Teriflunomide

Teriflunomide may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryo-fetal lethality occurred in animal reproduction studies in multiple animal species at plasma teriflunomide exposures similar to or lower than that in humans at the maximum recommended human dose (MRHD) of 14 mg/day

Teriflunomide is contraindicated for use in pregnant women and in females of reproductive potential not using effective contraception [

]. Exclude pregnancy before starting treatment with teriflunomide in females of reproductive potentialAdvise females of reproductive potential to use effective contraception during teriflunomide treatment and during an accelerated drug elimination procedure after teriflunomide treatmentIf a woman becomes pregnant while taking teriflunomide, stop treatment with teriflunomide, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve a plasma teriflunomide concentration of less than 0.02 mg/L

Upon discontinuing teriflunomide, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving teriflunomide treatment who wish to become pregnant must discontinue teriflunomide and undergo an accelerated drug elimination procedure, which includes verification that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL). Men wishing to father a child should also discontinue use of teriflunomide and either undergo an accelerated elimination procedure or wait until verification that the plasma teriflunomide concentration is less than 0.02 mg/L (0.02 mcg/mL)

Based on animal data, human plasma concentrations of teriflunomide of less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryofetal risk [

Teriflunomide is eliminated slowly from the plasma

. Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of teriflunomide. Elimination can be accelerated by either of the following procedures:

• Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used.
• Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.

If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly.

At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations.

Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to teriflunomide treatment.

Teriflunomide is 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.

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 [

]. 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 procedureThere are no human data pertaining to exposures later in the first trimester or beyond.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage in the indicated population is unknown.

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. The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L

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).

When teriflunomide (oral doses of 1 mg/kg/day, 3 mg/kg/day, 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 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 mg/kg/day, 3.5 mg/kg/day, 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 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 mg/kg/day, 0.1 mg/kg/day, 0.3 mg/kg/day, 0.6 mg/kg/day, or 1 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.

Exclude pregnancy prior to initiation of treatment with teriflunomide in females of reproductive potential. Advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment [

].

Females of reproductive potential should use effective contraception while taking teriflunomide. If teriflunomide is discontinued, use of contraception should be continued until  it is verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL, the level expected to have minimal fetal risk, based on animal data).

Females of reproductive potential who wish to become pregnant should undergo discontinue teriflunomide and an accelerated elimination procedure. Effective contraception should be used until it is verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL) [

].

Teriflunomide is detected in human semen. Animal studies to specifically evaluate the risk of male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use effective contraception. Men wishing to father a child should discontinue use of teriflunomide and either undergo an accelerated elimination procedure or wait until verification that the plasma teriflunomide concentration is less than 0.02 mg/L (0.02 mcg/mL) [

].

Teriflunomide is the principal active metabolite of leflunomide and is responsible for leflunomide's activity

. At recommended doses, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.

Based on a population analysis of teriflunomide in healthy adult volunteers and adult MS patients, median t_1/2was approximately 18 and 19 days after repeated doses of 7 mg and 14 mg respectively. It takes approximately 3 months respectively to reach steady-state concentrations. The estimated AUC accumulation ratio is approximately 30 after repeated doses of 7 or 14 mg.

Median time to reach maximum plasma concentrations is between 1 to 4 hours post-dose following oral administration of teriflunomide.

Food does not have a clinically relevant effect on teriflunomide pharmacokinetics.

Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma. The volume of distribution is 11 L after a single intravenous (IV) administration.

Teriflunomide is the major circulating moiety detected in plasma. The primary biotransformation pathway to minor metabolites of teriflunomide is hydrolysis, with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.

Teriflunomide is eliminated mainly through direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces). After a single IV administration, the total body clearance of teriflunomide is 30.5 mL/h.

Teriflunomide is not metabolized by Cytochrome P450 or flavin monoamine oxidase enzymes.

The Potential Effect of Teriflunomide on Other Drugs

• CYP2C8 Substrates

There was an increase in mean repaglinide C_maxand AUC (1.7- and 2.4-fold, respectively), following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8

. The magnitude of interaction could be higher at the recommended repaglinide dose.

• CYP1A2 Substrates

Repeated doses of teriflunomide decreased mean C_maxand AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2

• OAT3 Substrates

There was an increase in mean cefaclor C_maxand AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter 3 (OAT3)

.

• BCRP and OATP1B1/1B3 Substrates

There was an increase in mean rosuvastatin C_maxand AUC (2.65- and 2.51-fold, respectively), following repeated doses of teriflunomide , suggesting that teriflunomide is an inhibitor of BCRP transporter and organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3)

.

• Oral Contraceptives

There was an increase in mean ethinylestradiol C_maxand AUC_0-24(1.58- and 1.54-fold, respectively) and levonorgestrel C_maxand AUC_0-24(1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide

.

• Teriflunomide did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 substrate), and metoprolol (a CYP2D6 substrate).

The Potential Effect of Other Drugs on Teriflunomide

• Potent CYP and transporter inducers: Rifampin did not affect the pharmacokinetics of teriflunomide.

• Hepatic Impairment

Mild and moderate hepatic impairment had no impact on the pharmacokinetics of teriflunomide. The pharmacokinetics of teriflunomide in severe hepatic impairment has not been evaluated

.

• Renal Impairment

Severe renal impairment had no impact on the pharmacokinetics of teriflunomide

.

• Gender

In a population analysis, the clearance rate for teriflunomide is 23% less in females than in males.

• Race

Effect of race on the pharmacokinetics of teriflunomide cannot be adequately assessed due to a low number of patients who self-identified as Black or African American, Asian, or other races in the clinical trials.