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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="_NBK548002_"><span class="title" itemprop="name">Ixazomib</span></h1><p class="fm-aai"><a href="#_NBK548002_pubdet_">Publication Details</a></p></div></div><div class="body-content whole_rhythm" itemprop="text"><div id="Ixazomib.OVERVIEW"><h2 id="_Ixazomib_OVERVIEW_">OVERVIEW</h2><div id="Ixazomib.Introduction"><h3>Introduction</h3><p>Ixazomib is a small molecule proteasome inhibitor that is used in combination with other antineoplastic agents to treat refractory multiple myeloma. Ixazomib is associated with a low rate of serum enzyme elevations during treatment and to rare instances of clinically apparent, acute liver injury.</p></div><div id="Ixazomib.Background"><h3>Background</h3><p>Ixazomib (ix az' oh mib) is an orally available, small molecule inhibitor of the 26S proteasome, the intracellular complex that degrades proteins involved in cell signaling and cell cycle regulation. Blocking proteasome activity prevents activation of factors involved in cell growth and resistance to chemotherapy induced apoptosis, thereby leading to cancer cell death. Preclinical studies in vitro and in vivo suggested that ixazomib had activity against several hematologic malignancies. Clinical trials of the addition of ixazomib to lenalidomide and dexamethasone in patients with multiple myeloma showed improvements in progression free survival. Ixazomib given in combination with lenalidomide and dexamethasone received approval for use in the United States in 2015 for therapy of refractory multiple myeloma. Ixazomib is available in capsules of 2.3, 3 and 4 mg under the brand name Ninlaro. The recommended starting dose is 4 mg orally on days 1, 8 and 15 of 28-day cycles of lenalidomide and dexamethasone. A lower daily dose (3 mg) is recommended for patients with renal or hepatic impairment. Common side effects include nausea, diarrhea, constipation, anorexia, fatigue, peripheral edema, thrombocytopenia, neutropenia, anemia peripheral neuropathy, rash and fever. Uncommon, but potentially severe side effects include peripheral neuropathy, bone marrow suppression, thrombocytopenia, severe diarrhea and dehydration and embryo-fetal toxicity.</p></div><div id="Ixazomib.Hepatotoxicity"><h3>Hepatotoxicity</h3><p>In large clinical trials of ixazomib combined with lenalidomide and dexamethasone, elevations in serum aminotransferase levels were common, occurring in ~10% of patients. However, values greater than 5 times the upper limit of normal (ULN) were rare, occurring in <1% of recipients. Cases of clinically apparent liver injury including acute liver failure have been reported in patients receiving ixazomib, however in many instances multiple concomitant medications were being taken and the specific role of ixazomib in causing the liver injury was not always clear. The clinical features of cases of liver injury attributed to ixazomib have not been defined in any detail. Hepatotoxicity is listed as a warning in the product label for ixazomib and monitoring of serum enzymes during treatment is recommended.</p><p>Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).</p></div><div id="Ixazomib.Mechanism_of_Injury"><h3>Mechanism of Injury</h3><p>The mechanism of liver injury accounting for serum enzyme elevations and hepatic toxicity during ixazomib therapy is not known, but may be a direct effect of inhibition of hepatic proteasome activity. Ixazomib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic intermediate. Ixazomib is susceptible to drug-drug interactions with agents that are strong inhibitors or inducers hepatic CYP 3A activity.</p></div><div id="Ixazomib.Outcome_and_Management"><h3>Outcome and Management</h3><p>Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to dose reduction or temporary cessation. Clinically apparent liver injury should prompt immediate interruption of ixazomib therapy. Cases of hepatic failure attributed to ixazomib have been described, but no instance of chronic hepatitis or vanishing bile duct syndrome. The product label for ixazomib recommends monitoring of "hepatic enzymes" during treatment. There is little information on cross reactivity in risk for hepatic injury between ixazomib and other cancer chemotherapeutic agents including the tyrosine kinase inhibitors and other proteasome inhibitors such as carfilzomib and bortezomib but, because of the differences in chemical structure, there is little reason to suggest that there might be.</p><p>Drug Class: <a href="/books/n/livertox/AntineoplasticAgents/?report=reader">Antineoplastic Agents</a>, <a href="/books/n/livertox/ProteinKinaseInhibit/?report=reader">Protein Kinase Inhibitors</a></p><p>Related Drugs: <a href="/books/n/livertox/Bortezomib/?report=reader">Bortezomib</a>, <a href="/books/n/livertox/Carfilzomib/?report=reader">Carfilzomib</a>, <a href="/books/n/livertox/Thalidomide_Lenalido/?report=reader">Lenalidomide</a></p></div></div><div id="Ixazomib.PRODUCT_INFORMATION"><h2 id="_Ixazomib_PRODUCT_INFORMATION_">PRODUCT INFORMATION</h2><div id="Ixazomib.BPI" class="box boxed-text-box whole_rhythm hide-overflow"><p>
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<b>REPRESENTATIVE TRADE NAMES</b>
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</p><p>Ixazomib – Ninlaro®</p><p>
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<b>DRUG CLASS</b>
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</p><p>Antineoplastic Agents</p><p>
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<a href="https://dailymed.nlm.nih.gov/dailymed/search.cfm?label=all&query=Ixazomib" 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><div id="Ixazomib.CHEMICAL_FORMULA_AND_STRUCTURE"><h2 id="_Ixazomib_CHEMICAL_FORMULA_AND_STRUCTURE_">CHEMICAL FORMULA AND STRUCTURE</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figIxazomibT1"><a href="/books/NBK548002/table/Ixazomib.T1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figIxazomibT1" rid-ob="figobIxazomibT1"><img class="small-thumb" src="/books/NBK548002/table/Ixazomib.T1/?report=thumb" src-large="/books/NBK548002/table/Ixazomib.T1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="Ixazomib.T1"><a href="/books/NBK548002/table/Ixazomib.T1/?report=objectonly" target="object" rid-ob="figobIxazomibT1">Table</a></h4></div></div></div><div id="Ixazomib.ANNOTATED_BIBLIOGRAPHY"><h2 id="_Ixazomib_ANNOTATED_BIBLIOGRAPHY_">ANNOTATED BIBLIOGRAPHY</h2><p>References updated: 01 June 2017</p><ul class="first-line-outdent"><li><div class="bk_ref" id="Ixazomib.R1">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 proteasome inhibitors such as ixazomib or bortezomib).</i></div></div></li><li><div class="bk_ref" id="Ixazomib.R2">DeLeve LD. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 552.<div><i>(Review of hepatotoxicity of cancer chemotherapeutic agents; bortezomib is listed as being implicated in causing hepatocellular injury, but ixazomib is not mentioned).</i></div></div></li><li><div class="bk_ref" id="Ixazomib.R3">Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.<div><i>(Textbook of pharmacology and therapeutics).</i></div></div></li><li><div class="bk_ref" id="Ixazomib.R4">Laubach J, Hideshima T, Richardson P, Anderson K. Clinical translation in multiple myeloma: from bench to bedside. Semin Oncol 2013; 40: 549-53. [<a href="https://pubmed.ncbi.nlm.nih.gov/24135399" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24135399</span></a>]<div><i>(Review of recent development of new agents to treat multiple myeloma including bortezomib which showed activity against myeloma cell lines and was then evaluated clinically).</i></div></div></li><li><div class="bk_ref" id="Ixazomib.R5">Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol 2014; 15: 1503-12. [<a href="https://pubmed.ncbi.nlm.nih.gov/25456369" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25456369</span></a>]<div><i>(Among 65 patients with refractory multiple myeloma treated with ixazomib combined with lenalidomide and dexamethasone, dose limiting toxicities were nausea, diarrhea and skin rash).</i></div></div></li><li><div class="bk_ref" id="Ixazomib.R6">Assouline SE, Chang J, Cheson BD, Rifkin R, Hamburg S, Reyes R, Hui AM, et al. Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma. Blood Cancer J 2014; 4: e251. [<a href="/pmc/articles/PMC4220649/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4220649</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25325301" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25325301</span></a>]<div><i>(Among 30 patients with refractory lymphoma treated with different doses of ixazomib significant adverse events included neutropenia, thrombocytopenia, diarrhea, lymphopenia, rash and renal failure; no mention of ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="Ixazomib.R7">Kumar SK, Bensinger WI, Zimmerman TM, Reeder CB, Berenson JR, Berg D, Hui AM, et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood 2014; 124: 1047-55. [<a href="/pmc/articles/PMC4468583/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4468583</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24904120" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24904120</span></a>]<div><i>(Among 60 patients with refractory multiple myeloma treated with 4 different doses of ixazomib, dose limiting toxicities were nausea, diarrhea and skin rash; peripheral neuropathy developed in 40% of patients, and ALT elevations in 10%, which were above 5 times ULN in only 1 patient [2%]).</i></div></div></li><li><div class="bk_ref" id="Ixazomib.R8">Wang H, Guan F, Chen D, Dou QP, Yang H. An analysis of the safety profile of proteasome inhibitors for treating various cancers. Expert Opin Drug Saf 2014: 1-12. [<a href="https://pubmed.ncbi.nlm.nih.gov/25005844" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25005844</span></a>]<div><i>(Review of efficacy and safety of bortezomib and several second-generation proteasome inhibitors including carfilzomib, marizomib, ixazomib and oprozomib; no discussion of hepatotoxicity or serum enzyme elevations).</i></div></div></li><li><div class="bk_ref" id="Ixazomib.R9">Smith DC, Kalebic T, Infante JR, Siu LL, Sullivan D, Vlahovic G, Kauh JS, et al. Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-hematologic malignancies. Invest New Drugs 2015; 33: 652-63. [<a href="/pmc/articles/PMC4435632/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4435632</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25777468" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25777468</span></a>]<div><i>(Among 96 patients treated with intravenous ixazomib [twice weekly] toxicities included rash, thrombocytopenia, fatigue, dehydration and renal failure; no mention of ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="Ixazomib.R10">Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, et al; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2016; 374: 1621-34. [<a href="https://pubmed.ncbi.nlm.nih.gov/27119237" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27119237</span></a>]<div><i>(Among 722 patients with refractory or relapsed multiple myeloma treated with lenalidomide and dexamethasone, progression free survival was improved by addition of ixazomib while serious adverse event rates were not [47% vs 49%]; side effects more common in ixazomib recipients included rash [36% vs 23%], vomiting [23% vs 12%], severe thrombocytopenia [12% vs 7%] and peripheral neuropathy [27% vs 22%], but not "liver impairment" [7% vs 6%]).</i></div></div></li><li><div class="bk_ref" id="Ixazomib.R11">Three new drugs for multiple myeloma. Med Lett Drugs Ther 2016; 58 (1495): e70-1. [<a href="https://pubmed.ncbi.nlm.nih.gov/27192621" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27192621</span></a>]<div><i>(Concise summary of standard therapy for multiple myeloma and the mechanism of action, clinical efficacy, safety and costs of ixazomib, daratumumab and elotuzumab; does not mention liver related adverse events).</i></div></div></li><li><div class="bk_ref" id="Ixazomib.R12">Schlafer D, Shah KS, Panjic EH, Lonial S. Safety of proteasome inhibitors for treatment of multiple myeloma. Expert Opin Drug Saf 2017; 16: 167-83. [<a href="https://pubmed.ncbi.nlm.nih.gov/27841029" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27841029</span></a>]<div><i>(Review of the safety of proteasome inhibitors including bortezomib, carfilzomib and ixazomib; mentions that rates of liver impairment are not increased by addition of ixazomib to lenalidomide and dexamethasone).</i></div></div></li></ul></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK548002_pubdet_">Publication Details</h2><h3>Publication History</h3><p class="small">Last Update: <span itemprop="dateModified">June 1, 2017</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p><a href="https://www.niddk.nih.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Institute of Diabetes and Digestive and Kidney Diseases</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Ixazomib. [Updated 2017 Jun 1].<span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/livertox/Ixabepilone/?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/Ixekizumab/?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="boxed-text" id="figobIxazomibBPI"><div id="Ixazomib.BPI" class="box boxed-text-box whole_rhythm hide-overflow"><p>
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<b>REPRESENTATIVE TRADE NAMES</b>
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</p><p>Ixazomib – Ninlaro®</p><p>
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<b>DRUG CLASS</b>
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</p><p>Antineoplastic Agents</p><p>
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<a href="https://dailymed.nlm.nih.gov/dailymed/search.cfm?label=all&query=Ixazomib" 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></article><article data-type="table-wrap" id="figobIxazomibT1"><div id="Ixazomib.T1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK548002/table/Ixazomib.T1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Ixazomib.T1_lrgtbl__"><table><thead><tr><th id="hd_h_Ixazomib.T1_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">DRUG</th><th id="hd_h_Ixazomib.T1_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">CAS REGISTRY NO.</th><th id="hd_h_Ixazomib.T1_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">MOLECULAR FORMULA</th><th id="hd_h_Ixazomib.T1_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">STRUCTURE</th></tr></thead><tbody><tr><td headers="hd_h_Ixazomib.T1_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Ixazomib</td><td headers="hd_h_Ixazomib.T1_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/135268985" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1072833-77-2</a>
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</b>
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</td><td headers="hd_h_Ixazomib.T1_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">C14-H19-B-Cl2-N2-O4</td><td headers="hd_h_Ixazomib.T1_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<div class="graphic"><img src="/books/NBK548002/bin/Ixazomib_structure.jpg" alt="Ixazomib structure" /></div>
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