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Natalizumab

Pronunciation: NA-ta-LIZ-oo-mab
Class: Immunologic

Trade Names

Tysabri
- Injection, concentrate 20 mg/mL

Pharmacology

Exact mechanism of action is unknown; may inhibit interaction of alpha-4–expressing leukocytes with their ligands in the extracellular matrix and on parenchymal cells, thereby inhibiting further recruitment and inflammatory activity of activated immune cells.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Mean C max is approximately 101 mcg/mL (Crohn disease) and 110 mcg/mL (multiple sclerosis). After every 4 wk dosing, the time to steady state is approximately 16 to 24 wk.

Distribution

Vd is 5.2 to 5.7 L.

Elimination

The mean half-life is approximately 10 to 11 days; Cl is 16 to 22 mL/h.

Special Populations

Renal Function Impairment

Pharmacokinetics have not been studied.

Hepatic Function Impairment

Pharmacokinetics have not been studied.

Antibodies

The presence of persistent anti-natalizumab antibodies increased natalizumab Cl approximately 3-fold.

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

As monotherapy for the 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 or have had 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

  • For IV infusion only. Do not administer as an IV push or bolus injection.
  • 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.
  • Dilute in 100 mL of sodium chloride 0.9% injection. 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.
  • After the infusion is complete, flush with sodium chloride 0.9% injection.
  • Do not inject other medications into infusion set side ports or mix other medications with natalizumab.
  • Crohn disease
  • Do not use with concomitant immunosuppressants or inhibitors of TNF-alpha. Aminosalicylates may be continued during treatment with natalizumab.
  • 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 long-term 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. Do not treat patients with Crohn disease receiving natalizumab with concomitant immunosuppressants or inhibitors of TNF-alpha, and taper corticosteroids in those patients with Crohn disease who are on long-term corticosteroids when they start natalizumab therapy. Ordinarily, patients with multiple sclerosis receiving long-term immunosuppressant or immunomodulatory therapy should not be treated with natalizumab.

Live vaccines

Use of live vaccines may cause reduced effectiveness of the vaccine; patients may be at risk for vaccine-induced infection. Defer live vaccines until the immune system has improved.

Adverse Reactions

CNS

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

Dermatologic

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

EENT

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

GI

Nausea (17%); abdominal discomfort, gastroenteritis (11%); diarrhea (10%); dyspepsia (5%); constipation, lower abdominal pain, toothache (4%); flatulence (3%); aphthous stomatitis, intestinal obstruction or stenosis (2%); cholelithiasis (1%).

Genitourinary

UTI (21%); vaginitis (10%); urinary urgency/frequency (9%); vaginal infection (8%); dysmenorrhea (6%); irregular menstruation (5%); urinary incontinence (4%); amenorrhea, ovarian cyst (2%).

Hepatic

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

Hypersensitivity

Hypersensitivity reactions (5%); acute (within 2 h of infusion) hypersensitivity reactions (4%).

Metabolic-Nutritional

Weight increase or decrease (2%).

Musculoskeletal

Arthralgia (19%); pain in extremity (16%); back pain (12%); muscle cramp (5%); limb injury, 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, tooth infection (9%); herpes (8%); viral infection (7%); peripheral edema (6%); chest discomfort (5%); seasonal allergy, serious infection (3%).

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

Observe patients during the infusion and for 1 h after the infusion is complete. Evaluate the patient 3 and 6 mo after the first infusion and every 6 mo thereafter. Monitor patients for the development of PML or new infections.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

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 Hgb concentrations may occur.

Immune reconstitution inflammatory syndrome

Has been reported in patients who developed PML and subsequently discontinued natalizumab.

Immunogenicity

Anti-natalizumab antibodies may develop and may be associated with decreased efficacy and increased infusion-related reactions.

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.
  • Inform patients that medication may lower the ability of their immune system to fight infections and to contact their health care provider if symptoms of infection develop.
  • Inform patients that medication may cause liver injury and to contact their health care provider if they develop symptoms of hepatotoxicity.

Copyright © 2009 Wolters Kluwer Health.

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