Pyrimidine Synthesis Inhibitor

Teriflunomide

Approved 28 Feb 2020OralTablet

The FDA lists this product in 38 strengths and forms.

Indications

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 )

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. Reactions have included anaphylaxis, angioedema, and serious skin reactions [see Warnings and Precautions (5.5) ].
Coadministration with leflunomide [see Clinical Pharmacology (12.3) ].
Severe hepatic impairment ( 4 , 5.1 )
Pregnancy ( 4 , 5.2 , 8.1 )
Hypersensitivity ( 4 , 5.5 )
Current leflunomide treatment ( 4 )

Warnings and precautions

Elimination of teriflunomide tablets can be accelerated by administration of cholestyramine or activated charcoal for 11 days. ( 5.3 )
Teriflunomide tablets may decrease WBC. A recent CBC should be available before starting teriflunomide tablets. Monitor for signs and symptoms of infection. Consider suspending treatment with teriflunomide tablets in case of serious infection. Do not start teriflunomide tablets in patients with active infections. ( 5.4 )
Stop teriflunomide tablets if patient has anaphylaxis, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms; initiate rapid elimination. ( 5.3 , 5.5 , 5.6 , 5.7 )
If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing teriflunomide tablets. ( 5.8 )
Teriflunomide tablets may increase blood pressure. Measure blood pressure at treatment initiation and monitor blood pressure during treatment. ( 5.9 )

At a glance

Brand name: Teriflunomide
Pharmacologic class: Pyrimidine Synthesis Inhibitor
Route: Oral
Dosage form: Tablet
Applicant: Somerset Theraps LLC
Status: Discontinued
FDA approval: 28 Feb 2020
Application: ANDA209702-001

Indications

( 1 )

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. Reactions have included anaphylaxis, angioedema, and serious skin reactions [see Warnings and Precautions (5.5) ].
Coadministration with leflunomide [see Clinical Pharmacology (12.3) ].
Severe hepatic impairment ( 4 , 5.1 )
Pregnancy ( 4 , 5.2 , 8.1 )
Hypersensitivity ( 4 , 5.5 )
Current leflunomide treatment ( 4 )

Warnings and precautions

Elimination of teriflunomide tablets can be accelerated by administration of cholestyramine or activated charcoal for 11 days. ( 5.3 )
Teriflunomide tablets may decrease WBC. A recent CBC should be available before starting teriflunomide tablets. Monitor for signs and symptoms of infection. Consider suspending treatment with teriflunomide tablets in case of serious infection. Do not start teriflunomide tablets in patients with active infections. ( 5.4 )
Stop teriflunomide tablets if patient has anaphylaxis, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms; initiate rapid elimination. ( 5.3 , 5.5 , 5.6 , 5.7 )
If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing teriflunomide tablets. ( 5.8 )
Teriflunomide tablets may increase blood pressure. Measure blood pressure at treatment initiation and monitor blood pressure during treatment. ( 5.9 )

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) ] . Effect of Teriflunomide Tablets on Warfarin Coadministration of teriflunomide tablets with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide tablets may decrease peak INR by approximately 25%.

Effect of Teriflunomide Tablets on Oral Contraceptives Teriflunomide tablets may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with teriflunomide tablets [see Clinical Pharmacology (12.3) ] . Effect of Teriflunomide Tablets on CYP1A2 Substrates Teriflunomide may be a weak inducer of CYP1A2 in vivo . In patients taking teriflunomide tablets, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced.

Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required [see Clinical Pharmacology (12.3) ] . Effect of Teriflunomide Tablets on Organic Anion Transporter 3 (OAT3) Substrates Teriflunomide inhibits the activity of OAT3 in vivo . In patients taking teriflunomide tablets, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased.

Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required [see Clinical Pharmacology (12.3) ] . Effect of Teriflunomide Tablets on BCRP and Organic Anion Transporting Polypeptide B1 and B3 (OATP1B1/1B3) Substrates Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo . For a patient taking teriflunomide tablets, the dose of rosuvastatin should not exceed 10 mg once daily.

For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking teriflunomide tablets [see Clinical Pharmacology (12.3) ] .

Drugs metabolized by CYP2C8 and OAT3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. ( 7 )
Teriflunomide may increase exposure of ethinylestradiol and levonorgestrel. Choose an appropriate oral contraceptive. ( 7 )
Drugs metabolized by CYP1A2: Monitor patients because teriflunomide may decrease exposure of these drugs. ( 7 )
Warfarin: Monitor INR as teriflunomide may decrease INR. ( 7 )
Drugs metabolized by BCRP and OATP1B1/B3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. ( 7 )
Rosuvastatin: The dose of rosuvastatin should not exceed 10 mg once daily in patients taking teriflunomide tablets. ( 7 )

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Teriflunomide tablets are contraindicated for use in pregnant women and females of reproductive potential not using effective contraception because of the potential for fetal harm based on animal data [see Contraindications (4) and Warnings and Precautions (5.2) ] . In animal reproduction studies in rat and rabbit, oral administration of teriflunomide during organogenesis caused teratogenicity and embryolethality at plasma exposures (AUC) lower than that at the maximum recommended human dose (MRHD) of 14 mg/day [see Data ].

Available human data from pregnancy registries, clinical trials, pharmacovigilance cases, and published literature are too limited to draw any conclusions, but they do not clearly indicate increased birth defects or miscarriage associated with inadvertent teriflunomide exposure in the early first trimester when followed by an accelerated elimination procedure [see Clinical Considerations and Data ] . There are no human data pertaining to exposures later in the first trimester or beyond.

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 in the indicated population is unknown. Clinical Considerations Fetal/Neonatal Adverse Reactions Lowering the plasma concentration of teriflunomide by instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from teriflunomide tablets.

The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] . Data Human Data Available human data are limited. Prospectively reported data (from clinical trials and postmarketing reports) from > 150 pregnancies in patients treated with teriflunomide and > 300 pregnancies in patients treated with leflunomide have not demonstrated an increased rate of congenital malformations or miscarriage following teriflunomide exposure in the early first trimester when followed by an accelerated elimination procedure.

Specific patterns of major congenital malformations in humans have not been observed. Limitations of these data include an inadequate number of reported pregnancies from which to draw conclusions, the short duration of drug exposure in reported pregnancies, which precludes a full evaluation of the fetal risks, incomplete reporting, and the inability to control for confounders (such as underlying maternal disease and use of concomitant medications).

Animal Data When teriflunomide (oral doses of 1, 3, or 10 mg/kg/day) was administered to pregnant rats throughout the period of organogenesis, high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and fetal death were observed at doses not associated with maternal toxicity. Adverse effects on fetal development were observed following dosing at various stages throughout organogenesis.

Maternal plasma exposure at the no-effect level (1.0 mg/kg/day) for fetal developmental toxicity in rats was less than that in humans at the maximum recommended human dose (MRHD, 14 mg/day). Administration of teriflunomide (oral doses of 1, 3.5, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and fetal death at doses associated with minimal maternal toxicity.

Maternal plasma exposure at the no-effect dose (1.0 mg/kg/day) for fetal developmental toxicity in rabbits was less than that in humans at the MRHD. In studies in which teriflunomide (oral doses of 0.05, 0.1, 0.3, 0.6, or 1.0 mg/kg/day) was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of malformation (limb defects) and postnatal death were observed in the offspring at doses not associated with maternal toxicity.

Maternal plasma exposure at the no-effect dose for prenatal and postnatal developmental toxicity in rats (0.10 mg/kg/day) was less than that in humans at the MRHD. In animal reproduction studies of leflunomide, embryolethality and teratogenic effects were observed in pregnant rat and rabbit at or below clinically relevant plasma teriflunomide exposures (AUC). In published reproduction studies in pregnant mice, leflunomide was embryolethal and increased the incidence of malformations (craniofacial, axial skeletal, heart and great vessel).

Supplementation with exogenous uridine reduced the teratogenic effects in pregnant mice, suggesting that the mode of action (inhibition of mitochondrial enzyme dihydroorotate dehydrogenase) is the same for therapeutic efficacy and developmental toxicity. At recommended doses in humans, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.

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 (5.7) ]
Peripheral Neuropathy [see Warnings and Precautions (5.8) ]
Increased Blood Pressure [see Warnings and Precautions (5.9) ]
Respiratory Effects [see Warnings and Precautions (5.10) ]
Pancreatitis in Pediatric Patients [see Warnings and Precautions (5.11) ] Most common adverse reactions (≥ 10% and ≥ 2% greater than placebo): headache, diarrhea, nausea, alopecia, increase in ALT. ( 6 ) 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.

6.1Clinical 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 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.

6.2Postmarketing 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 [see Warnings and Precautions (5.4) ]
Gastrointestinal Disorders: Pancreatitis, colitis
Hepatobiliary Disorders: Drug-induced liver injury (DILI) [see Warnings and Precautions (5.1) ]
Immune System Disorders: Hypersensitivity reactions, some of which were severe, such as anaphylaxis and angioedema [see Warnings and Precautions (5.5) ]
Respiratory, Thoracic, and Mediastinal Disorders: Interstitial lung disease [see Warnings and Precautions (5.10) ]
Skin and Subcutaneous Tissue Disorders: Severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome [see Warnings and Precautions (5.6) ]; Drug reaction with eosinophilia and systemic symptoms (DRESS) [see Warnings and Precautions (5.7) ]; psoriasis or worsening of psoriasis (including pustular psoriasis and nail psoriasis); nail disorders

Teriflunomide

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Teriflunomide

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Hepatotoxicity

5.2Embryofetal Toxicity

5.3Procedure for Accelerated Elimination of Teriflunomide

5.4Bone Marrow Effects/Immunosuppression Potential/Infections Bone Marrow Effects

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information