Due to challenges with completion of required laboratory testing or imaging studies for REMS drugs because of self-isolation or quarantine during the COVID-19 public health emergency, the FDA is recommending health care providers prescribing and/or dispensing REMS drugs consider whether there are compelling reasons or not to complete these requirements during this public health emergency and weigh with the patient the benefits and risks of continuing treatment in the absence of the laboratory testing and imaging studies. The FDA will not take action against sponsors and others during the public health emergency for failing to adhere to REMS requirements.
Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-provides-update-patient-access-certain-rems-drugs-during-covid-19.
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 the presence of anti-JC virus antibodies, duration of therapy, and prior use of immunosuppressants. These factors should be considered in the context of expected benefit when initiating and continuing treatment with natalizumab.
Health care professionals should monitor patients on natalizumab for any new sign or symptom that may be suggestive of PML. Natalizumab dosing should be withheld 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.
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.
Crohn disease (alternative agent): IV: 300 mg infused over 1 hour every 4 weeks; discontinue if therapeutic benefit is not observed within initial 12 weeks of therapy (AGA [Feuerstein 2021]); Al Hashash 2021; manufacturer’s labeling).
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.
Multiple sclerosis, relapsing: Note: In high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other appropriate specialists (eg, liver specialists) regarding treatment options before initiating therapy (AAN [Farez 2019]).
IV: 300 mg infused over 1 hour every 4 weeks. Note: Limited evidence suggests extended interval infusion (administration every 5 to 8 weeks) may be associated with a lower risk of progressive multifocal leukoencephalopathy and similar efficacy (Clerico 2020; Ryerson 2016; Ryerson 2019; Yamout 2018).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult Drug Interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Discontinue use with jaundice or signs/symptoms of hepatic injury.
Refer to adult dosing.
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]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Concentrate, Intravenous:
Tysabri: 300 mg/15 mL (15 mL) [contains polysorbate 80]
Canada: Natalizumab is only available through a controlled distribution program called Biogen ONE Support Program (855-676-6300 or http://www.BIOGENcareforMS.ca). This program is associated with the prescribing, administration, and monitoring of Canadian patients receiving natalizumab. Clinicians are educated on the appropriate use of natalizumab and are expected to discuss the benefits/risks of therapy. Clinicians should evaluate patients every 6 months during treatment. Under this program, only prescribers and pharmacies registered with the program are able to prescribe and dispense natalizumab. In addition, natalizumab can only be dispensed to patients who are registered and meet all the conditions of the Biogen ONE Support Program.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125104s973s975lbl.pdf#page=32, must be dispensed with this medication.
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 all infusions. For the first 12 infusions, observe patients post-infusion or at least 1 hour after the infusion is complete; patients who have received 12 infusions without evidence of hypersensitivity may be observed post-infusion using clinical judgement for subsequent infusions. The infusion should be discontinued if a reaction occurs, and treatment of the reaction should be instituted. Following infusion, flush line with NS.
Crohn disease: Inducing and maintaining clinical response and remission in adults 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).
Limitations of use: Natalizumab is rarely used in the treatment of Crohn disease due to the risk of progressive multifocal leukoencephalopathy in patients with positive anti-JC virus status (al Hashash 2021). The American Gastroenterological Association (AGA) guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn disease recommends against routine use of natalizumab due to the adverse effect profile and availability of other medications to manage moderate to severe Crohn disease. Natalizumab should only be considered if the benefits of use outweigh the risks in patients who are JC virus antibody-negative and who agree to regular monitoring (AGA [Feurestein 2021]).
Multiple sclerosis, relapsing: As monotherapy for the treatment of patients with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. Natalizumab increases the risk of progressive multifocal leukoencephalopathy. 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.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Dermatologic: Skin rash (6% to 12%)
Gastrointestinal: Abdominal distress (11%), gastroenteritis (11%; cryptosporidial gastroenteritis: <1%), nausea (17%)
Genitourinary: Urinary tract infection (3% to 21%)
Infection: Influenza (12%)
Nervous system: Depression (19%), fatigue (10% to 27%), headache (32% to 38%)
Neuromuscular & skeletal: Arthralgia (8% to 19%), back pain (12%), limb pain (16%)
Respiratory: Flu-like symptoms (5% to 11%), lower respiratory tract infection (17%), upper respiratory tract infection (22%)
Miscellaneous: Infusion related reaction (11% to 24%; severe infusion related reaction: <1%)
1% to 10%:
Cardiovascular: Chest discomfort (5%), peripheral edema (5% to 6%)
Dermatologic: Dermatitis (7%), night sweats (1%), pruritus (4%), urticaria (2%), xeroderma (1%)
Endocrine & metabolic: Amenorrhea (2%), menstrual disease (5%), ovarian cyst (2%), weight changes (≤2%)
Gastrointestinal: Aphthous stomatitis (2%), cholelithiasis (≤1%), constipation (4%), diarrhea (10%), dyspepsia (5%), flatulence (3%), gastrointestinal stenosis (≤2%), intestinal obstruction (≤2%), lower abdominal pain (4%), tooth infection (9%), toothache (4%)
Genitourinary: Dysmenorrhea (2% to 6%), urinary frequency (≤9%), urinary incontinence (4%), urinary urgency (≤9%), vaginal infection (4% to 8%), vaginitis (10%)
Hepatic: Abnormal hepatic function tests (5%, including increased serum bilirubin, increased serum transaminases)
Hypersensitivity: Hypersensitivity reaction (acute: 2% to 4%; serious acute: ≤1%; delayed: ≤5%)
Immunologic: Antibody development (9% to 10%; antibodies correlated with a reduction in serum natalizumab levels; persistent antibody-positivity resulted in a decrease in effectiveness)
Infection: Herpes virus infection (8%), serious infection (2% to 3%) viral infection (3% to 7%)
Nervous system: Drowsiness (2%), rigors (3%), vertigo (6%)
Neuromuscular & skeletal: Joint swelling (2%), muscle cramps (5%), tremor (1%)
Respiratory: Cough (3% to 7%), pharyngolaryngeal pain (6%), sinusitis (8%), tonsillitis (7%)
<1%:
Gastrointestinal: Appendicitis
Hematologic & oncologic: Decreased hemoglobin (mild, transient)
Hypersensitivity: Anaphylaxis, nonimmune anaphylaxis
Infection: Fungal septicemia (cryptococcal), opportunistic infection (including aspergillosis [bronchopulmonary], infection [Burkholderia cepacian], pneumonia caused by Pneumocystis jirovecii, pulmonary infection [Mycobacterium avium intracellulare])
Nervous system: Meningitis (including cryptococcal meningitis), progressive multifocal leukoencephalopathy, suicidal ideation
Respiratory: Pneumonia (including Candida pneumonia)
Frequency not defined:
Hematologic & oncologic: Basophilia, eosinophilia, lymphocytosis, monocytosis
Respiratory: Nasopharyngitis
Postmarketing:
Cardiovascular: Pericarditis (Ref)
Hematologic & oncologic: Hemolytic anemia, thrombocytopenia (including immune thrombocytopenia)
Hepatic: Hepatic injury (including acute hepatic failure)
Immunologic: Immune reconstitution syndrome
Infection: JC virus infection
Nervous system: Encephalitis (varicella zoster), herpes simplex encephalitis, meningitis (herpes simplex and varicella zoster)
Ophthalmic: Retinopathy (acute retinal necrosis)
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)
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 or following multiple doses; may recur with treatment rechallenge; discontinue use with jaundice or signs/symptoms of hepatic injury.
• Herpes infection: Serious, life-threatening herpes infections, including fatalities (herpes encephalitis or herpes meningitis infections caused by herpes simplex and varicella zoster viruses) have occurred within a few months to several years of natalizumab treatment. Monitor patients for signs/symptoms of meningitis and encephalitis. In the presence of herpes encephalitis or meningitis, discontinue therapy. Acute retinal necrosis (ARN), a fulminant viral infection of the retina caused by the family of herpes viruses (eg, varicella zoster, herpes simplex virus) has also been observed during natalizumab treatment. Some cases occurred in patients with CNS herpes infections (eg, herpes meningitis, encephalitis); serious cases may result in blindness. Following diagnosis of ARN, consider discontinuation of natalizumab.
• 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, chest pain, 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. When using for the treatment of multiple sclerosis in high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other specialists (eg, liver specialists) regarding treatment options before initiating therapy (AAN [Farez 2019]).
• 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. Retrospective analyses suggest risk of developing PML may be associated with relative serum anti-JCV antibody levels compared to a calibrator as measured by ELISA. 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 with an MRI scan 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. Extended interval dosing (infusions every 5 to 6 weeks instead of every 4 weeks) may be associated with a lower PML risk (Ryerson 2019).
• Thrombocytopenia: Cases of thrombocytopenia, including immune thrombocytopenic purpura, have been reported; symptoms may include easy bruising, abnormal bleeding, and petechiae. Delayed diagnosis and treatment may lead to serious and life-threatening sequelae; discontinue use if thrombocytopenia is suspected.
Disease-related concerns:
• Crohn disease: Natalizumab should not be used in combination with immunosuppressants or tumor necrosis factor 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.
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.
• Discontinuation of therapy: Cases of rebound syndrome (clinical and radiological signs of severe exacerbation beyond what was expected) have been reported; may occur within the first 24 weeks after stopping natalizumab treatment in patients with multiple sclerosis of varying severity and duration. In some cases, relapses have occurred despite the initiation of other disease-modifying therapies. Patients who experience rebound symptoms may not return to the functional status attained during treatment with natalizumab. Monitor for development of severe increase in disability, especially during the first 12 weeks following discontinuation and begin appropriate treatment as needed. Initiating fingolimod within 12 weeks after discontinuation of natalizumab may prevent relapse (AAN [Rae-Grant 2019]; Clerico 2017; Sellner 2019).
• Immunizations: There are no data available concerning the effect of vaccination or secondary transmission of infection by live vaccines in patients receiving natalizumab. When using for the treatment of multiple sclerosis, avoid live-attenuated vaccines in patients who currently receive or have recently discontinued natalizumab; consider using live-attenuated vaccines only if risk of infection is high and killed vaccines are unavailable (AAN [Farez 2019]).
• 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).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
Corticosteroids (Systemic): May enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Immunosuppressants (Cytotoxic Chemotherapy): May enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Immunosuppressants (Miscellaneous Oncologic Agents): May enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Immunosuppressants (Therapeutic Immunosuppressant Agents): May enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Interferon Beta-1a: May enhance the adverse/toxic effect of Natalizumab. Specifically, the risk for progressive multifocal leukoencephalopathy (PML) may be increased. Interferon Beta-1a may increase the serum concentration of Natalizumab. Management: Consider alternatives to this combination whenever possible. Combined use may increase the risk for progressive multifocal leukoencephalopathy (PML). Risk D: Consider therapy modification
Methotrexate: May enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Vedolizumab: May enhance the adverse/toxic effect of Natalizumab. Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
In general, disease-modifying therapies for multiple sclerosis (MS) are stopped prior to a planned pregnancy except in patients at high risk of MS activity (AAN [Rae-Grant 2018]). Clinical rebound (new neurologic symptoms and increased lesions) has been reported when natalizumab was discontinued prior to pregnancy. Some studies suggest that continuing treatment until pregnancy is confirmed then restarting soon after delivery may prevent relapse in high-risk patients (De Giglio 2015; Kleerekooper 2017; Portaccio 2018b; Vukusic 2015). Consider use of agents other than natalizumab for patients at high risk of disease reactivation who are planning to become pregnant (ECTRIMS/EAN [Montalban 2018]).
Delaying pregnancy is recommended for patients with persistent high disease activity; however, when disease-modifying therapy is needed in these patients, natalizumab may be continued following a full discussion of potential risks (ECTRIMS/EAN [Montalban 2018]).
Inflammatory bowel disease is associated with adverse pregnancy outcomes; maternal disease and serum levels of biologic therapy should be optimized prior to conception. Biologics, such as natalizumab, may be continued in patients with inflammatory bowel disease planning to become pregnant (Mahadevan 2019). Treatment algorithms are available for use of biologics in patients with Crohn disease who are planning to become pregnant (Weizman 2019).
Natalizumab crosses the placenta (Haghikia 2014; Proschmann 2018).
Natalizumab is a humanized monoclonal antibody (IgG4). Human IgG crosses the placenta. Exposure is dependent upon the IgG subclass, maternal serum concentrations, placental integrity, newborn birth weight, and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis and the highest during the third trimester (Clements 2020; Palmeira 2012; Pentsuk 2009).
Outcome information related to the use of natalizumab in pregnancy is available from pregnancy registries and systematic reviews in which most females discontinued use once pregnancy was detected. The risk of adverse outcomes (such as spontaneous abortion or birth defects) was not consistent between studies (Ebrahimi 2015; Friend 2016; Peng 2019; Portaccio 2018a). Hematological abnormalities in the newborn, such as anemia and thrombocytopenia, have been noted following maternal use during the third trimester (Haghikia 2014; Proschmann 2018).
In general, disease-modifying therapies for multiple sclerosis (MS) are not initiated during pregnancy, except in females at high risk of MS activity (AAN [Rae-Grant 2018]). Clinical rebound (new neurologic symptoms and increased lesions) has been reported when natalizumab was discontinued prior to or during pregnancy. Some studies suggest that continuing treatment until pregnancy is confirmed then restarting soon after delivery may prevent relapse in high-risk patients (De Giglio 2015; Kleerekooper 2017; Portaccio 2018b; Vukusic 2015). When disease-modifying therapy is needed in these patients, natalizumab may be continued during pregnancy following a full discussion of potential risks (ECTRIMS/ EAN [Montalban 2018]).
Inflammatory bowel disease is associated with adverse pregnancy outcomes including an increased risk of miscarriage, premature delivery, delivery of a low birth weight infant, and poor maternal weight gain. Treatment decreases disease flares, disease activity, and the incidence of adverse pregnancy outcomes. When treatment for inflammatory bowel disease is needed in pregnant patients, appropriate biologic therapy can be continued without interruption. Serum levels should be evaluated prior to conception and optimized to avoid subtherapeutic concentrations or high levels which may increase placental transfer. Dosing can be adjusted so delivery occurs at the lowest serum concentration. For natalizumab, the final injection can be given 4 to 6 weeks prior to the estimated date of delivery, then continued 48 hours' postpartum (Mahadevan 2019).
Natalizumab is present in breast milk.
Breast milk concentrations of natalizumab were evaluated in a lactating female, 11.5 months postpartum, who was breastfeeding her infant three times daily. Breast milk was sampled prior to and for 50 days following maternal administration of natalizumab 300 mg IV over 1 hour every 4 weeks. Breast milk concentrations of natalizumab were below the limit of detection for 13 days following the first dose, and were variable until day 28 (second infusion administered on day 29). The highest breast milk concentration was observed on the last day of the study (day 50). Maternal plasma steady-state concentrations were not reached during the study period (Baker 2015). In a second study, breast milk concentrations of natalizumab were evaluated in four lactating females who had received between 9 and 55 doses of natalizumab prior to and during pregnancy. Breast milk was sampled for up to 145 days postpartum. Breast milk concentrations were highly variable but significantly correlated to the time since last infusion (Proschmann 2018). In a study of two women, only one had detectable breast milk concentrations; maximum concentrations occurred 24 hours after the infusion (Matro 2018).
Based on the limited data, recommendations related to natalizumab and breastfeeding vary (Almas 2016; Dobson 2019; Fragoso 2018). According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
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); signs/symptoms of meningitis and encephalitis; signs/symptoms of acute retinal necrosis; when using for the treatment of multiple sclerosis, latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline).
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).
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
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.
Concentrate (Tysabri Intravenous)
300 mg/15 mL (per mL): $628.47
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