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Natalizumab

Pronunciation: (nay-tal-IZ-oo-mab)
Class: Immunologic

Trade Names:
Tysabri
- Injection 20 mg/mL

Pharmacology

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Exact mechanism of action is unknown; however, animal data demonstrate a reduction of leukocyte migration into brain parenchyma and a reduction of plaque formation.

Pharmacokinetics

Absorption

Mean C _max is approximately 110 mcg/mL. Steady-state trough concentrations range from 23 to 29 mcg/mL. After 4 wk of dosing, the time to steady state is approximately 24 wk.

Distribution

Vd is 5.7 L.

Elimination

The mean t _½ is about 11 days; Cl is 16 mL/h.

Special Populations

Body weight

A less than proportional increase in Cl occurs as body weight increases, such that a 43% increase in body weight produces a 32% increase in Cl.

Indications and Usage

Treatment of relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations; inducing and maintaining clinical response and remission in adults with moderately to severely active Crohn disease with evidence of inflammation who have had an inadequate response to or are unable to tolerate conventional Crohn disease therapies and tumor necrosis factor (TNF)–alpha inhibitors.

Contraindications

Patients who have progressive multifocal leukoencephalopathy (PML); hypersensitivity to any component of the product.

Dosage and Administration

Adults

IV 300 mg infused over 1 h every 4 wk.

General Advice

Observe patient during infusion and for 1 h after infusion is complete. Promptly discontinue infusion upon the first signs or symptoms of a hypersensitivity reaction.
Each vial is intended for single use only.
Inspect vial for particulate material prior to dilution and administration. If particulates are observed or the liquid is discolored, do not use the vial.
Upon dilution, gently invert solution to mix completely. Do not shake.
Visually inspect the final solution for particulate material prior to administration.
Following dilution, infuse solution immediately or refrigerate at 36° to 46°F and use within 8 h. Do not freeze. Warm solution to room temperature prior to infusion.
Do not inject other medications into infusion set side ports or mix other medications with natalizumab.

Crohn disease
Discontinue therapy if patient has not experienced therapeutic benefit by 12 wk of induction therapy.
For patients with Crohn disease who start natalizumab while on chronic oral corticosteroids, start steroid tapering as soon as a therapeutic benefit of natalizumab has occurred.
If the patient cannot be tapered off oral corticosteroids within 6 mo of starting natalizumab, discontinue natalizumab.
Other than the initial 6-mo tapering period, consider discontinuation of natalizumab in patients requiring additional steroid use that exceeds 3 mo in a calendar year to control their Crohn disease.

Storage/Stability

Refrigerate between 36° and 46°F. Do not shake or freeze. Protect from light. Store diluted solution at 36° to 46°F; administer within 8 h of preparation.

Drug Interactions

Antineoplastic, corticosteroid, immunosuppressant, or immunomodulating agents

May increase the risk of infection.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Headache (38%); fatigue (27%); depression (19%); vertigo (6%); somnolence (2%); tremor (1%); herpes encephalitis, herpes meningitis (postmarketing); PML.

Dermatologic

Rash (12%); dermatitis (7%); pruritus (4%); acute urticaria, skin laceration (2%); dry skin, night sweats (1%).

EENT

Tonsillitis (7%); pharyngolaryngeal pain (6%).

GI

Dyspepsia, nausea (17%); abdominal discomfort, gastroenteritis (11%); diarrhea (10%); tooth infections (9%); constipation, lower abdominal pain, toothache (4%); flatulence (3%); aphthous stomatitis (2%).

Genitourinary

UTI (21%); vaginitis (10%); urinary urgency/frequency (9%); dysmenorrhea (6%); irregular menstruation (5%); urinary incontinence (4%); dysmenorrhea (3%); amenorrhea, ovarian cyst (2%).

Hepatic

Abnormal LFTs (5%); hepatic injury, including elevated LFT and bilirubin (postmarketing).

Metabolic-Nutritional

Weight increase or decrease (2%).

Musculoskeletal

Arthralgia (19%); pain in extremity (16%); back pain (12%); muscle cramp (5%); rigors (3%); joint swelling (2%).

Respiratory

Upper respiratory tract infection (22%); lower respiratory tract infection (17%); sinusitis (8%); cough (7%).

Miscellaneous

Infusion-related reactions (24%); influenza (12%); influenza-like illness (11%); detectable natalizumab antibodies (9%); herpes (8%); viral infection (7%); peripheral edema (6%); chest discomfort, other hypersensitivity reactions (5%); acute hypersensitivity reactions (4%); limb injury, seasonal allergy (3%); thermal burn (1%).

Precautions

Warnings

Natalizumab therapy increases the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability. Natalizumab is available only through a special restricted distribution program, and only prescribers, infusion centers, and pharmacies associated with registered infusion centers are able to prescribe, distribute, or infuse the product. The product must only be administered to patients who are enrolled in and meet the conditions of the prescribing program.

Monitor patients for any new signs or symptoms suggestive of PML. Withhold natalizumab immediately at the first sign or symptom suggestive of PML.

Monitor

Evaluate the patient 3 and 6 mo after the first infusion and every 6 mo thereafter.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Studies did not include sufficient numbers of patients 65 yr of age and older to determine whether they respond differently than younger patients.

Hypersensitivity

Has been associated with hypersensitivity reactions, including serious systemic reactions (eg, anaphylaxis).

Laboratory Test Abnormalities

Circulating basophils, eosinophils, lymphocytes, monocytes, and nucleated RBCs may be increased; transient, mild decreases in hemoglobin concentrations may occur.

Immunosuppression

The immune system effects of natalizumab may increase the risk of infection.

Hepatotoxicity

Clinically significant liver injury has been reported during postmarketing. Signs of liver injury have occurred as early as 6 days after the first dose.

Overdosage

Symptoms

Undetermined.

Patient Information

Instruct patient to read the Medication Guide before starting therapy and before each infusion.
Instruct patient to promptly report to health care provider any continuously worsening symptoms that persist over several days.
Advise patient to inform all health care providers that they are receiving natalizumab.
Advise patient to see health care provider 3 and 6 mo after the first infusion and at least every 6 mo thereafter.
Instruct patient to immediately report any symptoms consistent with hypersensitivity during or following an infusion.