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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Berotralstat - LiverTox - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]">
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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="_NBK605175_"><span class="title" itemprop="name">Berotralstat</span></h1><p class="fm-aai"><a href="#_NBK605175_pubdet_">Publication Details</a></p></div></div><div class="body-content whole_rhythm" itemprop="text"><div id="Berotralstat.OVERVIEW"><h2 id="_Berotralstat_OVERVIEW_">OVERVIEW</h2><div id="Berotralstat.Introduction"><h3>Introduction</h3><p>Berotralstat is a small molecule inhibitor of plasma kallikrein that is used to prevent acute attacks of hereditary angioedema (HAE) in adults and children 12 years of age or older. Berotralstat has been linked to occasional mild-to-moderate elevations in serum aminotransferase levels during therapy but has not been implicated in instances of clinically apparent liver injury with symptoms or jaundice.</p></div><div id="Berotralstat.Background"><h3>Background</h3><p>Berotralstat (ber” oh tral’ stat) is an orally available, small molecule inhibitor of plasma kallikrein used to prevent acute attacks of hereditary angioedema (HAE), an autosomal dominant condition marked by intermittent episodes of swelling and pain affecting multiple organs and tissues. HAE is caused by mutations in the SERPIN-G1 gene that encodes C1-esterase inhibitor, which is important in regulation of kallikrein and release of bradykinin. Elevated bradykinin levels cause an increase in vascular permeability resulting in the swelling and pain of acute attacks. Attacks commonly affect the gastrointestinal tract but may also involve the genitourinary tract, face, hands, feet, or skin. Potentially serious and even fatal attacks involve the larynx with laryngeal edema and airway compromise. In a registration randomized controlled trial, berotralstat therapy led to increases in serum C1-esterase inhibitor levels and a decrease in number and severity attacks of HAE. Berotralstat was approved in the United States in 2020 for prevention of acute attacks of HAE in adults and children 12 years of age or older, the first oral therapy for prophylaxis of attacks. Berotralstat is available in capsules of 150 and 110 mg under the brand name Orladeyo. The recommended initial dosage is 150 mg once daily with the lower dose of 110 mg daily for patients with possible drug-drug interactions, preexisting hepatic impairment, or gastrointestinal intolerance to treatment. In registration trials, the most frequent adverse events were abdominal pain, vomiting, diarrhea, back pain, and gastrointestinal reflux. Uncommon potentially severe adverse events include QTc prolongation.</p><p>Berotralstat should not be used to treat acute attacks of HAE. Several drugs are approved for therapy of acute attacks as well as for prevention of attacks in high risk individuals, but all require parenteral administration. These agents include human plasma derived preparations of C1-esterase inhibitor (Cinryze, Haegarda, Berinert), a recombinant human C1-esterase inhibitor (Ruconest), small protein inhibitors of plasma kallikrein (ecallantide, Kalbitor), a proteomimetic bradykinin B2 receptor blocker (icatibant, Firazyr), and a monoclonal antibody to kallikrein (lanadelumab, Takhzyro).</p></div><div id="Berotralstat.Hepatotoxicity"><h3>Hepatotoxicity</h3><p>In preregistration trials, mild, transient serum aminotransferase elevations occurred in 2% to 5% of patients receiving berotralstat vs 10% of those on placebo. Values above 5 times the upper limit of normal (ULN) were uncommon (less than 1%). Furthermore, bilirubin levels remained normal and no patient developed symptomatic acute liver injury. In many instances, other causes for the liver test abnormalities were present including preexisting nonalcoholic fatty liver disease, chronic viral hepatitis, or gallstone disease. Nevertheless, occasional patients required drug discontinuation because of liver test abnormalities. Since its licensure and more widescale clinical use, there have been no published reports of acute liver injury attributed to berotralstat.</p><p>Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).</p></div><div id="Berotralstat.Mechanism_of_Injury"><h3>Mechanism of Injury</h3><p>The causes of liver test abnormalities during berotralstat therapy of hereditary angioedema are often unrelated to the drug and are attributable to comorbidities, such as chronic viral hepatitis, gallstone disease, or malignancy. Nevertheless, berotralstat is metabolized in the liver, predominantly by CYP 2D6 and 3A4 and the hepatotoxicity or immunogenicity of a metabolite might be responsible for minor elevations in serum aminotransferase levels during therapy. In preregistration trials, liver test abnormalities were more frequent in patients with HAE who had been treated with androgenic steroids such as danazol in the recent past (typically stopping within the previous 2 weeks), a finding suggesting that the abnormalities related to the recent, precipitous withdrawal of the androgenic steroids.</p></div><div id="Berotralstat.Outcome_and_Management"><h3>Outcome and Management</h3><p>The product label for berotralstat does not recommend monitoring of routine liver tests during therapy, but testing patients before starting therapy is appropriate because of the frequency of comorbidities including liver disease in patients with HAE. A rise in serum aminotransferase levels during therapy should trigger evaluation for other possible causes. Persistence of unexplained ALT levels above 5 times the ULN or appearance of symptoms of liver injury or jaundice should lead to at least temporary discontinuation and more careful monitoring. Patients on chronic therapy with androgenic steroids for HAE should be gradually withdrawn from therapy and start treatment with berotralstat at least two weeks after stopping.</p><p>Drug Class: Genetic Disorder Agents, <a href="/books/n/livertox/HAEAgents/?report=reader">Hereditary Angioedema (HAE) Agents</a></p><p>Other Orally Active Drugs for Hereditary Angioedema: Danazol</p></div></div><div id="Berotralstat.PRODUCT_INFORMATION"><h2 id="_Berotralstat_PRODUCT_INFORMATION_">PRODUCT INFORMATION</h2><p>
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<b>REPRESENTATIVE TRADE NAMES</b>
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</p><p>Berotralstat – Orladeyo®</p><p>
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<b>DRUG CLASS</b>
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</p><p>Genetic Disorder Agents</p><p>
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<a href="https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=Berotralstat" 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="Berotralstat.CHEMICAL_FORMULA_AND_STRUCT"><h2 id="_Berotralstat_CHEMICAL_FORMULA_AND_STRUCT_">CHEMICAL FORMULA AND STRUCTURE</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figBerotralstatTc"><a href="/books/NBK605175/table/Berotralstat.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobBerotralstatTc"><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="Berotralstat.Tc"><a href="/books/NBK605175/table/Berotralstat.Tc/?report=objectonly" target="object" rid-ob="figobBerotralstatTc">Table</a></h4></div></div></div><div id="Berotralstat.BIBLIOGRAPHY"><h2 id="_Berotralstat_BIBLIOGRAPHY_">BIBLIOGRAPHY</h2><p>References updated: 20 June 2024</p><p>Abbreviations: HAE, hereditary angioedema; ULN, upper limit of the normal range.</p><ul class="first-line-outdent"><li><div class="bk_ref" id="Berotralstat.REF1">FDA. Integrated Review. 2020. <a href="https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/214094Orig1s000MultidisciplineR.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/2020/214094Orig1s000MultidisciplineR.pdf</a><div><i>(FDA Summary of the data on the safety and efficacy of berotralstat submitted in support of the application for approval as means of prevention of acute attacks of hereditary angioedema [HAE], mentions that ALT elevations were more frequent with placebo [10%] than berotralstat [2.4% to 5.1%], although one patient on the drug developed ALT elevations of above 5 times the upper limit of normal [ULN] and discontinued treatment with prompt resolution; no serious hepatic adverse events or liver injury with jaundice).</i></div></div></li><li><div class="bk_ref" id="Berotralstat.REF.ayg_renp_rs_n.2018.352">Aygören-Pürsün
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E, Bygum
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A, Grivcheva-Panovska
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V, Magerl
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M, Graff
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J, Steiner
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UC, Fain
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O, et al.
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Oral plasma kallikrein inhibitor for prophylaxis in hereditary angioedema.
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N Engl J Med.
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2018;379:352-362.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/30044938" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30044938</span></a>]<div><i>(Among 77 patients with HAE treated with berotralstat [62.5, 125, 250, or 350 mg] or placebo once daily for 28 days, acute HAE attacks were reduced by 47% to 75% by the higher doses, but adverse events also increased with dose including mild-to-moderate ALT elevations [but without symptoms or jaundice] of 7% and 11% at the two highest doses).</i></div></div></li><li><div class="bk_ref" id="Berotralstat.REF.lee.2021.405">Lee
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A.
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Berotralstat: first approval.
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Drugs.
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2021;81:405-409.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/33646555" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33646555</span></a>]<div><i>(Summary of the mechanism of action, history of development, pharmacology, clinical efficacy, and safety of berotralstat shortly after its approval in the US as a means of prevention of attacks of HAE, does not mention ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="Berotralstat.REF.zuraw.2021.164">Zuraw
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B, Lumry
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WR, Johnston
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DT, Aygören-Pürsün
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E, Banerji
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A, Bernstein
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JA, Christiansen
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SC, et al.
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Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial.
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J Allergy Clin Immunol.
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2021;148:164-172.e9.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/33098856" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33098856</span></a>]<div><i>(Among 120 patients with HAE [ages 23 years or older] treated with berotralstat [110 or 150 mg] or placebo once daily for 24 weeks, the acute attack rate was lower with berotralstat [1.7 and 1.3 vs 2.4 per month] while adverse events more frequent with drug included abdominal pain [10%-23% vs 10%], vomiting [10%-15% vs 3%], diarrhea [10%-15% vs 0%] and back pain [2%-10% vs 3%], and one patient on 150 mg daily developed an asymptomatic rise in ALT above 10 times ULN that resolved on discontinuation).</i></div></div></li><li><div class="bk_ref" id="Berotralstat.REF.wedner.2021.2305">Wedner
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HJ, Aygören-Pürsün
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E, Bernstein
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J, Craig
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T, Gower
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R, Jacobs
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JS, Johnston
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DT, et al.
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Randomized trial of the efficacy and safety of berotralstat (BCX7353) as an oral prophylactic therapy for hereditary angioedema: results of APeX-2 through 48 weeks (Part 2).
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J Allergy Clin Immunol Pract.
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2021;9:2305-2314.e4.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/33866032" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33866032</span></a>]<div><i>(Among 108 patients with HAE participating in a 24-week controlled trial [Zuraw 2021] treated with open label berotralstat [110 or 150 mg daily] for another 24 weeks, the monthly acute attack rate continued to decline particularly with the higher dose, while adverse events were largely mild-to-moderate gastrointestinal complaints; no mention of ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="Berotralstat.REF6">Berotralstat (Orladeyo) for prevention of hereditary angioedema.
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Med Lett Drugs Ther.
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2021;63(1629):e7-e8.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/34544111" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34544111</span></a>]<div><i>(Concise review of HAE, the mechanism of action of berotralstat, clinical efficacy, safety, and costs shortly after its approval in the US for prevention of acute attacks of HAE, mentions common adverse events of abdominal pain, vomiting, diarrhea, back pain, and reflux, and the possibility of prolongation of the QTc interval, but does not mention ALT elevations or hepatoxicity).</i></div></div></li><li><div class="bk_ref" id="Berotralstat.REF.ahuja.2023.1380">Ahuja
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M, Dorr
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A, Bode
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E, Boulton
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APR, Buckland
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M, Chee
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S, Dalley
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C, et al.
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Berotralstat for the prophylaxis of hereditary angioedema-real-world evidence data from the United Kingdom.
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Allergy.
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2023;78:1380-1383.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/36609839" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36609839</span></a>]<div><i>(Survey of 54 patients with HAE started on berotralstat in the UK found that numbers of average monthly acute attacks decreased from 12.9 to 4.5 by 6 months along with overall symptom severity scores, reported side effects included cramps, nausea, diarrhea, vomiting and headaches, but no discontinuations for side effects and no mention of liver related events).</i></div></div></li><li><div class="bk_ref" id="Berotralstat.REF.peter.2023.100841">Peter
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JG, Desai
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B, Tomita
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D, Collis
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P, Stobiecki
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M. Assessment of HAE prophylaxis transition from androgen therapy to berotralstat: A subset analysis of the APeX-S trial.
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World Allergy Organ J.
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2023;16:100841.
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[<a href="/pmc/articles/PMC10665923/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10665923</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/38020288" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 38020288</span></a>]<div><i>(Among 39 patients with HAE who discontinued androgen therapy within 60 days of starting berotralstat [150 mg daily], 7 developed ALT elevations [6 above 5 times ULN and 5 requiring discontinuation] all of whom had stopped androgens within 14 days of starting berotralstat).</i></div></div></li><li><div class="bk_ref" id="Berotralstat.REF.kianialikhan.2024.733">Kiani-Alikhan
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S, Gower
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R, Craig
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T, Wedner
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HJ, Kinaciyan
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T, Aygören-Pürsün
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E, Banerji
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A, et al.; APeX-2 investigators. Once-daily oral berotralstat for long-term prophylaxis of hereditary angioedema: the open-label extension of the APeX-2 randomized trial.
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J Allergy Clin Immunol Pract.
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2024;12:733-743.e10.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/38122865" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 38122865</span></a>]<div><i>(Among 81 patients with HAE treated in previous controlled trials who were continued on berotralstat [150 mg daily] for an additional 4 years, efficacy was maintained and 15% of patients had treatment related adverse events but none were serious; no mention of ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="Berotralstat.REF.riedl.2024.505">Riedl
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MA, Soteres
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D, Sublett
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JW, Desai
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B, Tomita
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D, Collis
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P, Bernstein
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JA; APeX-S Study Investigators. Hereditary angioedema outcomes in US patients switched from injectable long-term prophylactic medication to oral berotralstat.
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Ann Allergy Asthma Immunol.
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2024;132:505-511.e1.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/38006972" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 38006972</span></a>]<div><i>(Among 34 US patients with HAE who were switched from injectable long term prophylaxis to oral berotralstat monotherapy, the monthly attack rate was 0.29 to 0.58 while mild-to-moderate gastrointestinal adverse events occurred in 35%, but there were no serious adverse events and ALT elevations and hepatotoxicity were not mentioned).</i></div></div></li></ul></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK605175_pubdet_">Publication Details</h2><h3>Publication History</h3><p class="small">Last Update: <span itemprop="dateModified">June 20, 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-. Berotralstat. [Updated 2024 Jun 20].<span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/livertox/Berberine/?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/Betablockers/?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="figobBerotralstatTc"><div id="Berotralstat.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK605175/table/Berotralstat.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Berotralstat.Tc_lrgtbl__"><table><thead><tr><th id="hd_h_Berotralstat.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRUG</th><th id="hd_h_Berotralstat.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_Berotralstat.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_Berotralstat.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_Berotralstat.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Berotralstat</td><td headers="hd_h_Berotralstat.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/381608984" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1809010-50-1</a>
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</td><td headers="hd_h_Berotralstat.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">C30-H26-F4-N6-O</td><td headers="hd_h_Berotralstat.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/381608984" 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=381608984" alt="image 381608984 in the ncbi pubchem database" /></a>
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