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  • CLASSES

    MS Agents
    Selective Adhesion Molecule Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Humanized monoclonal antibody against alpha-4 integrin; an alpha-4-integrin inhibitor
    Used in adults for relapsing forms of multiple sclerosis and induces and maintains remission in moderately to severely active Crohn's Disease
    Only available via the TOUCH Prescribing Program, due to risk of progressive multifocal leukoencephalopathy (PML)

    HOW SUPPLIED

    Tysabri Intravenous Inj Sol: 15mL, 300mg

    DOSAGE & INDICATIONS

    For the monotherapy treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
    Intravenous infusion dosage
    Adults

    300 mg IV infusion given over 1 hour every 4 weeks. 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. Natalizumab is only available through the TOUCH restricted prescribing program. CLINICAL TRIALS: Of 627 patients who had not received any interferon beta or glatiramer acetate for at least 6 months, 67% remained relapse-free over 24 months on natalizumab 300 mg IV every 4 weeks as compared with 41% of 315 patients who received placebo. Similar results were obtained from patients who had experienced at least 1 relapse while receiving interferon beta-1a (Avonex) 30 mcg IM once weekly and had natalizumab or placebo added to their regimen. Of 589 patients who received natalizumab 300 mg IV every 4 weeks, 54% remained relapse-free over 24 months as compared with 32% of 582 patients who received placebo.

    Adolescents†

    Safety and efficacy have not been established; not FDA-approved. Dosage used has been the same as in adults, 300 mg IV infusion every 4 weeks. Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML); consider the benefits and risk of treatment prior to initiating or continuing treatment. Other agents are generally used first for pediatric MS.

    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. 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

    Adults

    300 mg q4 weeks IV.

    Elderly

    300 mg q4 weeks IV.

    Adolescents

    Safety and efficacy have not been established; data are limited. Maximum dosage not definitively established.

    Children

    >= 11 years: Safety and efficacy have not been established; data are limited. Maximum dosage not definitively established.
    < 11 years: Use not recommended.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    NOTE: The use of natalizumab requires enrollment of patients, prescribers, and pharmacies in the TOUCH Prescribing Program, in an attempt to identify cases of PML, a rare but serious adverse effect, (see Adverse Reactions) as early as possible. The TOUCH program has the following main features: (1) the drug will only be prescribed, distributed, and infused by prescribers, infusion centers, and pharmacies registered with the program; (2) the drug will only be administered to patients enrolled in the program; (3) prior to initiating the therapy, an MRI scan must be obtained for each patient to help differentiate potential, future MS symptoms from PML; and (4) 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 by calling 800—456—2255 or visiting the Tysabri website.

    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.
    The drug solution does not contain preservatives and once diluted must be used within 8 hours. If administration is not immediate, store for up to 8 hours between 2—8 degrees C (36—46 degrees F). Do not freeze. If refrigerated, allow solution to warm to room temperature before administration.
     
    Infusion administration:
    Infuse the diluted drug solution over 1 hour.
    Do not mix with other medicines or administer other medications through 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.
    During the drug infusion and for 1 hour after completion, observe the patient. Promptly discontinue the infusion if any signs or symptoms of a hypersensitivity reaction occur.

    STORAGE

    Generic:
    - Diluted product must be used within 8 hours
    - Protect from freezing
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton until time of use
    Tysabri:
    - Protect from freezing
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Progressive multifocal leukoencephalopathy

    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 PML risk, only prescribers, infusion centers, and pharmacies associated with infusion centers registered with the TOUCH prescribing program are able to prescribe, distribute, or infuse the product. Further, patients must be enrolled and meet all the program conditions. Cases of PML have been reported in patients taking natalizumab who were recently or concomitantly treated with immunomodulators or immunosuppressants, as well as in patients 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. For risk assessment purposes, a patients with a positive anti-JCV antibody test at any time is considered positive regardless of prior or future test results. 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 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.

    Human anti-murine antibody (HAMA), murine protein hypersensitivity, risk of serious hypersensitivity reactions or anaphylaxis

    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.

    Acquired immunodeficiency syndrome (AIDS), corticosteroid therapy, herpes infection, human immunodeficiency virus (HIV) infection, immunosuppression, infection, leukemia, lymphoma, organ transplant, visual disturbance

    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.

    Hepatic disease, hepatotoxicity, jaundice

    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).

    Immune thrombocytopenic purpura (ITP), thrombocytopenia

    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.

    Vaccination

    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.

    Pregnancy

    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). However, hematological abnormalities have been observed in infants following third-trimester exposure to natalizumab (10 of 13 infants).

    Breast-feeding

    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.

    Children, infants, neonates

    Natalizumab is not FDA-approved for use in neonates, 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 a risk for progressive multifocal leukoencephalopathy (PML).[63120]

    ADVERSE REACTIONS

    Severe

    GI obstruction / Delayed / 2.0-2.0
    infusion-related reactions / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    anaphylactic shock / Rapid / 0-1.0
    suicidal ideation / Delayed / 0.6-0.6
    retinopathy / Delayed / Incidence not known
    progressive multifocal leukoencephalopathy / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known

    Moderate

    depression / Delayed / 1.0-19.0
    vaginitis / Delayed / 4.0-10.0
    antibody formation / Delayed / 6.0-10.0
    peripheral edema / Delayed / 5.0-6.0
    elevated hepatic enzymes / Delayed / 5.0-5.0
    constipation / Delayed / 4.0-4.0
    urinary incontinence / Early / 4.0-4.0
    stomatitis / Delayed / 2.0-2.0
    meningitis / Delayed / 0-1.0
    cholelithiasis / Delayed / 0.3-1.0
    confusion / Early / Incidence not known
    ataxia / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    dyspnea / Early / Incidence not known
    hypertension / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    headache / Early / 32.0-38.0
    fatigue / Early / 10.0-27.0
    infection / Delayed / 0-22.0
    arthralgia / Delayed / 8.0-19.0
    nausea / Early / 17.0-17.0
    influenza / Delayed / 5.0-12.0
    back pain / Delayed / 12.0-12.0
    rash / Early / 6.0-12.0
    diarrhea / Early / 10.0-10.0
    urinary urgency / Early / 9.0-9.0
    increased urinary frequency / Early / 9.0-9.0
    sinusitis / Delayed / 8.0-8.0
    cough / Delayed / 3.0-7.0
    vertigo / Early / 6.0-6.0
    dysmenorrhea / Delayed / 2.0-6.0
    menstrual irregularity / Delayed / 5.0-5.0
    muscle cramps / Delayed / 5.0-5.0
    dyspepsia / Early / 5.0-5.0
    abdominal pain / Early / 4.0-4.0
    pruritus / Rapid / 4.0-4.0
    flatulence / Early / 3.0-3.0
    drowsiness / Early / 2.0-2.0
    amenorrhea / Delayed / 2.0-2.0
    weight loss / Delayed / 2.0-2.0
    weight gain / Delayed / 2.0-2.0
    urticaria / Rapid / 2.0-2.0
    tremor / Early / 1.0-1.0
    night sweats / Early / 1.0-1.0
    xerosis / Delayed / 1.0-1.0
    ocular pain / Early / Incidence not known
    weakness / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    dizziness / Early / Incidence not known
    fever / Early / Incidence not known
    flushing / Rapid / Incidence not known
    myalgia / Early / Incidence not known
    vomiting / Early / Incidence not known
    purpura / Delayed / Incidence not known

    DRUG INTERACTIONS

    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.
    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.
    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.
    Daclizumab: (Major) Natalizumab should not be used in combination with daclizumab 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 daclizumab and natalizumab.
    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.
    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.
    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.
    Rubella 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.
    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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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). However, hematological abnormalities have been observed in infants following third-trimester exposure to natalizumab (10 of 13 infants).

    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.

    MECHANISM OF ACTION

    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.

    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.