natalizumab (Tysabri)

Dosing and uses of Tysabri (natalizumab)

• Adult
• Pediatric

 

Adult dosage forms and strengths

injectable solution

• 300mg/15mL

 

Multiple Sclerosis

Indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations; when initiating and continuing treatment, physicians should consider whether expected benefit is sufficient to offset risk of PML

300 mg IV infusion over 1hr q4Weeks

 

Crohn Disease

Indicated for moderate-to-severe Crohn disease in adults who had inadequate/intolerent response to conventional treatment and TNF-alpha inhibitors

300 mg IV q4wk; infuse over 1 hr

 

Dosing Considerations

No information on safety/efficacy in chronic progressive multiple sclerosis

Because natalizumab increases risk of progressive multifocal leukoencephalopathy (PML), it is recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate multiple sclerosis therapy

Additional or previous immunosuppressive therapy increases risk for PML; therefore, do not administer concomitantly with immunosuppressants (eg, 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or TNF-alpha inhibitors

See Black box warnings

 

Pediatric dosage forms and strengths

<18 years: Safety and efficacy not established

 

Tysabri (natalizumab) adverse (side) effects

>10%

Abdominal discomfort

Arthralgia

Depression

Fatigue

Headache

Lower respiratory infection

UTI

 

1-10%

Abnnormal LFTs

Allergic reaction

Chest discomfort

Dermatitis

Gastroenteritis

Local bleeding

Menstrual disorder

Pruritus

Rash

Rigors

Syncope

Tonsillitis

Tremor

Urinary urgency/frequency

Vaginitis

 

Warnings

Black box warnings

Increased risk of progressive multifocal leukoencephalopathy, an opportunistic viral infection of the brain caused by the JC virus in immunocompromised patients that usually leads to death or severe disability

Immune reconstitution inflammatory syndrome may occur in patients who have developed PML; IRIS is a rare condition characterized by severe inflammatory response

Because of the risk of PML, natalizumab is available only through a special restricted distribution program; prescribers, infusion centers, and pharmacies associated with infusion centers registered with the program, are able to prescribe, distribute, or infuse the product to patients who are enrolled in and meet all the conditions of the TOUCH Prescribing Program

Healthcare professionals should monitor patients on natalizumab for any new sign or symptom that may be suggestive of PML

Withhold dose immediately at the first sign or symptom suggestive of PML

For diagnosis, an evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended

Consider assessing anti-JCV antibody status prior to treatment or during treatment if antibody status is unknown; the Stratify JCV Antibody ELISA test (Focus Diagnostics) was cleared by FDA on January 20, 2012

Factors known to increase risk of PML in natalizumab-treated patients

• Longer treatment duration, especially beyond 2 years
• Prior treatment with an immunosuppressant (eg, mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate)
• Presence of anti-JCV antibodies
• Patients with all 3 known risk factors have an estimated risk of PML of 11/1,000
• The risks and benefits of continuing treatment with natalizumab should be carefully considered in patients who are found to be anti-JCV antibody positive and have 1 or more additional risk factors
• PML has been reported following discontinuation in patients who did not have findings suggestive of PML at the time of discontinuation; continue to monitor for any new signs or symptoms that may be suggestive of PML for ~6 months following discontinuation

 

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

Increased risk of developing encephalitis and meningitis caused by HSV and VZV; serious, life-threatening, and sometimes fatal cases reported; discontinue therapy if this occurs and treat appropriately

Severe hepatic injury reported as early as 6 days following therapy initiation, including markedly elevated LFTs and bilirubin; discontinue in patients with jaundice or with significant liver injury

 

Pregnancy and lactation

Pregnancy category: C

Lactation: do not nurse

 

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.

 

Pharmacology of Tysabri (natalizumab)

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)

 

Administration

IV Preparation

Concentrate is a colorless opalescent solution

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

Withdraw the 15 mL concentrate 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