Dosing & Uses
Dosage Forms & Strengths
injectable solution
- 300mg/15mL
Biosimilars to Tysabri
- Tyruko (natalizumab-sztn)
Multiple Sclerosis
Indicated as monotherapy for patients with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
300 mg IV infusion q4wk
When initiating and continuing treatment, consider whether expected benefit is sufficient to offset risk of PML
Crohn Disease
Indicated for moderate-to-severe Crohn disease in adults who had inadequate/intolerant response to conventional treatment and TNF-alpha inhibitors
300 mg IV q4wk
Dosing Considerations
Because natalizumab increases risk of progressive multifocal leukoencephalopathy (PML), it is recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate multiple sclerosis therapy
Additional or previous immunosuppressive therapy increases risk for PML; therefore, do not administer concomitantly with immunosuppressants (eg, 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or TNF-alpha inhibitors
<18 years: Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (19)
- axicabtagene ciloleucel
natalizumab, axicabtagene ciloleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
axicabtagene ciloleucel, natalizumab. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. - baricitinib
baricitinib, natalizumab. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. Baricitinib is not recommended in combination with other JAK inhibitors, biologic DMARDs, or potent immunosuppressives.
- beclomethasone, inhaled
beclomethasone, inhaled increases toxicity of natalizumab by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. Before initiating natalizumab, taper of steroids patients receiving chronic corticosteroids .
- brexucabtagene autoleucel
natalizumab, brexucabtagene autoleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
brexucabtagene autoleucel, natalizumab. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. - certolizumab pegol
natalizumab and certolizumab pegol both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. Avoid combination because of an increased risk of serious infection.
- ciltacabtagene autoleucel
natalizumab, ciltacabtagene autoleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
ciltacabtagene autoleucel, natalizumab. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. - idecabtagene vicleucel
natalizumab, idecabtagene vicleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
idecabtagene vicleucel, natalizumab. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. - ifosfamide
ifosfamide, natalizumab. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. Concomitant therapy is expected to increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects.
- influenza virus vaccine quadrivalent, adjuvanted
natalizumab decreases effects of influenza virus vaccine quadrivalent, adjuvanted by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressive drugs may reduce the immune response to influenza vaccine.
- influenza virus vaccine trivalent, adjuvanted
natalizumab decreases effects of influenza virus vaccine trivalent, adjuvanted by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressive drugs may reduce the immune response to influenza vaccine.
- lisocabtagene maraleucel
natalizumab, lisocabtagene maraleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
lisocabtagene maraleucel, natalizumab. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. - lomustine
lomustine and natalizumab both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. Concomitant therapy is expected to increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects.
- mechlorethamine
mechlorethamine, natalizumab. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. Concomitant therapy is expected to increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects.
- melphalan
melphalan, natalizumab. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. Concomitant therapy is expected to increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects.
- ocrelizumab
ocrelizumab increases toxicity of natalizumab by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. Coadministration of ocrelizumab with immunosuppressants may increase the risk of immunosuppression.
- procarbazine
procarbazine, natalizumab. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Monitor for bone marrow suppression at least monthly in patients concomitantly using leflunomide and another immunosuppressant.
- tisagenlecleucel
natalizumab, tisagenlecleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
tisagenlecleucel, natalizumab. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. - upadacitinib
natalizumab, upadacitinib. Either increases effects of the other by immunosuppressive effects; risk of infection. Contraindicated.
- vedolizumab
vedolizumab, natalizumab. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid coadministration because of the potential for increased risk of PML and other infections.
Monitor Closely (13)
- belatacept
belatacept and natalizumab both increase immunosuppressive effects; risk of infection. Use Caution/Monitor.
- cabazitaxel
natalizumab and cabazitaxel both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Concomitant use of natalizumab and immunosuppressive agents should be avoided.
- denosumab
natalizumab, denosumab. Other (see comment). Use Caution/Monitor. Comment: Caution should be taken in patients on concomitant immunosuppressants or with impaired immune systems because of increased risk for serious infections.
- fingolimod
natalizumab increases effects of fingolimod by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Concomitant therapy is expected to increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects. .
- hydroxyurea
natalizumab, hydroxyurea. Other (see comment). Use Caution/Monitor. Comment: Avoid combination. Potential for increased risk of concurrent infection.
- meningococcal group B vaccine
natalizumab decreases effects of meningococcal group B vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Individuals with altered immunocompetence may have reduced immune responses to the vaccine.
- ofatumumab SC
ofatumumab SC, natalizumab. Either increases effects of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with coadministration. When switching from therapies with immune effects, take into account the duration and mechanism of action of these therapies when initiating ofatumumab SC.
- olaparib
natalizumab and olaparib both increase pharmacodynamic synergism. Use Caution/Monitor. Coadministration with other other myelosuppressive anticancer agents, including DNA damaging agents, may potentiate and prolongate the myelosuppressive toxicity.
- ponesimod
ponesimod and natalizumab both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.
- sipuleucel-T
natalizumab decreases effects of sipuleucel-T by pharmacodynamic antagonism. Modify Therapy/Monitor Closely.
- trastuzumab
trastuzumab, natalizumab. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Neutropenia or febrile neutropenia incidence were increased when trastuzumab was coadministered with myelosuppressive chemotherapy. .
- trastuzumab deruxtecan
trastuzumab deruxtecan, natalizumab. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Neutropenia or febrile neutropenia incidence were increased when trastuzumab was coadministered with myelosuppressive chemotherapy. .
- ublituximab
ublituximab and natalizumab both increase immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Owing to potential additive immunosuppressive effects, consider duration of effect and mechanism of action of these therapies if coadministered
Minor (1)
- interferon beta 1a
interferon beta 1a increases levels of natalizumab by decreasing renal clearance. Minor/Significance Unknown.
Adverse Effects
>10%
Fatigue (10%)
Diarrhea (10%)
Urinary urgency/frequency (9%)
Sinusitis (8%)
Vaginal infections (8%)
Arthralgia (8%)
Cough (3-7%)
Viral infection (7%)
Dermatitis (7%)
Pharyngolaryngeal pain (6%)
Peripheral edema (6%)
Rash (6%)
Dysmenorrhea (2-6%)
Vertigo (6%)
Dyspepsia (5%)
Abnormal liver function test (5%)
Irregular menstruation (5%)
Urinary incontinence (4%)
Toothache (4%)
Pruritus (4%)
Lower abdominal pain (4%)
Constipation (4%)
Vaginal infections (4%)
Limb injury (3%)
Viral infections (3%)
Urinary tract infections (3%)
Flatulence (3%)
Skin laceration (2%)
Aphthous stomatitis (2%)
Amenorrhea (2%)
Ovarian cyst (2%)
Somnolence (2%)
Acute hypersensitivity reactions (2%)
Thermal burn (1%)
Dry skin (1%)
Tremor (1%)
Night sweats (1%)
Postmarketing Reports
Hemolytic anemia
Warnings
Black Box Warnings
Increased risk of progressive multifocal leukoencephalopathy, an opportunistic viral infection of the brain caused by the JC virus in immunocompromised patients that usually leads to death or severe disability
Immune reconstitution inflammatory syndrome may occur in patients who have developed PML; IRIS is a rare condition characterized by severe inflammatory response
Because of the risk of PML, natalizumab is available only through a special restricted distribution program under a risk evaluation and mitigation strategy (REMS); prescribers, infusion centers, and pharmacies associated with infusion centers registered with the program, are able to prescribe, distribute, or infuse the product to patients who are enrolled in and meet all the conditions of the TOUCH Prescribing Program
Healthcare professionals should monitor patients on natalizumab for any new sign or symptom that may be suggestive of PML
Withhold dose immediately at the first sign or symptom suggestive of PML
For diagnosis, an evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended
Consider assessing anti-JCV antibody status prior to treatment or during treatment if antibody status is unknown; the Stratify JCV Antibody ELISA test (Focus Diagnostics) was cleared by FDA on January 20, 2012
Factors known to increase risk of PML in natalizumab-treated patients
- Longer treatment duration, especially beyond 2 years
- Prior treatment with an immunosuppressant (eg, mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate)
- Presence of anti-JCV antibodies
- Patients with all 3 known risk factors have an estimated risk of PML of 11/1,000
- The risks and benefits of continuing treatment with natalizumab should be carefully considered in patients who are found to be anti-JCV antibody positive and have 1 or more additional risk factors
- PML has been reported following discontinuation in patients who did not have findings suggestive of PML at the time of discontinuation; continue to monitor for any new signs or symptoms that may be suggestive of PML for ~6 months following discontinuation
Contraindications
Hypersensitivity
Active/history of progressive multifocal leukoencephalopathy
Cautions
Do not use with other immunosuppressives; may increase the risk for certain infections; monitor patients for development of infections
Anaphylactic reactions may occur; observe patients during and for 1 hr after infusion to see if symptoms of hypersensitivity-type reactions develop
Herpes infections
- May increase risk of developing encephalitis and meningitis caused by herpes simplex and varicella-zoster viruses; serious, life-threatening, and sometimes fatal cases reported in the postmarketing setting in multiple sclerosis patients
- Duration of treatment before onset ranged from a few months to several years; monitor for signs and symptoms of meningitis and encephalitis
- If herpes encephalitis or meningitis occurs, discontinue therapy, and administer appropriate treatment for herpes encephalitis/meningitis
Acute renal necrosis (ARN)
- ARN is a fulminant viral infection of retina caused by the family of herpes viruses (eg, varicella zoster, herpes simplex virus); a higher risk of ARN observed in treated patients
- Eye symptoms include decreased visual acuity, redness, or eye pain; if ARN is suspected, refer patients for retinal screening; some ARN cases occurred in patients with CNS) herpes infections (eg, herpes meningitis or encephalitis)
- Serious cases of ARN leading to blindness of one or both eyes reported in some patients; following clinical diagnosis of ARN, consider discontinuing therapy
Hepatotoxicity
- Clinically significant liver injury, including acute liver failure requiring transplant, reported in postmarketing setting
- Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, reported as early as six days after first dose; signs of liver injury have also been reported for first time after multiple doses
- In some patients, liver injury recurred upon rechallenge, providing evidence that treatment caused the injury; the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or need for a liver transplant in some patients
- Discontinue if jaundice or other evidence of significant liver injury (eg, laboratory evidence) occurs
Progressive multifocal leukoencephalopathy
- Infection by the JC virus is required for the development of PML; do not use anti-JCV antibody testing to diagnose PML
- Patients with a negative anti-JCV antibody test result should be retested periodically
- For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered anti-JCV antibody positive regardless of results of any prior or subsequent anti-JCV antibody testing; when assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay
- After plasma exchange (PLEX), wait at least two weeks to test for anti-JCV antibodies to avoid false-negative test results caused by removal of serum antibodies; after infusion of intravenous immunoglobulin (IVIg), wait at least 6 months (5 half-lives) for the IVIg to clear in order to avoid false positive anti-JCV antibody test results
- Monitor for any new sign or symptom suggestive of PML; symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes
- The progression of deficits usually leads to death or severe disability over weeks or months; withhold dosing immediately and perform an appropriate diagnostic evaluation at first sign or symptom suggestive of PML
- MRI findings may be apparent before clinical signs or symptoms; cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported
- Many patients subsequently became symptomatic with PML; monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present
- Consider monitoring patients at high risk for PML more frequently; lower PML-related mortality and morbidity have been reported following discontinuation in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis
- Unknown whether these differences are due to early detection and discontinuation of therapy or due to differences in disease in these patients
- There are no known interventions that can reliably prevent PML or that can adequately treat PML if it occurs; PML reported after discontinuing therapy in patients who did not have findings suggestive of PML at time of discontinuation; continue to monitor for any new signs or symptoms that may be suggestive of PML for at least 6 months following discontinuation
- Obtain an MRI scan before initiating therapy
- For diagnosis of PML, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA is recommended; if initial evaluations for PML are negative but clinical suspicion for PML remains, continue to withhold dosing, and repeat the evaluations
- Adverse events which may occur during PLEX include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema; although PLEX has not been prospectively studied in treated patients with PML, it has been used in such patients in the postmarketing setting to remove drug more quickly from the circulation
- There is no evidence that PLEX has any benefit in the treatment of opportunistic infections such as PML
- JC virus infection of granule cell neurons in the cerebellum (ie, JC virus granule cell neuronopathy [JCV GCN]) reported in patients treated with drug; JCV GCN can occur with or without concomitant PML; JCV GCN can cause cerebellar dysfunction (eg, ataxia, incoordination, apraxia, visual disorders), and neuroimaging can show cerebellar atrophy
- For diagnosis of JCV GCN, an evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA, is recommended; JCV GCN should be managed similarly to PML
- Immune reconstitution inflammatory syndrome (IRIS) has been reported in most treated patients who developed PML and subsequently discontinued therapy; in all cases, IRIS occurred after PLEX was used to eliminate circulating drug
- Immune reconstitution presents as a clinical decline in patient’s condition after drug removal (and in some cases after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes in the MRI
- Therapy has not been associated with IRIS in patients discontinuing treatment for reasons unrelated to PML; in treated patients with PML, IRIS has been reported within days to several weeks after PLEX; monitoring for development of IRIS and appropriate treatment of associated inflammation should be undertaken
TOUCH prescribing program
- Available only through a restricted program called TOUCH prescribing program because of risk of PML
-
For prescribers and patients, program has 2 components:
- MS TOUCH® (for patients with multiple sclerosis)
- CD TOUCH® (for patients with Crohn disease)
-
Prescribers must be certified and comply with the following:
- Review prescriber educational materials, including full prescribing information
- Review, complete, and sign prescriber enrollment form
- Educate patients on benefits and risks of treatment, ensure that patients receive the Medication Guide, and encourage them to ask questions
- Review, complete, and sign Patient Enrollment Form for each patient
- Evaluate 3 and 6 months after first infusion, every 6 months thereafter, and for at least 6 months after discontinuing therapy
- Determine every 6 months whether to continue treatment and, if so, authorize treatment for another 6 months
- Submit to Biogen the “TYSABRI Patient Status Report and Reauthorization Questionnaire” 6 months after initiating treatment and every 6 months thereafter
- Complete an “Initial Discontinuation Questionnaire” when discontinued, and a “6-Month Discontinuation Questionnaire” following discontinuation
- Report cases of PML, hospitalizations due to opportunistic infections, and deaths to Biogen at 1-800-456-2255 as soon as possible
- Enroll patients TOUCH® Prescribing Program, read the Medication Guide, understand the drug-associated risks, and complete and sign the Patient Enrollment Form
- Pharmacies and infusion centers must be specially certified to dispense or infuse drug
Pregnancy & Lactation
Pregnancy
There are no adequate data on risk of major birth defects, miscarriage, or other adverse maternal outcomes associated with use of drug in pregnant women; adverse fetal outcomes of neonatal thrombocytopenia, at times associated with anemia, reported
Cases of neonatal thrombocytopenia, at times associated with anemia, in infants born to women exposed to drug during pregnancy reported in post-marketing setting; therefore, a CBC should be obtained in neonates who were exposed to the drug in utero
Animal data
- In animal studies, administration of natalizumab during pregnancy produced fetal immunologic and hematologic effects in monkeys at doses similar to the human dose and reduced offspring survival in guinea pigs at doses greater than the human dose
- Doses were not maternally toxic but produced the expected pharmacological effects in maternal animals
Lactation
Natalizumab has been detected in human milk
No data available on the effects of this exposure on the breastfed infant or the effects of the drug on milk production
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Recombinant humanized monoclonal antibody that binds to the α4-subunit of α4β1 and α4β7 integrins, prevents leukocyte-endothelial adhesion and leukocyte extravasation
Absorption
Peak plasma concentration: 64-132 mcg/mL
Distribution
Vd: 5.7 L (multiple sclerosis); 5.2L (Crohn disease)
Elimination
Half-Life: 7-15 days (multiple sclerosis); 3-17 days (Crohn disease)
Administration
IV Compatibility
0.9% NaCl
IV Incompatibility H3
No other IV diluents may be used to prepare diluted solution
IV Preparation
Concentrate is a colorless opalescent solution
Visually inspect for particulate matter or discoloration - do not use if either present
Withdraw 15 mL from the vial and dilute in 100 mL 0.9% NaCl; no other diluent should be used
Gently invert to mix - do not shake
Make sure no particulate matter is present
After dilution, use immediately or within 8 hr (keep refrigerated at 2-8°C)
If refrigerated, warm before using
Do not freeze
IV Administration
Infuse over 1 hr
After infusion is complete flush with 0.9% NaCl
Do not coadminister any other drugs either through Y-site or dissolved in same solution
Observe patients during infusion and for 1 hr after infusion is complete
Promptly discontinue infusion upon any signs or symptoms consistent with a hypersensitivity-type reaction
Use of filtration devices during administration has not been evaluated
Other medications should not be injected into infusion set side ports or mixed with natalizumab
Storage
Unopened vials: Refrigerate at 2-8°C (36-46°F); do not use beyond expiration date on the carton and vial label; do not freeze or shake; protect from light
Diluted solution: Refrigerate at 2-8°C; use within 8 hr
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Formulary
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