OVERVIEW

CASE REPORT

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Natalizumab – Tysabri®

DRUG CLASS

Gastrointestinal Agents; Multiple Sclerosis Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

CITED REFERENCE

1.

Bezabeh S, Flowers CM, Kortepeter C, Avigan M. Clinically significant liver injury in patients treated with natalizumab. Aliment Pharmacol Ther. 2010;31:1028–35. [PubMed: 20163378]

ANNOTATED BIBLIOGRAPHY

References updated: 15 April 2020

Abbreviations: TNF, tumor necrosis factor; PML, progressive multifocal leukoencephalopathy.

• 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.

  (Expert review of hepatotoxicity published in 1999, well before the availability of most antibody therapies).
• Reuben A. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2011, pp. 569-91.

  (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).
• 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.

  (Textbook of pharmacology and therapeutics).
• 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. Gastroenterology. 2001;121:268–74. [PubMed: 11487536]

  (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).
• 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. N Engl J Med. 2003;348:15–23. [PubMed: 12510038]

  (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).
• Keeley KA, Rivey MP, Allington DR. Natalizumab for the treatment of multiple sclerosis and Crohn's disease. Ann Pharmacother. 2005;39:1833–43. [PubMed: 16219898]

  (Literature review of safety and efficacy of natalizumab; abnormal liver tests were reported in 5% of natalizumab and 3% of placebo recipients).
• 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. N Engl J Med. 2005;353:1912–25. [PubMed: 16267322]

  (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).
• Calabrese LH, Zein NN, Vassilopoulos D. Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies. Ann Rheum Dis. 2006;65:983–9. [PMC free article: PMC1798254] [PubMed: 16627542]

  (Review of the problem of reactivation of hepatitis B in patients with rheumatic diseases treated with immunosuppressive agents, with recommendations on prevention).
• 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. N Engl J Med. 2006;354:899–910. [PubMed: 16510744]

  (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).
• 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. N Engl J Med. 2006;354:911–23. [PubMed: 16510745]

  (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).
• 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. Inflamm Bowel Dis. 2007;13:2–11. [PubMed: 17206633]

  (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).
• 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. Gastroenterology. 2007;132:1672–83. [PubMed: 17484865]

  (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).
• Natalizumab (Tysabri) for Crohn's disease. Med Lett Drugs Ther. 2008;50:34–6. [PubMed: 18458669]

  (Concise summary of use of natalizumab for Crohn disease mentions that postmarketing hepatic toxicity had occurred).
• Kaiser T, Moessner J, Patel K, McHutchison JG, Tillmann HL. Life threatening liver disease during treatment with monoclonal antibodies. BMJ. 2009;338:b508. [PubMed: 19224957]

  (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).
• Khokhar OS, Lewis JH. Hepatotoxicity of agents used in the management of inflammatory bowel disease. Dig Dis. 2010;28:508–18. [PubMed: 20926880]

  (Review of the hepatotoxicity of drugs used to treat inflammatory bowel disease focusing upon sulfasalazine, thiopurines, TNF inhibitors, and methotrexate).
• Bezabeh S, Flowers CM, Kortepeter C, Avigan M. Clinically significant liver injury in patients treated with natalizumab. Aliment Pharmacol Ther. 2010;31:1028–35. [PubMed: 20163378]

  (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).
• 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. Dermatol Online J. 2010;16:14. [PubMed: 20579469]

  (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).
• Aithal GP. Hepatotoxicity related to antirheumatic drugs. Nat Rev Rheumatol. 2011;7:139–50. [PubMed: 21263458]

  (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).
• 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. Am J Gastroenterol. 2011;106:1594–602. [PubMed: 21844919]

  (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).
• 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. J Neuroimmunol. 2012;243:103–5. [PubMed: 22226471]

  (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).
• Lisotti A, Azzaroli F, Brillanti S, Mazzella G. Severe acute autoimmune hepatitis after natalizumab treatment. Dig Liver Dis. 2012;44:356–7. [PubMed: 22154948]

  (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).
• 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. Mult Scler. 2013;19:1234–5. [PubMed: 23069876]

  (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).
• 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. Neurology. 2014;83:78–86. [PMC free article: PMC4114173] [PubMed: 24898925]

  (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).
• 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. J Neurol Neurosurg Psychiatry. 2014;85:1190–7. [PMC free article: PMC4215289] [PubMed: 24532785]

  (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).
• 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. Erratum in Neurol Neuroimmunol Neuroinflamm. 2015;2:e97. [PMC free article: PMC4335813] [PubMed: 25815364]

  (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).
• Antezana A, Sigal S, Herbert J, Kister I. Natalizumab-induced hepatic injury: A case report and review of literature. Mult Scler Relat Disord. 2015;4:495–8. [PubMed: 26590653]

  (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).
• Drugs for multiple sclerosis. Med Lett Drugs Ther. 2016;58(1496):71–4. [PubMed: 27249095]

  (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).
• 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. Expert Opin Drug Saf. 2017;16:963–72. [PubMed: 28641055]

  (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).
• Van Obberghen EK, Cohen M, Rocher F, Lebrun-Frenay C. Multiple immune disorders after natalizumab discontinuation: After the CIRIS, the SIRIS? Rev Neurol (Paris). 2017;173:222–4. [PubMed: 28372806]

  (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).
• 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. Front Neurol. 2018;9:1071. [PMC free article: PMC6292961] [PubMed: 30581413]

  (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).
• 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). J Neurol Neurosurg Psychiatry. 2020 Mar 31; [Epub ahead of print] [PMC free article: PMC7279201] [PubMed: 32234967]

  (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).