natal

Action

Binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the α4-mediated adhesion of leukocytes to their counterreceptor(s). The receptors for the α4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal address in cell adhesion molecule-1 (MAdCAM-1) present on vascular endothelial cells of the GI tract. Disruption of these molecular interactions prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. Specific mechanisms by which drug exerts its effects in multiple sclerosis (MS) and Crohn's disease haven't been fully defined.

Availability

Solution for infusion: 300 mg/15-ml vial (20 mg/ml)

Indications and dosages

➣ Relapsing forms of MS; moderately to severely active Crohn's disease in patients with evidence of inflammation who have had inadequate response to or can't tolerate conventional therapy

Adults: 300 mg by I.V. infusion over approximately 1 hour q 4 weeks. In Crohn's disease, discontinue in patient who hasn't experienced therapeutic benefit by 12 weeks of induction therapy and in patient who can't discontinue long-term concomitant steroids within 6 months of starting natalizumab.

Contraindications

• Hypersensitivity to drug

• History of or current PML

Precautions

Use cautiously in:

• hepatic impairment

• infections, immune reconstitution inflammatory syndrome

• concurrent use of TNFa inhibitors, antineoplastics, prolonged immunosuppressant or immunomodulatory therapy; systemic medical condition resulting in significantly compromised immune system (avoid use)

• pregnant or breastfeeding patients

• children younger than age 18 (safety and efficacy not established).

Administration

Don't give as I.V. push or bolus.

• To prepare solution, withdraw 15 ml of drug concentrate from vial. Inject concentrate into 100 ml 0.9% sodium chloride injection, leading to concentration of 2.6 mg/ml. Don't use other I.V. diluents or mix with other drugs. Gently invert vial to mix completely; don't shake. Following dilution, infuse solution immediately or refrigerate at 2° to 8° C (36° to 46° F), and use within 8 hours.

• Infuse 300 mg in 100 ml 0.9% sodium chloride injection over approximately 1 hour (infusion rate approximately 5 mg/minute). After infusion is complete, flush with 0.9% sodium chloride injection.

Observe patient during infusion and for 1 hour after infusion is complete. Promptly discontinue infusion at first sign or symptom consistent with a hypersensitivity reaction.

Obtain MRI scan in MS patients before starting therapy to help differentiate subsequent MS signs and symptoms from those of PML. Withhold drug immediately at first sign or symptom suggestive of PML.

• Be aware that a baseline brain MRI in patients with Crohn's disease may help distinguish preexisting lesions from newly developed lesions.

For patients with Crohn's disease who start drug while taking long-term corticosteroids, start steroid withdrawal as soon as therapeutic benefit has occurred. If patient can't discontinue systemic corticosteroids within 6 months, discontinue natalizumab.

Discontinue drug in patients with jaundice or other evidence of significant liver injury.

Adverse reactions

CNS: headache, fatigue, depression, somnolence, vertigo, tremor, PML

EENT: tonsillitis, pharyngolaryngeal pain, sinusitis

GI: nausea, diarrhea, constipation, dyspepsia, gastroenteritis, abdominal discomfort, flatulence, aphthous stomatitis, exacerbation of Crohn's disease, intestinal obstruction or stenosis

GU: vaginitis; irregular menstruation; dysmenorrhea; amenorrhea; ovarian cyst; urinary tract infection; urinary incontinence, urgency, frequency

Hepatic: abnormal liver function test values

Musculoskeletal: arthralgia, extremity pain, back pain, muscle cramps, joint swelling, limb injury

Respiratory: upper and lower respiratory tract infections, cough

Skin: rash, dermatitis, pruritus, urticaria, dry skin, skin laceration, thermal burn

Other: infections, chest discomfort, seasonal allergy, weight changes, tooth infections, toothache, herpes infection, night sweats, rigors, peripheral edema, influenza-like illness, immunosuppression, infusion reactions, hypersensitivity reactions including anaphylaxis

Interactions

Drug-drug. Corticosteroids, immunosuppressants (such as azathioprine, cyclosporine, 6-mercaptopurine, methotrexate), TNFα inhibitors: increased risk of PML and other infections

Drug-diagnostic tests. Circulating basophils, eosinophils, lymphocytes, monocytes, nucleated RBCs: increased levles

Hemoglobin: decreased level

Patient monitoring

• Monitor CBC with differential and hepatic function tests.

Continue to monitor patient for hypersensitivity reactions; infection; hepatotoxicity; signs and symptoms of immune reconstitution inflammatory syndrome (including unanticipated clinical decline in patient's condition after return of immune function and in some cases after apparent clinical improvement; and PML signs and symptoms (such as progressive weakness on one side of the body, limb clumsiness, vision disturbances, and changes in thinking, memory, and orientation leading to confusion and personality changes).

Patient teaching

• Explain the TOUCH Prescribing Program to patient.

Instruct patient to immediately report hypersensitivity reactions (such as flushing, nausea, headache, dizziness, fatigue, hives, or itching); signs and symptoms of infections; signs and symptoms of hepatotoxicity (such as yellowing of skin or eyes, dark urine, or right upper abdominal pain or discomfort); unanticipated clinical decline in condition or new signs and symptoms; or signs and symptoms of PML (such as progressive weakness on one side of the body, limb clumsiness, vision disturbances, and changes in thinking, memory, and orientation leading to confusion and personality changes).

• Instruct patient to tell prescriber about all drugs he's taking, because some drugs have potential for serious drug interactions and shouldn't be taken with natalizumab.

• Advise female patient of childbearing age that drug should be used during pregnancy only if potential benefit justifies potential risk to fetus.

• Advise breastfeeding patient that she should decide whether to discontinue breastfeeding or discontinue drug, taking into account importance of drug for her treatment.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs and tests mentioned above.