Natalizumab, a humanized monoclonal antibody, is an alpha-4 integrin antagonist in a class of agents known as selective adhesion molecule inhibitors. Natalizumab was the first FDA-approved alpha-4-integrin inhibitor. Natalizumab has a different mechanism of action and side-effect profile than other available therapies for multiple sclerosis (MS) and is indicated for adults with relapsing forms of multiple sclerosis. Natalizumab reduces MS relapse rates, decreases the appearance of brain lesions, and decreases the risk of disability progression; the drug also has been reported to improve quality of life for patients with MS. The benefit of relapse reduction with natalizumab appears to cease with drug discontinuation; several investigations looking at treatment interruption with natalizumab found an increase in clinical and/or MRI activity. Natalizumab receipt within 24 to 96 hours of an acute clinical MS relapse does not appear to hasten clinical recovery. In addition to multiple sclerosis, natalizumab is used for the treatment of moderately to severely active Crohn's disease (CD) in adults; the drug is indicated to induce and maintain clinical response and remission in patients with evidence of inflammation who have had an inadequate response to or are unable to tolerate conventional CD therapies and TNF blockers. Natalizumab may cause hypersensitivity reactions and increases the risk for progressive multifocal leukoencephalopathy (PML), a rare and frequently fatal demyelinating disease of the central nervous system. Due to the risk of PML, natalizumab is only available under risk evaluation and mitigation programs, including the TOUCH Prescribing Program for Tysabri and the Tyruko REMS Program.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: The use of natalizumab requires enrollment of patients, prescribers, and pharmacies in either the TOUCH Prescribing Program for Tysabri or the Tyruko REMS Program due to the risk of progressive multifocal leukoencephalopathy (PML). The programs have the following main features: (1) the drug will only be prescribed, distributed, and infused by prescribers, infusion centers, and pharmacies registered with the programs; (2) the drug will only be administered to patients enrolled in the program; (3) patients are to be evaluated 3 and 6 months after the first infusion and every 6 months thereafter, with their status reported to the manufacturer. Additional information can be obtained about the TOUCH Prescribing Program by calling 800-456-2255 or visiting the Tysabri website. Additional information can be obtained about the Tyruko REMS Program by calling 800-525-8747.
Route-Specific Administration
Injectable Administration
-Administer as an intravenous infusion only. Do not give as an IV push or bolus injection.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Infusion preparation:
-Before and after dilution, the drug solution in the vial should be colorless and clear to slightly opalescent. Do not use if the solution has visible particles, flakes, color, or is cloudy. Check to ensure that the expiration date has not passed.
-Using aseptic technique, withdraw the 15 mL concentrated drug solution from the vial and add to 100 mL of 0.9% Sodium Chloride Injection, USP. No other diluents are appropriate.
-Do not shake the bag. Gently invert the bag to mix the solution. Ensure that the solution is not cloudy and has no visible particles, flakes, or color.
-Storage: Infuse diluted solution immediately. Drug solutions do not contain preservatives.
--Tysabri: If necessary, store diluted solution between 2 to 8 degrees C (36 to 46 degrees F), and use within 48 hours. Do not freeze. If refrigerated, allow solution to warm to room temperature before administration.
-Tyruko: If necessary, store diluted solution for up to 4 hours between 2 to 8 degrees C (36 to 46 degrees F). Do not freeze. If refrigerated, allow solution to warm to room temperature before administration.
Intravenous Infusion administration:
-Infuse the diluted drug solution over 1 hour.
-Do not mix with other medicines or administer other medications through the infusion set side ports during infusion. Use of filtration devices during administration has not been evaluated.
-Upon completion of the infusion, flush the intravenous line with 0.9% Sodium Chloride Injection, USP.
-Observe the patient for hypersensitivity reactions during all drug infusions. Monitor patients for 1 hour after infusion completion for the first 12 infusions. Subsequent post-infusion monitoring may occur according to clinical judgement. Promptly discontinue the infusion if any signs or symptoms of a hypersensitivity reaction occur.
Infusion-related reactions were reported in 11% to 24% of patients during clinical trials. Serious reactions occurred in less than 1% of patients. These reactions may be related to a hypersensitivity reaction. Additionally, patients who became persistently positive for antibodies to natalizumab were more likely to have an infusion-related reaction than those who were antibody-negative. Allergic reactions have been observed in patients receiving natalizumab, including serious systemic reactions (anaphylaxis) which occurred in less than 1% of patients. Serious acute allergic reactions usually occur during or within 2 hours post-infusion, although a reaction can occur at any time. Acute hypersensitivity reactions, which may be infusion-related, were reported in 0.5% to 4% of patients during clinical trials, while other hypersensitivity reactions were reported in 1% to 5% of patients. Seasonal allergy was reported in 3% of patients. Patients who receive natalizumab for a short exposure (1 to 2 infusions) followed by an extended period without treatment are at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity reactions on re-exposure, compared to patients who received regularly scheduled treatment. Immediately discontinue natalizumab and initiate appropriate treatment if anaphylactic shock or anaphylactoid reactions occur. If a patient develops a hypersensitivity reaction, the presence of antibodies should be considered. Patients who have experienced a hypersensitivity reaction should not be retreated with natalizumab.
Patients who receive natalizumab may be at a greater risk of infection. Certain types of infections including pneumonias/lower respiratory tract infections (17%), urinary tract infections (including serious cases) (21%), gastroenteritis (11%), vaginal infections/vaginitis (10%), tooth infections (9%), tonsillitis (7%), influenza, upper respiratory tract infections, and herpes infections (8%) occurred more often in natalizumab-treated multiple sclerosis patients than in placebo-treated patients. In 1 clinical trial, the incidence of serious infection was approximately 3% in natalizumab-treated patients and in placebo-treated patients. Most patients did not interrupt treatment during infections. The only opportunistic infection in the multiple sclerosis clinical trials was a case of cryptosporidial gastroenteritis with a prolonged course. In a long-term safety study of multiple sclerosis patients treated with natalizumab, pulmonary mycobacterium avium intracellulare, aspergilloma, cryptococcal fungemia and meningitis, and Candida pneumonia were observed in less than 1% of patients. In clinical studies for Crohn's disease, 2 serious non-bacterial meningitides occurred in natalizumab-treated patients compared to none in placebo-treated patients. Infections in general were reported in 3.2% of Crohn's disease patients, including urinary tract infection (0.8% to 3%), pneumonia (0.6%), upper respiratory tract infection (22%), sinusitis (8%), vaginal infections (4% to 8%), viral infections (3% to 7%), influenza/influenza-like symptoms (5% to 12%). Serious infections were reported in 2.1% to 3.3% of patients. Opportunistic infections (e.g., Pneumocystis carinii pneumonia, pulmonary Mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and Burkholderia cepacia) were observed in less than 1% of patients; some of these patients were receiving concurrent immunosuppressants. An increase in infections was seen in patients concurrently receiving corticosteroids in both patients with MS and patients with Crohn's disease. The increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids for both disease states. Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections, including PML and other opportunistic infections, over the risk observed with use of natalizumab alone. The safety and efficacy of natalizumab in combination with antineoplastic, immunosuppressant, or immunomodulating agents have not been established. Patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not ordinarily be treated with natalizumab. Patients with Crohn's disease who are on chronic oral corticosteroids need to stop the corticosteroid within 6 months of natalizumab initiation. In postmarketing experience, serious and fatal cases of encephalitis and meningitis caused by herpes simplex and varicella zoster viruses have been observed in multiple sclerosis patients. Natalizumab treatment duration at the time of infection ranged from a few months to several years. Monitor patients for symptoms of encephalitis or meningitis. If these infections develop, discontinue natalizumab, and administer appropriate treatment. Acute retinal necrosis (ARN), a retinopathy caused by herpes viruses, has been observed in patients treated with natalizumab; serious cases that led to blindness occurred. Some ARN cases occurred in patients with CNS herpes infections. Refer patients with symptoms of ARN (e.g., decreased visual acuity or visual impairment, eye redness, or ocular pain) for retinal screening. If ARN is diagnosed, consider discontinuing natalizumab. ARN can progress into other conditions such as uveitis, retinal detachment, and ultimately can lead to blindness. Treatment of reported cases has included antiviral therapy and surgery. Report serious opportunistic and atypical infections to the manufacturer by calling 1-800-456-2255 and to the Food and Drug Administration's MedWatch Program by calling 1-800-FDA-1088.
Three patients who received natalizumab in clinical trials for either multiple sclerosis or Crohn's disease developed progressive multifocal leukoencephalopathy (PML), which is an opportunistic viral infection of the brain caused by the JC virus (JCV) that usually leads to death or severe disability; additional cases have been reported post-marketing including cases after natalizumab discontinuation in patients who did not have findings suggestive of PML at the time of drug discontinuation. JCV granule cell neuronopathy (JCV GCN), an infection of granule cell neurons in the cerebellum, has also been reported in patients treated with natalizumab; JCV GCN may occur with or without concurrent PML. Three factors are known to increase the risk of PML: treatment more than 2 years, prior immunosuppressant treatment, and anti-JC virus (JCV) antibody presence; data beyond 6 years of treatment are limited. An estimated risk of PML of 12 to 13 per 1,000 exists for patients with all 3 risk factors. An estimated risk of PML of less than 1 case per 1,000 exists for patients who are anti-JCV antibody positive with no prior immunosuppressant use and natalizumab exposure of 1 to 24 months. Consider testing patients for anti-JCV antibody status using an analytically and clinically validated immunoassay before and during natalizumab receipt; a positive result at any time is considered anti-JCV antibody positive regardless of the results of any prior or subsequent tests. As patients who are anti-JCV antibody negative are still at risk for the development of PML, periodically retest these patients due to the potential for a new JCV infection or a previous false negative test result, Do not perform anti-JCV antibody testing during or for at least 2 weeks after plasma exchange due to the removal of antibodies from the serum. Following infusion of intravenous immunoglobulin (IVIG), wait a minimum of 6 months (5 half-lives) for the IVIG to clear to avoid false-positive anti-JCV antibody test results. Carefully consider the risks and benefits of natalizumab for patients who are anti-JCV antibody positive and have one or more additional risk factors. Prior to initiating natalizumab, a magnetic resonance imaging (MRI) scan must be obtained for each patient with multiple sclerosis (MS) to help differentiate potential, future symptoms of MS from PML. A baseline brain MRI may also be helpful in patients with Crohn's disease, although baseline lesions are uncommon. Periodic monitoring for radiographic signs consistent with PML should be considered to allow for early diagnosis; cases of PML diagnosed based on MRI findings with JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms of PML have occurred. Consider monitoring patients at high risk for PML more frequently. Lower PML-related morbidity and mortality have been reported following natalizumab discontinuation in patients with PML who were initially asymptomatic compared to those with clinical symptoms at the time of diagnosis. Monitor patients for any new sign or symptom that may be suggestive of PML both during natalizumab receipt and for 6 months after drug discontinuation. Immediately withhold treatment at the first sign or symptom suggestive of PML. An evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended for diagnosis of PML and JCN GCN. Typical symptoms of PML are diverse and progress over days to weeks. Monitor patients both during natalizumab receipt and for 6 months after drug discontinuation for any new sign or symptom that may be suggestive of PML such as progressive weakness on one side of the body or clumsiness of limbs, disturbances of vision (visual impairment), and changes in thinking, memory, and orientation leading to confusion and personality changes. Symptoms of JCV GCN include cerebellar dysfunction (e.g., ataxia, incoordination, apraxia, visual disorders). Neuroimaging can show cerebellar atrophy. If the initial evaluations for PML are negative but clinical suspicion remains, continue to withhold natalizumab and repeat the evaluations. No known treatment, prevention, or cure for PML exists. Three sessions of plasma exchange over 5 to 8 days were shown to accelerate natalizumab clearance in a study of 12 patients with multiple sclerosis who did not have PML, although, in most patients, alpha-4 integrin receptor binding remained high. Plasma exchange has not been studied in patients taking natalizumab with PML, but it has been used in these patients post-marketing to remove natalizumab more quickly from the circulation. JCV GCN should be managed similarly to PML. A rare condition called immune reconstitution inflammatory syndrome (IRIS) or immune reconstitution syndrome has been reported in patients who discontinue natalizumab after developing PML but not in patients who discontinue the drug for other reasons. In almost all cases, PML-associated IRIS occurred after plasma exchange was used to eliminate circulating natalizumab. The condition developed days to several weeks after these treatments. IRIS is characterized by a severe inflammatory response to an infection that can occur during or after immune system recovery; the severe inflammatory response causes an unexpected decline in a patient's condition after return of immune function. PML-associated IRIS is often followed by characteristic changes in the MRI. Monitor patients for the development of IRIS and institute appropriate treatment for the associated inflammation.
Depression (1-19%) that may include suicidal ideation or suicide attempt (0.6%) may be an adverse effect of natalizumab. Somnolence/drowsiness (2%) and vertigo (6%) have also been reported. Dizziness may occur and may be a component of infusion-related hypersensitivity. Generally, this type of reaction is more common in patients with antibodies to natalizumab. Anxiety may also be more common in patients with antibodies.
Menstrual disorders have been reported with natalizumab therapy and include dysmenorrhea (2-6%), menstrual irregularity (5%), amenorrhea (2%), and ovarian cyst (2%). The mechanism of the potentially-related adverse events is unknown. Females of child-bearing potential may not be applicable candidates for natalizumab receipt (see Contraindications). Menstrual irregularity may be associated with infertility, but no data are available.
Antibody formation occurs with natalizumab exposure, as antibodies were detected in approximately 9% of patients with multiple sclerosis at least once during treatment. Patients were tested for antibodies every 12 weeks. Approximately 6% of patients had positive antibodies on more than one occasion. In Crohn's disease studies, 10% of patients had antibody formation on at least one occasion and 5% of patients had positive antibodies on more than one occasion. The presence of antibodies was correlated with a reduction in serum natalizumab concentrations. In one trial, the week 12 pre-infusion mean natalizumab serum concentration in antibody-negative patients was 15 mcg/mL as compared with 1.3 mcg/mL in antibody-positive patients. Approximately 82% of patients who became persistently antibody positive developed detectable antibodies by 12 weeks of therapy. In vitro, the anti-natalizumab antibodies were neutralizing. In clinical studies, patients who were persistently antibody positive had a substantial reduction in effectiveness. For example, the annualized relapse rate and the risk of increased disability were similar between patients who received placebo and patients who received natalizumab and had persistent antibody positivity. If the presence of persistent antibodies is suspected, perform antibody testing. Antibodies may be detected and confirmed with sequential serum antibody tests. Antibodies detected within the first 6 months of treatment initiation may be transient and disappear with continued dosing. Repeat testing at 3 months after the initial positive result is recommended in patients in whom antibodies are detected to confirm that antibodies are persistent. Consider the overall benefits and risks of natalizumab in a patient with persistent antibodies. The long-term immunogenicity and the effects of low to moderate antibody concentrations are unknown. Patients with persistent antibodies are more likely to experience certain side effects, infusion-related reactions, and allergic reactions to the drug. Patients who receive natalizumab for a short exposure (1 to 2 infusions) followed by an extended period without treatment are at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity reactions on re-exposure, compared to patients who received regularly scheduled treatment. Given that patients with persistent antibodies to natalizumab experience reduced efficacy and that hypersensitivity reactions are more common in such patients, consider testing for the presence of antibodies in patients who wish to recommence therapy after a dose interruption. After a period of dose interruption, patients who are antibody negative before natalizumab reinitiation have a risk of antibody development with retreatment that is similar to patients who have never received natalizumab.
Peripheral edema may be associated with natalizumab receipt. Of 589 patients with relapsing-remitting multiple sclerosis who received natalizumab 300 mg IV once monthly for up to 28 months, 5% had peripheral edema as compared with 1% of 582 patients who received placebo. All of these patients also received interferon beta-1a 30 mcg IM once weekly. Peripheral edema was not noted in the trial of patients who only received natalizumab. Peripheral edema was also reported in 6% of patients during Crohn's disease trials.
Natalizumab may cause clinically significant liver injury, including hepatic failure requiring liver transplant. In the post-marketing setting, signs of hepatic injury, including markedly elevated hepatic enzymes (5%) and hyperbilirubinemia (elevated total bilirubin), occurred as early as six days after the first dose. Signs of liver injury have also been reported for the first time after multiple doses. In some patients, liver injury recurred upon rechallenge. 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 the need for a liver transplant. Discontinue natalizumab in patients with jaundice or other evidence of significant liver injury such as laboratory evidence. Report any serious adverse events possibly associated with natalizumab by calling 1-800-456-2255 or 1- 800-332-1088.
General adverse events reported during natalizumab clinical trials include headache (32-38%), fatigue (10-27%), chest discomfort (5%), rigors (3%), weight loss (2%), weight gain (2%), nonspecific limb injury (3%), tremor (1%), and toothache (4%). Headache, fatigue, feeling cold, tremor, fever, rigors, flushing, and chest pain (unspecified) may be a component of infusion-related hypersensitivity. Generally, this type of reaction is more common in patients with antibodies to natalizumab.
Musculoskeletal adverse events reported during natalizumab clinical trials include arthralgia (8-19%), pain in the extremity (16%), muscle cramps (5%), joint swelling (2%), and back pain (12%). Myalgia may be associated with positive antibodies to natalizumab.
Gastrointestinal adverse events reported during natalizumab clinical trials include cholelithiasis (0.3-1%), appendicitis (0.8%), abdominal discomfort (11%), diarrhea (10%), intestinal/GI obstruction or stenosis (2%), abdominal adhesions (0.3%), nausea (17%), dyspepsia (5%), constipation (4%), flatulence (3%), aphthous stomatitis (2%), and lower abdominal pain (4%). Nausea and vomiting may be a component of infusion-related hypersensitivity. Generally, this type of reaction is more common in patients with antibodies to natalizumab.
Skin and soft tissue adverse events reported during natalizumab clinical trials include rash (unspecified) (6-12%), dermatitis (7%), pruritus (4%), night sweats (1%), skin laceration (2%), thermal burn (1%), and xerosis (1%). Urticaria (2%), rash, and pruritus may be a component of infusion-related hypersensitivity. Generally, this type of reaction is more common in patients with antibodies to natalizumab.
Urinary adverse events reported during natalizumab clinical trials include urinary incontinence (4%), urinary urgency (9%), increased urinary frequency (9%).
Respiratory adverse events reported during natalizumab clinical trials include pharyngolaryngeal pain (6%) and cough (3-7%). Dyspnea may occur and may be a component of infusion-related hypersensitivity. Generally, this type of reaction is more common in patients with antibodies to natalizumab.
Hypotension may occur and may be a component of infusion-related hypersensitivity. Generally, this type of reaction is more common in patients with antibodies to natalizumab. Additionally, hypertension and sinus tachycardia may be more common in patients with positive natalizumab antibodies.
Hemolytic anemia has been observed during postmarketing experience with natalizumab. During clinical trials, natalizumab induced increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. These changes persisted during natalizumab exposure, but were reversible, returning to baseline concentrations within 16 weeks after the last dose. Elevations in neutrophils were not observed. Transient, mild decreases in hemoglobin concentrations (mean decrease of 0.6 grams/dL) have occurred. Cases of thrombocytopenia, including immune thrombocytopenic purpura (ITP), have been reported with the use of natalizumab during postmarketing observation. Delay in the diagnosis and treatment of thrombocytopenia may lead to serious and life-threatening sequelae. If thrombocytopenia is suspected, natalizumab therapy should be discontinued. Neonatal thrombocytopenia, occasionally associated with anemia, was reported during postmarketing observation in neonates following in utero exposure to natalizumab. Obtain a CBC in neonates with in utero exposure to natalizumab.
It is not clear if use of natalizumab increases the risk for new primary malignancy. Skin melanomas have been reported to the FDA as a possible effect of natalizumab. An analysis is ongoing to determine if there is a safety problem that requires further evaluation.
Natalizumab is contraindicated for use by patients who have or have had progressive multifocal leukoencephalopathy (PML). Natalizumab increases the risk of PML, which is an opportunistic viral infection of the brain caused by the JC virus (JCV) that usually leads to death or severe disability. JCV granule cell neuronopathy (JCV GCN), an infection of granule cell neurons in the cerebellum, has also been reported in patients treated with natalizumab; JCV GCN may occur with or without concurrent PML. Due to the risk of PML, natalizumab is only available under risk evaluation and mitigation programs, including the TOUCH Prescribing Program for Tysabri and the Tyruko REMS Program. Cases of PML have been reported in patients taking natalizumab who were recently or concomitantly treated with immunomodulators or immunosuppressants, as well as in those receiving natalizumab monotherapy. Three factors are known to increase the risk of PML: longer treatment duration, especially more than 2 years, prior immunosuppressant treatment, and anti-JCV antibody presence. Consider testing patients for anti-JCV antibody status using an analytically and clinically validated immunoassay. Patients with a negative status are still at risk for PML because of the potential for a new infection or a false negative test result; periodically retest these patients. Do not test for at least 2 weeks after plasma exchange due to antibody removal from the serum. Following infusion of intravenous immunoglobulin (IVIG), wait a minimum of 6 months (5 half-lives) for the IVIG to clear to avoid false-positive anti-JCV antibody test results. Carefully consider the risks and benefits of natalizumab in patients who are anti-JC antibody-positive with 1 or more additional factors. A patient with a positive anti-JCV antibody test at any time is considered positive regardless of prior or future test results. Before initiating natalizumab, a magnetic resonance imaging (MRI) scan must be obtained for each patient with multiple sclerosis (MS) to help differentiate potential, future symptoms of MS from PML. A baseline brain MRI may also be helpful in patients with Crohn's disease who will receive natalizumab, although baseline lesions in these patients are uncommon. Periodic monitoring for radiographic signs consistent with PML should be considered to allow for early diagnosis; cases of PML diagnosed based on MRI findings with JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms of PML have occurred. Consider monitoring patients at high risk for PML more frequently. Lower PML-related morbidity and mortality have been reported following natalizumab discontinuation in patients with PML who were initially asymptomatic compared to those with clinical symptoms at the time of diagnosis. Monitor patients for any new sign or symptom that may be suggestive of PML both during natalizumab receipt and for 6 months after drug discontinuation. Immediately withhold treatment at the first sign or symptom suggestive of PML. JCV GCN should be managed similarly to PML. An evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended for PML and JCV GCN diagnosis. Monitor for the development of immune reconstitution inflammatory syndrome (IRIS) (also known as immune reconstitution syndrome), in patients treated with natalizumab who develop PML and subsequently discontinue treatment. Cases of PML-associated IRIS were reported in most natalizumab-treated patients who developed PML and then had natalizumab treatment discontinued. PML-associated IRIS may lead to rapid onset of serious neurological complications or death, and is often associated with characteristic changes on MRI. Appropriately treat any inflammation associated with IRIS.
Natalizumab is contraindicated for use by a patient who has had a hypersensitivity reaction to the drug; natalizumab should not be used in patients with a known history of murine protein hypersensitivity. There is a risk of serious hypersensitivity reactions or anaphylaxis with natalizumab infusion; acute hypersensitivity has occurred within 2 hours of an infusion, though delayed reactions are also possible. Patients treated with natalizumab may develop human anti-murine antibody (HAMA) production. Hypersensitivity reactions, urticaria, rigors, nausea, vomiting, flushing, myalgia, hypertension, dyspnea, anxiety, or tachycardia are more common in patients with antibodies as compared with patients without detectable antibody formation. Persistent antibody formation against natalizumab during 12 months of drug receipt occurred in 6% of 1216 patients and approximately 90% of the patients were positive for antibody production by 12 weeks of therapy. In vitro, the anti-natalizumab antibodies were neutralizing. In clinical studies, patients who were persistently antibody positive had a substantial reduction in the effectiveness of natalizumab. If the presence of persistent antibodies is suspected, perform antibody testing. Antibodies may be detected and confirmed with sequential serum antibody tests. Antibodies detected within the first 6 months of treatment initiation may be transient and disappear with continued dosing. Repeat testing at 3 months after the initial positive result is recommended in patients in whom antibodies are detected to confirm that antibodies are persistent. Consider the overall benefits and risks of natalizumab in a patient with persistent antibodies. The long-term immunogenicity and the effects of low to moderate antibody concentrations are unknown. Patients who receive natalizumab for a short exposure (1 to 2 infusions) followed by an extended period without treatment are at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity reactions on re-exposure, compared to patients who received regularly scheduled treatment. Given that patients with persistent antibodies to natalizumab experience reduced efficacy and that hypersensitivity reactions are more common in such patients, consider testing for the presence of antibodies in patients who wish to recommence therapy after a dose interruption. After a period of dose interruption, patients who are antibody negative before natalizumab reinitiation have a risk of antibody development with retreatment that is similar to patients who have never received natalizumab. Natalizumab should be immediately discontinued and appropriate treatment initiated if anaphylactic shock or anaphylactoid reactions such as angioedema occur. Patients who have experienced a hypersensitivity reaction should not be retreated with natalizumab.
Natalizumab use and the resultant immune system effects increase the risk for serious infection; monitor patients for development of infections during therapy. Inform all patients to promptly report any signs or symptoms of an infection to their health care provider. Life-threatening and fatal cases of herpes infection have occurred, including cases of herpes encephalitis and meningitis infections. Blindness has occurred in patients developing acute retinal necrosis (ARN). ARN is a fulminant viral infection of the retina caused by the family of herpes viruses (e.g., varicella zoster, herpes simplex virus). Patients presenting with eye symptoms or visual disturbance, redness, or eye pain, should be referred for retinal screening for ARN. Discontinue natalizumab if these infections occur and treat appropriately. In a long-term safety study of patients treated with natalizumab for multiple sclerosis, opportunistic infections (pulmonary mycobacterium avium intracellulare, aspergilloma, cryptococcal fungemia and meningitis, and Candida pneumonia) have been observed in less than 1% of natalizumab-treated patients. In Crohn's disease clinical studies, opportunistic infections (Pneumocystis carinii pneumonia, pulmonary Mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and Burkholderia cepacia) have been observed in less than 1% of treated patients; some of these patients were receiving concurrent immunosuppressants. Patients with immunosuppression, exposure to tuberculosis, or who have frequent infection may be more susceptible to infections when taking natalizumab. Patients receiving chronic immunosuppressant or immunomodulatory therapy such as chemotherapy or corticosteroid therapy or who have systemic compromised immune system function should not ordinarily be treated with natalizumab. For patients with Crohn's disease who start natalizumab while on chronic systemic corticosteroids, commence steroid withdrawal as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. Patients with a weakened immune system, including patients taking an immunosuppressant such as natalizumab, are most likely to get progressive multifocal leukoencephalopathy (PML). Those patients with leukemia, lymphoma, organ transplant, human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) are also expected to have increased susceptibility to serious infections during natalizumab treatment.
Natalizumab may cause clinically significant hepatotoxicity; use with caution in patients with known hepatic disease. Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with natalizumab in the postmarketing setting. Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose; signs of liver injury have also been reported for the first time after multiple doses. In some patients, liver injury recurred upon rechallenge, providing evidence that the drug 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 the need for a liver transplant in some patients. Natalizumab should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence).
Cases of thrombocytopenia, including immune thrombocytopenic purpura (ITP), have been reported with the use of natalizumab in the postmarketing setting. Symptoms of thrombocytopenia may include easy bruising, abnormal bleeding, and petechiae. Delay in the diagnosis and treatment of thrombocytopenia may lead to serious and life-threatening sequelae. If thrombocytopenia is suspected, natalizumab therapy should be discontinued.
There are no data examining the responses to vaccination in patients receiving natalizumab. No data are available on the secondary transmission of infection by live vaccines in patients receiving natalizumab.
There are no adequate data on the developmental risk associated with the use of natalizumab during human pregnancy. 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. These doses were not maternally toxic but produced the expected pharmacological effects in maternal animals. Results from a study of pregnancy exposure registry data of women exposed to natalizumab during pregnancy or within 3 months of conception revealed 57 birth defects (major and minor) among 363 pregnancy outcomes. A major birth defect rate of 5.05% (16 of 316 live births and 1 elective abortion; 95% CI, 2.9% to 8.1%) was reported. No specific patterns of congential malformations suggested a drug effect. Major birth defects included major structural or chromosomal abnormalities, and the most frequently observed defects included torticollis (4 of 57 events), ventricular septal defect (3), and hydronephrosis (2). The following major birth defects were observed in 1 of 57 events: hip dysplasia, polydactyly, absent right femur, atrial shunt, Tetralogy of Fallot, tricuspid valve atresia, unspecified nose anomaly, chordee with hypospadias, penile concealment, colpocephaly, holoprosensephaly, hydrocephalus, myelomeningocele, unspecified agenesis of corpus callosum, cystic dysplasia, vesicoureteral reflux, partial trisomy 9, phenylketonuria, and disconjugate gaze. The spontaneous abortion rate was 9% (95% CI, 6.3% to 12.5%), which is similar to that of the general population. Most infants were born at full term (267 of 316, 84.5%), mean infant weight was 3,161.7 grams (95% CI, 3,099.5 to 3,223.9 grams), and mean infant length was 49.7 cm (range 34 to 89 cm). Low birth weight occurred in 22 (7.6%) of 290 singleton births. Pregnancies resulting in live births with defects were last exposed within 3 months prior to conception or between 1 to 4 weeks gestation; no birth defects were observed in infants exposed to natalizumab throughout pregnancy (n = 4). Hematological abnormalities have been observed in infants following third-trimester exposure to natalizumab (10 of 13 infants). Neonatal thrombocytopenia, occasionally associated with anemia, was reported during postmarketing observation in neonates following in utero exposure to natalizumab. Obtain a CBC in neonates with in utero exposure to natalizumab.
Natalizumab has been detected in human milk. There are no data on the effects of this exposure on the breastfed infant or the effects of the drug on milk production. Due to the potential for serious adverse reactions from natalizumab in a nursing infant, it may be prudent to avoid breast-feeding until more data are available, although some experts suggest use is probably compatible with breast-feeding based on the limited data available and natalizumab's molecular weight and structure, which should limit oral absorption in the infant. If a decision is made to continue breast-feeding, health care providers are advised to monitor the breastfed infant for signs of infection as well as other drug-associated adverse effects. Glatiramer and interferon beta may be potential alternatives to natalizumab to consider for the patient with multiple sclerosis who is breast-feeding. Infliximab and other agents may be considered for the patient with Crohn's disease. However, indication and patient-specific factors should be assessed before choosing an alternative agent. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition.
Natalizumab is not FDA-approved for use in infants, children, and adolescents less than 18 years of age. Safety and efficacy have not been established in pediatric patients for multiple sclerosis or Crohn's disease. There are limited data available for adolescent patients for these uses, and the data are not sufficient given the known drug risks, such as the risk for progressive multifocal leukoencephalopathy (PML).
For the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease:
Intravenous dosage:
Adults: 300 mg IV every 4 weeks.
Adolescents*: 300 mg IV every 4 weeks. Other agents are generally used first for pediatric multiple sclerosis.
For the treatment of moderately to severely active Crohn's disease to induce and maintain clinical response and remission in patients who have had an inadequate response to or are unable to tolerate conventional Crohn's disease therapies and TNF-blockers:
Intravenous infusion dosage:
Adults: 300 mg IV infusion given over 1 hour every 4 weeks. Discontinue natalizumab if the patient has not experienced therapeutic benefit by 12 weeks of induction therapy. Also, discontinue natalizumab if a patient on chronic oral corticosteroids cannot be tapered off corticosteroids within 6 months of starting natalizumab. Commence steroid tapering as soon as a therapeutic benefit of natalizumab has occurred. Consider natalizumab discontinuation for patients who require additional steroid use that exceeds 3 months in a calendar year to control their Crohn's disease (excluding the initial 6-month taper). LIMITS OF USE: Do not use in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or TNF-blockers. Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML); consider the benefits and risk of treatment prior to initiating or continuing treatment. Evaluate the patient 3 months after the first infusion, 6 months after the first infusion, every 6 months thereafter, and for a minimum of 6 months following discontinuation. Determine every 6 months whether patients should continue on treatment. Reauthorization of treatment is needed every 6 months. The American College of Gastroenterology states that natalizumab is more effective than placebo; consider use for induction of symptomatic response in patients with active Crohn's disease and only use for maintenance in patients who have responded to the drug; also use natalizumab for maintenance only if serum antibody to John Cunningham (JC) virus is negative. Testing for anti-JC virus antibody should be repeated every 6 months and treatment stopped if the result is positive.
Maximum Dosage Limits:
-Adults
300 mg every 4 weeks IV.
-Geriatric
300 mg every 4 weeks IV.
-Adolescents
Safety and efficacy have not been established; data are limited. Maximum dosage not definitively established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Adalimumab: (Major) Natalizumab for Crohn's disease should not be used in combination with tumor necrosis factor (TNF) modifiers. Coadministration may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy and other opportunistic infections. Ordinarily, patients with mulitple sclerosis who are receiving chronic TNF-modifier therapy should not be treated with natalizumab.
Albuterol; Budesonide: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Alemtuzumab: (Major) Natalizumab should not be used in combination with alemtuzumab because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, multiple sclerosis patients receiving chronic immunomodulatory therapy should not be treated with natalizumab. No formal studies have studied the combination of alemtuzumab and natalizumab.
Azathioprine: (Major) Natalizumab for Crohn's disease should not be used in combination with immunosuppressants such as azathiorpine because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, patients with mulitple sclerosis who are receiving chronic immunosuppressant therapy should not be treated with natalizumab, for similar reasons.
Azelastine; Fluticasone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) The immune response to vaccines or toxoids may be decreased in patients who receive natalizumab; however, no data are available. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Basiliximab: (Major) The concomitant use of natalizumab and immunosuppressives, such as basiliximab, may further increase the risk of serious infections over the risk observed with use of natalizumab alone. The safety and efficacy of natalizumab in combination with basiliximab has not been evaluated. Patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab.
Beclomethasone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Betamethasone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Budesonide: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Budesonide; Formoterol: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Budesonide; Glycopyrrolate; Formoterol: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Certolizumab pegol: (Major) Natalizumab for Crohn's disease should not be used in combination with tumor necrosis factor (TNF) modifiers. Coadministration may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy and other opportunistic infections. Ordinarily, patients with mulitple sclerosis who are receiving chronic TNF-modifier therapy should not be treated with natalizumab.
Chikungunya Vaccine, Live: (Contraindicated) The immune response to vaccines or toxoids may be decreased in patients who receive natalizumab; however, no data are available. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciclesonide: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Corticosteroids: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Cortisone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Cyclophosphamide: (Major) Natalizumab for Crohn's disease should not be used in combination with immunosuppressants such as cyclophosphamide. Ordinarily, patients with multiple sclerosis who are receiving chronic immunosuppressant therapy (including with cyclophosphamide) should not be treated with natalizumab for similar reasons. The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with cyclophosphamide is also a risk factor for PML.
Cyclosporine: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with cyclosporine.
Deflazacort: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Dexamethasone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Etanercept: (Major) Natalizumab for Crohn's disease should not be used in combination with tumor necrosis factor (TNF) modifiers. Coadministration may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy and other opportunistic infections. Ordinarily, patients with mulitple sclerosis who are receiving chronic TNF-modifier therapy should not be treated with natalizumab.
Everolimus: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with everolimus.
Fludrocortisone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Flunisolide: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Fluticasone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Fluticasone; Salmeterol: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Fluticasone; Umeclidinium; Vilanterol: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Fluticasone; Vilanterol: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Formoterol; Mometasone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Golimumab: (Major) Natalizumab for Crohn's disease should not be used in combination with tumor necrosis factor (TNF) modifiers. Coadministration may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy and other opportunistic infections. Ordinarily, patients with mulitple sclerosis who are receiving chronic TNF-modifier therapy should not be treated with natalizumab.
Hydrocortisone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Infliximab: (Major) Natalizumab for Crohn's disease should not be used in combination with tumor necrosis factor (TNF) modifiers. Coadministration may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy and other opportunistic infections. Ordinarily, patients with mulitple sclerosis who are receiving chronic TNF-modifier therapy should not be treated with natalizumab.
Interferon Beta-1a: (Major) Natalizumab should be used with caution with interferon beta because of the potential for increased risk of progressive multifocal leukoencephalopathy (PML) and other serious infections with combined use. Ordinarily, multiple sclerosis (MS) patients receiving chronic immunomodulatory therapy should not be treated with natalizumab; however, in some multiple sclerosis clinical trials, patients were allowed to continue interferon beta therapy. Due to the risk for infection and PML, natalizumab is only approved for monotherapy of MS. The safety and efficacy of natalizumab as an add-on therapy to interferon beta treatments has not been established. Sequential therapy (e.g., interferon beta followed by natalizumab) does not appear to increase the risk for PML.
Interferon Beta-1b: (Major) Natalizumab should be used with caution with interferon beta because of the potential for increased risk of progressive multifocal leukoencephalopathy (PML) and other serious infections with combined use. Ordinarily, multiple sclerosis (MS) patients receiving chronic immunomodulatory therapy should not be treated with natalizumab; however, in some multiple sclerosis clinical trials, patients were allowed to continue interferon beta therapy. Due to the risk for infection and PML, natalizumab is only approved for monotherapy of MS. The safety and efficacy of natalizumab as an add-on therapy to interferon beta treatments has not been established. Sequential therapy (e.g., interferon beta followed by natalizumab) does not appear to increase the risk for PML.
Intranasal Influenza Vaccine: (Contraindicated) The immune response to vaccines or toxoids may be decreased in patients who receive natalizumab; however, no data are available. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Live Vaccines: (Contraindicated) The immune response to vaccines or toxoids may be decreased in patients who receive natalizumab; however, no data are available. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) The immune response to vaccines or toxoids may be decreased in patients who receive natalizumab; however, no data are available. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) The immune response to vaccines or toxoids may be decreased in patients who receive natalizumab; however, no data are available. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Mercaptopurine, 6-MP: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. Natalizumab for Crohn's disease should not be used in combination with immunosuppressants such as 6-mercaptopurine. Ordinarily, patients with mulitple sclerosis who are receiving chronic immunosuppressant therapy should not be treated with natalizumab, for similar reasons.
Methotrexate: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. Natalizumab for Crohn's disease should not be used in combination with immunosuppressants such as methotrexate. Ordinarily, patients with mulitple sclerosis who are receiving chronic immunosuppressant therapy should not be treated with natalizumab, for similar reasons.
Methylprednisolone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Mitoxantrone: (Major) Natalizumab should not be used in combination with mitoxantrone because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, multiple sclerosis patients receiving chronic immunomodulatory therapy should not be treated with natalizumab.
Mometasone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Mycophenolate: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with mycophenolate.
Nanoparticle Albumin-Bound Sirolimus: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with sirolimus.
Ocrelizumab: (Major) Natalizumab should not be used in combination with ocrelizumab because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, multiple sclerosis patients receiving chronic immunomodulatory therapy should not be treated with natalizumab.
Ofatumumab: (Major) Natalizumab should generally not be used in combination with ofatumumab because of the potential for increased risk of progressive multifocal leukoencephalopathy (PML) and other serious infections. Ordinarily, patients receiving other chronic immunomodulatory therapy should not be treated with natalizumab.
Olopatadine; Mometasone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Ozanimod: (Major) Avoid coadministration of ozanimod and natalizumab. Natalizumab should not be used in combination with ozanimod because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, multiple sclerosis patients receiving chronic immunomodulatory therapy should not be treated with natalizumab.
Prednisolone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Prednisone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Rituximab: (Major) Natalizumab should not be used in combination with rituximab because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, multiple sclerosis patients receiving chronic immunomodulatory therapy should not be treated with natalizumab.
Rituximab; Hyaluronidase: (Major) Natalizumab should not be used in combination with rituximab because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, multiple sclerosis patients receiving chronic immunomodulatory therapy should not be treated with natalizumab.
Rotavirus Vaccine: (Contraindicated) The immune response to vaccines or toxoids may be decreased in patients who receive natalizumab; however, no data are available. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Sirolimus: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with sirolimus.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) The immune response to vaccines or toxoids may be decreased in patients who receive natalizumab; however, no data are available. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) The immune response to vaccines or toxoids may be decreased in patients who receive natalizumab; however, no data are available. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Tacrolimus: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with tacrolimus.
Triamcinolone: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently.
Tumor Necrosis Factor modifiers: (Major) Natalizumab for Crohn's disease should not be used in combination with tumor necrosis factor (TNF) modifiers. Coadministration may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy and other opportunistic infections. Ordinarily, patients with mulitple sclerosis who are receiving chronic TNF-modifier therapy should not be treated with natalizumab.
Typhoid Vaccine: (Contraindicated) The immune response to vaccines or toxoids may be decreased in patients who receive natalizumab; however, no data are available. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) The immune response to vaccines or toxoids may be decreased in patients who receive natalizumab; however, no data are available. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Vedolizumab: (Major) Avoid concomitant use of vedolizumab and natalizumab. The concomitant use of vedolizumab and natalizumab may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy and other opportunistic infections, over the risk observed with use of vedolizumab alone. The safety and efficacy of vedolizumab in combination with natalizumab have not been established.
Yellow Fever Vaccine, Live: (Contraindicated) The immune response to vaccines or toxoids may be decreased in patients who receive natalizumab; however, no data are available. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Natalizumab, a humanized monoclonal antibody, binds and inhibits alpha-4 integrins from adhering to their counter-receptors. Integrins are a family of cell surface glycoproteins. The alpha-4 integrins are heterodimeric receptors that contain either a beta1 or a beta7 subunit. The glycoprotein alpha-4/beta1 integrin, also known as very late antigen 4, and the glycoprotein alpha-4/beta7 integrin, also known as lamina propria-associated molecule 1, are important mediators of cell adhesion, transendothelial migration, and immune cell activation within inflamed tissue. The interaction of alpha-4/beta1 integrin to the endothelial counter-receptor vascular-cell adhesion molecule 1 (VCAM-1) is required for lymphocytes to enter the central nervous system (CNS). Likewise, the interaction of alpha4/beta7 integrin to mucosal addressin-cell adhesion molecule 1 (MAdCAM-1) is required for lymphocytes to enter the intestine. Natalizumab blocks the ability of alpha-4/beta1 integrin and alpha-4/beta7 integrin to bind to their respective endothelial counter-receptors, VCAM-1 and MAdCAM-1. Due to inhibition of transmigration out of the vascular space, the number of circulating leukocytes including lymphocytes, monocytes, basophils, and eosinophils is increased. Transmigration of neutrophils out of the vascular space is not impeded by natalizumab.
Inflammation and demyelination of CNS white matter characteristic of multiple sclerosis may involve lymphocytes and monocytes that migrate into the CNS. Expression of VCAM-1 is induced in the CNS endothelium of patients with multiple sclerosis. Inhibiting alpha-4/beta1 integrin from binding to VCAM-1 prevents T lymphocytes from passing through the blood-brain barrier; the inhibition of T-cell infiltration is thought to impede the demyelinating process of multiple sclerosis. Natalizumab may exert additional pathologic event blockade beyond T cell migration inhibition. The alpha-4 integrins interact not only with VCAM-1 on endothelial cells but also on nonendothelial cells and with the extracellular matrix protein, fibronectin. Blockade of the alpha-4/beta1 integrin interaction with connecting segment-1 (an alternatively spliced domain of fibronectin) and/or with osteopontin expressed by brain parenchymal cells may also contribute to the beneficial effects of natalizumab for multiple sclerosis.
Interaction of the alpha-4/beta7 integrin with MAdCAM-1 mediates homing of lymphocytes to the gut. In patients with inflammatory bowel disease, increased expression of MAdCAM-1 on the vascular endothelium is apparent at sites of inflammation. In the intestine, binding inhibition of alpha-4/beta7 integrin to MAdCAM-1 (selectively expressed in the gut venules and associated lymphoid tissues) by natalizumab attenuates T-cell mediated intestinal inflammation. Secondary actions of natalizumab may also involve the inhibition of alpha-4/beta1 integrin, as vascular -cell adhesion molecule 1 (VCAM-1) is up-regulated on the vascular endothelium at many sites of chronic inflammation. Data suggest intestinal inflammation involves other pathways of leukocyte recruitment beyond alpha-integrin binding to endothelial counter-receptors. For example, the inflammatory infiltrate from patients with Crohn's disease is dominated by neutrophils, which rely upon beta-2 integrins to travel to inflammatory sites. Natalizumab may be effective for Crohn's disease because T cells are essential for inducing the secondary signaling molecules such as cytokines and chemokines that are necessary for sustained neutrophil recruitment.
Inhibition of the interaction between alpha-4 integrins and their endothelial counter-receptors may be deleterious. Patients who receive natalizumab may be at a higher risk of infection development (see Adverse Reactions). The alpha-4/beta1 - VCAM-1 pathway mediates interactions between bone marrow stroma cells and developing B cells; the interaction is necessary for B cell maturation. Furthermore, the alpha-4/beta1 - VCAM-1 pathway mediates the homing and retention of IgG-producing plasma cells and hematopoietic progenitor cells in the bone marrow. Also, the important B-cell communication with follicular dendritic cells for high-affinity antibody production to microbial agents is mediated by the alpha-4/beta1 - VCAM-1 pathway. Lastly, the alpha-4/beta7 -MAdCAM-1 pathway helps maintain intestinal mucosal immunity by mediating the homing of naive lymphocytes and the migration of gut-homing memory cells to the intestinal lamina propria.
Pharmacokinetics:
Natalizumab is administered parenterally as an intravenous infusion. Distribution of natalizumab approximates plasma volume, and the mean half-life is 11 +/- 4 days after repeat administration of 300 mg IV to patients with multiple sclerosis. Natalizumab clearance increased with body weight in a less than proportional manner such that a 43% increase in body weight resulted in a 32% increase in clearance. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold (see Adverse Reactions). The increased concentration of circulating lymphocytes, monocytes, basophils, red blood cells, and eosinophils during natalizumab receipt return to baseline concentrations usually within 16 weeks of the last natalizumab dose.
-Route-Specific Pharmacokinetics
Intravenous Route
Seventy-five minutes after the end of a single 3 mg/kg infusion, the mean natalizumab serum concentration was 69.7 mcg/ml, and adequate serum concentrations to maintain saturation of the glycoprotein alpha-4 integrin receptor appear to last approximately 4 weeks. The observed time to steady-state was approximately 24 weeks after every 4 weeks of dosing. The mean AUC and the mean Cmax increased with increasing doses across the single dose range of 0.03 mg/kg to 3 mg/kg. Also, both parameters were dose proportional for 0.3 mg/kg, 1 mg/kg, and 3 mg/kg.
-Special Populations
Hepatic Impairment
Data are unavailable regarding the pharmacokinetics of natalizumab when used in patients with hepatic impairment.
Renal Impairment
Data are unavailable regarding the pharmacokinetics of natalizumab when used in patients with renal impairment.
Pediatrics
Natalizumab pharmacokinetic data are not available for pediatric patients less than 18 years of age.