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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="_NBK548623_"><span class="title" itemprop="name">Natalizumab</span></h1><p class="fm-aai"><a href="#_NBK548623_pubdet_">Publication Details</a></p></div></div><div class="body-content whole_rhythm" itemprop="text"><div id="Natalizumab.OVERVIEW"><h2 id="_Natalizumab_OVERVIEW_">OVERVIEW</h2><div id="Natalizumab.Introduction"><h3>Introduction</h3><p>Natalizumab is a monoclonal antibody to human alpha-4 integrin which has potent immune suppressive activity and is used in the therapy of severe inflammatory bowel disease and relapsing multiple sclerosis. Natalizumab has been linked to rare instances of idiosyncratic acute liver injury that has features of autoimmunity and seen largely in patients being treated for multiple sclerosis.</p></div><div id="Natalizumab.Background"><h3>Background</h3><p>Natalizumab (na" ta liz' ue mab) is a humanized monoclonal antibody to alpha-4 integrin, which binds avidly to the cellular adhesion molecule found on leukocytes blocking their ability to migrate to inflammatory foci. Inhibition of alpha-4 integrin activity leads to modulation of inflammatory pathways that are activated in autoimmune disorders. Natalizumab was shown to improve vision and motor function in patients with multiple sclerosis and to decrease inflammation, symptoms and relapses in patients with Crohn disease. Natalizumab was approved for use in the United States in 2005 and indications included severe Crohn disease and relapsing multiple sclerosis. However, after its general availability, natalizumab was linked to several instances of progressive multifocal leukoencephalopathy (PML), a severe neurological condition which is believed to be due to reactivation of the JC virus in neural cells. Because of this severe complication (which is often fatal), natalizumab has been restricted in use and is available only by a special program that requires thorough assessment of risks and careful monitoring and reporting. Natalizumab is available in 15 mL vials of 300 mg under the brand name Tysabri. The recommended dose is 300 mg intravenously every 4 weeks. Common side effects include headache, fatigue and infusion reactions. Natalizumab is also capable of causing immune suppression, resulting in an increased susceptibility to severe viral and bacterial infections as well as immune reconstitution reactions when it is withdrawn.</p></div><div id="Natalizumab.Hepatotoxicity"><h3>Hepatotoxicity</h3><p>In large clinical trials, serum aminotransferase elevations occurred in an average of 5% of patients on natalizumab therapy and in a slightly lower, although similar proportion (~3%) of those who received placebo. While there were no individual case reports of liver injury attributed to natalizumab therapy, at least 59 instances of hepatic injury were reported to the Adverse Event Reporting System maintained by the FDA within 4 years of its initial approval. In a report summarizing six clinically apparent cases of liver injury attributable to natalizumab, all were associated with jaundice and all occurred in patients receiving natalizumab for multiple sclerosis. The onset of injury followed the initial infusion of natalizumab in 4 patients, and after 5 and 12 courses of treatment in the other two reported cases. The pattern of liver injury was hepatocellular in 5 cases and cholestatic in one. Several cases were accompanied by autoantibodies and were treated with corticosteroids (Case 1), but autoimmune features were not prominent and immunoallergic features (fever, rash, eosinophilia) were not reported. The clinical cases were moderate in severity and no patient developed acute liver failure or progressed to chronic liver injury or vanishing bile duct syndrome. Since that initial summary, several more case reports of clinically apparent liver injury attributable to natalizumab have appeared, many of which have features of autoimmunity and almost all arising in patients with multiple sclerosis. Natalizumab can cause immune suppression and has been linked to bacterial and viral infections, but interestingly has not been reported to cause reactivation of tuberculosis or hepatitis B.</p><p>Likelihood score: B (likely cause of clinically apparent liver injury).</p></div><div id="Natalizumab.Mechanism_of_Injury"><h3>Mechanism of Injury</h3><p>The mechanism of liver injury caused by natalizumab is probably immunologically mediated, perhaps as a result of its effects on leukocyte function. It is a monoclonal antibody and like other proteins it is taken up by cells by endocytosis and is metabolized into amino acids.</p></div><div id="Natalizumab.Outcome_and_Management"><h3>Outcome and Management</h3><p>The hepatotoxicity of natalizumab is usually moderate in severity and reversible with discontinuation of infusions. Recurrence of injury with a shorter latency and more severe course has been reported. In cases with persistent injury, the addition of prednisone has appeared to hasten recovery, but in most instances, corticosteroid therapy can ultimately be discontinued. There is little information about cross sensitivity to liver injury with other monoclonal antibodies or immune modulating agents, but in most instances other disease modifying agents have been tolerated without recurrence of injury, although many of these are capable of causing liver injury on their own.</p><p>Drug Class: <a href="/books/n/livertox/GastrointestinalAgen/?report=reader">Gastrointestinal Agents</a>, Inflammatory Bowel Disease Agents; <a href="/books/n/livertox/MonoclonalAntibodies/?report=reader">Monoclonal Antibodies</a>, <a href="/books/n/livertox/MultipleSclerosisAge/?report=reader">Multiple Sclerosis Agents</a></p></div></div><div id="Natalizumab.CASE_REPORT"><h2 id="_Natalizumab_CASE_REPORT_">CASE REPORT</h2><div id="Natalizumab.Case_1_Acute_hepatocellular"><h3>Case 1. Acute hepatocellular injury due to natalizumab.(<a class="bibr" href="#Natalizumab.REF.1" rid="Natalizumab.REF.1">1</a>)</h3><p>A 43 year old man with multiple sclerosis developed fatigue, fever and back pain 8 days after the fifth monthly dose of natalizumab. On hospital admission, he was found to have elevations in serum enzymes but was not jaundiced. Serum ALT was 410 U/L, AST 134 U/L, INR 1.17 and bilirubin 0.4 mg/dL. Over the next several days, his liver tests worsened, serum bilirubin peaking at 3.0 mg/dL. A liver biopsy showed acute lobular and portal hepatitis with mild fibrosis. Recovery was slow and prednisone was given. Natalizumab was not continued. Over the next 6 months liver tests returned to normal, whereupon natalizumab was restarted. After the second monthly infusion, however, he redeveloped fatigue and jaundice and liver tests were again abnormal: ALT 3494 U/L, AST 1259 U/L and bilirubin 13.4 mg/dL. The antinuclear antibody, which was negative during the first episode, was positive in titers >1:320. Natalizumab was again stopped and prednisone was given with subsequent improvement.</p><div id="Natalizumab.Key_Points"><h4>Key Points</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figNatalizumabTc"><a href="/books/NBK548623/table/Natalizumab.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figNatalizumabTc" rid-ob="figobNatalizumabTc"><img class="small-thumb" src="/books/NBK548623/table/Natalizumab.Tc/?report=thumb" src-large="/books/NBK548623/table/Natalizumab.Tc/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="Natalizumab.Tc"><a href="/books/NBK548623/table/Natalizumab.Tc/?report=objectonly" target="object" rid-ob="figobNatalizumabTc">Table</a></h4></div></div></div><div id="Natalizumab.Comment"><h4>Comment</h4><p>This patient developed clinically apparent acute hepatocellular injury within 2 weeks of receiving his fifth monthly infusion of natalizumab for relapsing multiple sclerosis. The injury was moderate in severity, but slow to resolve. Liver histological features suggested an element of autoimmunity, and he was treated with prednisone but tolerated its withdrawal and had normal liver tests six months later. Upon reexposure, he redeveloped the liver injury with a shorter latency and with a more severe course. At this point, he was found to have high titers of ANA and prednisone was restarted. Although compatible with spontaneous autoimmune hepatitis (which has been reported in patients with multiple sclerosis), the timing of onset and recurrence of similar injury upon reexposure is reasonably convincing evidence that it was due to natalizumab, perhaps an autoimmune hepatitis that was triggered by the immunomodulatory therapy. This example was case 2 from the six case series reported by the FDA, which were based upon review of spontaneous adverse event reports during the first 4 years of general availability of natalizumab. The six cases were selected as the clinically apparent examples among a total of 59 separate reports of liver injury. The authors estimated the frequency of idiosyncratic clinically apparent liver injury from natalizumab to be 17 per 100,000 exposed patients. Events occurring at this low rate are unlikely to be detected in premarketing studies. Interestingly, virtually all of the published cases of natalizumab-hepatotoxicity have occurred in patients with multiple sclerosis, an autoimmune condition in which spontaneous autoimmune hepatitis is not infrequent.</p></div></div></div><div id="Natalizumab.PRODUCT_INFORMATION"><h2 id="_Natalizumab_PRODUCT_INFORMATION_">PRODUCT INFORMATION</h2><p>
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<b>REPRESENTATIVE TRADE NAMES</b>
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</p><p>Natalizumab – Tysabri®</p><p>
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<b>DRUG CLASS</b>
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</p><p>Gastrointestinal Agents; Multiple Sclerosis Agents</p><p>
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<a href="https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c5fdde91-1989-4dd2-9129-4f3323ea2962" 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="Natalizumab.CHEMICAL_FORMULA_AND_STRUCTU"><h2 id="_Natalizumab_CHEMICAL_FORMULA_AND_STRUCTU_">CHEMICAL FORMULA AND STRUCTURE</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figNatalizumabTd"><a href="/books/NBK548623/table/Natalizumab.Td/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figNatalizumabTd" rid-ob="figobNatalizumabTd"><img class="small-thumb" src="/books/NBK548623/table/Natalizumab.Td/?report=thumb" src-large="/books/NBK548623/table/Natalizumab.Td/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="Natalizumab.Td"><a href="/books/NBK548623/table/Natalizumab.Td/?report=objectonly" target="object" rid-ob="figobNatalizumabTd">Table</a></h4></div></div></div><div id="Natalizumab.CITED_REFERENCE"><h2 id="_Natalizumab_CITED_REFERENCE_">CITED REFERENCE</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="Natalizumab.REF.1">Bezabeh S, Flowers CM, Kortepeter C, Avigan M. Clinically significant liver injury in patients treated with natalizumab. <span><span class="ref-journal">Aliment Pharmacol Ther. </span>2010;<span class="ref-vol">31</span>:1028–35.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20163378" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20163378</span></a>]</div></dd></dl></dl></div><div id="Natalizumab.ANNOTATED_BIBLIOGRAPHY"><h2 id="_Natalizumab_ANNOTATED_BIBLIOGRAPHY_">ANNOTATED BIBLIOGRAPHY</h2><p>References updated: 15 April 2020</p><p>Abbreviations: TNF, tumor necrosis factor; PML, progressive multifocal leukoencephalopathy.</p><ul class="first-line-outdent"><li><div class="bk_ref" id="Natalizumab.REF.zimmerman.1999">Zimmerman HJ. Drugs used to treat rheumatic and musculospastic disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 517-54.<div><i>(Expert review of hepatotoxicity published in 1999, well before the availability of most antibody therapies).</i></div></div></li><li><div class="bk_ref" id="Natalizumab.REF.reuben.2011">Reuben A. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2011, pp. 569-91.<div><i>(Review of hepatotoxicity of immunosuppressive agents mentions the report of six cases of severe liver injury attributed to natalizumab report to the FDA Adverse Event Reporting System database).</i></div></div></li><li><div class="bk_ref" id="Natalizumab.REF.macnaughton.2018">MacNaughton WK, Sharkey KA. Pharmacotherapy of inflammatory bowel disease. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 945-54.<div><i>(Textbook of pharmacology and therapeutics).</i></div></div></li><li><div class="bk_ref" id="Natalizumab.REF.gordon.2001.268">Gordon FH, Lai CW, Hamilton MI, Allison MC, Srivastava ED, Fouweather MG, Donoghue S, et al. A randomized placebo-controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn's disease. <span><span class="ref-journal">Gastroenterology. </span>2001;<span class="ref-vol">121</span>:268–74.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11487536" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11487536</span></a>]<div>
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<i>(Randomized controlled trial of natalizumab in 30 patients with mild-to-moderate Crohn's disease found no difference in side effects compared to placebo; no mention of ALT elevations or hepatotoxicity).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.miller.2003.15">Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer-Hulme AJ, et al. International Natalizumab Multiple Sclerosis Trial Group. A controlled trial of natalizumab for relapsing multiple sclerosis. <span><span class="ref-journal">N Engl J Med. </span>2003;<span class="ref-vol">348</span>:15–23.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12510038" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12510038</span></a>]<div>
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<i>(Randomized controlled trial of 6 months of natalizumab versus placebo in 213 patients with relapsing multiple sclerosis; adverse events were similar in natalizumab and placebo treated patients, but no mention of liver toxicity or ALT levels).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.keeley.2005.1833">Keeley KA, Rivey MP, Allington DR. Natalizumab for the treatment of multiple sclerosis and Crohn's disease. <span><span class="ref-journal">Ann Pharmacother. </span>2005;<span class="ref-vol">39</span>:1833–43.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16219898" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16219898</span></a>]<div>
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<i>(Literature review of safety and efficacy of natalizumab; abnormal liver tests were reported in 5% of natalizumab and 3% of placebo recipients).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.sandborn.2005.1912">Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, Panaccione R, et al. International Efficacy of Natalizumab as Active Crohn's Therapy(ENACT-1) Trial Group. Evaluation of Natalizumab as Continuous Therapy(ENACT-2) Trial Group. Natalizumab induction and maintenance therapy for Crohn's disease. <span><span class="ref-journal">N Engl J Med. </span>2005;<span class="ref-vol">353</span>:1912–25.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16267322" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16267322</span></a>]<div>
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<i>(Summary of two controlled trials of natalizumab in 905 patients with active Crohn disease; total as well as serious adverse events were similar between the two groups; no mention of liver toxicity or ALT elevations).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.calabrese.2006.983">Calabrese LH, Zein NN, Vassilopoulos D. Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies. <span><span class="ref-journal">Ann Rheum Dis. </span>2006;<span class="ref-vol">65</span>:983–9.</span> [<a href="/pmc/articles/PMC1798254/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1798254</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16627542" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16627542</span></a>]<div>
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<i>(Review of the problem of reactivation of hepatitis B in patients with rheumatic diseases treated with immunosuppressive agents, with recommendations on prevention).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.polman.2006.899">Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, et al. AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. <span><span class="ref-journal">N Engl J Med. </span>2006;<span class="ref-vol">354</span>:899–910.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16510744" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16510744</span></a>]<div>
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<i>(Randomized controlled trial of natalizumab vs placebo in 942 patients with relapsing multiple sclerosis; fatigue and allergic reactions were more common in natalizumab treated patients; abnormal liver tests were reported in 5% of natalizumab vs 4% of placebo recipients).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.rudick.2006.911">Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, et al. SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. <span><span class="ref-journal">N Engl J Med. </span>2006;<span class="ref-vol">354</span>:911–23.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16510745" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16510745</span></a>]<div>
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<i>(Among 1171 patients with multiple sclerosis receiving interferon beta-1a who received the addition of natalizumab or placebo monthly for up to 2.5 years, the relapse rate was lower in those receiving natalizumab [23% vs 29%] and adverse event rates were similar including “abnormal liver function values” of <1% in both groups).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.sands.2007.2">Sands BE, Kozarek R, Spainhour J, Barish CF, Becker S, Goldberg L, Katz S, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab. <span><span class="ref-journal">Inflamm Bowel Dis. </span>2007;<span class="ref-vol">13</span>:2–11.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17206633" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17206633</span></a>]<div>
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<i>(Randomized controlled trial of natalizumab vs placebo in 79 patients with Crohn disease who were receiving infliximab; adverse events were similar in the two groups and no clinically significant abnormalities were observed in laboratory parameters).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.targan.2007.1672">Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH, Spehlmann ME, et al. International Efficacy of Natalizumab in Crohn's Disease Response and Remission(ENCORE) Trial Group. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial. <span><span class="ref-journal">Gastroenterology. </span>2007;<span class="ref-vol">132</span>:1672–83.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17484865" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17484865</span></a>]<div>
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<i>(Randomized controlled trial of natalizumab vs placebo in 509 patients with active Crohn disease reported side effects of headache, nausea, fatigue, abdominal pain and dizziness; no mention of liver toxicity or ALT elevations).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.natalizumab_tysabri_for_crohns_disease.2008.34">Natalizumab (Tysabri) for Crohn's disease. <span><span class="ref-journal">Med Lett Drugs Ther. </span>2008;<span class="ref-vol">50</span>:34–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18458669" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18458669</span></a>]<div>
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<i>(Concise summary of use of natalizumab for Crohn disease mentions that postmarketing hepatic toxicity had occurred).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.kaiser.2009.b508">Kaiser T, Moessner J, Patel K, McHutchison JG, Tillmann HL. Life threatening liver disease during treatment with monoclonal antibodies. <span><span class="ref-journal">BMJ. </span>2009;<span class="ref-vol">338</span>:b508.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19224957" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19224957</span></a>]<div>
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<i>(66 year old man with psoriasis was treated with efalizumab [anti-CD11a] and then adalimumab [anti-TNF], and 11 days later developed jaundice and severe hepatitis [bilirubin 9.1 rising to 52 mg/dL, ALT 549 U/L, Alk P 131 U/L], with HBsAg being detected and slow but eventual recovery).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.khokhar.2010.508">Khokhar OS, Lewis JH. Hepatotoxicity of agents used in the management of inflammatory bowel disease. <span><span class="ref-journal">Dig Dis. </span>2010;<span class="ref-vol">28</span>:508–18.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20926880" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20926880</span></a>]<div>
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<i>(Review of the hepatotoxicity of drugs used to treat inflammatory bowel disease focusing upon sulfasalazine, thiopurines, TNF inhibitors, and methotrexate).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.bezabeh.2010.1028">Bezabeh S, Flowers CM, Kortepeter C, Avigan M. Clinically significant liver injury in patients treated with natalizumab. <span><span class="ref-journal">Aliment Pharmacol Ther. </span>2010;<span class="ref-vol">31</span>:1028–35.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20163378" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20163378</span></a>]<div>
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<i>(Summary of 6 clinically apparent hepatic adverse events reported to the FDA over a 4 year period included 1 man and 5 women, ages 26 to 59 years, all with multiple sclerosis, injury arising after the first to 11th dose [bilirubin 4.5 to 16.1 mg/dL, ALT 753-3494 U/L, Alk P 46-1043 U/L], all resolving, all were icteric and symptomatic and 5 were hepatocellular; 3 had autoantibodies but immune features were not prominent: Case 1).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.andr_.2010.14">André MC, Pacheco D, Antunes J, Silva R, Filipe P, Soares de Almeida LM. Generalized skin drug eruption to natalizumab in a patient with multiple sclerosis. <span><span class="ref-journal">Dermatol Online J. </span>2010;<span class="ref-vol">16</span>:14.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20579469" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20579469</span></a>]<div>
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<i>(29 year old man with multiple sclerosis developed generalized rash 30 days after starting natalizumab with abnormal liver tests [bilirubin not given, ALT 185 U/L, GGT 320 U/L, eosinophils 2150 cells/L], resolving within 3 weeks).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.aithal.2011.139">Aithal GP. Hepatotoxicity related to antirheumatic drugs. <span><span class="ref-journal">Nat Rev Rheumatol. </span>2011;<span class="ref-vol">7</span>:139–50.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21263458" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21263458</span></a>]<div>
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<i>(Review of liver injury due to antirheumatic drugs discusses ALT elevations caused by anti-TNF agents and autoimmune hepatitis due to infliximab; no mention of natalizumab).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.van_assche.2011.1594">Van Assche G, Lewis JD, Lichtenstein GR, Loftus EV, Ouyang Q, Panes J, Siegel CA, et al. The London position statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organisation: safety. <span><span class="ref-journal">Am J Gastroenterol. </span>2011;<span class="ref-vol">106</span>:1594–602.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21844919" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21844919</span></a>]<div>
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<i>(Systematic review of the literature and position statement on use and safety of anti-TNF agents and natalizumab in Crohn disease; no specific discussion of hepatotoxicity or reactivation of hepatitis B).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.mulero.2012.103">Mulero P, Caminero AB, Neri Crespo MJ, Fernández-Herranz R, Téllez Lara N. Latent tuberculosis seems not to reactivate in multiple sclerosis patients on natalizumab. <span><span class="ref-journal">J Neuroimmunol. </span>2012;<span class="ref-vol">243</span>:103–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22226471" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22226471</span></a>]<div>
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<i>(Among 27 patients with multiple sclerosis treated with natalizumab, 6 had a reactive tuberculin test, but none had clinical evidence of reactivation during an average of 19 months of therapy; furthermore, worldwide at least 88,100 patients have been treated with natalizumab, but there have been no reports of tuberculosis associated with treatment in the literature).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.lisotti.2012.356">Lisotti A, Azzaroli F, Brillanti S, Mazzella G. Severe acute autoimmune hepatitis after natalizumab treatment. <span><span class="ref-journal">Dig Liver Dis. </span>2012;<span class="ref-vol">44</span>:356–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22154948" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22154948</span></a>]<div>
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<i>(31 year old woman developed ALT elevations after a first injection of natalizumab and jaundice after a second [bilirubin 23.1 mg/dL, ALT > 50 times ULN, "mild elevation" in Alk P, INR 2.6, ANA 1:160], with response to corticosteroid therapy and no recurrence on long term azathioprine).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.mart_nezlapiscina.2013.1234">Martínez-Lapiscina EH, Lacruz F, Bolado-Concejo F, Rodríguez-Pérez I, Ayuso T, Garaigorta M, Urman JM. Natalizumab-induced autoimmune hepatitis in a patient with multiple sclerosis. <span><span class="ref-journal">Mult Scler. </span>2013;<span class="ref-vol">19</span>:1234–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23069876" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23069876</span></a>]<div>
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<i>(51 year old woman with multiple sclerosis on long term natalizumab [32 months] developed jaundice [bilirubin 3.4 mg/dL, ALT 1324 U/L, ALT 255 U/L] and responded to prednisone).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.oconnor.2014.78">O'Connor P, Goodman A, Kappos L, Lublin F, Polman C, Rudick RA, Hauswirth K, et al. Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study. <span><span class="ref-journal">Neurology. </span>2014;<span class="ref-vol">83</span>:78–86.</span> [<a href="/pmc/articles/PMC4114173/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4114173</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24898925" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24898925</span></a>]<div>
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<i>(Among 1094 patients with multiple sclerosis formerly enrolled in clinical trials of natalizumab and continued on therapy [300 mg every 4 weeks] for up to 5 years, 171 [16%] had at least one serious adverse event including 7 listed as "hepatobiliary" [without specific details] and 8 confirmed cases of PML).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.butzkueven.2014.1190">Butzkueven H, Kappos L, Pellegrini F, Trojano M, Wiendl H, Patel RN, Zhang A, et al. TYSABRI Observational Program (TOP) Investigators. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. <span><span class="ref-journal">J Neurol Neurosurg Psychiatry. </span>2014;<span class="ref-vol">85</span>:1190–7.</span> [<a href="/pmc/articles/PMC4215289/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4215289</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24532785" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24532785</span></a>]<div>
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<i>(Among 4821 patients with multiple sclerosis being treated with natalizumab enrolled in a prospective observational program, 3599 continued on treatment, among whom there were 465 serious adverse events including 7 were abnormal liver tests [0.1% yearly], 18 cases of PML [0.4%] and 9 deaths, but none due to liver disease).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.hillen.2015.e97">Hillen ME, Cook SD, Samanta A, Grant E, Quinless J, Rajasingham J. Fatal acute liver failure with hepatitis B virus infection during natalizumab treatment in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2015; 2: e72. <span><span class="ref-journal">Erratum in Neurol Neuroimmunol Neuroinflamm. </span>2015;<span class="ref-vol">2</span>:e97. </span> [<a href="/pmc/articles/PMC4335813/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4335813</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25815364" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25815364</span></a>]<div>
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<i>(28 year old woman with multiple sclerosis on long term natalizumab [22 months] developed acute hepatitis B [bilirubin 1.0 mg/dL, ALT 1564 U/L, Alk P 70 U/L, HBsAg positive, IgM anti-HBc positive] that progressed to acute liver failure and death).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.antezana.2015.495">Antezana A, Sigal S, Herbert J, Kister I. Natalizumab-induced hepatic injury: A case report and review of literature. <span><span class="ref-journal">Mult Scler Relat Disord. </span>2015;<span class="ref-vol">4</span>:495–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26590653" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26590653</span></a>]<div>
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<i>(26 year old woman with multiple sclerosis developed abnormal liver tests 2 weeks after a 2nd monthly infusion of natalizumab [bilirubin 24.9 mg/dL, ALT 856 U/L, Alk P 165 U/L] with slow but eventual recovery after stopping; review of literature identified 12 cases of acute liver injury due to natalizumab, half of which were “autoimmune” in character).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF28">Drugs for multiple sclerosis. <span><span class="ref-journal">Med Lett Drugs Ther. </span>2016;<span class="ref-vol">58</span>(1496):71–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27249095" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27249095</span></a>]<div>
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<i>(Concise review of the mechanism of action, clinical efficacy, safety, costs and relative role of the medications approved for use in multiple sclerosis mentions that beta interferon and natalizumab can cause clinically apparent liver injury and that fingolimod and teriflunomide are associated with frequent serum enzyme elevations).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.clerico.2017.963">Clerico M, Artusi CA, Di Liberto A, Rolla S, Bardina V, Barbero P, De Mercanti SF, et al. Long-term safety evaluation of natalizumab for the treatment of multiple sclerosis. <span><span class="ref-journal">Expert Opin Drug Saf. </span>2017;<span class="ref-vol">16</span>:963–72.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28641055" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28641055</span></a>]<div>
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<i>(Review of the literature and adverse event databases identified 12 case reports of significant liver injury attributed to natalizumab and spontaneous reports of 22 cases of liver failure to the FDA).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.van_obberghen.2017.222">Van Obberghen EK, Cohen M, Rocher F, Lebrun-Frenay C. Multiple immune disorders after natalizumab discontinuation: After the CIRIS, the SIRIS? <span><span class="ref-journal">Rev Neurol (Paris). </span>2017;<span class="ref-vol">173</span>:222–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28372806" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28372806</span></a>]<div>
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<i>(35 year old woman with multiple sclerosis stopped natalizumab therapy because of pregnancy and developed rash, diabetes, hypothyroidism and abnormal liver tests [values not given] most, but not all, of which resolved after delivery and restarting natalizumab, suggesting that the abnormalities were due to natalizumab withdrawal and reconstitution autoimmunity).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.kaufmann.2018.1071">Kaufmann M, Haase R, Proschmann U, Ziemssen T, Akgün K. Real-world lab data in natalizumab treated multiple sclerosis patients up to 6 years long-term follow up. <span><span class="ref-journal">Front Neurol. </span>2018;<span class="ref-vol">9</span>:1071.</span> [<a href="/pmc/articles/PMC6292961/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6292961</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30581413" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30581413</span></a>]<div>
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<i>(Results of routine laboratory results taken every 3 months for up to 6 years during natalizumab therapy in 120 patients with multiple sclerosis demonstrated that ALT and AST elevations were rare and usually mild; only one ALT value was above 3 times ULN, which was normal on retesting despite drug continuation).</i>
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</div></div></li><li><div class="bk_ref" id="Natalizumab.REF.butzkueven.2020">Butzkueven H, Kappos L, Wiendl H, Trojano M, Spelman T, Chang I, Kasliwal R, et al. Tysabri Observational Program (TOP) Investigators. Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the Tysabri Observational Program (TOP). <span><span class="ref-journal">J Neurol Neurosurg Psychiatry. </span>2020 Mar 31;</span> [Epub ahead of print] [<a href="/pmc/articles/PMC7279201/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7279201</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32234967" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32234967</span></a>]<div>
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<i>(A long term observational study enrolled 6148 patients from 17 countries with multiple sclerosis as they started natalizumab with follow up for up to 11 years [median=5.2 years]; 829 patients [13.5%] had at least one serious adverse event including PML in 53 [0.9%], malignancy in 66 [1.1%] and hepatic events in 12 [0.2%] described as drug induced liver injury in 4, autoimmune hepatitis in 2 and acute liver failure, fulminant hepatitis, hepatitis and liver injury in 1 each: no specific details given).</i>
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</div></div></li></ul></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK548623_pubdet_">Publication Details</h2><h3>Publication History</h3><p class="small">Last Update: <span itemprop="dateModified">April 15, 2020</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-. Natalizumab. [Updated 2020 Apr 15].<span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/livertox/Naproxen/?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/Nateglinide/?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="figobNatalizumabTc"><div id="Natalizumab.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK548623/table/Natalizumab.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Natalizumab.Tc_lrgtbl__"><table><tbody><tr><th id="hd_b_Natalizumab.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Medication:</th><td headers="hd_b_Natalizumab.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Natalizumab (300 mg infusions monthly for 5 months)</td></tr><tr><th id="hd_b_Natalizumab.Tc_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pattern:</th><td headers="hd_b_Natalizumab.Tc_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hepatocellular (R=21.5)</td></tr><tr><th id="hd_b_Natalizumab.Tc_1_1_3_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Severity:</th><td headers="hd_b_Natalizumab.Tc_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3+ (jaundice, hospitalization)</td></tr><tr><th id="hd_b_Natalizumab.Tc_1_1_4_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Latency:</th><td headers="hd_b_Natalizumab.Tc_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">11 days after 5th monthly infusion initially; shortly after second monthly infusion on rechallenge 6 months later</td></tr><tr><th id="hd_b_Natalizumab.Tc_1_1_5_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Recovery:</th><td headers="hd_b_Natalizumab.Tc_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6 months initially, unknown upon rechallenge</td></tr><tr><th id="hd_b_Natalizumab.Tc_1_1_6_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Other medications:</th><td headers="hd_b_Natalizumab.Tc_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Spirulina (food supplement), multivitamins, prednisone</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobNatalizumabTd"><div id="Natalizumab.Td" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK548623/table/Natalizumab.Td/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Natalizumab.Td_lrgtbl__"><table><thead><tr><th id="hd_h_Natalizumab.Td_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRUG</th><th id="hd_h_Natalizumab.Td_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_Natalizumab.Td_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MOLECULAR FORMULA</th><th id="hd_h_Natalizumab.Td_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_Natalizumab.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Natalizumab</td><td headers="hd_h_Natalizumab.Td_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/135314782" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">189261-10-7</a>
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</td><td headers="hd_h_Natalizumab.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Monoclonal Antibody</td><td headers="hd_h_Natalizumab.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not Available</td></tr></tbody></table></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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