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Mechanism of Action

Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The exact mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis is unknown but may involve a reduction in the number of activated lymphocytes in CNS.


Potential to prolong the QT interval

In a placebo controlled thorough QT study performed in healthy subjects, there was no evidence that teriflunomide caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).


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 volunteers and MS patients, median t½ was 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.

Drug Interactions

Teriflunomide is not metabolized by Cytochrome P450 or flavin monoamine oxidase enzymes. Based on in vitro studies, teriflunomide is a substrate of the efflux transporter Breast Cancer Resistant Protein (BCRP). BCRP inhibitors (such as cyclosporine, eltrombopag, gefitinib) may increase exposure of teriflunomide.

In vitro and in vivo studies suggested teriflunomide is an inhibitor of CYP2C8 and an in vivo study with caffeine indicated that teriflunomide induces CYP1A2. Teriflunomide is also an inhibitor of BCRP, hepatic uptake transporter (OATP1B1), and renal uptake transporter (OAT3). In vivo studies to confirm transporter based interaction have not been conducted.

Potential of Other Drugs to Affect AUBAGIO

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

Potential of AUBAGIO to Affect Other Drugs

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).

Special populations

Hepatic Impairment: Mild and moderate hepatic impairment had no impact on the pharmacokinetics of teriflunomide. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated [see CONTRAINDICATIONS].

Renal Impairment: Severe renal impairment had no impact on the pharmacokinetics of teriflunomide [see Use In Specific Populations].

Gender: In a population analysis, there was a 23% decrease in clearance in females compared to 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.

Clinical Studies

The efficacy of AUBAGIO was demonstrated in Study 1, a double-blind, placebo-controlled study that evaluated once daily doses of teriflunomide 7 mg and 14 mg in patients with relapsing forms of multiple sclerosis (RMS) over 108 weeks. All patients had a definite diagnosis of MS exhibiting a relapsing clinical course, with or without progression, and experienced at least 1 relapse over the year preceding the trial or at least 2 relapses over the 2 years preceding the trial. Subjects had not received interferon-beta for at least 4 months or any other preventive MS medications for at least 6 months before entering the study, nor were these medications permitted during the study. Neurological evaluations were performed at screening, every 12 weeks until week 108 and at unscheduled visits for suspected relapse. MRI was performed at screening, weeks, 24, 48, 72, and 108. The primary endpoint was the annualized relapse rate (ARR).

A total of 1088 patients with RMS were randomized to receive 7 mg (n=366) or 14 mg (n=359) of teriflunomide or placebo (n=363). At entry, patients had an Expanded Disability Status Scale (EDSS) score ≤ 5.5. The mean age of the study population was 37.9 years, the mean disease duration was 5.33 years, and the mean EDSS at baseline was 2.68. A total of 91.4% had relapsing remitting MS (RRMS) and 8.6% had a progressive form of MS with relapses. The mean time on placebo was 631 days, on 7mg AUBAGIO 635 days, and on 14 mg AUBAGIO 627 days.

The ARR was significantly reduced in patients treated with either 7 mg or 14 mg of AUBAGIO compared to patients who received placebo (see Table 2). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior MS therapy, and baseline disease activity.

The time to disability progression sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS ≤ 5.5 or a 0.5 point increase for those with a baseline EDSS > 5.5) was statistically significantly reduced only in the teriflunomide 14 mg group compared to placebo (see Table 2 and Figure 1).

The effect of teriflunomide on several magnetic resonance imaging (MRI) variables including the total lesion volume of T2 and hypointense T1 lesions was assessed. The change in total lesion volume from baseline was significantly lower in the 7 mg and 14 mg groups than in the placebo group. Patients in both teriflunomide groups had significantly fewer gadoliniumenhancing lesions per T1-weighted scan than those in the placebo group (See Table 2).

Table 2 : Clinical and MRI Results of Study 1

  TN 14 mg
TN 7 mg
Clinical Endpoints
Annualized relapse rate (primary endpoint) 0.369 (p = 0.0005) 0.370 (p = 0.0002) 0.539
  Relative risk reduction 31% 31%
Percent of patients remaining relapse-free at week 108 56.5% 53.7% 45.6%
Percent disability progression at week 108 20.2% (p = 0.028) 21.7% (p = 0.084) 27.3%
  Hazard ratio 0.70 0.76
MRI Endpoints
Median change from baseline in Total lesion volume1 (mL) at week 108 0.345 (p = 0.0003)2 0.755 (p= 0.0317 ) 2 1.127
Mean number of Gd-enhancing T1-lesions per scan 0.261 (p < 0.0001) 0.570 (p < 0.0001) 1.331
1 Total lesion volume: sum of T2 and hypointense T1 lesion volume in mL
2 p-values based on cubic root transformed data for total lesion volume

Figure 1: Kaplan-Meier plot of time to disability progression sustained for 12 weeks – ITT Population

Kaplan-Meier plot of time to disability progression sustained for 12 weeks -  Illustration

The effect of teriflunomide on MRI activity was also demonstrated in Study 2, a randomized, double-blind, placebo-controlled study of MS subjects with relapse. A total of 179 patients were treated with twice the usual dose for the first week and then received 7 mg (n=61) or 14 mg (n=57) of teriflunomide or placebo (n= 61) for the remainder of the 36-week treatment period. The primary endpoint was the average number of unique active lesions/MRI scan during treatment. MRI was performed at baseline, 6 weeks, 12 weeks, 18 weeks, 24 weeks, 30 weeks and 36 weeks. Baseline demographics were consistent across treatment groups. The mean number of unique active lesions per brain MRI scan during the 36-week treatment period was lower in patients treated with teriflunomide 14 mg (0.98) and 7 mg (1.06) as compared to placebo (2.69), the difference being statistically significant for both (p=0.0052 and p=0.0234, respectively).

Last reviewed on RxList: 9/21/2012
This monograph has been modified to include the generic and brand name in many instances.


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