times ULN, and not requiring dose adjustment or discontinuation).</i></div></div></li><li><div class="bk_ref" id="Fezolinetant.REF.fraser.2020.382">Fraser
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GL, Lederman
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S, Waldbaum
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A, Kroll
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R, Santoro
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N, Lee
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M, Skillern
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L, et al.
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A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause.
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Menopause.
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2020;27:382-392.
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[<a href="/pmc/articles/PMC7147405/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7147405</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32102086" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32102086</span></a>]<div><i>(Among 352 women with moderate-to-severe vasomotor symptoms due to menopause treated with varying doses of fezolinetant [15 to 90 mg twice daily or 30 to 120 mg once daily] or placebo for 12 weeks, vasomotor symptoms were reduced in frequency and severity with all regimens compared to placebo, and total adverse event rates were similar, but ALT or AST elevations arose in 9 [3%] patients on fezolinetant and were above 8 times ULN in 3 who were receiving 60 mg or more daily; all abnormalities resolved once drug was stopped and there were no ALT elevations accompanied by jaundice).</i></div></div></li><li><div class="bk_ref" id="Fezolinetant.REF.fraser.2021.e3519">Fraser
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GL, Obermayer-Pietsch
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B, Laven
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J, Griesinger
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G, Pintiaux
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A, Timmerman
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D, Fauser
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BCJM, et al.
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Randomized controlled trial of neurokinin 3 receptor antagonist fezolinetant for treatment of polycystic ovary syndrome.
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J Clin Endocrinol Metab.
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2021;106:e3519-e3532.
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[<a href="/pmc/articles/PMC8372662/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8372662</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34000049" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34000049</span></a>]<div><i>(Among 73 women with polycystic ovary syndrome treated with fezolinetant [60 or 180 mg] or placebo once daily for 12 weeks, FSH and LH levels were suppressed in a dose-dependent manner with fezolinetant and therapy was well tolerated, there were “no clinically relevant changes in clinical laboratory parameters” and “treatment-emergent ALT increases…were equally distributed over the treatment groups”, only one fezolinetant treated patient had an ALT elevation above 3 times ULN and it resolved spontaneously without dose adjustment).</i></div></div></li><li><div class="bk_ref" id="Fezolinetant.REF.nealperry.2023.737">Neal-Perry
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G, Cano
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A, Lederman
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S, Nappi
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RE, Santoro
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N, Wolfman
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W, English
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M, et al.
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Safety of fezolinetant for vasomotor symptoms associated with menopause: a randomized controlled trial.
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Obstet Gynecol.
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2023;141:737-747.
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[<a href="/pmc/articles/PMC10026946/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10026946</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/36897180" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36897180</span></a>]<div><i>(Among 1830 women with vasomotor symptoms due to menopause treated with fezolinetant [30 or 45 mg] or placebo once daily for 52 weeks, total and severe adverse event rates were similar in the 3 groups as were discontinuations for adverse events; ALT and AST elevations of greater than 3 times ULN were uncommon [1.4% and 2.0% vs 1.0%], and no patient developed clinically apparent liver injury with jaundice).</i></div></div></li><li><div class="bk_ref" id="Fezolinetant.REF.lederman.2023.1091">Lederman
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S, Ottery
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FD, Cano
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A, Santoro
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N, Shapiro
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M, Stute
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P, Thurston
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RC, et al.
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Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study.
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Lancet.
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2023;401:1091-1102.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/36924778" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36924778</span></a>]<div><i>(Among 527 women with moderate-to-severe vasomotor symptoms due to menopause treated with fezolinetant [30 or 45 mg] or placebo once daily for 12 weeks, followed by an extension study in which all received fezolinetant, improvements in frequency and severity of vasomotor symptoms were greater with fezolinetant, arising within 1 week of starting and maintained for 52 weeks, while adverse events were similar in the 3 groups, ALT elevations during the 12 week period arose in 4 [2.3%] patients on placebo and 4 [1.1%] on fezolinetant, which were above 3 times ULN in 0.6% of both groups).</i></div></div></li><li><div class="bk_ref" id="Fezolinetant.REF8">Fezolinetant (Veozah) for menopausal vasomotor symptoms.
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Med Lett Drugs Ther.
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2023;65:97-99.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/37339088" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 37339088</span></a>]<div><i>(Concise review of the mechanism of action, clinical efficacy, safety, and costs of fezolinetant, mentions that therapy can cause serum aminotransferase elevations and patients should be monitored for liver function and injury tests at baseline and at regular times thereafter).</i></div></div></li><li><div class="bk_ref" id="Fezolinetant.REF.johnson.2023.1981">Johnson
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KA, Martin
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N, Nappi
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RE, Neal-Perry
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G, Shapiro
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M, Stute
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P, Thurston
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RC, et al.
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Efficacy and safety of fezolinetant in moderate to severe vasomotor symptoms associated with menopause: a phase 3 RCT.
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J Clin Endocrinol Metab.
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2023;108:1981-1997.
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[<a href="/pmc/articles/PMC10348473/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10348473</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/36734148" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36734148</span></a>]<div><i>(Among 501 women with moderate-to-severe vasomotor symptoms due to menopause treated with fezolinetant [30 or 45 mg] or placebo once daily for 12 weeks and then continued on either 30 or 45 mg of fezolinetant, treatment led to a rapid decrease in frequency and severity of vasomotor symptoms which was maintained during extended therapy, and ALT elevations above 3 times ULN arose in 5 [1.5%] on fezolinetant and 1 [0.6%] on placebo, but all abnormalities resolved and there were no instances of clinically apparent liver injury with jaundice).</i></div></div></li><li><div class="bk_ref" id="Fezolinetant.REF.lee.2023.1137">Lee
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A.
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Fezolinetant: first approval.
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Drugs.
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2023;83:1137-1141.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/37462862" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 37462862</span></a>]<div><i>(Summary of the mechanism of action, history of development, pharmacology, clinical efficacy, and safety of fezolinetant shortly after its approval in the US, mentions that total and serious adverse event rates were similar in fezolinetant- and placebo-treated subjects and that adverse events more frequent with fezolinetant included abdominal pain [4.3% vs 2.1%], diarrhea [3.9% vs 2.6%], insomnia [3.9% vs 1.8%], back pain [3.0% vs 2.1%], hot flush [2.5% vs 1.6%], and serum aminotransferase elevations [2.3% vs 0.8%]).</i></div></div></li><li><div class="bk_ref" id="Fezolinetant.REF11">Drugs for menopausal symptoms.
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Med Lett Drugs Ther.
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2024;66:33-38.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/38412276" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 38412276</span></a>]<div><i>(Concise review of drugs that are approved for therapy of genitourinary and vasomotor symptoms related to menopause, briefly discusses fezolinetant, a nonhormonal therapy for vasomotor symptoms, which can cause adverse events such as abdominal pain, diarrhea, insomnia, back pain, and hepatic aminotransferase elevations).</i></div></div></li><li><div class="bk_ref" id="Fezolinetant.REF.rani.2024">Rani
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P, Zehra
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D, Mansoor
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M, Rani
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P.
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FDA approved fezolinetant (Veozah): a critical evaluation of its efficacy and safety for menopausal vasomotor symptoms, calling for prospective research.
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Arch Womens Ment Health.
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2024. Epub ahead of print.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/38478035" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 38478035</span></a>]<div><i>(Short review of the data on efficacy and safety of fezolinetant that supported the FDA decision for its approval as therapy of women with moderate-to-severe vasomotor symptoms due to menopause, mentions that serum aminotransferase elevations arose in a small proportion of treated patients [2.3%] but there were no cases of liver injury with jaundice).</i></div></div></li></ul></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK608428_pubdet_">Publication Details</h2><h3>Publication History</h3><p class="small">Last Update: <span itemprop="dateModified">October 10, 2024</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-. Fezolinetant. [Updated 2024 Oct 10].<span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/livertox/Fexofenadine/?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/Fibrates/?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="figobFezolinetantTc"><div id="Fezolinetant.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK608428/table/Fezolinetant.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Fezolinetant.Tc_lrgtbl__"><table><thead><tr><th id="hd_h_Fezolinetant.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRUG</th><th id="hd_h_Fezolinetant.Tc_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CAS REGISTRY NUMBER</th><th id="hd_h_Fezolinetant.Tc_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MOLECULAR FORMULA</th><th id="hd_h_Fezolinetant.Tc_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">STRUCTURE</th></tr></thead><tbody><tr><td headers="hd_h_Fezolinetant.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fezolinetant</td><td headers="hd_h_Fezolinetant.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/315496205" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1629229-37-3</a>
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</td><td headers="hd_h_Fezolinetant.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">C16-H15-FN6-OS</td><td headers="hd_h_Fezolinetant.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/315496205" 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=315496205" alt="image 315496205 in the ncbi pubchem database" /></a>
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