natalizumab (Rx)

>10%

Fatigue (10%)

Diarrhea (10%)

Urinary urgency/frequency (9%)

Sinusitis (8%)

Vaginal infections (8%)

Arthralgia (8%)

Cough (3-7%)

Viral infection (7%)

Dermatitis (7%)

Pharyngolaryngeal pain (6%)

Peripheral edema (6%)

Rash (6%)

Dysmenorrhea (2-6%)

Vertigo (6%)

Dyspepsia (5%)

Abnormal liver function test (5%)

Irregular menstruation (5%)

Urinary incontinence (4%)

Toothache (4%)

Pruritus (4%)

Lower abdominal pain (4%)

Constipation (4%)

Vaginal infections (4%)

Limb injury (3%)

Viral infections (3%)

Urinary tract infections (3%)

Flatulence (3%)

Skin laceration (2%)

Aphthous stomatitis (2%)

Amenorrhea (2%)

Ovarian cyst (2%)

Somnolence (2%)

Acute hypersensitivity reactions (2%)

Thermal burn (1%)

Dry skin (1%)

Tremor (1%)

Night sweats (1%)

Postmarketing Reports

Hemolytic anemia

Contraindications

Hypersensitivity

Active/history of progressive multifocal leukoencephalopathy

Cautions

Increased risk of PML with prolonged duration of therapy, prior treatment with immunosuppressants, or positive anti-JCV antibody status (see Black Box Warnings)

Do not use with other immunosuppressives; may increase the risk for certain infections; monitor patients for development of infections

Possibility of anaphylactic reaction; observe patients during and for 1 hr after infusion to see if symptoms of hypersensitivity-type reactions develop

Herpes infections

• Therapy increases risk of developing encephalitis and meningitis caused by herpes simplex and varicella-zoster viruses; serious, life-threatening, and sometimes fatal cases reported in the postmarketing setting in multiple sclerosis patients receiving therapy; laboratory confirmation in those cases was based on positive PCR for viral DNA in cerebrospinal fluid
• The duration of treatment with drug prior to onset ranged from a few months to several years; monitor patients receiving drug for signs and symptoms of meningitis and encephalitis
• If herpes encephalitis or meningitis occurs, discontinue therapy, and administer appropriate treatment for herpes encephalitis/meningitis

Acute renal necrosis

• Acute retinal necrosis (ARN) is a fulminant viral infection of retina caused by the family of herpesviruses (eg, varicella zoster, herpes simplex virus); a higher risk of ARN observed in patients being administered treatment
• Patients presenting with eye symptoms, including decreased visual acuity, redness, or eye pain, should be referred for retinal screening for ARN; some ARN cases occurred in patients with central nervous system (CNS) herpes infections (eg, herpes meningitis or encephalitis)
• Serious cases of ARN leading to blindness of one or both eyes reported in some patients; following clinical diagnosis of ARN, consider discontinuation of therapy; the treatment reported in ARN cases included anti-viral therapy and, in some cases, surgery

Hepatotoxicity

• Clinically significant liver injury, including acute liver failure requiring transplant, reported in patients treated in the postmarketing setting
• Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, reported as early as six days after first dose; signs of liver injury have also been reported for the first time after multiple doses
• In some patients, liver injury recurred upon rechallenge, providing evidence that treatment caused the injury; the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients
• Therapy should be discontinued in patients with jaundice or other evidence of significant liver injury (eg, laboratory evidence)

Progressive multifocal leukoencephalopathy

• Infection by the JC virus is required for the development of PML; do not use anti-JCV antibody testing to diagnose PML; anti-JCV antibody negative status indicates that antibodies to the JC virus have not been detected; patients who are anti-JCV antibody negative have a lower risk of PML than those who are positive; patients who are anti-JCV antibody negative are still at risk of developing PML due to potential for a new JCV infection or a false negative test result
• Some patients’ serostatus may change intermittently; patients with a negative anti-JCV antibody test result should be retested periodically
• For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered anti-JCV antibody positive regardless of results of any prior or subsequent anti-JCV antibody testing; when assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay
• After plasma exchange (PLEX), wait at least two weeks to test for anti-JCV antibodies to avoid false-negative test results caused by removal of serum antibodies; after infusion of intravenous immunoglobulin (IVIg), wait at least 6 months (5 half-lives) for the IVIg to clear in order to avoid false positive anti-JCV antibody test results
• Healthcare professionals should monitor patients on treatment for any new sign or symptom suggestive of PML; symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes
• The progression of deficits usually leads to death or severe disability over weeks or months; withhold dosing immediately and perform an appropriate diagnostic evaluation at first sign or symptom suggestive of PML
• MRI findings may be apparent before clinical signs or symptoms; cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported
• Many patients subsequently became symptomatic with PML; monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present
• Consider monitoring patients at high risk for PML more frequently; lower PML-related mortality and morbidity have been reported following discontinuation in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis
• It is not known whether these differences are due to early detection and discontinuation of therapy or due to differences in disease in these patients
• There are no known interventions that can reliably prevent PML or that can adequately treat PML if it occurs; PML has been reported following discontinuation of drug in patients who did not have findings suggestive of PML at time of discontinuation; patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for at least six months following discontinuation of treatment
• There are no known interventions that can reliably prevent PML; PML has been reported following discontinuation of treatment in patients who did not have findings suggestive of PML at time of discontinuation; patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for at least six months following discontinuation of treatment
• In multiple sclerosis patients, an MRI scan should be obtained prior to initiating therapy; this MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PM; in Crohn’s disease patients, a baseline brain MRI may also be helpful to distinguish pre-existent lesions from newly developed lesions, but brain lesions at baseline that could cause diagnostic difficulty while on therapy are uncommon
• For diagnosis of PML, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended; if the initial evaluations for PML are negative but clinical suspicion for PML remains, continue to withhold dosing, and repeat the evaluations
• There are no known interventions that can adequately treat PML if it occurs; three sessions of PLEX over 5 to 8 days have been shown to accelerate drugclearance in a study of 12 patients with MS who did not have PML, although in the majority of patients, alpha-4 integrin receptor binding remained high
• Adverse events which may occur during PLEX include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema; although PLEX has not been prospectively studied in treated patients with PML, it has been used in such patients in the postmarketing setting to remove drug more quickly from the circulation
• There is no evidence that PLEX has any benefit in the treatment of opportunistic infections such as PML
• JC virus infection of granule cell neurons in the cerebellum (ie, JC virus granule cell neuronopathy [JCV GCN]) reported in patients treated with drug; JCV GCN can occur with or without concomitant PML; JCV GCN can cause cerebellar dysfunction (eg, ataxia, incoordination, apraxia, visual disorders), and neuroimaging can show cerebellar atrophy
• For diagnosis of JCV GCN, an evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA, is recommended; JCV GCN should be managed similarly to PML
• Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of treated patients who developed PML and subsequently discontinued therapy; in almost all cases, IRIS occurred after PLEX was used to eliminate circulating drug
• Immune reconstitution presents as a clinical decline in patient’s condition after drug removal (and in some cases after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes in the MRI
• Therapy has not been associated with IRIS in patients discontinuing treatment for reasons unrelated to PML; in treated patients with PML, IRIS has been reported within days to several weeks after PLEX; monitoring for development of IRIS and appropriate treatment of associated inflammation should be undertaken

Pregnancy

There are no adequate data on the developmental risk associated with use in pregnant women

Animal data

• In animal studies, administration of natalizumab during pregnancy produced fetal immunologic and hematologic effects in monkeys at doses similar to the human dose and reduced offspring survival in guinea pigs at doses greater than the human dose
• Doses were not maternally toxic but produced the expected pharmacological effects in maternal animals

Lactation

Natalizumab has been detected in human milk

No data available on the effects of this exposure on the breastfed infant or the effects of the drug on milk production

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Recombinant humanized monoclonal antibody that binds to the α4-subunit of α4β1 and α4β7 integrins, prevents leukocyte-endothelial adhesion and leukocyte extravasation

Absorption

Peak plasma concentration: 64-132 mcg/mL

Distribution

Vd: 5.7 L (multiple sclerosis); 5.2L (Crohn disease)

Elimination

Half-Life: 7-15 days (multiple sclerosis); 3-17 days (Crohn disease)

IV Compatibility

0.9% NaCl

IV Incompatibility H3

No other IV diluents may be used to prepare diluted solution

IV Preparation

Concentrate is a colorless opalescent solution

Visually inspect for particulate matter or discoloration - do not use if either present

Withdraw 15 mL from the vial and dilute in 100 mL 0.9% NaCl; no other diluent should be used

Gently invert to mix - do not shake

Make sure no particulate matter is present

After dilution, use immediately or within 8 hr (keep refrigerated at 2-8°C)

If refrigerated, warm before using

Do not freeze

IV Administration

Infuse over 1 hr

After infusion is complete flush with 0.9% NaCl

Do not coadminister any other drugs either through Y-site or dissolved in same solution

Observe patients during infusion and for 1 hr after infusion is complete

Promptly discontinue infusion upon any signs or symptoms consistent with a hypersensitivity-type reaction

Use of filtration devices during administration has not been evaluated

Other medications should not be injected into infusion set side ports or mixed with natalizumab

Storage

Unopened vials: Refrigerate at 2-8°C (36-46°F); do not use beyond expiration date on the carton and vial label; do not freeze or shake; protect from light

Diluted solution: Refrigerate at 2-8°C; use within 8 hr