Teriflunomideside effects

The following serious adverse reactions are described elsewhere in the prescribing information:

Hepatotoxicity

Bone Marrow Effects/Immunosuppression Potential/Infections

Hypersensitivity Reactions

Serious Skin Reactions

Drug Reaction with Eosinophilia and Systemic Symptoms

Peripheral Neuropathy

Increased Blood Pressure

Respiratory Effects

Pancreatitis in Pediatric Patients Most common adverse reactions (≥ 10% and ≥ 2% greater than placebo): headache, diarrhea, nausea, alopecia, increase in ALT. To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 clinical practice. A total of 2047 patients receiving teriflunomide tablets (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo-controlled studies in patients with relapsing forms of multiple sclerosis; of these, 71% were female. The average age was 37 years. Table 1 lists adverse reactions in placebo-controlled trials with rates that were at least 2% for teriflunomide tablets patients and also at least 2% above the rate in placebo patients. The most common were headache, an increase in ALT, diarrhea, alopecia, and nausea. The adverse reaction most commonly associated with discontinuation was an increase in ALT (3.3%, 2.6%, and 2.3% of all patients in the teriflunomide tablets 7 mg, teriflunomide tablets 14 mg, and placebo treatment arms, respectively).

Table 1: Adverse Reactions in Pooled Placebo-Controlled Studies in Patients with Relapsing Forms of Multiple Sclerosis Teriflunomide Tablets 7 mg Teriflunomide Tablets 14 mg Placebo Adverse Reaction (N = 1045) (N = 1002) (N = 997) Headache 18% 16% 15% Increase in Alanine aminotransferase 13% 15% 9% Diarrhea 13% 14% 8% Alopecia 10% 13% 5% Nausea 8% 11% 7% Paresthesia 8% 9% 7% Arthralgia 8% 6% 5% Neutropenia 4% 6% 2% Hypertension 3% 4% 2% Cardiovascular Deaths Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to teriflunomide tablets in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. A relationship between teriflunomide tablets and cardiovascular death has not been established. Acute Renal Failure In placebo-controlled studies, creatinine values increased more than 100% over baseline in 8/1045 (0.8%) patients in the 7 mg teriflunomide tablets group and 6/1002 (0.6%) patients in the 14 mg teriflunomide tablets group versus 4/997 (0.4%) patients in the placebo group. These elevations were transient. Some elevations were accompanied by hyperkalemia. Teriflunomide tablets may cause acute uric acid nephropathy with transient acute renal failure because teriflunomide tablets increase renal uric acid clearance. Hypophosphatemia In clinical trials, 18% of teriflunomide tablets-treated patients had hypophosphatemia with serum phosphorus levels of at least 0.6 mmol/L, compared to 7% of placebo-treated patients; 4% of teriflunomide tablets-treated patients had hypophosphatemia with serum phosphorus levels at least 0.3 mmol/L but less than 0.6 mmol/L, compared to 0.8% of placebo-treated patients. No patient in any treatment group had a serum phosphorus below 0.3 mmol/L.

6.2 Postmarketing

Experience The following adverse reactions have been identified during postapproval use of teriflunomide tablets. 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: Thrombocytopenia

Gastrointestinal Disorders: Pancreatitis, colitis

Hepatobiliary Disorders: Drug-induced liver injury (DILI)

Immune System Disorders: Hypersensitivity reactions, some of which were severe, such as anaphylaxis and angioedema

Respiratory, Thoracic, and Mediastinal Disorders: Interstitial lung disease

Skin and Subcutaneous Tissue Disorders: Severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome; Drug reaction with eosinophilia and systemic symptoms (DRESS); psoriasis or worsening of psoriasis (including pustular psoriasis and nail psoriasis); nail disorders