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Natalizumab

Pronunciation

(na ta LIZ u mab)

Index Terms

  • AN100226
  • Anti-4 Alpha Integrin
  • IgG4-Kappa Monoclonal Antibody

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Slideshow: New Oral Agents for Multiple Sclerosis: A Healthcare Professional's Guide

Concentrate, Intravenous [preservative free]:

Tysabri: 300 mg/15 mL (15 mL) [contains polysorbate 80]

Brand Names: U.S.

  • Tysabri

Pharmacologic Category

  • Gastrointestinal Agent, Miscellaneous
  • Monoclonal Antibody, Selective Adhesion-Molecule Inhibitor

Pharmacology

Natalizumab is a monoclonal antibody against the alpha-4 subunit of integrin molecules. These molecules are important to adhesion and migration of cells from the vasculature into inflamed tissue. Natalizumab blocks integrin association with vascular receptors, limiting adhesion and transmigration of leukocytes. Efficacy in specific disorders may be related to reduction in specific inflammatory cell populations in target tissues. In multiple sclerosis, efficacy may be related to blockade of T-lymphocyte migration into the central nervous system; treatment results in a decreased frequency of relapse. In Crohn disease, natalizumab decreases inflammation by binding to alpha-4 integrin, blocking adhesion and migration of leukocytes in the gut.

Distribution

Crohn disease: 2.4 to 8 L; Multiple sclerosis: 3.8 to 7.6 L

Half-Life Elimination

Crohn disease: 3 to 17 days; Multiple sclerosis: 7 to 15 days

Special Populations Note

Antibodies

The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately threefold.

Body weight

A less than proportional increase in clearance occurs as body weight increases, such that a 43% increase in body weight produces a 32% increase in clearance.

Use: Labeled Indications

Crohn disease: For inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional Crohn disease therapies and inhibitors of tumor necrosis factor-alpha (TNF-alpha).

Multiple sclerosis: As monotherapy for the treatment of patients with relapsing forms of multiple sclerosis (MS). Natalizumab increases the risk of PML. When initiating and continuing treatment with natalizumab, consider whether the expected benefit of natalizumab is sufficient to offset this risk.

Canada labeling: Treatment of relapsing forms of multiple sclerosis in patients who have had an inadequate response to, or are unable to tolerate, other therapies for multiple sclerosis.

Contraindications

Hypersensitivity to natalizumab or any component of the formulation; current or history of progressive multifocal leukoencephalopathy (PML)

Canada labeling: Additional contraindications (not in US labeling): Immunocompromised patients as a result of immunosuppressant or antineoplastic therapy, or immunodeficiencies (eg, HIV, leukemia, lymphoma)

Dosage

Multiple sclerosis: Adults: IV: 300 mg infused over 1 hour every 4 weeks

Crohn disease: Adults: IV: 300 mg infused over 1 hour every 4 weeks; discontinue if therapeutic benefit is not observed within initial 12 weeks of therapy

Concomitant use with corticosteroids: For patients who begin treatment while on chronic oral corticosteroids, begin tapering oral steroids when the onset of natalizumab therapeutic benefit is observed; discontinue use if patient cannot be tapered off of oral corticosteroids within 6 months of therapy initiation. If additional concomitant corticosteroids are required and exceed 3 months/year (in addition to initial corticosteroid taper), consider discontinuing therapy.

Concomitant use with immunosuppressants (eg, azathioprine, cyclosporine, 6-mercaptopurine, or methotrexate) or inhibitors of TNF-alpha: Avoid concomitant use.

Dosage adjustment in renal impairment: There are no dosage adjustments provided in manufacturer’s labeling (has not been studied).

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in manufacturer’s labeling (has not been studied). Discontinue use with jaundice or signs/symptoms of hepatic injury.

Reconstitution

Dilute natalizumab 300 mg in NS 100 mL to a final concentration of 2.6 mg/mL. Gently invert to mix; do not shake.

Administration

If stored under refrigeration, allow solution to warm to room temperature prior to administration. Diluted solution should be infused over 1 hour; do not administer by IV bolus or push. Patients should be closely monitored for signs and symptoms of hypersensitivity during the infusion and for at least 1 hour after the infusion is complete. The infusion should be discontinued if a reaction occurs, and treatment of the reaction should be instituted. Following infusion, flush line with NS.

Storage

Store concentrated solution under refrigeration between 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Do not shake. Following dilution, may store refrigerated for use within 8 hours.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Immunosuppressants: May enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Exceptions: Cytarabine (Liposomal). Avoid combination

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Vedolizumab: May enhance the adverse/toxic effect of Natalizumab. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Headache (32% to 38%), fatigue (10% to 27%), depression (≤19%)

Dermatologic: Rash (6% to 12%)

Gastrointestinal: Nausea (≤17%), gastroenteritis (≤11%), abdominal discomfort (≤11%)

Genitourinary: Urinary tract infection (3% to 21%)

Neuromuscular & skeletal: Arthralgia (8% to 19%), extremity pain (16%), back pain (≤12%)

Respiratory: Upper respiratory infection (≤22%), lower respiratory infection (≤17%)

Miscellaneous: Infusion-related reaction (11% to 24%), influenza (≤12%), flu-like syndrome (≤11%)

1% to 10%:

Cardiovascular: Peripheral edema (5% to 6%), chest discomfort (≤5%)

Central nervous system: Vertigo (≤6%), dysesthesia (3%), syncope (≤2%), somnolence (≤2%)

Dermatologic: Dermatitis (≤7%), pruritus (≤4%), urticaria (≤2%), dry skin (≤1%)

Endocrine & metabolic: Dysmenorrhea (2% to 6%), menstrual irregularities (≤5%), amenorrhea (≤2%), ovarian cyst (≤2%)

Gastrointestinal: Diarrhea (10%), dyspepsia (≤5%), abdominal pain (≤4%), constipation (≤4%), flatulence (≤3%), aphthous stomatitis (≤2%), weight changes (≤2%), cholelithiasis (≤1%), gingival infection (1%)

Genitourinary: Vaginitis/vaginal infections (4% to 10%), urinary frequency (≤9%), urinary incontinence (≤4%)

Hematologic: Hematoma (1%)

Hepatic: Transaminase increased (≤5%)

Local: Bleeding at injection site (≤3%)

Neuromuscular & skeletal: Muscle cramp (≤5%), tremor (1% to 3%), rigors (≤3%), joint swelling (≤2%)

Respiratory: Sinusitis (≤8%), cough (≤7%), tonsillitis (≤7%), pharyngolaryngeal pain (≤6%), epistaxis (2%)

Miscellaneous: Antibody formation (9% to 10%), tooth infection (≤9%), herpes infection (≤8%), viral infection (≤7%), hypersensitivity reactions (acute: 2% to 4%; serious acute: ≤1%; delayed: ≤5%), toothache (≤4%), limb injury (3%), serious infection (2% to 3%), laceration (2%), thermal injury (1%), night sweats (≤1%)

<1% (Limited to important or life-threatening): Acne, agitation, anaphylaxis/anaphylactoid reactions, anemia, angina, appendicitis, bilirubin increased, bronchopulmonary aspergillosis, Burkholderia cepacia, Crohn’s disease exacerbation, cryptosporidial gastroenteritis, cytomegalovirus hepatitis, dizziness, dyspnea, erythema. fever, flushing, hemoglobin decreased (mild, transient), hepatic failure, hepatotoxicity, herpes encephalitis, herpes meningitis, hypotension, IRIS, joint stiffness, lethargy, leukocytosis, nasopharyngitis, opportunistic infections (including progressive multifocal leukoencephalopathy [PML], meningitis, and bronchopulmonary infections), muscle spasms, muscle weakness, onychorrhexis, paresis, pericarditis (case report), petechiae, pharyngitis, Pneumocystis jirovecii pneumonia, pneumonia, psychomotor hyperactivity, pulmonary Mycobacterium avium intracellulare, suicidal ideation, tachycardia, thrombocytopenia, thrombophlebitis, varicella pneumonia, vasodilatation

ALERT: U.S. Boxed Warning

Progressive multifocal leukoencephalopathy:

Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability.

Risk factors for the development of PML include duration of therapy, prior use of immunosuppressants, and presence of anti–JC virus (JCV) antibodies. These factors should be considered in the context of expected benefit when initiating and continuing treatment with natalizumab.

Because of the risk of PML, natalizumab is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the TOUCH prescribing program.

Monitor patients on natalizumab for any new sign or symptom that may be suggestive of PML. Withhold natalizumab dosing immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation that includes a gadolinium-enhanced magnetic resonance imaging (MRI) scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended.

Warnings/Precautions

Concerns related to adverse effects:

• Hepatotoxicity: Hepatotoxicity, including acute liver failure requiring transplant, has been reported with use. Signs of hepatotoxicity, including transaminase and bilirubin elevation occurred as early as 6 days after the first dose; may recur with treatment rechallenge; discontinue use with jaundice or signs/symptoms of hepatic injury.

• Herpes infection: Serious herpes infections (including herpes encephalitis or herpes meningitis caused by herpes simplex and varicella zoster viruses) have occurred within a few months to several years of natalizumab treatment. In the presence of herpes encephalitis or meningitis, discontinue therapy until successful resolution of the infection.

• Hypersensitivity/infusion-related reactions: Infusion-related reactions have occurred and serious systemic reactions (including anaphylaxis) occurred in <1% of patients. Symptoms associated with reactions may include dizziness, fever, flushing, rigors, hypotension, dyspnea, nausea, pruritus, rash, and urticaria. Reactions typically occur within 2 hours of the start of infusion. Patients with an extended interruption in therapy may be at an increased risk for hypersensitivity reactions following reinitiation of therapy. Re-treatment is contraindicated in patients who have developed hypersensitivity reactions. Reactions are generally associated with antibodies to natalizumab. Antibody formation (which occurs in about 10% of patients) is associated with a decrease in natalizumab levels and a decrease in the efficacy of natalizumab. Antibody testing should be performed in any patient when there is a suspicion of persistent antibodies and should be considered in patients that resume therapy following a period of dosage interruption.

• Immune reconstitution inflammatory syndrome (IRIS): IRIS has been reported in patients after discontinuing natalizumab due to PML. In most cases, this occurred within days to weeks after plasma exchange was used in an attempt to remove natalizumab. IRIS is a rare condition which is characterized by severe inflammation during or following immune system recovery, which can result in a decline in patient condition, including neurological symptoms and death.

• Infections: Use may be associated with an increased risk of infections, including opportunistic infections and serious herpes infections (rare, postmarketing reports; concurrent use of antineoplastic, immunosuppressant [including short-course corticosteroids], or immunomodulating agents may increase this risk); discontinue therapy until successful resolution of the infection.

• Lab test abnormalities: Reversible increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells may occur; changes persist during natalizumab exposure but usually return to baseline within 16 weeks after the last dose. Mild transient decreases in hemoglobin levels may also occur.

• Progressive multifocal leukoencephalopathy: [US Boxed Warning]: Natalizumab increases the risk of developing fatal or disabling progressive multifocal leukoencephalopathy (PML, an opportunistic viral infection of the brain caused by the JC virus). Risk factors for development of PML include duration of therapy (especially >2 years), prior use of immunosuppressants (eg, azathioprine, cyclophosphamide, methotrexate, mitoxantrone, mycophenolate), and the presence of anti JC virus antibodies. Monitor for any new signs/symptoms suggestive of PML; immediately withhold treatment at the first sign or symptom suggesting PML. For diagnosis of PML, an evaluation should include a gadolinium-enhanced MRI scan of the brain and (if indicated) analysis of CSF for JCV DNA. Signs/symptoms of PML include progressive weakness on one side of the body, limb clumsiness, visual disturbance, changes in thinking, memory, personality or orientation. Patients who are anti-JCV antibody negative are still at risk for developing PML, although the risk is lower. Anti-JCV antibody testing prior to or during treatment may be considered; testing should not be used to diagnose PML and should not be performed for at least 2 weeks after plasma exchange. A brain MRI scan (baseline) should be obtained prior to initiating therapy in MS patients and should be considered in patients with Crohn disease. Use should ordinarily be avoided in patients who are significantly immunocompromised or receiving chronic immunosuppressant or immunomodulatory therapy. Patients should be monitored for signs and symptoms of PML for at least 6 months after discontinuation of therapy.

Disease-related concerns:

• Crohn disease: Natalizumab should not be used in combination with immunosuppressants or tumor necrosis factor (TNF) inhibitors in patients with Crohn disease; aminosalicylates may be used concurrently with natalizumab. For patients who begin treatment while on chronic oral corticosteroids, begin tapering oral steroids when the onset of natalizumab therapeutic benefit is observed; discontinue use if patient cannot be tapered off of oral corticosteroids within 6 months of therapy initiation. If additional concomitant corticosteroids are required and exceed 3 months/year (in addition to initial corticosteroid taper), consider discontinuing therapy.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Immunizations: There are no data available concerning the effect of vaccination or secondary transmission of infection by live vaccines in patients receiving natalizumab.

Other warnings/precautions:

• Appropriate use: Use should be restricted to patients with inadequate response to or intolerant of other therapies for Crohn disease or multiple sclerosis. Carefully evaluate the overall benefit to risk in patients that develop persistent antibodies to natalizumab.

• REMS program: [US Boxed Warning]: Access is restricted through a REMS program called the TOUCH Prescribing Program; prescribers and pharmacies must be certified with the Tysabri Outreach Unified Commitment to Health (TOUCH) Prescribing Program.Patients must also be enrolled in the TOUCH Prescribing Program (800-456-2255) to receive natalizumab (MS-TOUCH for multiple sclerosis or CD-TOUCH for Crohn disease).

Monitoring Parameters

Monitor for symptoms of hepatotoxicity (eg, elevated serum transaminases, bilirubin); hypersensitivity reactions during, and for 1 hour after, infusion; symptoms of persistent antibody-positivity (eg, anxiety, dizziness, dyspnea, feeling cold, flushing, headache, hypertension, myalgia, nausea, pruritus, pyrexia, rigors, tachycardia, tremor, urticaria or, vomiting). Antibody testing is recommended if persistent antibodies are suspected and repeated in 3 months in all patients with documented positivity on initial test. Consider antibody testing in patients that resume therapy following a period of dosage interruption.

Baseline brain MRI scan; if PML is suspected, obtain gadolinium-enhanced brain MRI scan and CSF analysis for JC viral DNA. Evaluate for signs or symptoms of progressive multifocal leukoencephalopathy during treatment and for 6 months after discontinuation. Note: Transient and reversible leukocytosis (excluding neutrophils) and mildly reduced hemoglobin may occur with treatment and may require ~4 months for return to baseline values after the last dose; anti-JCV antibody (prior to therapy and periodically during therapy)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Natalizumab crosses the placenta (Haghikia 2015). Hematological alterations such as anemia and thrombocytopenia have been noted following maternal use during pregnancy. The risk of spontaneous abortion may also be increased (Amato 2015; Ebrahimi 2015; Haghikia 2015).

Pregnant women exposed to natalizumab should be enrolled in the Tysabri Pregnancy Exposure Registry 1-800-456-2255.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dyspepsia, diarrhea, asthenia, or arthralgia. Have patient report immediately to prescriber signs of infection, signs of hepatic impairment, suicidal ideation, depression, severe nausea, dizziness, flushing, dyspnea, angina, syncope, significant headache, or illogical thinking (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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