Natalizumab 1979482 224036545 2008-07-07T01:03:28Z SieBot 4005189 robot Adding: [[pl:Natalizumab]] {{drugbox-mab | | image = | source = [[Humanized antibody|Humanized]] | target = Alpha-4 [[integrin]] | CAS_number = 189261-10-7 | ATC_prefix = L04 | ATC_suffix = AA23 | ATC_supplemental = | PubChem = | DrugBank = BTD00083 | chemical_formula = | molecular_weight = 149 [[Atomic mass unit|kDa]] | bioavailability = n/a | protein_bound = | metabolism = | elimination_half-life = 11 ± 4 days | licence_EU= Natalizumab | licence_US= Natalizumab | pregnancy_AU = C | pregnancy_US = C | legal_status = Rx-only | routes_of_administration = [[Intravenous infusion]] }} '''Natalizumab''' is a [[humanized antibody|humanized]] [[monoclonal antibody]] against the [[cellular adhesion molecule]] [[integrin|α4-integrin]]. Natalizumab is used in the treatment of [[multiple sclerosis]] and [[Crohn's disease]]. It is co-marketed by [[Biogen Idec]] and [[Élan]] as '''Tysabri''', and was previously named '''Antegren'''. Natalizumab is administered by [[Intravenous therapy|intravenous infusion]] every 28 days. The drug is believed to work by reducing the ability of [[Inflammation|inflammatory]] [[Immune system|immune cells]] to attach to and pass through the cell layers lining the [[intestine]]s and [[blood-brain barrier]]. Natalizumab has proven effective in treating the symptoms of both diseases, preventing relapse, vision loss, cognitive decline and [[statistical significance|significantly]] improving [[quality of life]] in people with multiple sclerosis, as well as increasing rates of remission and preventing relapse in Crohn's disease. Natalizumab was approved in 2004 by the [[United States Food and Drug Administration]]. It was subsequently [[list of withdrawn drugs|withdrawn from the market]] by its manufacturer after it was linked with three cases of the rare neurological condition [[progressive multifocal leukoencephalopathy]] when administered in combination with [[interferon beta-1a]], another [[immunosuppressive drug]] often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. In the [[European Union]], it has been approved only for the treatment of multiple sclerosis. == Indications == Natalizumab is FDA-approved for the treatment of [[multiple sclerosis]] and [[Crohn's disease]] and approved for treatment of multiple sclerosis in Europe.<ref name = PREU>{{cite web | url = http://www.emea.europa.eu/pdfs/human/press/pr/15260806en.pdf | title = Press release - European Medicines Agency: Committee for Medicinal Products for Human Use 24-27 April 2006 | date = 2006-04-28 | publisher = [[European Medicines Agency]] | format = PDF | accessdate = 2008-04-02 }}</ref> ===Multiple sclerosis=== {{further|[[Multiple sclerosis]]}} Natalizumab was evaluated in two randomized, double-blind, placebo-controlled trials in people with multiple sclerosis. Both studies enrolled individuals with MS who experienced at least one clinical relapse during the prior year and had a Kurtzke [[Expanded Disability Status Scale|EDSS]] score between 0 and 5. In these trials natalizumab was shown to reduce relapses in individuals with MS by 68% vs. [[placebo]], a margin far greater than had been seen for other approved MS therapies.<ref name = Polman>{{cite journal |author=Polman CH, O'Connor PW, Havrdova E, ''et al'' |title=A randomized, placebo-controlled trial of natalizumab for relapsing forms of multiple sclerosis |journal=[[N. Engl. J. Med.]] |volume=354 |issue=9 |pages=899–910 |year=2006 |pmid=16510744 |doi=10.1056/NEJMoa044397}}</ref> Natalizumab also slowed the progression of disability in patients with relapsing MS.<ref name = Polman/><ref name = EU>{{cite web | url = http://www.emea.europa.eu/humandocs/PDFs/EPAR/tysabri/H-603-PI-en.pdf | format = PDF | title = TYSABRI: ANNEX I - SUMMARY OF PRODUCT CHARACTERISTICS | publisher = [[European Medicines Agency]] | accessdate = 2008-03-09 }}</ref> In combination with [[interferon beta-1a]] (IB1A), relapsing and disability progression were reduced more than IB1A alone.<ref name="pmid18354844"/> Other benefits of natalizumab use by patients with relapsing MS included reduced visual loss,<ref>{{cite journal |author=Balcer LJ, Galetta SL, Calabresi PA, ''et al'' |title=Natalizumab reduces visual loss in patients with relapsing multiple sclerosis |journal=Neurology |volume=68 |issue=16 |pages=1299–304 |year=2007 |pmid=17438220 |doi=10.1212/01.wnl.0000259521.14704.a8}}</ref> a significant increase in the proportion of disease-free individuals,<ref>{{cite conference | first = S | last = Galetta | authorlink = | coauthors = ''et al'' | title = Natalizumab Increases the Proportion of Patients Free of Clinical or MRI Disease Activity in Relapsing MultipleSclerosis | date = 2008-04-18 | booktitle = unpublished/unpresented conference poster | url = http://www.abstracts2view.com/aan2008chicago/view.php?nu=AAN08L_P02.156 | accessdate = 2008-03-11}}; industry publication - {{cite web | url = http://www.elan.com/news/full.asp?ID=1061738 | title = New TYSABRI Data to Be Presented at the European Committee for Treatment and Research in Multiple Sclerosis | publisher = [[Élan]] | accessdate = 2008-03-09 | date = 2007-10-11}}</ref> significantly improved assessments of health-related quality of life in relapsing individuals,<ref>{{cite journal |author=Rudick RA, Miller D, Hass S, ''et al'' |title=Health-related quality of life in multiple sclerosis: effects of natalizumab |journal=Ann. Neurol. |volume=62 |issue=4 |pages=335–46 |year=2007 |pmid=17696126 |doi=10.1002/ana.21163}}</ref> reduced cognitive decline of a portion of individuals with MS,<ref>{{cite web | url = http://www.pslgroup.com/dg/265832.htm | title = New Data on Natalizumab Demonstrate Significant Improvement in Cognitive Function in Patients With Multiple Sclerosis | publisher = Doctor's Guide | date = 2006-09-28 | accessdate = 2008-03-09 }}</ref> reduced hospitalizations and [[steroid]] use,<ref>{{cite web | url = http://www.webwire.com/ViewPressRel.asp?aId=21727 | title = New Pharmacoeconomic Data On TYSABRI Demonstrate Significant Reduction In Steroid Use And Hospitalizations In Patients With Multiple Sclerosis | publisher = webwire | date = 2006-10-06 | accessdate = 2008-03-09 }}</ref> and prevention of the formation of new [[lesion]]s.<ref name = Polman/><ref>{{cite journal |author=Miller DH, Soon D, Fernando KT, ''et al'' |title=MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS |journal=Neurology |volume=68 |issue=17 |pages=1390–401 |year=2007 |pmid=17452584 |doi=10.1212/01.wnl.0000260064.77700.fd}}</ref> Approximately 6% of individuals receiving natalizumab have been found to develop persistent [[Antibody|antibodies]] to the drug, which reduces its efficacy<ref name="pmid18360634">{{cite journal |author=Hutchinson M |title=Natalizumab: A new treatment for relapsing remitting multiple sclerosis |journal=Ther Clin Risk Manag |volume=3 |issue=2 |pages=259–268 |year=2007 |pmid=18360634 |doi=10.2147/tcrm.2007.3.2.259| url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18360634 | accessdate = 2008-04-22}}</ref><ref>{{cite journal |author=Calabresi PA, Giovannoni G, Confavreux C, ''et al'' |title=The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL |journal=Neurology |volume=69 |issue=14 |pages=1391–403 |year=2007 |pmid=17761550 |doi=10.1212/01.wnl.0000277457.17420.b5}}</ref><ref name="pmid18354844">{{cite journal |author= |title=Natalizumab: new drug. Multiple sclerosis: risky market approval |journal=Prescrire Int |volume=17 |issue=93 |pages=7–10 |year=2008 |pmid=18354844 |doi= |url=}}</ref> and produce reactions during the [[infusion]] of the drug, as well as hypersensitivity.<ref name="pmid18354844"/> Natalizumab is approved in the United States and the European Union. It is indicated as [[monotherapy]] (not combined with other drugs) for the treatment of highly active relapsing remitting MS in spite of prior treatments.<ref name = EU>{{cite web | url = http://www.emea.europa.eu/humandocs/PDFs/EPAR/tysabri/H-603-Annex-en.pdf | format = PDF | title = Annex: Conditions or restrictions with regard to the safe and effective use of the medicinal product to be implemented by the member states | publisher = [[European Medicines Agency]] | accessdate = 2008-03-09 }}</ref> Natalizumab offers a limited improvement in efficacy compared to other treatments for MS, but due to the lack of information about long-term use, as well as potentially fatal adverse events, reservations have been expressed over the use of the drug outside of comparative research with existing medications.<ref name="pmid18354844"/> ===Crohn's disease=== {{Further|[[Crohn's disease]]}} Several [[randomized controlled trial]]s have demonstrated that natalizumab is effective in increasing rates of [[remission (medicine)|remission]]<ref name="pmid12510039">{{cite journal |author=Ghosh S, Goldin E, Gordon F, Malchow H, Rask-Madsen J, Rutgeerts P, Vyhnálek P, Zádorová Z, Palmer T, Donoghue S |title=Natalizumab for active Crohn's disease |journal=N. Engl. J. Med. |volume=348 |issue=1 |pages=24–32 |year=2003 |pmid=12510039 |doi=10.1056/NEJMoa020732}}</ref> and maintaining symptom-free status<ref>{{cite journal |author=Feagan BG, Sandborn WJ, Hass S, Niecko T, White J |title=Health-related quality of life during natalizumab maintenance therapy for Crohn's disease |journal=Am. J. Gastroenterol. |volume=102 |issue=12 |pages=2737–46 |year=2007 |pmid=18042106 |doi=10.1111/j.1572-0241.2007.01508.x}}</ref> in patients with [[Crohn's disease]]. Natalizumab may be appropriate in patients who do not respond to medications that block [[tumor necrosis factor-alpha]] such as [[infliximab]],<ref>{{cite journal |author=Michetti P, Mottet C, Juillerat P, ''et al'' |title=Severe and steroid-resistant Crohn's disease |journal=Digestion |volume=76 |issue=2 |pages=99–108 |year=2007 |pmid=18239400 |doi=10.1159/000111023}}</ref> with some evidence to support combination treatment of Crohn's disease with natalizuma and infliximab may be helpful in inducing remission.<ref name = Sands>{{cite journal |author=Sands BE, Kozarek R, Spainhour J, ''et al'' |title=Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab |journal=Inflamm. Bowel Dis. |volume=13 |issue=1 |pages=2–11 |year=2007 |pmid=17206633 |doi=10.1002/ibd.20014 |url=}}</ref> Treatment of adolescent patients with natalizumab demonstrates an effectiveness similar to that of adult patients.<ref name = Hyams>{{cite journal |author=Hyams JS, Wilson DC, Thomas A, ''et al'' |title=Natalizumab therapy for moderate to severe Crohn disease in adolescents |journal=J. Pediatr. Gastroenterol. Nutr. |volume=44 |issue=2 |pages=185–91 |year=2007 |pmid=17255829 |doi=10.1097/01.mpg.0000252191.05170.e7 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00005176-200702000-00006}}</ref> In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease,<ref>{{cite web | url = http://www.fda.gov/bbs/topics/NEWS/2008/NEW01775.html | publisher = [[Food and Drug Administration]] | title = FDA Approves Tysabri to Treat Moderate-to-Severe Crohn's Disease | date = 2008-01-14 | accessdate = 2008-03-09 }}</ref> though it has not been approved for this use in the European Union due to concerns over its risk/benefit ratio.<ref>{{cite web | url = http://www.emea.europa.eu/humandocs/PDFs/EPAR/natalizumab/H-624-RAR-en.pdf | title = Refusal CHMP assessment report for natalizumab | format = PDF | date = 2007-11-15 | publisher = [[European Medicines Agency]] | accessdate = 2008-04-02 }} {{PDF|[http://www.emea.europa.eu/pdfs/human/opinion/Natalizumab_Q&A_53096407en.pdf lay-summary]|78.5&nbsp;KB}} </ref> == Adverse effects == Common adverse effects include [[fatigue (medical)|fatigue]] and [[Allergy|allergic reactions]] with a low risk of [[anaphylaxis]],<ref name="pmid17876741">{{cite journal |author=Horga A, Horga de la Parte JF |title=[Natalizumab in the treatment of multiple sclerosis] |language=Spanish; Castilian |journal=Rev Neurol |volume=45 |issue=5 |pages=293–303 |year=2007 |pmid=17876741 |doi= |issn=}}</ref> [[headache]], [[nausea]], [[Common cold|colds]] and exacerbation of Crohn's disease in a minority of patients with the condition.<ref name = Sands/> Adolescents with Crohn's disease experience headache, [[fever]] and exacerbation of Crohn's disease.<ref name = Hyams/> Natalizumab is [[Contraindication|contraindicated]] for people with known hypersensitivity to the drug or its components and in patients with a history of PML (see [[#Interactions|interactions]]). [[Postmarketing surveillance]] in early 2008 revealed that 0.1% of people taking natalizumab experience clinically significant [[liver]] injury, leading to the FDA, EMEA and manufacturers recommending that the medication be discontinued in patients with [[jaundice]] or other evidence of significant liver damage.<ref name="FDA Safety Alerts for Drugs">{{cite web |url=http://www.fda.gov/medwatch/safety/2008/safety08.htm#Tysabri |title=FDA MedWatch - 2008 Safety Information Alerts | publisher = [[Food and Drug Administration]] |accessdate=2008-04-05 | date = 2008-02-28}}</ref><ref name="EMEA press release">{{cite web |url=http://emea.europa.eu/humandocs/PDFs/EPAR/tysabri/PR_Tysabri_13948908en.pdf |title=EMEA concludes new advice to doctors and patients for Tysabri (natalizumab) needed |accessdate=2008-04-05 |date=2008-03-20 |publisher=[[European Medicines Agency]] |pages= |language=English |quote=}}</ref><ref name=Q&A>{{cite web | url = http://emea.europa.eu/humandocs/PDFs/EPAR/tysabri/Q&A_Tysabri_14590808en.pdf | format = PDF | title = Questions and answers on Tysabri and liver injury | publisher = [[European Medicines Agency]] | date = 2008-03-20 | accessdate = 2008-04-14 }}; [http://www.nelm.nhs.uk/Record%20Viewing/vR.aspx?id=591422 lay-summary], [http://www.medscape.com/viewarticle/570796 second summary]</ref> This rate is comparable to other immune-suppressing drugs.<ref name="titleMultiple Sclerosis - Natalizumab (Tysabri) Can Rarely Cause Liver Problems">{{cite web |url=http://www.healthcentral.com/multiple-sclerosis/c/6639/21073/liver/ |title=Multiple Sclerosis - Natalizumab (Tysabri) Can Rarely Cause Liver Problems |author=Kenneth Gross, M.D. |date=2008-03-03 |accessdate=2008-04-05 |format= |work=}}</ref> Evidence of [[hepatotoxicity]] in the form of elevated blood levels of [[bilirubin]] and [[elevated transaminases|liver enzymes]] can appear as soon as six days after an initial dose; reactions are unpredictable and may appear even if the patient does not react to previous treatment.<ref name = DHP>{{cite web |url=http://www.fda.gov/medwatch/safety/2008/Tysabri_dhcp_letter.pdf| format = PDF | title = Important safety information: Dear Healthcare Practitioner letter | publisher =[[Biogen Idec]] and [[Élan]] | date = 2008-02-01 | accessdate = 2008-04-11 | last = Panzara | first = M | coauthors = Francis V }}; [http://www.medpagetoday.com/ProductAlert/Prescriptions/tb/8522 lay summary]</ref> Such signs reoccur upon [[Challenge-dechallenge-rechallenge|rechallenge]] in some patients, indicating that damage is not coincidental.<ref name = DHP/> In the absence of any blockage these [[liver function tests]] are predictors of severe liver injury with possible [[sequela]]e of [[liver transplantation]] or [[death]].<ref name = DHP/> Natalizumab has also been linked to [[melanoma]], though the association is unclear.<ref>{{cite journal |author=Mullen JT, Vartanian TK, Atkins MB |title=Melanoma complicating treatment with natalizumab for multiple sclerosis |journal=N. Engl. J. Med. |volume=358 |issue=6 |pages=647–8 |year=2008 |pmid=18256405 |doi=10.1056/NEJMc0706103}}</ref> The long-term effects of the drug are unknown<ref name="pmid18389881">{{cite journal |author=van Bronswijk H, Dubois EA, van Gerven JM, Cohen AF |title=[New drugs; natalizumab] |language=Dutch; Flemish |journal=Ned Tijdschr Geneeskd |volume=152 |issue=9 |pages=499–500 |year=2008 |pmid=18389881 |doi= |url=}}</ref> and concern has been expressed over the risks of [[infection]] and [[cancer]].<ref name="pmid18354844"/> <!-- == Overdose == --> <!-- == Physical and chemical properties == --> <!-- == Pharmacokinetics == --> == Mechanism of action == [[Image:AntibodyChains.svg|thumb|200px|Structure of a generic [[antibody]]]] Natalizumab is a [[humanized antibody|humanized]] [[Monoclonal antibodies|monoclonal antibody]] against alpha-4 (α4) [[integrin]], the first drug developed in the class of selective adhesion molecule inhibitors. α4-integrin is required for [[white blood cell]]s to move into [[Organ (anatomy)|organs]]; natalizumab's [[mechanism of action]] is believed to be the inhibition these immune cells from crossing blood vessel walls to reach affected organs.<ref name=Rice2005>{{cite journal |author=Rice GP, Hartung HP, Calabresi PA |title=Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale |journal=Neurology |volume=64 |issue=8 |pages=1336–42 |year=2005 |pmid=15851719 |doi=10.1212/01.WNL.0000158329.30470.D0 |doi_brokendate=2008-06-23}}</ref> === In multiple sclerosis === The [[Multiple sclerosis signs and symptoms|symptom]]-causing [[lesion]]s of MS are believed to be caused when [[Inflammation|inflammatory]] cells such as [[T-lymphocyte]]s pass through the [[blood-brain barrier]] through interaction with receptors on the [[endothelium|endothelial cells]]. Natalizumab appears to reduce the transmission of immune cells into the [[central nervous system]] by interfering with the [[VLA-4|α4β1-integrin receptor molecules]] on the surfaces of cells. The affect appears to occur on endothelial cells expressing the [[VCAM-1]] gene, and in [[parenchyma]]l cells expressing the [[osteopontin]] gene. In animals used to model MS and test therapies, repeated administration of natalizumab reduced migration of [[leukocyte]]s into the brain's parenchyma, and also reduced lesioning, though it is uncertain if this is clinically significant for humans.<ref name="Tysabri label">{{cite web |url=http://tysabri.com/en_US/tysb/footer/TYSABRI-pi.pdf |title=Final TYSABRI PI |accessdate=2008-03-13 |format= |work=}}</ref> Individuals with MS dosed with natalizumab demonstrated increased [[CD34]]-expressing cells, with research suggesting a peak in expression after 72 hours.<ref name="pmid18235044">{{cite journal |author=Zohren F, Toutzaris D, Klarner V, Hartung HP, Kieseier B, Haas R |title=The monoclonal anti-VLA4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans |journal=[[Blood]] |volume= 111|issue= |pages= 3893|year=2008 |pmid=18235044 |doi=10.1182/blood-2007-10-120329 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=18235044 |issn=}}</ref> === In Crohn's disease === The interaction of the α4β7 integrin and the [[addressin]] (also known as MADCAM1) endothelial cell receptor is believed to contribute to the chronic bowel inflammation that causes Crohn's disease. Addressin is primarily expressed in the endothelium of [[venules]] in the small intestine and are critical in guiding T-lymphocytes to [[Lymphatic system|lymphatic tissues]] in [[Peyer's patches]]. In CD patients, sites of active inflammation of the bowel in CD patients have increased expression of addressin, suggesting a connection between the inflammation and the receptor. Natalizumab may block interaction between the α4β7 integrin and addressin at sites of inflammation. [[Animal model]]s have found higher levels of VCAM-1 expression in mice with [[irritable bowel syndrome]] and the VCAM-1 gene may also play a part in CD but its role is not yet clear.<ref name = "Tysabri label"/> == Interactions == Natalizumab appears to interact with other immune-modulating drugs to cause [[progressive multifocal leukoencephalopathy]] (PML), an often-fatal [[Opportunistic infection|opportunistic viral infection]]. In 2005, two people taking natalizumab in combination with [[interferon beta-1a]] developed PML. One died, and the other recovered with disabling [[sequela]]e.<ref name = "nejm-pml1">{{cite journal |author=Kleinschmidt-DeMasters BK, Tyler KL |title=Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis |journal=N. Engl. J. Med. |volume=353 |issue=4 |pages=369–74 |year=2005 |pmid=15947079 |doi=10.1056/NEJMoa051782}}</ref><ref name = "nejm-pml2">{{cite journal |author=Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D |title=Progressive multifocal leukoencephalopathy in a patient treated with natalizumab |journal=N. Engl. J. Med. |volume=353 |issue=4 |pages=375–81 |year=2005 |pmid=15947078 |doi=10.1056/NEJMoa051847}}</ref> A third fatal case initially attributed to an [[astrocytoma]] was reported in a patient being treated for Crohn's disease.<ref name=Van_Assche>{{cite journal |author=Van Assche G, Van Ranst M, Sciot R, ''et al'' |title=Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease |journal=N. Engl. J. Med. |volume=353 |issue=4 |pages=362–8 |year=2005 |pmid=15947080 |doi=10.1056/NEJMoa051586 | url = http://content.nejm.org/cgi/content/full/353/4/362 }}</ref> Though the patient was being treated with natalizumab in combination with [[azathioprine]], [[corticosteroid]]s and [[infliximab]], indications of PML infection appeared only after natalizumab monotherapy was re-introduced.<ref name=Van_Assche/> No deaths have been linked to natalizumab when it was not combined with other immune-modulating drugs<ref name = Yousry>{{cite journal |author=Yousry TA, Major EO, Ryschkewitsch C, ''et al'' |title=Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy |journal=N. Engl. J. Med. |volume=354 |issue=9 |pages=924–33 |year=2006 |pmid=16510746 |doi=10.1056/NEJMoa054693}}</ref> and other rates of opportunistic infections are not increased in patients taking natalizumab<ref name="pmid17136224"/> possibly due to the drug’s mechanism of action.<ref name="pmid17521672">{{cite journal |author=Ransohoff RM |title="Thinking without thinking" about natalizumab and PML |journal=J. Neurol. Sci. |volume=259 |issue=1-2 |pages=50–2 |year=2007 |pmid=17521672 |doi=10.1016/j.jns.2006.04.011}}</ref> Other than a prior history of PML, there is no known method to identify patients at risk of developing PML.<ref name="pmid17122725">{{cite journal |author=Aksamit AJ |title=Review of progressive multifocal leukoencephalopathy and natalizumab |journal=Neurologist |volume=12 |issue=6 |pages=293–8 |year=2006 |pmid=17122725 |doi=10.1097/01.nrl.0000250948.04681.96}}</ref> Natalizumab's label indicates that it is [[Contraindication|contraindicated]] for [[Immunosuppression|immunosuppressed]] individuals or those with a history of PML.<ref name="Tysabri label"/> Due to the uncertain risk of PML, natalizumab is only available through a restricted distribution program.<ref name="Tysabri label" /> As of 2008, no other cases of PML associated with natalizumab have been reported.<ref name="pmid17122725"/> Though the small number of cases precludes conclusion on the ability of natalizumab alone to induce PML, its [[black box warning]] states that the drug has only been linked to PML when combined with other immune-modulating drugs and natalizumab is contraindicated for use with other immunomodulators.<ref name="Tysabri label" /> [[Corticosteroid]]s may produce immunosuppression, and the Tysabri prescribing information recommends that people taking corticosteroids for the treatment of Crohn's disease have their doses reduced before starting natalizumab treatment.<ref name="Tysabri label" /> The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months<ref name="pmid18360634"/><ref name="pmid17136224">{{cite journal |author=Berger JR |title=Natalizumab |journal=Drugs Today |volume=42 |issue=10 |pages=639–55 |year=2006 |pmid=17136224 |doi=10.1358/dot.2006.42.10.1042190 |issn=}}</ref><ref name="pmid17434098">{{cite journal |author=Kappos L, Bates D, Hartung HP, ''et al'' |title=Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring |journal=Lancet Neurol |volume=6 |issue=5 |pages=431–41 |year=2007 |pmid=17434098 |doi=10.1016/S1474-4422(07)70078-9}}</ref> though the longer term risks of PML are unknown.<ref name="pmid18360634"/> == Legal status == Natalizumab was originally approved for treatment of [[multiple sclerosis]] in 2004, through the FDA's accelerated [[FDA Fast Track Development Program|Fast Track program]], due to the drug's efficacy in one-year [[clinical trial]]s. In February 2005, four months after its approval, natalizumab was withdrawn voluntarily by the manufacturer after two cases of progressive multifocal leukoencephalopathy. Groups representing individuals with MS lobbied to have the drug returned to the US market<ref name = NYT>{{cite news | url = http://www.nytimes.com/2006/03/09/business/09drug.html?_r=1&scp=2&sq=natalizumab&st=nyt&oref=slogin | title = F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk | last = Pollack | first = A | work = [[The New York Times]] | date = 2006-03-09 | accessdate = 2008-03-13 }}</ref> and in June, 2006, after recommendation by an advisory committee and a review of two years of safety and efficacy data, the FDA re-approved natalizumab for patients with all relapsing forms of MS (relapse-remitting, secondary-progressive, and progressive-relapsing) as a [[First-line treatment|first-line]] or second-line therapy.<ref>{{cite web | url = http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4313b1-02-FDA-Errata.pdf | format = PDF | title = Errata to FDA Background document for the Tysabri (natalizumab) Advisory Committee on July 31, 2007 | date = 2007-07-20 | accessdate = 2008-03-09 | publisher = [[Food and Drug Administration]] }}</ref><ref>{{cite journal |author=Fiore D |title=Multiple sclerosis and Natalizumab |journal=Am J Ther |volume=14 |issue=6 |pages=555–60 |year=2007 |pmid=18090880 |doi=10.1097/MJT.0b013e31804bfa6a}}</ref> Patients taking natalizumab must enter into a registry for monitoring.<ref name = NYT/> Natalizumab is the only drug after [[alosetron]] withdrawn for safety reasons that returns to the US market. In April, 2006 the [[Committee for Medicinal Products for Human Use]] recommended authorizing natalizumab to treat relapsing-remitting MS, and several weeks later the [[European Medicines Agency]] approved natalizumab in the European Union for highly-active relapsing remitting MS.<ref name = PREU/> [[Health Canada]] added natalizumab to Schedule F of the Food and Drug Regulations on April 3rd, 2008 as a [[prescription drug]] requiring oversight from a [[physician]].<ref>{{cite web | url = http://canadagazette.gc.ca/partII/2008/20080416/html/sor101-e.html#1 | publisher = [[Canada Gazette]] | title = Regulations Amending the Food and Drug Regulations (1528 — Schedule F) | date = 2008-04-16 | accessdate = 2008-04-23 }}</ref> ==References== {{reflist|2}} == External links == *[http://www.tysabri.com/ Tysabri Natalizumab] *[http://www.elan.com/Products/united_states/tysabri_information_center.asp Elan's Tysabri information center] *[http://www.biogenidec.com/site/019_2.html Biogen's Tysabri information center] {{Immunosuppressants}} {{Humanizedmonoclonals}} [[Category:Immunosuppressive agents]] [[Category:Monoclonal antibodies]] [[de:Natalizumab]] [[es:Natalizumab]] [[it:Natalizumab]] [[he:טיסברי]] [[nl:Natalizumab]] [[pl:Natalizumab]] [[pt:Natalizumab]]