Brand name: Tysabri
Drug class: Immunomodulatory Agents
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.
Risk factors include duration of therapy (e.g., >2 years), prior use of immunosuppressants, and presence of anti-JC virus (JCV) antibodies. When initiating and continuing treatment with natalizumab, consider these risk factors in the context of expected benefit.
Because of risk of PML, available only through a restricted distribution program (TOUCH Prescribing Program).
Monitor patients during therapy for any new signs or symptoms suggestive of PML; immediately withhold the drug at first such sign or symptom.
For diagnosis of PML, an evaluation that includes a gadolinium-enhanced MRI brain scan and, when indicated, CSF analysis for JC viral DNA recommended.
Risk Evaluation and Mitigation Strategy (REMS):
FDA approved a REMS for natalizumab to ensure that the benefits 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 https://www.accessdata.fda.gov/scripts/cder/rems/. (Also see Restricted Distribution Program under Dosage and Administration.)
Biologic response modifier; a recombinant humanized anti-α4-integrin monoclonal antibody.
Uses for Natalizumab
Multiple Sclerosis (MS)
Monotherapy for relapsing forms of MS (e.g., relapsing-remitting MS [RRMS]).
Natalizumab is one of several disease-modifying therapies used in the management of RRMS. Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing MRI lesions, and disability progression.
The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with RRMS who have had recent relapses and/or MRI activity. Clinicians should consider adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate therapy.
Because of risk of PML, consider whether expected benefits of natalizumab are sufficient to offset this risk when initiating or continuing therapy. (See Boxed Warning.) Because a few cases of PML have occurred in patients receiving natalizumab concomitantly with interferon beta-1a, the drug is currently restricted to use as monotherapy.
Safety in conjunction with other disease-modifying agents (e.g., glatiramer acetate, interferon beta) not established.
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).
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.
Aminosalicylates may be used in patients receiving natalizumab.
Natalizumab Dosage and Administration
Because of risk of PML, natalizumab is available only through a restricted distribution program (TOUCH Prescribing Program).
Clinicians, pharmacies, infusion centers, and patients must enroll in and meet all conditions of the TOUCH program before they can prescribe, dispense, infuse, or receive natalizumab.
Information about TOUCH program available at 800-456-2255 or [Web].
Administer by IV infusion. Do not administer by rapid IV injection.
Vials are for single use only.
Do not infuse or admix with any other drug.
Use of filtration devices during IV infusion not evaluated.
Allow solution to warm to room temperature prior to administration.
Following completion of infusion, flush infusion set with 0.9% sodium chloride injection.
Observe patients closely for signs or symptoms of hypersensitivity or infusion-related reactions during and for 1 hour after the IV infusion.
Use strict aseptic technique since drug product contains no preservatives.
The concentrate for injection containing 300 mg/15 mL must be diluted in 0.9% sodium chloride prior to IV infusion. Do not use other IV diluents.
Withdraw 15 mL of the concentrate from a single-use vial and add to 100 mL of 0.9% sodium chloride injection. Gently invert diluted solution to mix completely; do not shake.
Rate of Administration
Administer IV infusions over approximately 1 hour.
300 mg once every 4 weeks.
Efficacy for long-term use (i.e., >2 years) not established.
300 mg once every 4 weeks.
In patients receiving chronic oral corticosteroid therapy, start tapering corticosteroid dosage as soon as a therapeutic benefit of natalizumab occurs. Discontinue natalizumab if patient cannot be tapered off oral corticosteroids within 6 months of initiating natalizumab. 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.
Discontinue natalizumab if no therapeutic benefit is evident by 12 weeks of therapy.
Safety of doses >300 mg not adequately evaluated; maximum safe dosage not determined.
No special population recommendations at this time.
Cautions for Natalizumab
Known hypersensitivity to natalizumab or any ingredient in the formulation.
Current or previous history of PML. (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. As of January 2012, 201 cases reported among 96,582 patients treated with natalizumab worldwide; cases continue to be reported during postmarketing surveillance.
PML typically occurs in immunocompromised patients (e.g., patients with HIV infection) and usually leads to death or severe disability.
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.
JC virus granule cell neuronopathy with or without concomitant PML also reported.
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.
Generally, not recommended in patients receiving chronic immunosuppressant or immunomodulatory therapy or in those with systemic medical conditions that result in clinically important compromised immune system. (See Specific Drugs under Interactions.)
Consider testing for anti-JCV antibody status (using an analytically and clinically validated immunoassay). In patients undergoing plasma exchange, do not perform anti-JCV antibody test during or for at least 2 weeks after the procedure to avoid false-negative results. To avoid false-positive results in patients receiving IV immunoglobulin, allow at least 6 months to elapse before performing antibody test.
Positive anti-JCV antibody test indicates individual has been exposed to JCV in the past. Carefully weigh risks and benefits of initiating or continuing natalizumab treatment in those with positive anti-JCV antibody test. 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.
Negative anti-JCV antibody test indicates exposure to JCV has not been detected. 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. Periodically retest patients with negative anti-JCV antibody test.
Interventions that can reliably prevent or adequately treat PML not known.
Prior to initiating natalizumab in patients with MS, perform baseline MRI scan since this may help differentiate subsequent MS symptoms from PML. 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.
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); seizures and headache also reported rarely. The progression of deficits usually leads to death or severe disability over weeks or months.
Immediately withhold natalizumab at the first sign or symptom of PML and perform appropriate diagnostic evaluation. MRI signs may be apparent before clinical manifestations develop; any suspicious findings on MRI should be followed by further evaluation.
Do not use anti-JCV antibody test to diagnose PML. An evaluation that includes a gadolinium-enhanced MRI brain scan and, when indicated, CSF analysis for JC viral DNA recommended to diagnose PML. If clinical suspicion remains despite an initial negative evaluation for PML, do not reinitiate natalizumab until the evaluation has been repeated and confirmed.
Because of risk of PML, natalizumab is available only through a restricted distribution program (TOUCH Prescribing Program).
Promptly report any case of PML, serious opportunistic infection, atypical infection, or death to Biogen Idec or Elan at 800-456-2255 and to FDA’s MedWatch program at 800-332-1088.
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; not reported to date when natalizumab discontinued for reasons unrelated to PML.
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. 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.
Monitor patients for development of IRIS; if IRIS occurs, treat the associated inflammation as appropriate (e.g., corticosteroids).
Serious hypersensitivity reactions (e.g., anaphylaxis/anaphylactoid reaction) reported in <1% of patients; usually occurred within 2 hours after initiation of IV infusion and generally associated with antibodies to the drug. (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.
Do not reinitiate in any patient who experienced a hypersensitivity reaction to the drug.
Consider possibility of anti-natalizumab antibodies in patients who have hypersensitivity reactions.
Antibodies to natalizumab may develop.
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.
Long-term immunogenicity remains to be determined; effects of low to moderate levels of antibodies against natalizumab not known. Patients who receive natalizumab for a short period (1–2 infusions) followed by an extended period without such treatment may be at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity reactions upon re-exposure.
Consider testing for presence of antibodies to natalizumab in patients who wish to resume treatment following an interruption in therapy. 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.
Perform sequential antibody testing if presence of persistent antibodies suspected. 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.
Consider overall benefits and risks of the drug in patients who have persistent antibodies.
Other Warnings and Precautions
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. Liver dysfunction may recur upon rechallenge indicating that natalizumab caused the injury.
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.
Discontinue natalizumab in patients with jaundice or other evidence of clinically important liver injury (e.g., laboratory evidence).
Immunosuppression and Infectious Complications
Possible increased risk of infections, including opportunistic infections (e.g., PML). (See Progressive Multifocal Leukoencephalopathy under Cautions.)
Pneumonia, urinary tract infections (sometimes severe), influenza, gastroenteritis, vaginal infections, tooth infections, tonsillitis or pharyngitis, and herpes infections reported in MS patients. Most infections were mild to moderate and did not require interruption of therapy. At least 1 case of cryptosporidial gastroenteritis with a prolonged course reported in an MS patient.
Increased incidence of infections observed in patients receiving corticosteroids concomitantly with natalizumab; however, incidence similar to that observed in patients receiving corticosteroids alone.
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.
Serious, sometimes fatal, CNS herpes infections including herpes simplex virus (HSV) encephalitis, HSV meningitis, and herpes zoster meningitis and encephalitis reported during postmarketing experience. If herpes encephalitis or meningitis occurs, discontinue drug and treat patient appropriately.
Acute retinal necrosis, a fulminant viral infection of the retina caused by herpes viruses, reported; in some cases, resulted in blindness. Screen patients who experience ocular manifestations (e.g., decreased visual acuity, redness, eye pain). If a diagnosis of acute retinal necrosis is confirmed, consider discontinuance of the drug.
Concomitant use of natalizumab and antineoplastic agents, immunosuppressive agents, or immunomodulating agents may further increase risk of infections, including PML and other opportunistic infections. Safety and efficacy of natalizumab in combination with antineoplastic, immunosuppressive, or immunomodulating agents not established. (See Specific Drugs under Interactions.)
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. Increased neutrophil counts not reported.
Mild, transient decreases in hemoglobin levels reported.
No adequate data on developmental risk associated with use of natalizumab during pregnancy; fetal immunologic and hematologic changes and reduced offspring survival were observed in animal studies.
Distributed into milk; effects of the drug on nursing infants or on milk production not known.
Consider benefits of breastfeeding along with the woman's clinical need for natalizumab and any potential adverse effects on the breastfed infant from the drug or underlying maternal condition.
Safety and efficacy not established in patients <18 years of age with MS or Crohn's disease. Not indicated for use in pediatric patients.
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.
Clinically important liver dysfunction reported in patients receiving natalizumab. (See Hepatotoxicity under Cautions.)
Not studied in patients with renal impairment.
Common Adverse Effects
Patients with MS: Headache, fatigue, infusion-related reactions, arthralgia or extremity pain, depression, lower respiratory or urinary tract infections, gastroenteritis, rash, vaginitis, abdominal discomfort, diarrhea.
Patients with Crohn's disease: Headache, fatigue, upper respiratory infection, nausea.
Interactions for Natalizumab
Increased incidence of infection
Immunosuppressive agents (e.g., azathioprine, cyclosporine, mercaptopurine, methotrexate) and TNF inhibitors
Potential for increased risk of PML and other infections
Do not use concomitantly in patients with Crohn's disease
Generally avoid natalizumab in MS patients receiving chronic immunosuppressive or immunomodulatory therapy
Potential increased natalizumab serum concentrations and half-life; no apparent effect on interferon beta-1a pharmacokinetics
Pharmacokinetic interaction may not be clinically important
Safety of concomitant interferon beta not established
Data not available on effects of vaccination, including secondary transmission of infection from live viral vaccines, in patients receiving natalizumab
Mean half-life is 11 days.
Clearance increases with body weight in less than proportional manner.
Presence of persistent anti-natalizumab antibodies appears to increase drug clearance approximately threefold. (See Antibody Formation under Cautions.)
Concentrate for IV Infusion
2–8°C; protect from light. Do not shake or freeze.
Following dilution, infuse immediately or refrigerate at 2–8°C and use within 8 hours. Do not freeze diluted solution.
For information on systemic interactions resulting from concomitant use, see Interactions.
Sodium chloride 0.9%
Mechanism of action in MS not fully elucidated; may involve blockade of α4β1 integrin-mediated leukocyte migration from peripheral blood into CNS.
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).
May also block α4-mediated cell binding to ligands such as osteopontin and CS-1 of fibronectin.
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. 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.
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.
Advice to Patients
Importance of patients being counseled on and understanding the benefits and risks of natalizumab before the initial prescription is written.
Provide natalizumab medication guide to the patient; importance of patient reading the medication guide prior to initiating natalizumab therapy and before each dose of the drug. (See REMS.)
Importance of promptly informing clinicians of any new or worsening symptoms that persist over several days.
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.
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. Patients must understand the signs and symptoms and risk of PML and contact their clinician if they develop any symptoms of PML.
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.
Importance of patients informing all their clinicians that they are receiving natalizumab.
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.
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.
Risk of liver injury; importance of contacting clinician if symptoms of hepatotoxicity develop.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Natalizumab is available only through a restricted distribution program (TOUCH Prescribing Program).
For injection, concentrate, for IV infusion only
300 mg/15 mL
AHFS DI Essentials™. © Copyright 2023, Selected Revisions August 19, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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