Generic Name: Natalizumab
Class: Biologic Response Modifiers
VA Class: IM700
Chemical Name: Disulfide with human-mouse monoclonal AN100226 light chain immunoglobulin G 4 (human-mouse monoclonal AN100226 4-chain anti-human integrin 4) dimer
CAS Number: 189261-10-7
Increased risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain; usually leads to death or severe disability.1 13 14 15 16 (See Progressive Multifocal Leukoencephalopathy under Cautions.)
PML cases reported in patients receiving natalizumab who were recently or concomitantly treated with immunomodulators or immunosuppressants, as well as in patients receiving natalizumab monotherapy.1
Monitor patients during therapy for any new signs or symptoms suggestive of PML; immediately withhold the drug at first such sign or symptom.1
For diagnosis of PML, an evaluation that includes a gadolinium-enhanced MRI brain scan and, when indicated, CSF analysis for JC viral DNA recommended.1
FDA approved a REMS for natalizumab to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of natalizumab and consists of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center (). (Also see Restricted Distribution under Dosage and Administration.)
Biologic response modifier; a recombinant humanized anti-α4-integrin monoclonal antibody.1
Uses for Tysabri
Safety and efficacy in patients with chronic progressive MS not established.1
Safety and efficacy for long-term use (i.e., >2 years) not established.1
Because of risk of PML, generally recommended only in patients who have had an inadequate response to or are unable to tolerate other MS therapies.1 (See Progressive Multifocal Leukoencephalopathy under Cautions.) In addition, available only through restricted distribution program.1 2 3 (See Restricted Distribution Program under Dosage and Administration.)
Used to induce and maintain clinical response and remission in adults with moderately to severely active Crohn's disease with evidence of inflammation who have had an inadequate response to or who do not tolerate conventional therapies and inhibitors of tumor necrosis factor (TNF; TNF-α).1 21 22 23 24 26 28
Do not use in combination with immunosuppressants (e.g., mercaptopurine, azathioprine, cyclosporine, methotrexate) or TNF inhibitors in patients with Crohn's disease, because of potential for increased risk of PML and other infections. (See Progressive Multifocal Leukoencephalopathy under Cautions and see Immunosuppression and Infectious Complications under Cautions.)1
Aminosalicylates may be used in patients receiving natalizumab.1
Tysabri Dosage and Administration
Restricted Distribution Program
TOUCH program was designed to assess the risk of PML associated with the drug, minimize risk of PML, minimize death and disability due to PML, and promote informed risk versus benefit decisions regarding use of the drug.3
Vials are for single use only.1
Do not infuse or admix with any other drug.1
Use of filtration devices during IV infusion not evaluated.1
Allow solution to warm to room temperature prior to administration.1
Following completion of infusion, flush infusion set with 0.9% sodium chloride injection.1
Observe patients closely for signs or symptoms of hypersensitivity or infusion-related reactions during and for 1 hour after the IV infusion.1 (See Acute Infusion Reactions under Cautions.)
Use strict aseptic technique since drug product contains no preservatives.1
Rate of Administration
Administer IV infusions over approximately 1 hour.1
Relapsing-remitting Multiple Sclerosis
300 mg once every 4 weeks.1
Efficacy for long-term use (i.e., >2 years) not established.1
300 mg once every 4 weeks.1
In patients receiving chronic oral corticosteroid therapy, start tapering corticosteroid dosage as soon as a therapeutic benefit of natalizumab occurs.1 Discontinue natalizumab if patient cannot be tapered off oral corticosteroids within 6 months of initiating natalizumab.1 Consider discontinuing natalizumab in patients who require additional corticosteroid use that exceeds 3 months in a calendar year to control Crohn's disease other than the 6-month corticosteroid taper.1
Discontinue natalizumab if no therapeutic benefit is evident by 12 weeks of therapy.1
Relapsing-remitting Multiple Sclerosis
Safety of doses >300 mg not adequately evaluated; maximum safe dosage not determined.1
No special population recommendations at this time.1
Cautions for Tysabri
Known hypersensitivity to natalizumab or any ingredient in the formulation.1
Current or previous history of PML.1 (See Progressive Multifocal Leukoencephalopathy under Cautions.)
Progressive Multifocal Leukoencephalopathy
PML, an opportunistic viral infection of the brain caused by the JC virus (JCV), reported in patients receiving natalizumab.1 13 14 15 16 32 34 37 As of January 2012, 201 cases reported among 96,582 patients treated with natalizumab worldwide.38
Has been reported in patients receiving natalizumab who were recently or concomitantly treated with immunomodulators or immunosuppressants (i.e., interferon beta-1a in MS patients, infliximab and azathioprine in Crohn’s patients); also reported in patients receiving natalizumab without concomitant immunomodulatory drugs.1 27
The 3 factors known to increase risk of PML in natalizumab-treated patients are longer treatment duration (especially >2 years), prior treatment with immunosuppressants (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil), and presence of anti-JCV antibodies.1 38 Estimated risk of PML in patients with all 3 risk factors is 11 cases per 1000 patients.1
Based on postmarketing data available as of September 2011, estimated incidence of PML in patients with positive anti-JCV antibody test who received 1–24 or 25–48 months of natalizumab treatment is <1 or 4 cases per 1000 patients, respectively, in those with no history of prior immunosuppressant treatment and 2 or 11 cases per 1000 patients, respectively, in those who previously received immunosuppressant therapy.1 38 Data beyond 4 years (48 months) of treatment are limited.1 38
Do not use in patients receiving chronic immunosuppressant or immunomodulatory therapy or in those with systemic medical conditions that result in clinically important compromised immune system.1 (See Specific Drugs under Interactions.)
Consider testing for anti-JCV antibody status prior to initiating natalizumab or during natalizumab treatment if antibody status is unknown.1
Positive anti-JCV antibody test indicates individual has been exposed to JCV in the past.38 Carefully weigh risks and benefits of continued natalizumab treatment in those with positive anti-JCV antibody test who have ≥1 additional risk factors.1 38 For purposes of risk assessment, consider patient anti-JCV antibody positive if they had a positive test at any time, regardless of results of prior or subsequent anti-JCV antibody tests.1
Negative anti-JCV antibody test indicates exposure to JCV has not been detected.1 Such patients are still at risk for PML because of potential for subsequent JCV infection or possibility of false-negative results for anti-JCV antibody.1 Retest patients with negative anti-JCV antibody test every 6 months.1
Use an analytically and clinically validated immunoassay to test for anti-JCV antibody1 (e.g., Stratify JCV antibody ELISA test approved by FDA in January 2012).38 In patients undergoing plasma exchange, do not perform anti-JCV antibody test during or for at least 2 weeks after the procedure since serum antibodies may have been removed during the procedure.1
Interventions that can reliably prevent or adequately treat PML not known; also not known whether early detection of PML and discontinuance of drug will mitigate the disease.1
Prior to initiating natalizumab in patients with MS, perform baseline magnetic resonance imaging (MRI) scan since this may help differentiate subsequent MS symptoms from PML.1 Baseline brain MRI scan also may be useful in patients with Crohn's disease, but baseline brain lesions that could cause diagnostic difficulty are uncommon in these patients.1
Monitor patients for any new signs or symptoms suggestive of PML (i.e., progressive weakness on one side of the body; clumsiness of limbs; disturbance of vision; changes in thinking, memory, and orientation leading to confusion and personality changes);1 seizures and headache also reported rarely.32 33 36 The progression of deficits usually leads to death or severe disability over weeks or months.1
Immediately withhold natalizumab at the first sign or symptom of PML.1
Do not use anti-JCV antibody test to diagnose PML.1 An evaluation that includes a gadolinium-enhanced MRI brain scan and, when indicated, CSF analysis for JC viral DNA recommended to diagnose PML.1 If clinical suspicion remains despite an initial negative evaluation for PML, do not reinitiate natalizumab until the evaluation has been repeated and confirmed.1
Immune Reconstitution Inflammatory Syndrome
Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of natalizumab-treated patients who discontinued the drug after developing PML;1 32 not reported to date when natalizumab discontinued for reasons unrelated to PML.1 32
IRIS is a severe inflammatory response occurring during or after immune system recovery; usually presents as clinical decline (sometimes after apparent clinical improvement) and may progress rapidly, leading to serious neurologic complications or death.1 32 34 36 In MS patients with PML who developed IRIS after discontinuing natalizumab, IRIS generally developed within days to several weeks after the patient received plasma exchange or immunoadsorption to enhance natalizumab removal.1 32 34
Serious hypersensitivity reactions (e.g., anaphylaxis/anaphylactoid reaction) reported in <1% of patients;1 10 11 usually occurred within 2 hours after initiation of IV infusion and generally associated with antibodies to the drug.1 (See Antibody Formation under Cautions.)
If hypersensitivity reactions (e.g., anaphylaxis, urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, chest pain) occur, discontinue immediately and initiate appropriate therapy.1
Do not reinitiate in any patient who experienced a hypersensitivity reaction to the drug.1
Consider possibility of anti-natalizumab antibodies in patients who have hypersensitivity reactions.1
Antibodies against natalizumab may be neutralizing and persistent antibody-positivity may be associated with decreased natalizumab serum concentrations, decreased efficacy, increased rate of myalgia, hypertension, dyspnea, anxiety and tachycardia, and increased risk of infusion-related reactions.1 (See Acute Infusion Reactions under Cautions.)
Long-term immunogenicity remains to be determined; effects of low to moderate levels of antibodies against natalizumab not known.1 Experience with monoclonal antibodies (e.g., natalizumab) suggests that patients who receive therapeutic antibodies after an extended period without such treatment may be at higher risk of hypersensitivity reactions than patients who receive regularly scheduled treatment; not known if this will occur with natalizumab.1
Consider testing for presence of antibodies to natalizumab in patients who wish to resume treatment following an interruption in therapy.1 Patients who have tested negative for antibodies against natalizumab prior to retreatment have a risk of antibody development with retreatment that is similar to natalizumab-naive patients.1
Perform sequential antibody testing if presence of persistent antibodies suspected.1 Antibodies detected early in treatment course (e.g., within first 6 months) may be transient and disappear with continued use; repeat testing at 3 months after initial positive result to confirm persistent antibodies.1
Consider overall benefits and risks of the drug in patients who have persistent antibodies.1
Acute Infusion Reactions
In patients with MS, headache, dizziness, fatigue, urticaria, pruritus, and rigors reported more frequently in patients receiving the drug compared with those receiving placebo, while in patients with Crohn's disease, headache, nausea, urticaria, pruritus, and flushing reported more frequently in patients receiving the drug compared with those receiving placebo.1
Infusion-related reactions reported more frequently in patients persistently positive for anti-natalizumab antibodies.1 (See Antibody Formation under Cautions.) Infusion-related reactions usually associated with persistent antibody-positivity include urticaria, rigors, nausea, vomiting, headache, flushing, dizziness, pruritus, tremor, feeling cold, and pyrexia.1
Immunosuppression and Infectious Complications
Possible increased risk of infections, including opportunistic infections.1
PML, an opportunistic viral infection of the brain that usually is fatal or associated with severe disability, reported in patients receiving natalizumab.1 (See Progressive Multifocal Leukoencephalopathy under Cautions.)
Pneumonia (sometimes severe), urinary tract infections (sometimes severe), influenza, gastroenteritis, vaginal infections, tooth infections, tonsillitis or pharyngitis, and herpes infections reported in MS patients.1 10 Most infections were mild to moderate10 and did not require interruption of therapy.1 10 At least 1 case of cryptosporidial gastroenteritis with a prolonged course reported in an MS patient receiving natalizumab.1
Increased incidence of infections observed in patients receiving short courses of corticosteroids concomitantly with natalizumab; however, incidence in those receiving corticosteroids concomitantly with placebo was similar.1
Pneumocystis jiroveci (formerly P. carinii) pneumonia, pulmonary Mycobacterium avium complex (MAC) infections, bronchopulmonary aspergillosis, and Burkholderia cepacia infection reported rarely in patients with Crohn’s disease.1 Increased incidence of infection observed in those receiving corticosteroids concomitantly with natalizumab; however, incidence in those receiving corticosteroids concomitantly with placebo was similar.1
CNS herpes infections, including herpes simplex virus (HSV) encephalitis, HSV meningitis, and herpes zoster meningitis, reported in postmarketing experience.1
Concomitant use of natalizumab and antineoplastic agents, immunosuppressive agents, or immunomodulating agents may further increase risk of infections, including PML and other opportunistic infections.1 Safety and efficacy of natalizumab in combination with antineoplastic, immunosuppressive, or immunomodulating agents not established.1 (See Specific Drugs under Interactions.)
Clinically important liver dysfunction (e.g., elevated hepatic enzymes, elevated total bilirubin) reported as early as 6 days after administration of the first dose of natalizumab and also after multiple doses.1 30 Liver dysfunction may recur upon rechallenge indicating that natalizumab caused the injury.1
Elevated transaminase levels together with elevated bilirubin (without evidence of obstruction) generally is recognized as an important predictor of severe liver injury that may lead to death or the need for liver transplantation.1 30
In clinical trials, natalizumab induced reversible increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated RBCs; increases usually persisted during treatment but returned to baseline within 16 weeks after last dose.1 10 11 Increased neutrophil counts not reported.1 10 11
Mild, transient decreases in hemoglobin levels reported.1
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1
Clinically important liver dysfunction reported in patients receiving natalizumab.1 (See Hepatotoxicity under Cautions.)
Not studied in patients with renal impairment.1
Common Adverse Effects
Patients with MS: Headache,1 fatigue,1 infusion-related reactions,1 arthralgia or extremity pain,1 depression,1 lower respiratory or urinary tract infections,1 gastroenteritis,1 rash,1 vaginitis,1 abdominal discomfort,1 diarrhea.1
Interactions for Tysabri
Increased incidence of infection1
Immunosuppressive agents (e.g., azathioprine, cyclosporine, mercaptopurine, methotrexate) and TNF inhibitors
Potential for increased risk of PML and other infections 1
Do not use concomitantly in patients with Crohn's disease1
Generally avoid natalizumab in MS patients receiving chronic immunosuppressive or immunomodulatory therapy1
Potential increased natalizumab serum concentrations and half-life; no apparent effect on interferon beta-1a pharmacokinetics8
Pharmacokinetic interaction may not be clinically important8
Safety of concomitant interferon beta not established1
Data not available on effects of vaccination, including secondary transmission of infection from live viral vaccines, in patients receiving natalizumab1
Mean half-life is 11 days.1
Clearance increases with body weight in less than proportional manner.1
Presence of persistent anti-natalizumab antibodies appears to increase drug clearance approximately threefold.1 (See Antibody Formation under Cautions.)
Concentrate for IV Infusion
For information on systemic interactions resulting from concomitant use, see Interactions.
Sodium chloride 0.9%
Binds specifically to α4-subunits of α4β1 and α4β7 integrins expressed on the surface of all leukocytes (except neutrophils) and inhibits α4-mediated adhesion of leukocytes to their counterreceptors, including vascular cell adhesion molecule-1 (VCAM-1).1 5
May also block α4-mediated cell binding to ligands such as osteopontin and CS-1 of fibronectin.1
In Crohn's disease, interaction of α4β7 integrin with the endothelial receptor mucosal addressin cell adhesion molecule-1 (MAdCAM-1) implicated as an important contributor to the chronic inflammation of the disease.1 MAdCAM-1 expression found to be increased at active sites of inflammation suggesting that it may play a role in the recruitment of leukocytes to mucosa and contribute to the inflammatory response characteristic of the disease.1
Mechanism of action in Crohn's disease not fully elucidated; may involve blockade of the interaction of α4β7 integrin receptor with MAdCAM-1 expressed on the vascular endothelium at inflammatory foci.1
Advice to Patients
Importance of patients being counseled on and understanding the benefits and risks of natalizumab before the initial prescription is written.1
Importance of promptly informing clinicians of any new or worsening symptoms that persist over several days.1
Advise patients that they will need to be evaluated by their prescriber at 3 and 6 months after the first natalizumab infusion and at least once every 6 months during therapy.1
Importance of informing patients that PML has occurred in patients treated with natalizumab and that PML usually leads to death or severe disability over weeks or months.1 Patients must understand the signs and symptoms and risk of PML and contact their clinician if they develop any symptoms of PML.1
Importance of promptly informing clinicians of any new or worsening symptoms suggestive of PML (e.g., progressive weakness on one side of the body; clumsiness of limbs; disturbance of vision; changes in thinking, memory, personality, orientation leading to confusion) that have progressed over days to weeks.1 4
Importance of discontinuing natalizumab and reporting any symptoms consistent with a hypersensitivity reaction (e.g., urticaria, pruritus, difficulty breathing) that occur during or following IV infusion of the drug.1 4
Importance of informing patients that natalizumab may increase risk of infection and of informing clinicians if fever or infection (including shingles or any unusually long-lasting infection) occurs.1 4
Risk of liver injury; importance of contacting clinician if symptoms of hepatotoxicity develop.1
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Natalizumab available only through a restricted distribution program (TOUCH Prescribing Program).1 (See Restricted Distribution Program under Dosage and Administration.)
For injection, concentrate, for IV infusion only
300 mg/15 mL
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2013, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
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3. Food and Drug Administration. Tysabri risk minimization action plan: summary of Touch. From FDA website. Accessed 2006 Jul 6.
4. Biogen Idec. Tysabri (natalizumab) medication guide. Cambridge, MA; 2010 July
5. Anon. Natalizumab: AN 100226, anti-4alpha integrin monoclonal antibody. Drugs R&D. 2004; 5: 102-7.
6. Goodin DS. The return of natalizumab: weighing benefit against risk. Lancet. 2006; 5:375-7.
7. Goodin DS, Frohman EM, Garmany GP Jr et al. Disease modifying therapies in multiple sclerosis: report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology and the MS council for clinical practice guidelines. Neurology. 2002; 58:169-178. [IDIS 475332] [PubMed 11805241]
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24. MacDonald JK, McDonald JWD. Natalizumab for induction of remission of Crohn’s disease. Cochrane Database Syst Rev. 2006; 3:CD006097.
25. Biogen Idec, San Diego, CA and Cambridge, MA: Personal communication.
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28. Food and Drug Administration. Natalizumab (Tysabri) for Crohn's Disease (CD) briefing book. 2007 Jun 21. From FDA website.
29. Food and Drug Administration. FDA news. FDA approves Tysabri to treat moderate-to-severe Crohn's disease. 2008 Jan 14. From FDA website.
30. Food and Drug Administration. MedWatch: 2008 safety information alerts. Tysabri (natalizumab). 2008 Feb. From FDA website.
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32. Food and Drug Administration. FDA Drug Safety Communication: Risk of Progressive Multifocal Leukoencephalopathy (PML) with the use of Tysabri (natalizumab). 2010 Feb. From FDA website.
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37. Food and Drug Administration. FDA Drug Safety Communication: Safety update on Progressive Multifocal Leukoencephalopathy (PML) associated with Tysabri (natalizumab). 2011 Apr 22. From FDA website.
38. Food and Drug Administration. FDA Drug Safety Communication: New risk factor for Progressive Multifocal Leukoencephalopathy (PML) associated with Tysabri (natalizumab). 2012 Jan 20. From FDA website.