Fingolimodside effects

The following serious adverse reactions are described elsewhere in labeling: Bradyarrhythmia and Atrioventricular Blocks Infections Progressive Multifocal Leukoencephalopathy Macular Edema Liver Injury Posterior Reversible Encephalopathy Syndrome Respiratory Effects Fetal Risk Severe Increase in Disability After Stopping Fingolimod Tumefactive Multiple Sclerosis Increased Blood Pressure Malignancies Immune System Effects Following fingolimod Discontinuation Hypersensitivity Reactions Most common adverse reactions (incidence ≥10% and greater than placebo): Headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity. To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical

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. Adults In clinical trials (Studies 1, 2, and 3), a total of 1,212 patients with relapsing forms of multiple sclerosis received fingolimod capsule 0.5 mg. This included 783 patients who received fingolimod capsule 0.5 mg in the 2-year placebo-controlled trials (Studies 1 and 3) and 429 patients who received fingolimod capsule 0.5 mg in the 1-year active-controlled trial (Study 2). The overall exposure in the controlled trials was equivalent to 1,716 person-years. Approximately 1,000 patients received at least 2 years of treatment with fingolimod capsule 0.5 mg. In all clinical studies, including uncontrolled extension studies, the exposure to fingolimod capsule 0.5 mg was approximately 4,119 person-years. In placebo-controlled trials, the most frequent adverse reactions (incidence ≥10% and greater than placebo) for fingolimod capsule 0.5 mg were headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity. Adverse events that led to treatment discontinuation and occurred in more than 1% of patients taking fingolimod capsule 0.5 mg, were serum transaminase elevations (4.7% compared to 1% on placebo) and basal cell carcinoma (1% compared to 0.5% on placebo). Table 1 lists adverse reactions in clinical studies in adults that occurred in ≥ 1% of fingolimod-treated patients and ≥ 1% higher rate than for placebo.

Table 1: Adverse Reactions Reported in Adult Studies 1 and 3 (Occurring in ≥1% of Patients and Reported for fingolimod capsule 0.5 mg at ≥1% Higher Rate Than for Placebo) Adverse drug reactions Fingolimod capsule 0.5 mg N=783% Placebo N=773 % Infections Influenza 11 8 Sinusitis 11 8 Bronchitis 8 5 Herpes zoster 2 1 Tinea versicolor 2 ˂1 Cardiac disorders Bradycardia 3 1 Nervous system disorders Headache 25 24 Migraine 6 4 Gastrointestinal disorders Nausea 13 12 Diarrhea 13 10 Abdominal pain 11 10 General disorders and administration-site conditions Asthenia 2 1 Musculoskeletal and connective tissue disorders Back pain 10 9 Pain in extremity 10 7 Skin and subcutaneous tissue disorders Alopecia 3 2 Actinic keratosis 2 1 Investigations Liver transaminase elevations (ALT/GGT/AST) 15 4 Blood triglycerides increased 3 1 Respiratory, thoracic, and mediastinal disorders Cough 12 11 Dyspnea 9 7 Eye disorders Vision blurred 4 2 Vascular disorders Hypertension 8 4 Blood and lymphatic system disorders Lymphopenia 7 ˂1 Leukopenia 2 ˂1 Neoplasms benign, malignant, and unspecified (including cysts and polyps) Skin papilloma 3 2 Basal cell carcinoma 2 1 Abbreviations: ALT, alanine transaminase; AST, aspartate transferase; GGT, gamma-glutamyl transferase. Adverse reactions of seizure, dizziness, pneumonia, eczema, and pruritus were also reported in Studies 1 and 3, but did not meet the reporting rate criteria for inclusion in Table 1 (difference was less than 1%). Adverse reactions with fingolimod capsule 0.5 mg in Study 2, the 1-year active-controlled (versus interferon beta-1a) study were generally similar to those in Studies 1 and 3. Vascular Events Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received fingolimod doses (1.25 mg to 5 mg) higher than recommended for use in MS. Similar events have been reported with fingolimod in the postmarketing setting although a causal relationship has not been established. Seizure Cases of seizures, including status epilepticus, have been reported with the use of fingolimod in clinical trials and in the postmarketing setting in adults. In adult clinical trials, the rate of seizures was 0.9% in fingolimod-treated patients and 0.3% in placebo-treated patients. It is unknown whether these events were related to the effects of multiple sclerosis alone, to fingolimod, or to a combination of both. Pediatric Patients 10 Years of Age and Older In the controlled pediatric trial (Study 4), the safety profile in pediatric patients receiving fingolimod 0.25 mg or 0.5 mg daily was similar to that seen in adult patients. In the pediatric study, cases of seizures were reported in 5.6% of fingolimod-treated patients and 0.9% of interferon beta-1a-treated patients.

6.2 Postmarketing

Experience The following adverse reactions have been identified during postapproval use of fingolimod. 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 and Lymphatic System Disorders: Hemolytic anemia and thrombocytopenia Hepatobiliary Disorders: Liver injury Infections: Infections, including cryptococcal infections, human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancer, progressive multifocal leukoencephalopathy Musculoskeletal and Connective Tissue Disorders: Arthralgia, myalgia Nervous System Disorders: Posterior reversible encephalopathy syndrome, seizures, including status epilepticus Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps): Melanoma, Merkel cell carcinoma, cutaneous T-cell lymphoma (including mycosis fungoides), Kaposi’s sarcoma, squamous cell carcinoma Skin and Subcutaneous Tissue Disorders: Hypersensitivity