TYSABRI

Natalizumab is a recombinant humanized

IgG4κ monoclonal antibody that binds to α4-integrin.

While natalizumab was originally approved by the FDA to treat multiple sclerosis in 2004, it was withdrawn from the market following multiple reports of fatal progressive multifocal leukoencephalopathy (PML).

In 2006, the FDA reintroduced the drug to the market for multiple sclerosis.

Natalizumab was further approved by the FDA for the treatment of Crohn's Disease in January 2008.

On August 24, 2023, the first biosimilar to natalizumab, natalizumab-sztn, was approved by the FDA.

Natalizumab was approved by the European Commission on September 22, 2023.

Natalizumab is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults. 6, 7, 9 It is also indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn's disease with evidence of inflammation who have had an inadequate response to or are unable to tolerate, conventional therapies and inhibitors of TNF-α.

It is not to be used in combination with immunosuppressants or inhibitors of TNF-α. 6,

Natalizumab is a disease-modifying drug that works to alleviate the symptoms of multiple sclerosis and Crohn's disease by attenuating inflammation. 2, 4 A reduction in lesions was observed in patients with multiple sclerosis who received natalizumab.

Natalizumab increases the number of circulating leukocytes, including lymphocytes, monocytes, basophils, and eosinophils; 3, 6 this effect is attributed to natalizumab inhibiting their transmigration out of the vascular space.

Natalizumab does not affect the absolute count of circulating neutrophils.

Following the repeat intravenous administration of a 300 mg dose of natalizumab in patients with multiple sclerosis, the mean ± SD maximum observed serum concentration was 110 ± 52 mcg/mL.

Mean average steady-state trough concentrations ranged from 23 mcg/mL to 29 mcg/mL.

The observed time to steady-state was approximately 24 weeks after every four weeks of dosing.

In patients with

Crohn's Disease, the mean ± SD maximum observed serum concentration was 101 ± 34 mcg/mL.

The mean ± SD average steady-state trough concentration was 10 ± 9 mcg/mL.

The estimated time to steady-state was approximately 16-24 weeks after every four weeks of dosing.

Following the repeat intravenous administration of a 300 mg dose of natalizumab in patients with multiple sclerosis, the mean ± SD volume of distribution was 5.7 ± 1.9 L. In patients with Crohn's Disease, it was 5.2 ± 2.8 L.

No information is available.

Following the repeat intravenous administration of a 300 mg dose of natalizumab in patients with multiple sclerosis, the mean ± SD half-life was 11 ± 4 days.

In patients with

Crohn's Disease, it was 10 ± 7 days.

Following the repeat intravenous administration of a 300 mg dose of natalizumab in patients with multiple sclerosis, the mean ± SD clearance was 16 ± 5 mL/hour.

In patients with

Crohn's Disease, it was 22 ± 22 mL/hour.

Natalizumab clearance increased with body weight in a less-than-proportional manner.

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

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There is limited information regarding the acute toxicity (LD 50 ) and overdosage of natalizumab.

The safety of doses higher than 300 mg has not been adequately evaluated.

The maximum amount of natalizumab that can be safely administered has not been determined.

is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML) .

TYSABRI is contraindicated in patients who have had a hypersensitivity reaction to TYSABRI.

Observed reactions range from urticaria to anaphylaxis.

Patients who have or have had PML Patients who have had a hypersensitivity reaction to TYSABRI.

mg infused intravenously over one hour, every four weeks.

Do not give as an intravenous push or bolus TYSABRI solution must be administered within 48 hours of preparation Observe patients during all infusions.

Post-infusion, for the first 12 infusions, observe patients for one hour after the infusion is complete.

For patients who have received 12 infusions without evidence of a hypersensitivity reaction, observe patients post-infusion for the 13th and subsequent infusions according to clinical judgment.

In CD, discontinue in patients that have not experienced therapeutic benefit by 12 weeks of induction therapy, and in patients that cannot discontinue chronic concomitant steroids within six months of starting therapy 2.1 Multiple Sclerosis (MS) Only prescribers registered in the MS TOUCH ® Prescribing Program may prescribe TYSABRI for multiple sclerosis.

The recommended dose of

TYSABRI for multiple sclerosis is 300 mg intravenous infusion over one hour every four weeks. 2.2 Crohn's Disease (CD) Only prescribers registered in the CD TOUCH ® Prescribing Program may prescribe TYSABRI for Crohn's disease.

The recommended dose of TYSABRI for

Crohn's disease is 300 mg intravenous infusion over one hour every four weeks.

TYSABRI should not be used with concomitant immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or concomitant inhibitors of TNF-α.

Aminosalicylates may be continued during treatment with TYSABRI.

If the patient with

Crohn's disease has not experienced therapeutic benefit by 12 weeks of induction therapy, discontinue TYSABRI.

For patients with

Crohn's disease who start TYSABRI while on chronic oral corticosteroids, commence steroid tapering as soon as a therapeutic benefit of TYSABRI has occurred; if the patient with Crohn's disease cannot be tapered off of oral corticosteroids within six months of starting TYSABRI, discontinue TYSABRI.

Other than the initial six-month taper, prescribers should consider discontinuing TYSABRI for patients who require additional steroid use that exceeds three months in a calendar year to control their Crohn's disease. 2.3 Dilution Instructions Use aseptic technique when preparing TYSABRI solution for intravenous infusion.

Each vial is intended for single use only.

Discard any unused portion.

TYSABRI is a colorless, clear to slightly opalescent solution.

Inspect the

TYSABRI vial for particulate material and discoloration prior to dilution and administration.

If visible particulates are observed and/or the liquid in the vial is discolored, the vial must not be used.

To prepare the diluted solution, withdraw 15 mL of TYSABRI from the vial using a sterile needle and syringe.

TYSABRI into 100 mL of 0.9% Sodium Chloride Injection, USP.

No other intravenous diluents may be used to prepare the TYSABRI diluted solution.

Gently invert the

TYSABRI diluted solution to mix completely.

Do not shake.

Inspect the solution visually for particulate material prior to administration.

The final dosage diluted solution has a concentration of 2.6 mg/mL.

Following dilution, infuse TYSABRI solution immediately, or refrigerate the diluted solution at 2°C to 8°C, and use within 48 hours.

If stored at 2°C to 8°C, allow the diluted solution to warm to room temperature prior to infusion.

FREEZE. 2.4 Administration Instructions Infuse TYSABRI 300 mg in 100 mL 0.9% Sodium Chloride Injection, USP, over approximately one hour (infusion rate approximately 5 mg per minute).

Do not administer

TYSABRI as an intravenous push or bolus injection.

After the infusion is complete, flush with 0.9% Sodium Chloride Injection, USP.

Observe patients during all infusions.

Promptly discontinue the infusion upon the first observation of 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 TYSABRI.

(natalizumab) injection, a sterile, preservative-free, colorless and clear to slightly opalescent solution for dilution prior to intravenous infusion, is supplied as one 300 mg/15 mL (20 mg/mL) single-dose vial per carton (NDC 64406-008-01).

TYSABRI is available only through registered infusion centers participating in the TOUCH ® Prescribing Program.

To locate these infusion centers, contact Biogen at 1-800-456-2255.

TYSABRI single-dose vials must be refrigerated between 2°C to 8°C (36°F to 46°F).

Do not use beyond the expiration date stamped on the carton and vial label.

Protect from light.

Store diluted

TYSABRI solution refrigerated at 2°C to 8°C (36°F to 46°F).

There are no adequate data on the risk of major birth defects, miscarriage, or other adverse maternal outcomes associated with the use of TYSABRI in pregnant women.

Adverse fetal outcomes of neonatal thrombocytopenia and anemia have been reported.

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.

These doses were not maternally toxic but produced the expected pharmacological effects in maternal animals.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

Fetal/Neonatal Adverse Reactions Cases of neonatal thrombocytopenia and anemia in infants born to women exposed to TYSABRI during pregnancy were reported in the post-marketing setting.

Therefore, a CBC should be obtained in neonates who were exposed to TYSABRI in utero.

In developmental toxicity studies conducted in guinea pigs and monkeys, at natalizumab doses up to 30 mg/kg (7 times the recommended human dose based on body weight [mg/kg]), transplacental transfer and in utero exposure of the embryo/fetus was demonstrated in both species.

In a study in which pregnant guinea pigs were administered natalizumab (0, 3, 10, or 30 mg/kg) by intravenous (IV) infusion on alternate days throughout organogenesis (gestation days [GD] 4-30), no effects on embryofetal development were observed.

When pregnant monkeys were administered natalizumab (0, 3, 10, or 30 mg/kg) by IV infusion on alternative days throughout organogenesis (GDs 20-70), serum levels in fetuses at delivery were approximately 35% of maternal serum natalizumab levels.

There were no effects on embryofetal development; however, natalizumab-related immunological and hematologic changes were observed in the fetuses at the two highest doses.

These changes included decreases in lymphocytes (CD3+ and CD20+), changes in lymphocyte subpopulation percentages, mild anemia, reduced platelet count, increased spleen weights, and reduced liver and thymus weights associated with increased splenic extramedullary hematopoiesis, thymic atrophy, and decreased hepatic hematopoiesis.

In a study in which monkeys were exposed to natalizumab during pregnancy (IV infusion of 30 mg/kg) on alternate days from GD20 to GD70 or GD20 to term, abortions were increased approximately 2-fold compared to controls.

In offspring born to mothers administered natalizumab on alternate days from GD20 until delivery, hematologic effects (decreased lymphocyte and platelet counts) were also observed.

These effects were reversed upon clearance of natalizumab.

There was no evidence of anemia in these offspring.

Offspring exposed in utero and during lactation had a normal immune response to challenge with a T-cell dependent antigen.

In a study in which pregnant guinea pigs were exposed to natalizumab (30 mg/kg IV) on alternate dates during GDs 30-64, a reduction in pup survival was observed.

Safety and effectiveness in pediatric patients with multiple sclerosis or Crohn's disease below the age of 18 years have not been established.

TYSABRI is not indicated for use in pediatric patients.

Clinical studies of

TYSABRI did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.