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mechanism of action is Dihydroorotate Dehydrogenase Inhibitors [MoA]

Teriflunomide

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Teriflunomide Prescribing Information

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 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. Patients with pre-existing liver disease and patients taking other hepatotoxic drugs may be at increased risk for developing liver injury when taking teriflunomide tablets. Clinically significant liver injury can occur at any time during treatment with teriflunomide tablets.
Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with teriflunomide tablets. Teriflunomide tablets is contraindicated in patients with severe hepatic impairment
[see
Contraindications
(4)]
.
In placebo-controlled trials in adult patients, ALT greater than three times the ULN occurred in 61/1045 (5.8%) and 62/1002 (6.2%) of patients receiving teriflunomide tablets 7 mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, teriflunomide tablet was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3)]. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months.
One patient in the controlled trials in adult patients developed ALT 32 times the ULN and jaundice 5 months after initiation of teriflunomide tablets 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure.
Teriflunomide-induced liver injury in this patient could not be ruled out.
Obtain serum transaminase and bilirubin levels within 6 months before initiation of teriflunomide tablet therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide tablets. Consider additional monitoring when teriflunomide tablet is given with other potentially hepatotoxic drugs.
Consider discontinuing teriflunomide tablets if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on teriflunomide tablet therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be teriflunomide-induced, discontinue teriflunomide tablets and start an accelerated elimination procedure
[see
Warnings and Precautions
(5.3)]
and monitor liver tests weekly until normalized. If teriflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of teriflunomide tablet therapy may be considered.
]
. 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. Monitor ALT levels at least monthly for six months after starting teriflunomide tablets
[see Warnings and Precautions

5.1 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. Patients with pre-existing liver disease and patients taking other hepatotoxic drugs may be at increased risk for developing liver injury when taking teriflunomide tablets. Clinically significant liver injury can occur at any time during treatment with teriflunomide tablets.
Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with teriflunomide tablets. Teriflunomide tablets is contraindicated in patients with severe hepatic impairment
[see
Contraindications
(4)]
.
In placebo-controlled trials in adult patients, ALT greater than three times the ULN occurred in 61/1045 (5.8%) and 62/1002 (6.2%) of patients receiving teriflunomide tablets 7 mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, teriflunomide tablet was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3)]. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months.
One patient in the controlled trials in adult patients developed ALT 32 times the ULN and jaundice 5 months after initiation of teriflunomide tablets 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure.
Teriflunomide-induced liver injury in this patient could not be ruled out.
Obtain serum transaminase and bilirubin levels within 6 months before initiation of teriflunomide tablet therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide tablets. Consider additional monitoring when teriflunomide tablet is given with other potentially hepatotoxic drugs.
Consider discontinuing teriflunomide tablets if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on teriflunomide tablet therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be teriflunomide-induced, discontinue teriflunomide tablets and start an accelerated elimination procedure
[see
Warnings and Precautions
(5.3)]
and monitor liver tests weekly until normalized. If teriflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of teriflunomide tablet therapy may be considered.
]
. If drug induced liver injury is suspected, discontinue teriflunomide tablets and start an accelerated elimination procedure with cholestyramine or charcoal

[see Warnings and Precautions

5.3 Procedure for Accelerated Elimination of Teriflunomide
Teriflunomide is eliminated slowly from the plasma
[see Clinical Pharmacology ]
. 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 tablets. 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 tablet treatment.
)]
. Teriflunomide tablet is contraindicated in patients with severe hepatic impairment

[see Contraindications (

4 CONTRAINDICATIONS
Teriflunomide tablet is 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)].

Co-administration with leflunomide
[see
Clinical Pharmacology
(12.3)
].

Severe hepatic impairment
Pregnancy
Hypersensitivity

Current leflunomide treatment

].
Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking teriflunomide tablets.

Embryofetal Toxicity

Teriflunomide tablet is contraindicated for use in pregnant women and in females of reproductive potential who are not using effective contraception because of the potential for fetal harm. Teratogenicity and embryolethality occurred in animals at plasma teriflunomide exposures lower than that in humans. Exclude pregnancy before the start of treatment with teriflunomide tablets in females of reproductive potential. Advise females of reproductive potential to use effective contraception during teriflunomide tablet treatment and during an accelerated drug elimination procedure after teriflunomide tablet treatment. Stop teriflunomide tablets and use an accelerated drug elimination procedure if the patient becomes pregnant
[see Contraindications (
4 CONTRAINDICATIONS
Teriflunomide tablet is 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)].

Co-administration with leflunomide
[see
Clinical Pharmacology
(12.3)
].

Severe hepatic impairment
Pregnancy
Hypersensitivity

Current leflunomide treatment
), Warnings and Precautions (

5.2 Embryofetal Toxicity
Teriflunomide may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryofetal 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
[see Use in Specific Populations (8.1)]
.
Teriflunomide tablet is contraindicated for use in pregnant women and in females of reproductive potential not using effective contraception
[see Contraindications (4)]
. Exclude pregnancy before starting treatment with teriflunomide tablets in females of reproductive potential
[see
Dosage and Administration
(2)]
.
Advise females of reproductive potential to use effective contraception during teriflunomide tablets treatment and during an accelerated drug elimination procedure after teriflunomide tablets treatment
[see Use in Specific Populations (
8.3
)]
.
If a woman becomes pregnant while taking teriflunomide tablets, stop treatment with teriflunomide tablets, 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
[see Warnings and Precautions (
5.3
)]
.
Upon discontinuing teriflunomide tablets, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving teriflunomide tablets treatment who wish to become pregnant must discontinue teriflunomide tablets 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 tablets 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)
[see Use in Specific Population (
8.3
)]
.
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
[see Contraindications (
4
), Warnings and Precautions (
5.3
),
and
Use in Specific Populations (
8.1
)]
.
,
5.3 Procedure for Accelerated Elimination of Teriflunomide
Teriflunomide is eliminated slowly from the plasma
[see Clinical Pharmacology ]
. 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 tablets. 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 tablet treatment.
), Use in Specific Populations (

8.1 Pregnancy
Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Teriflunomide during pregnancy. Healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2.
Risk Summary

Teriflunomide tablet 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
[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 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.
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 tablets 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.
,

8.3 Females and Males of Reproductive Potential
Pregnancy Testing

Exclude pregnancy prior to initiation of treatment with teriflunomide tablets in females of reproductive potential. Advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment
[see Warnings and Precautions (
5.2
,
5.3
) and Use in Specific Populations (
8.1
)].
Contraception

Females
Females of reproductive potential should use effective contraception while taking teriflunomide tablets. If teriflunomide tablet 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 discontinue teriflunomide tablets and undergo 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)
[see Warnings and Precautions (
5.2
,
5.3
) and Use in Specific Populations (
8.1
)]
.
Males
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 tablets 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)
[see Warnings and Precautions (
5.3
)]
.
), and Clinical Pharmacology (

12.3 Pharmacokinetics
Teriflunomide is the principal active metabolite of leflunomide and is responsible for leflunomide’s activity
in vivo
. 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.
Absorption

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.
Distribution

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.
Metabolism

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.
Elimination

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.
Drug Interaction Studies

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

The potential effect of teriflunomide tablets 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
in vivo
. The magnitude of interaction could be higher at the recommended repaglinide dose
[see Drug Interactions (7)]
.
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
in vivo [see Drug Interactions (
7
)].
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)
in vivo
[see Drug Interactions (7)]
.
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)
[see Drug Interactions (7)]
.
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
[see Drug Interactions (7)]
.
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 tablets
Potent CYP and transporter inducers: Rifampin did not affect the pharmacokinetics of teriflunomide.
Specific Populations
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
[see Contraindications (
4
), Warnings and Precautions (
5.1
), and Use in Specific Populations (
8.6
)]
.
Renal impairment
Severe renal impairment had no impact on the pharmacokinetics of teriflunomide
[see Use in Specific Populations (
8.7
)]
.
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 non-white patients in the clinical trials.
)]

Boxed Warning 11/2020

Warnings and Precautions (

5.1 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. Patients with pre-existing liver disease and patients taking other hepatotoxic drugs may be at increased risk for developing liver injury when taking teriflunomide tablets. Clinically significant liver injury can occur at any time during treatment with teriflunomide tablets.

Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with teriflunomide tablets. Teriflunomide tablets is contraindicated in patients with severe hepatic impairment

[see

Contraindications

(4)]

In placebo-controlled trials in adult patients, ALT greater than three times the ULN occurred in 61/1045 (5.8%) and 62/1002 (6.2%) of patients receiving teriflunomide tablets 7 mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, teriflunomide tablet was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3)]. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months.

One patient in the controlled trials in adult patients developed ALT 32 times the ULN and jaundice 5 months after initiation of teriflunomide tablets 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure.

Teriflunomide-induced liver injury in this patient could not be ruled out.

Obtain serum transaminase and bilirubin levels within 6 months before initiation of teriflunomide tablet therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide tablets. Consider additional monitoring when teriflunomide tablet is given with other potentially hepatotoxic drugs.

Consider discontinuing teriflunomide tablets if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on teriflunomide tablet therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be teriflunomide-induced, discontinue teriflunomide tablets and start an accelerated elimination procedure

[see

Warnings and Precautions

(5.3)]

and monitor liver tests weekly until normalized. If teriflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of teriflunomide tablet therapy may be considered.

5.6 Serious Skin Reactions

Cases of serious skin reactions, sometimes fatal, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)

[see Warnings and Precautions (

5.7

)]

, have been reported with teriflunomide tablets. Fatal outcomes were reported in one case of TEN and one case of DRESS.

Inform patients of the signs and symptoms that may signal a serious skin reaction. Instruct patients to discontinue teriflunomide tablets and seek immediate medical care should these signs and symptoms occur. Unless the reaction is clearly not drug related, discontinue teriflunomide tablets and begin an accelerated elimination procedure immediately

[see Warnings and Precautions (

5.3

)]

. In such cases, patients should not be re-exposed to teriflunomide

[see Contraindications (

)]

5.7 Drug Reaction with Eosinophilia and Systemic Symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with teriflunomide tablets. One fatal case of DRESS that occurred in close temporal association (34 days) with the initiation of teriflunomide tablets treatment has been reported in the postmarketing setting. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately.

Discontinue teriflunomide tablets, unless an alternative etiology for the signs or symptoms is established, and begin an accelerated elimination procedure immediately

[see Warnings and Precautions (

5.3

)]

. In such cases, patients should not be re-exposed to teriflunomide

[see Contraindications (

)]

) 11/2020

Warnings and Precautions (

5.11 Pancreatitis in Pediatric Patients

Teriflunomide tablet is not approved for use in pediatric patients [

see

Use in Specific Populations

]. If pancreatitis is suspected, discontinue teriflunomide and start an accelerated elimination procedure

[

see

Warnings and Precautions ]

Pediatric information describing a clinical study in which efficacy was not demonstrated is approved for Sanofi-Aventis U.S. LLC’s Aubagio^®(teriflunomide) tablets. However, due to Sanofi-Aventis U.S. LLC’s marketing exclusivity rights, this drug product is not labeled with that information

) 04/2021

The recommended dose of teriflunomide tablets is 7mg 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 tablet therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide tablets

[see

Warnings and Precautions
5.1 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. Patients with pre-existing liver disease and patients taking other hepatotoxic drugs may be at increased risk for developing liver injury when taking teriflunomide tablets. Clinically significant liver injury can occur at any time during treatment with teriflunomide tablets.
Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with teriflunomide tablets. Teriflunomide tablets is contraindicated in patients with severe hepatic impairment
[see
Contraindications
(4)]
.
In placebo-controlled trials in adult patients, ALT greater than three times the ULN occurred in 61/1045 (5.8%) and 62/1002 (6.2%) of patients receiving teriflunomide tablets 7 mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, teriflunomide tablet was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3)]. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months.
One patient in the controlled trials in adult patients developed ALT 32 times the ULN and jaundice 5 months after initiation of teriflunomide tablets 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure.
Teriflunomide-induced liver injury in this patient could not be ruled out.
Obtain serum transaminase and bilirubin levels within 6 months before initiation of teriflunomide tablet therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide tablets. Consider additional monitoring when teriflunomide tablet is given with other potentially hepatotoxic drugs.
Consider discontinuing teriflunomide tablets if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on teriflunomide tablet therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be teriflunomide-induced, discontinue teriflunomide tablets and start an accelerated elimination procedure
[see
Warnings and Precautions
(5.3)]
and monitor liver tests weekly until normalized. If teriflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of teriflunomide tablet therapy may be considered.
]

.
Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with teriflunomide tablets. Further monitoring should be based on signs and symptoms of infection

[see

Warnings and Precautions
5.4 Bone Marrow Effects/Immunosuppression Potential/Infections
Bone Marrow Effects

A mean decrease compared to baseline in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo-controlled trials in adult patients with 7 mg and 14 mg of teriflunomide tablets. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies in adult patient, neutrophil count < 1.5 x 10⁹/L was observed in 12% and 16% of patients receiving teriflunomide tablets 7 mg and 14 mg, respectively, compared with 7% of patients receiving placebo; lymphocyte count < 0.8 x 10⁹/L was observed in 10% and 12% of patients receiving teriflunomide tablets 7 mg and 14 mg, respectively, compared with 6% of patients receiving placebo. No cases of serious pancytopenia were reported in premarketing clinical trials of teriflunomide tablets but rare cases of pancytopenia and agranulocytosis have been reported in the postmarketing setting with leflunomide. A similar risk would be expected for teriflunomide tablets
[see Clinical Pharmacology (
12.3
)]
. Cases of thrombocytopenia with teriflunomide tablets, including rare cases with platelet counts less than 50,000/mm³, have been reported in the postmarketing setting. Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with teriflunomide tablets. Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression.
Risk of Infection/Tuberculosis Screening

Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection consider suspending treatment with teriflunomide tablets and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving teriflunomide tablets to report symptoms of infections to a physician. Teriflunomide tablet is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Medications like teriflunomide tablets that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections.
In placebo-controlled studies of teriflunomide tablets in adult patients, no overall increase in the risk of serious infections was observed with teriflunomide tablets 7 mg (2.2%) or 14 mg (2.7%) compared to placebo (2.2%).
However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking teriflunomide tablets 14 mg for 1.7 years. Fatal infections have been reported in the postmarketing setting in patients receiving leflunomide, especially
Pneumocystis jirovecii
pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. In clinical studies with teriflunomide tablets, cytomegalovirus hepatitis reactivation has been observed.
In clinical studies with teriflunomide tablets in adult patients, cases of tuberculosis have been observed. Prior to initiating teriflunomide tablets, screen patients for latent tuberculosis infection with a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection. Teriflunomide tablet has not been studied in patients with a positive tuberculosis screen, and the safety of teriflunomide tablets in individuals with latent tuberculosis infection is unknown. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with teriflunomide tablets.
Vaccination

No clinical data are available on the efficacy and safety of live vaccinations in patients taking teriflunomide tablets. Vaccination with live vaccines is not recommended. The long half-life of teriflunomide tablets should be considered when contemplating administration of a live vaccine after stopping teriflunomide tablets.
Malignancy

The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with teriflunomide tablets. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the teriflunomide tablets clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with teriflunomide tablets.
]

.
Prior to initiating teriflunomide tablets, screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for mycobacterium tuberculosis infection

[
see Warnings and Precautions
5.4 Bone Marrow Effects/Immunosuppression Potential/Infections
Bone Marrow Effects

A mean decrease compared to baseline in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo-controlled trials in adult patients with 7 mg and 14 mg of teriflunomide tablets. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies in adult patient, neutrophil count < 1.5 x 10⁹/L was observed in 12% and 16% of patients receiving teriflunomide tablets 7 mg and 14 mg, respectively, compared with 7% of patients receiving placebo; lymphocyte count < 0.8 x 10⁹/L was observed in 10% and 12% of patients receiving teriflunomide tablets 7 mg and 14 mg, respectively, compared with 6% of patients receiving placebo. No cases of serious pancytopenia were reported in premarketing clinical trials of teriflunomide tablets but rare cases of pancytopenia and agranulocytosis have been reported in the postmarketing setting with leflunomide. A similar risk would be expected for teriflunomide tablets
[see Clinical Pharmacology (
12.3
)]
. Cases of thrombocytopenia with teriflunomide tablets, including rare cases with platelet counts less than 50,000/mm³, have been reported in the postmarketing setting. Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with teriflunomide tablets. Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression.
Risk of Infection/Tuberculosis Screening

Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection consider suspending treatment with teriflunomide tablets and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving teriflunomide tablets to report symptoms of infections to a physician. Teriflunomide tablet is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Medications like teriflunomide tablets that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections.
In placebo-controlled studies of teriflunomide tablets in adult patients, no overall increase in the risk of serious infections was observed with teriflunomide tablets 7 mg (2.2%) or 14 mg (2.7%) compared to placebo (2.2%).
However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking teriflunomide tablets 14 mg for 1.7 years. Fatal infections have been reported in the postmarketing setting in patients receiving leflunomide, especially
Pneumocystis jirovecii
pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. In clinical studies with teriflunomide tablets, cytomegalovirus hepatitis reactivation has been observed.
In clinical studies with teriflunomide tablets in adult patients, cases of tuberculosis have been observed. Prior to initiating teriflunomide tablets, screen patients for latent tuberculosis infection with a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection. Teriflunomide tablet has not been studied in patients with a positive tuberculosis screen, and the safety of teriflunomide tablets in individuals with latent tuberculosis infection is unknown. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with teriflunomide tablets.
Vaccination

No clinical data are available on the efficacy and safety of live vaccinations in patients taking teriflunomide tablets. Vaccination with live vaccines is not recommended. The long half-life of teriflunomide tablets should be considered when contemplating administration of a live vaccine after stopping teriflunomide tablets.
Malignancy

The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with teriflunomide tablets. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the teriflunomide tablets clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with teriflunomide tablets.
]
.
Exclude pregnancy prior to initiation of treatment with teriflunomide tablets in females of reproductive potential

[see

Warnings and Precautions
5.2 Embryofetal Toxicity
Teriflunomide may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryofetal 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
[see Use in Specific Populations (8.1)]
.
Teriflunomide tablet is contraindicated for use in pregnant women and in females of reproductive potential not using effective contraception
[see Contraindications (4)]
. Exclude pregnancy before starting treatment with teriflunomide tablets in females of reproductive potential
[see
Dosage and Administration
(2)]
.
Advise females of reproductive potential to use effective contraception during teriflunomide tablets treatment and during an accelerated drug elimination procedure after teriflunomide tablets treatment
[see Use in Specific Populations (
8.3
)]
.
If a woman becomes pregnant while taking teriflunomide tablets, stop treatment with teriflunomide tablets, 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
[see Warnings and Precautions (
5.3
)]
.
Upon discontinuing teriflunomide tablets, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving teriflunomide tablets treatment who wish to become pregnant must discontinue teriflunomide tablets 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 tablets 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)
[see Use in Specific Population (
8.3
)]
.
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
[see Contraindications (
4
), Warnings and Precautions (
5.3
),
and
Use in Specific Populations (
8.1
)]
.
].
Check blood pressure before start of teriflunomide tablet treatment and periodically thereafter

[see

Warnings and Precautions
5.9 Increased Blood Pressure
In placebo-controlled studies in adult patients, the mean change from baseline to the end of study in systolic blood pressure was +2.3 mmHg and +2.7 mmHg for teriflunomide tablets 7 mg and 14 mg, respectively, and -0.6 mmHg for placebo. The change from baseline in diastolic blood pressure was +1.4 mmHg and +1.9 mmHg for teriflunomide tablets 7 mg and 14 mg, respectively, and -0.3 mmHg for placebo. Hypertension was an adverse reaction in 3.1% and 4.3% of patients treated with 7 mg or 14 mg of teriflunomide tablets compared with 1.8% for placebo. Check blood pressure before start of teriflunomide tablets treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with teriflunomide tablets.
)].

Teriflunomide tablets are available as 7 mg and 14 mg tablets.

The 14 mg tablet is a blue (pale blue to pastel blue) colored, round, biconvex, film-coated tablet debossed with the dose strength “14” on one side. Each tablet contains 14 mg of teriflunomide.

The 7 mg tablet is a green (light greenish-blue grey to pale greenish-blue) colored, round, biconvex, film-coated tablet debossed with the dose strength “7” on one side. Each tablet contains 7 mg of teriflunomide.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Teriflunomide during pregnancy. Healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2.

Risk Summary

Teriflunomide tablet 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

[see Contraindications (

4 CONTRAINDICATIONS

Teriflunomide tablet is 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)].
Co-administration with leflunomide
[see
Clinical Pharmacology
(12.3)
].

Severe hepatic impairment
Pregnancy
Hypersensitivity
Current leflunomide treatment

) and Warnings and Precautions (

5.2 Embryofetal Toxicity

Teriflunomide may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryofetal 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

[see Use in Specific Populations (8.1)]

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

[see Contraindications (4)]

. Exclude pregnancy before starting treatment with teriflunomide tablets in females of reproductive potential

[see

Dosage and Administration

(2)]

Advise females of reproductive potential to use effective contraception during teriflunomide tablets treatment and during an accelerated drug elimination procedure after teriflunomide tablets treatment

[see Use in Specific Populations (

8.3

)]

If a woman becomes pregnant while taking teriflunomide tablets, stop treatment with teriflunomide tablets, 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

[see Warnings and Precautions (

5.3

)]

Upon discontinuing teriflunomide tablets, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving teriflunomide tablets treatment who wish to become pregnant must discontinue teriflunomide tablets 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 tablets 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)

[see Use in Specific Population (

8.3

)]

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

[see Contraindications (

), Warnings and Precautions (

5.3

and

Use in Specific Populations (

8.1

)]

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

Human 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

Fetal/Neonatal adverse reactions

and

Data

Human data

]

. There 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.

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 Procedure for Accelerated Elimination of Teriflunomide

Teriflunomide is eliminated slowly from the plasma

[see Clinical Pharmacology ]

. 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 tablets. 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 tablet treatment.

) and Clinical Pharmacology (

12.3 Pharmacokinetics

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

in vivo

. 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.

Absorption

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.

Distribution

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.

Metabolism

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.

Elimination

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.

Drug Interaction Studies

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

The potential effect of teriflunomide tablets 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

in vivo

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

[see Drug Interactions (7)]

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

in vivo [see Drug Interactions (

)].

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)

in vivo

[see Drug Interactions (7)]

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)

[see Drug Interactions (7)]

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

[see Drug Interactions (7)]

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 tablets

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

Specific Populations

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

[see Contraindications (

), Warnings and Precautions (

5.1

), and Use in Specific Populations (

8.6

)]

Renal impairment

Severe renal impairment had no impact on the pharmacokinetics of teriflunomide

[see Use in Specific Populations (

8.7

)]

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 non-white patients in the clinical trials.

)].

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 tablets 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.

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