(na ta LIZ u mab)
- Anti-4 Alpha Integrin
- IgG4-Kappa Monoclonal Antibody
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Concentrate, Intravenous [preservative free]:
Tysabri: 300 mg/15 mL (15 mL) [contains polysorbate 80]
Brand Names: U.S.
- Gastrointestinal Agent, Miscellaneous
- Monoclonal Antibody, Selective Adhesion-Molecule Inhibitor
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.
Crohn disease: 2.4 to 8 L; Multiple sclerosis: 3.8 to 7.6 L
Crohn disease: 3 to 17 days; Multiple sclerosis: 7 to 15 days
Special Populations Note
Antibodies: The presence of persistent anti-natalizumab antibodies increases 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.
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)
Multiple sclerosis: IV: 300 mg infused over 1 hour every 4 weeks
Crohn disease: 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.
Refer to adult dosing.
Dosing: Renal Impairment
There are no dosage adjustments provided in manufacturer’s labeling (has not been studied).
Dosing: 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.
Dilute natalizumab 300 mg in NS 100 mL to a final concentration of 2.6 mg/mL. Gently invert to mix; do not shake.
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.
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.
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
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
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
Central nervous system: Headache (32% to 38%), fatigue (10% to 27%), depression (≤19%)
Dermatologic: Skin rash (6% to 12%)
Gastrointestinal: Nausea (≤17%), gastroenteritis (≤11%), abdominal distress (≤11%)
Genitourinary: Urinary tract infection (3% to 21%)
Infection: Influenza (≤12%)
Neuromuscular & skeletal: Arthralgia (8% to 19%), limb pain (16%), back pain (≤12%)
Respiratory: Upper respiratory tract infection (≤22%), lower respiratory tract infection (≤17%), flu-like symptoms (≤11%)
Miscellaneous: Infusion related reaction (11% to 24%)
1% to 10%:
Cardiovascular: Peripheral edema (5% to 6%), chest discomfort (≤5%), syncope (≤2%)
Central nervous system: Vertigo (≤6%), dysesthesia (3%), rigors (≤3%), drowsiness (≤2%)
Dermatologic: Dermatitis (≤7%), pruritus (≤4%), urticaria (≤2%), thermal injury (1%), night sweats (≤1%), xeroderma (≤1%)
Endocrine & metabolic: Menstrual disease (≤5%), amenorrhea (≤2%), ovarian cyst (≤2%), weight changes (≤2%)
Gastrointestinal: Diarrhea (10%), tooth infection (≤9%), dyspepsia (≤5%), abdominal pain (≤4%), constipation (≤4%), toothache (≤4%), flatulence (≤3%), aphthous stomatitis (≤2%), cholelithiasis (≤1%), gingival disease (infection: 1%)
Genitourinary: Vaginal infection (≤10%), vaginitis (≤10%), urinary frequency (≤9%), dysmenorrhea (2% to 6%), urinary incontinence (≤4%)
Hematologic & oncologic: Hematoma (1%)
Hepatic: Increased serum transaminases (≤5%)
Hypersensitivity: Hypersensitivity reaction (acute: 2% to 4%; serious acute: ≤1%; delayed: ≤5%)
Immunologic: Antibody development (9% to 10%)
Infection: Herpes virus infection (≤8%), viral infection (≤7%), serious infection (2% to 3%)
Local: Bleeding at injection site (≤3%)
Neuromuscular & skeletal: Muscle cramps (≤5%), tremor (1% to 3%), joint swelling (≤2%)
Respiratory: Sinusitis (≤8%), cough (≤7%), tonsillitis (≤7%), pharyngolaryngeal pain (≤6%), epistaxis (2%)
Miscellaneous: Limb injury (3%), laceration (2%)
<1% (Limited to important or life-threatening): Acne vulgaris, agitation, anaphylactoid reaction, anaphylaxis, anemia, angina pectoris, appendicitis, aspergillosis (bronchopulmonary), decreased hemoglobin (mild, transient), dizziness, dyspnea, erythema, exacerbation of Crohn’s disease, fever, flushing, gastroenteritis (cryptosporidial), hepatic failure, hepatitis (cytomegalovirus), hepatotoxicity, herpes simplex encephalitis, hypotension, immune reconstitution syndrome, increased serum bilirubin, infection (Burkholderia cepacia), joint stiffness, lethargy, leukocytosis, meningitis (herpes), nasopharyngitis, opportunistic infection (including bronchopulmonary infections, meningitis, and progressive multifocal leukoencephalopathy [PML]), muscle spasm, myasthenia, nail disease (onychorrhexis), paresis, pericarditis (case report), petechiae, pharyngitis, pneumonia (includes pneumonia caused by Pneumocystis jirovecii and varicella), psychomotor disturbance (hyperactivity), pulmonary infection (Mycobacterium avium intracellulare), suicidal ideation, tachycardia, thrombocytopenia, thrombophlebitis, vasodilatation
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/antibody formation: Hypersensitivity reactions including serious systemic reactions (eg, anaphylaxis) have occurred in <1% of patients. Symptoms may include dizziness, fever, flushing, rigors, hypotension, dyspnea, nausea, pruritus, rash, and urticaria and typically occur within 2 hours of starting the infusion. Reactions are generally associated with antibodies to natalizumab; consider the possibility of antibodies in patients who have hypersensitivity reactions. Patients with an extended interruption in therapy following a short exposure (1 to 2 infusions) to natalizumab may be at an increased risk for developing anti-natalizumab antibodies and/or hypersensitivity reactions following reinitiation of therapy. If a hypersensitivity reaction occurs, discontinue use; patients who have developed hypersensitivity reactions should not be re-treated. 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. Cases of PML have been diagnosed based on MRI findings and the detection of JCV DNA in the CSF without specific PML signs/symptoms (including progressive weakness on one side of the body, limb clumsiness, visual disturbance, changes in thinking, memory, personality or orientation) reported. Use should ordinarily be avoided in patients who are significantly immunocompromised or receiving chronic immunosuppressant or immunomodulatory therapy. For an early diagnosis of PML, consider periodic monitoring for radiographic signs of PML. 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. Patients who are anti-JCV antibody negative are still at risk for developing PML, although the risk is lower; therefore, patients with a negative anti-JCV antibody test result should be retested periodically. A brain MRI scan (baseline) should be obtained prior to initiating therapy in MS patients and should be considered in patients with Crohn disease. PML has also been reported following discontinuation in patients who did not have findings suggestive of PML at the time of discontinuation; patients should be monitored for signs and symptoms of PML for at least 6 months after discontinuation of therapy.
• 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.
• 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).
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); radiographic signs of PML periodically. 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
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.
• 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 abdominal pain, diarrhea, back pain, painful extremities, loss of strength and energy, or joint pain. Have patient report immediately to prescriber signs of infection, signs of progressive multifocal leukoencephalopathy (confusion, depression, memory impairment, behavioral changes, change in strength on one side, difficulty speaking, change in balance, or vision changes), signs of a urinary tract infection (hematuria, burning or pain when passing urine, polyuria, fever, lower abdominal pain, or pelvic pain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), depression, severe nausea, severe vomiting, vaginitis, dizziness, flushing, shortness of breath, angina, passing out, severe headache, or confusion (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 health care 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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