Teriflunomide (Aubagio)


Indication: Teriflunomide (Aubagio), is indicated for the treatment of patients with relapsing forms of multiple sclerosis.1

Pharmacology: 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 the CNS.1

Clinical Trials: Teriflunomide efficacy was demonstrated by the results of a double- blind, placebo-controlled phase 3 study that evaluated once daily dosing of teriflunomide 7 mg and 14 mg over a 2-year period in 1088 patients with relapsing-remitting multiple sclerosis (MS).2,3 This trial included patients with MS 18 to 55 years of age with 5.5 on the Expanded Disability Status Scale and at least 1 relapse in the previous year, or 2 relapses in 2 years. Patients were randomly assigned placebo, 7 mg, or 14 mg of teriflunomide once daily for 108 weeks. The results showed annualized relapse rates (RRs) fell 31.2% (P=0.0002) and 31.5% (P=0.0005) in the 7-mg and 14-mg groups, respectively. Both teriflunomide doses were superior to placebo on a range of end points measured by magnetic resonance imaging. It shows that teriflunomide significantly reduces RRs vs placebo.2,3

These findings followed a phase2 clinical trial that found that the 7-mg dose of teriflunomide decreased RRs 28% and the 14-mg dose decreased RRs 32%, compared with placebo.4 Both doses achieved statistically significant reductions in the number of gadolinium-enhanced lesions.

Warnings/Precautions: Hepatotoxicity has been observed in some patients treated with teriflunomide. Those who have liver problems may be at risk of developing higher serum alanine aminotransferase (ALT). Patients who have preexisting acute or chronic liver disease or those with serum alanine aminotransferase (ALT) greater than 2 times  the upper limit of normal, should not initiate the therapy. Aubagio may decrease the white blood cell (WBC) count during first 6 weeks, and WBCs may remain low during the treatment.1

Pregnancy: Among the most significant potential adverse events of concern with teriflunomide is the potential for fetal malformation. The parent compound has been associated with fetal malformation and carries a black box warning for fetal malformation.1,3 Teriflunomide has been designated for Pregnancy Category X. There are no adequate and well-controlled studies evaluating teriflunomide in pregnant women, but animal studies suggest that it may increase the risk of teratogenic effects or fetal death when given to pregnant women.1 Women of childbearing potential must not be started on teriflunomide until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Pregnant women may enroll themselves, by calling 1-800-745-4447.

In males, teriflunomide is detected in human semen; therefore, patients must use latex/synthetic protection when having sexual contact. Men wishing to father a child should discontinue use of teriflunomide and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L.1

Adverse Reactions: Hepatotoxicity, bone marrow effects, peripheral neuropathy, acute renal failure, hyperkalemia, serious skin reactions, blood pressure effects, and respiratory effects may occur. The most frequent adverse reaction (occurring in >10%) were increased ALT, alopecia, diarrhea, influenza, nausea, and paresthesia. Alopecia was the most common cause of discontinuation.1

Drug Interactions: Teriflunomide is an inhibitor of CYP2C8 and an in vivo study with caffeine indicated that teriflunomide induces CYP1A2. Teriflunomide is also an inhibitor of breast cancer resistant protein (BCRP), hepatic uptake transporter (OATP1B1), and renal uptake transporter (OAT3). BCRP inhibitors (such as cyclosporine, eltrombopag, gefitinib) may increase exposure of teriflunomide.

In vivo studies to confirm transporter-based interaction have not been conducted. There was an increase in mean repaglinide Cmax and 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. Therefore, monitoring patients with concomitant use of drugs metabolized by CYP2C8, such as repaglinide, paclitaxel, pioglitazone, or rosiglitazone is recommended as they may have higher exposure. A 25% decrease in peak international normalized ratio (INR) was observed when teriflunomide was coadministered with warfarin; therefore, when given concomitantly, closely monitor INR. Also, patients should be monitored when teriflunomide is coadministered with drugs metabolized by CYP1A2 (such as duloxetine, alosetron, theophylline, and tizanidine), as the efficacy of such drugs could be reduced.1

Dosage and Administration: The recommended dose of teriflunomide is 7 mg or 14 mg orally once daily. Teriflunomide can be taken with or without food. Patients should have transaminase and bilirubin levels monitored within 6 months before initiation of teriflunomide therapy, and ALT levels at least monthly for 6 months after starting the drug. A complete blood cell count (CBC) should be obtained within 6 months before the initiation of treatment with teriflunomide. Further monitoring should be based on signs and symptoms of infection. Prior to initiating teriflunomide, it is important to screen patients for latent tuberculosis infection with a tuberculin skin test, and to check blood pressure before initiating the therapy and periodically thereafter.1


  1. Aubagio [package insert]. Cambridge, MA: Genzyme Corp; 2012. http://products.sanofi.us/aubagio/aubagio.pdf. Accessed April 10, 2013.
  2. O’Connor P, Wolinsky J, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:1293-1303.
  3. Jeffery DR. Recent advances in treating multiple sclerosis: efficacy, risks and place in therapy. Ther Adv Chronic Dis. 2013;4:45-51.
  4. O’Connor P, Li D, Freedman M, et al. A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006;66:894-900.

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