Overview
11 DESCRIPTION Teriflunomide is an oral de novo pyrimidine synthesis inhibitor of the DHO-DH enzyme, with the chemical name (Z)-2-Cyano-α,α,α-trifluoro-3-hydroxy-4-crotonotoluidide. Its molecular weight is 270.21, and the molecular formula is C 12 H 9 F 3 N 2 O 2 with the following chemical structure: Teriflunomide is a white to almost white powder that is sparingly soluble in acetone, slightly...
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The exact mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis is unknown but may involve a reduction in the number of activated lymphocytes in CNS. 12.2 Pharmacodynamics Potential to Prolong the QT Interval In a placebo-controlled thorough QT study performed in healthy adult subjects, there was no evidence that teriflunomide caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms). 12.
Indications
- 1 INDICATIONS AND USAGE Teriflunomide tablets are indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Teriflunomide tablets are a pyrimidine synthesis inhibitor indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. ( 1 )
Common Doses
- 7 mg
- 14 mg
Dosage
2 DOSAGE AND ADMINISTRATION The recommended dose of teriflunomide tablets is 7 mg or 14 mg orally once daily. Teriflunomide tablets can be taken with or without food. Monitoring to Assess Safety: • Obtain transaminase and bilirubin levels within 6 months before initiation of teriflunomide tablets therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide tablets [see Warnings and Precautions (5.1) ] . • Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with teriflunomide tablets.
Black Box Warning
WARNING: HEPATOTOXICITY and EMBRYOFETAL TOXICITY • Hepatotoxicity: Clinically significant and potentially life-threatening liver injury, including acute liver failure requiring transplant, has been reported in patients treated with teriflunomide tablets in the postmarketing setting [see Warnings and Precautions (5.1) ] . Concomitant use of teriflunomide tablets with other hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of teriflunomide tablets therapy.
Contraindications
- 4 CONTRAINDICATIONS Teriflunomide tablets are contraindicated in/with: • Patients with severe hepatic impairment [see Warnings and Precautions (5.1) ] . • Pregnant women and females of reproductive potential not using effective contraception. Teriflunomide tablets may cause fetal harm [see Warnings and Precautions (5.2 , 5.3) and Use in Specific Populations (8.1) ] . • Patients with a history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any of the inactive ingredients in teriflunomide tablets.
Side Effects
- 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the prescribing information: • Hepatotoxicity [see Contraindications (4) and Warnings and Precautions (5.1) ] • Bone Marrow Effects/Immunosuppression Potential/Infections [see Warnings and Precautions (5.4) ] • Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.5) ] • Serious Skin Reactions [see Warnings and Precautions (5.6) ] • Drug Reaction with Eosinophilia and Systemic Symptoms [see Warnings and Precautions (5.
Interactions
- 7 DRUG INTERACTIONS Effect of Teriflunomide Tablets on CYP2C8 Substrates Teriflunomide is an inhibitor of CYP2C8 in vivo . In patients taking teriflunomide tablets, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required [see Clinical Pharmacology (12.3) ] .