Generic Name
Natalizumab
Brand Names
Tyruko, Tysabri
FDA approval date: November 23, 2004
Classification: Integrin Receptor Antagonist
Form: Injection
What is Tyruko (Natalizumab)?
TYRUKO is an integrin receptor antagonist indicated for treatment of: Multiple Sclerosis TYRUKO is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Natalizumab products increase the risk of PML [see Warnings and Precautions.
Approved To Treat
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Brand Information
TYRUKO (natalizumab-sztn)
WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
Natalizumab products increase the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include the presence of anti-JCV antibodies, duration of therapy, and prior use of immunosuppressants. These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYRUKO
- Healthcare professionals should monitor patients on TYRUKO for any new sign or symptom that may be suggestive of PML. TYRUKO dosing should be withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation that includes a gadolinium-enhanced magnetic resonance imaging (MRI) scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended
- Because of the risk of PML, TYRUKO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TYRUKO REMS Program
1DOSAGE FORMS AND STRENGTHS
Injection: 300 mg/15 mL (20 mg/mL) colorless and clear to slightly opalescent solution in a single-dose vial for dilution prior to infusion.
2CONTRAINDICATIONS
- TYRUKO is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML)
- TYRUKO is contraindicated in patients who have had a hypersensitivity reaction to natalizumab products or any of the ingredients in TYRUKO. Observed reactions range from urticaria to anaphylaxis
3ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the labeling:
- Progressive Multifocal Leukoencephalopathy (PML)
- Herpes Infections
- Hepatotoxicity
- Hypersensitivity/Antibody Formation
- Immunosuppression/Infections
- Hematological Abnormalities
3.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most common adverse reactions (incidence ≥10%) were headache and fatigue in both the multiple sclerosis (MS) and Crohn’s disease (CD) studies. Other common adverse reactions (incidence ≥10%) in the MS population were arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash. Other common adverse reactions (incidence ≥10%) in the CD population were upper respiratory tract infections and nausea.
The most frequently reported adverse reactions resulting in clinical intervention (i.e., discontinuation of natalizumab) in the MS studies were urticaria (1%) and other hypersensitivity reactions (1%), and in the CD studies (Studies CD1 and CD2) were the exacerbation of Crohn’s disease (4.2%) and acute hypersensitivity reactions (1.5%)
A total of 1617 multiple sclerosis patients in controlled studies received natalizumab, with a median duration of exposure of 28 months. A total of 1563 patients received natalizumab in all CD studies for a median exposure of 5 months; of these patients, 33% (n=518) received at least one year of treatment and 19% (n=297) received at least two years of treatment.
3.2Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of natalizumab or of other natalizumab products.
Patients in Study MS1
The presence of anti-natalizumab antibodies was correlated with a reduction in serum natalizumab levels. In Study MS1, the Week 12 pre-infusion mean natalizumab serum concentration in antibody-negative patients was 15 mcg/mL compared to 1.3 mcg/mL in antibody-positive patients. Persistent antibody-positivity resulted in a substantial decrease in the effectiveness of natalizumab. The risk of increased disability and the annualized relapse rate were similar in persistently antibody-positive natalizumab-treated patients and patients who received placebo. A similar phenomenon was also observed in Study MS2.
Infusion-related reactions that were most often associated with persistent antibody-positivity included urticaria, rigors, nausea, vomiting, headache, flushing, dizziness, pruritus, tremor, feeling cold, and pyrexia. Additional adverse reactions more common in persistently antibody-positive patients included myalgia, hypertension, dyspnea, anxiety, and tachycardia.
Patients in CD studies
The long-term immunogenicity of natalizumab products and the effects of low to moderate levels of antibody to natalizumab products are unknown
3.3Postmarketing Experience
The following adverse reactions have been identified during post approval use of natalizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood disorders: hemolytic anemia, thrombocytopenia (including immune thrombocytopenic purpura)
4DRUG INTERACTIONS
Because of the potential for increased risk of PML and other infections, Crohn’s disease patients receiving natalizumab products should not be treated with concomitant immunosuppressants (e.g., 6‑ mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α, and corticosteroids should be tapered in those patients with Crohn’s disease who are on chronic corticosteroids when they start TYRUKO therapy
5OVERDOSAGE
Safety of doses higher than 300 mg has not been adequately evaluated. The maximum amount of natalizumab products that can be safely administered has not been determined.
6DESCRIPTION
Natalizumab-sztn is a recombinant humanized IgG4ĸ monoclonal antibody produced in a Chinese hamster ovary (CHO) mammalian cell expression system. Natalizumab-sztn contains human framework regions and the complementarity-determining regions of an antibody that binds to α4-integrin. The molecular weight of natalizumab-sztn is 149 kilodaltons.
TYRUKO (natalizumab-sztn) injection is supplied as a sterile, preservative-free, colorless, and clear to slightly opalescent solution for intravenous infusion. Each 15 mL of solution contains 300 mg natalizumab-sztn; histidine (6.36 mg); L-histidine hydrochloride monohydrate (22.86 mg); polysorbate 80, USP/NF (3 mg); sodium chloride, USP (131.49 mg); and Water for Injection, USP at pH 5.7.
7REFERENCES
- Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn's Disease Activity Index, National Cooperative Crohn's Disease Study. Gastroenterology 1976; 70(3): 439-444.
8HOW SUPPLIED/STORAGE AND HANDLING
TYRUKO (natalizumab-sztn) 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 61314-543-94).
TYRUKO is available only through registered infusion centers participating in the TYRUKO REMS Program. To locate these infusion centers, contact Sandoz Inc. at 1-800-525-8747.
TYRUKO 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. DO NOT SHAKE OR FREEZE. Protect from light.
Store diluted TYRUKO solution refrigerated at 2°C to 8°C (36°F to 46°F)
9PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
10Medication Guide
TYRUKO