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Teriflunomide is an orally available immunomodulatory agent used to treat relapsing multiple sclerosis. Teriflunomide is associated with transient serum enzyme elevations during therapy and with rare instances of clinically apparent acute liver injury.

Teriflunomide (ter" i floo' noe mide) is the active metabolite of leflunomide, an immunomodulatory agent similar to thalidomide, and is used in the treatment of multiple sclerosis . The mechanism of action of teriflunomide appears to be based, at least in part, upon inhibition of the enzyme dihydro-orotate dehydrogenase, which is an important step in pyrimidine synthesis. The activation and proliferation of lymphocytes are dependent upon pyrimidine synthesis and is acutely sensitive to its inhibition, resulting in suppression of ongoing immune reactivity. Teriflunomide has other activities including inhibition of NF-kappa B pathways that may contribute to its immunomodulatory actions. In animal models of multiple sclerosis, teriflunomide was shown to have beneficial effects which led to its critical evaluation in this disease. In several large, randomized controlled trials, teriflunomide was found to reduce relapse rates and improve neuro-radiologic outcomes in adult patients with relapsing-remitting multiple sclerosis. Teriflunomide was approved for use for multiple sclerosis in the United States in 2012 and is now available in tablets of 7 and 14 mg generically and under the brand name Aubagio. The recommended dose in adults is 7 or 14 mg orally once daily. Common side effects are headache, diarrhea, nausea , paresthesia, arthralgia, neutropenia, hypertension, and hair loss (alopecia). Rare, but potentially serious adverse events include bone marrow suppression, increased risk of severe infections, liver injury, peripheral neuropathy, reactivation of tuberculosis , serious skin reactions, hypersensitivity reactions, and embryofetal toxicity .

In large randomized controlled trials of teriflunomide, serum ALT elevations occurred in 13% to 15% of teriflunomide compared to 9% of placebo recipients. Elevations above 3 times the upper limit of normal occurred in 6% of teriflunomide versus 4% of placebo recipients, usually within the first 6 months of therapy. The enzyme elevations were usually transient and not associated with symptoms or jaundice, but led to drug discontinuation in 2% to 3% of patients. The abnormalities resolved rapidly with drug discontinuation and resolved spontaneously in at least half of patients without drug modification. During preregistration trials, a single case of severe liver injury with jaundice was described, ALT elevations appearing 5 months after starting teriflunomide. Because of this and the known hepatotoxic potential of leflunomide, teriflunomide was given a "black box" warning regarding hepatotoxicity, and routine monitoring of liver tests is recommended monthly for the first 6 months and intermittently thereafter. Since approval and more wide scale usage, there have been at least six cases of clinical ly apparent liver injury published in the medical literature and the current package label mentions instances of severe hepatitis and fatal hepatic failure as possible adverse events. Clinically apparent liver injury also occurs with leflunomide, generally presenting with a hepatocellular or mixed pattern of serum enzyme elevations within 1 to 6 months of starting therapy. Immunoallergic and autoimmune features have not been prominent in most cases although single instances of DRESS syndrome have been reported. As with teriflunomide, rare cases of acute liver failure and death have been reported with leflunomide . The clinical features of the liver injury reported with leflunomide are similar to those that occur with teriflunomide.

Likelihood score: C ( probable rare cause of clinically apparent liver injury).

The mechanism by which teriflunomide might cause liver injury is not known. It is extensively metabolized by the liver largely by the cytochrome P450 system (largely CYP2C8) and is susceptible to drug-drug interactions, particularly with warfarin, oral contraceptives and agents that are metabolized by CYP 2C8 (paclitaxel, pioglitazone) and possibly others.

While chronic therapy with teriflunomide can be associated with mild-to-moderate serum aminotransferase elevations, it has only rarely been linked to cases of clinically apparent liver injury . Nevertheless, monitoring of liver tests before starting teriflunomide therapy and monthly for the first 6 months of treatment followed by intermittently thereafter is recommended . In instances of suspected teriflunomide toxicity, elimination of the drug can be accelerated by cholestyramine or activated charcoal. Teriflunomide is eliminated slowly from the serum probably due to enterohepatic recirculation. Without an accelerated elimination procedure using activated charcoal (50 g every 12 hours for 11 days) or cholestyramine (8 grams every 8 hours for 11 days), drug levels can remain elevated for months. Cross sensitivity to hepatic injury is likely between teriflunomide and leflunomide as well as thalidomide, but there have been no reports of cross sensitivity with other disease-modifying agents used to treat multiple sclerosis such as glatiramer acetate, dimethyl fumarate, fingolimod or interferon beta.

Drug Class: Multiple Sclerosis Agents

REPRESENTATIVE TRADE NAMES

Teriflunomide – Generic, Aubagio®

DRUG CLASS

Multiple Sclerosis Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

References updated: 20 September 2025

Abbreviations used: ULN, upper limit of the normal range

Zimmerman HJ. Oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 697-8.

(Expert review of hepatotoxicity published in 1999 before the availability of teriflunomide).

Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013.

(Multi-authored textbook of hepatotoxicity published in 2013 does not discuss the drugs for multiple sclerosis).

Krensky AM, Azzi JR, Hafler DA . I mmunotherapy for multiple sclerosis. Immunosuppressants and tolerogens. In, Brunton LL, Hilal-Dandan , Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 1 3 th ed. New York: McGraw-Hill, 201 8 , pp. 649-652 .

(Textbook of pharmacology and therapeutics).

O'Connor PW, Li D, Freedman MS, Bar-Or A, Rice GP, Confavreux C, Paty DW, Stewart JA, et al.; Teriflunomide Multiple Sclerosis Trial Group; University of British Columbia MS/MRI Research Group. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 2006; 66: 894-900. PMID: 16567708

(Among 179 patients with multiple sclerosis treated with teriflunomide [7 or 14 mg daily] or placebo for 36 weeks, ALT elevations occurred in 12-16% of teriflunomide vs 10% of placebo treated patients, but rates of discontinuation because of liver test abnormalities were similar in all groups).

O'Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, Benzerdjeb H, et al.; TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365: 1293-303. PMID: 21991951

(Among 1088 patients with relapsing multiple sclerosis treated with teriflunomide [7 or 14 mg daily] or placebo for 2 years, relapse rates were lower, but ALT elevations were more common with teriflunomide [54% and 57%] than placebo [36%], although elevations above 3 times the ULN were similar in all groups [~6.5%] and no patient developed clinically apparent liver injury attributable to treatment).

Gold R. Oral therapies for multiple sclerosis: a review of agents in phase III development or recently approved. CNS Drugs 2011; 25: 37-52. PMID: 21128693

(Review of oral medications for multiple sclerosis under development, including dimethyl fumarate [BG-12], fingolimod, teriflunomide, laquinimod and cladribine, mentions that ALT elevations are more frequent with teriflunomide than placebo treatment so that monitoring of liver enzymes during therapy is recommended).

Killestein J, Rudick RA, Polman CH. Oral treatment for multiple sclerosis. Lancet Neurol 2011; 10: 1026-34. PMID: 22014437

(Review of the clinical usefulness and safety of 5 new oral therapies for relapsing multiple sclerosis mentions that liver enzyme elevations can occur with teriflunomide and fingolimod therapy).

Confavreux C, Li DK, Freedman MS, Truffinet P, Benzerdjeb H, Wang D, Bar-Or A, et al; Teriflunomide Multiple Sclerosis Trial Group. Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years. Mult Scler. 2012; 18: 1278-89. PMID: 22307384

(Among 147 patients enrolled in clinical trials of teriflunomide who were entered into an open label extension study, mild elevations in ALT levels were common occurring in ~63% of patients, but were above 3 times ULN in only 12%, but no elevation was associated with symptoms or jaundice).

New drugs for relapsing multiple sclerosis. Med Lett Drugs Ther 2012; 54 (1403): 89-91. PMID: 23183318

(Concise review of efficacy, safety and costs of new disease modifying drugs for multiple sclerosis lists side effects in a table including "transaminase elevations" for interferon beta, fingolimod and teriflunomide, and "hepatotoxicity" for natalizumab, but not for glatiramer or mitoxantrone).

Brunetti L, Wagner ML, Maroney M, Ryan M. Teriflunomide for the treatment of relapsing multiple sclerosis: a review of clinical data. Ann Pharmacother 2013; 47: 1153-60. PMID: 24259730

(Systematic review of 6 phase II and III trials of teriflunomide in relapsing multiple sclerosis reports ALT elevations above 3 times ULN in 12-14% of teriflunomide vs 7% of control subjects; no mention of clinically apparent liver injury).

Garnock-Jones KP. Teriflunomide: a review of its use in relapsing multiple sclerosis. CNS Drugs 2013; 27: 1103-23. PMID: 24198223

(Review of the structure, mechanism of action, clinical efficacy and safety of teriflunomide in relapsing multiple sclerosis, mentions that ALT elevations are more frequent with teriflunomide than placebo, but are generally mild and asymptomatic with only a few cases having an accompanying elevation in bilirubin, rates being no higher with teriflunomide than with placebo; most ALT elevations occurred during the first year of therapy and, in half, the elevations returned to normal without stopping treatment).

Oh J, O'Connor PW. Safety, Tolerability, and Efficacy of Oral Therapies for Relapsing-Remitting Multiple Sclerosis. CNS Drugs 2013; 27: 591-609. PMID: 23801528

(Review of efficacy and safety or oral agents for multiple sclerosis, including fingolimod, teriflunomide, dimethyl fumarate, laquinimod and cladribine, none of which have raised major issues of hepatotoxicity).

Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS, Olsson TP, Bauer D, Benamor M, Truffinet P, O'Connor PW; TOPIC Study Group. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis(TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014; 13: 977-86. PMID: 25192851

(Among 614 patients with early multiple sclerosis treated with teriflunomide [7 or 14 mg daily] or placebo for up to 2 years, relapse rates were less while ALT elevations above 3 times ULN were more frequent with teriflunomide [12%] than placebo [9.5%], and there were no cases of clinically apparent liver injury).

Confavreux C, O'Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, Wolinsky JS, et al.; TOWER Trial Group. Oral teriflunomide for patients with relapsing multiple sclerosis(TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014; 13 (3): 247-56. PMID: 24461574

(Among 1169 patients with relapsing multiple sclerosis treated with teriflunomide [7 or 14 mg daily] or placebo for at least 48 weeks, the relapse rate was decreased, but ALT elevations occurred in 8% of teriflunomide and 6% of placebo-treated subjects; two patients developed jaundice with ALT elevations, and all recovered with discontinuation).

Pawate S, Bagnato F. Newer agents in the treatment of multiple sclerosis. Neurologist 2015; 19: 104-17. PMID: 25888198

(Summary of the efficacy and safety of new drugs for multiple sclerosis mentions that fingolimod, laquinimod and teriflunomide have been associated with serum enzyme elevations during treatment, but no specifics given).

Papadopoulou A, Kappos L, Sprenger T. Safety of teriflunomide for the management of relapsing-remitting multiple sclerosis. Expert Opin Drug Saf 2015; 14: 749-59. PMID: 25687236

(Review of the mechanism of action, efficacy and safety of teriflunomide in relapsing multiple sclerosis states that ALT elevations were more frequent with teriflunomide [11% to 14%] than placebo [7% to 8%], but that the elevations were mostly mild and asymptomatic, and rates of severe elevations and those accompanied by bilirubin increases were the same with teriflunomide as with placebo).

English C, Aloi JJ. New FDA-approved disease-modifying therapies for multiple sclerosis. Clin Ther 2015; 37: 691-715. PMID: 25846320

(Systematic review of efficacy and safety of the newer disease modifying therapies of multiple sclerosis lists ALT elevations as adverse events associated with fingolimod, teriflunomide and dimethyl fumarate, but not peginterferon beta or alemtuzumab).

Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-1352. PMID: 25754159

(Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 7 [0.8%] were attributed to interferon beta, but none were linked to teriflunomide or other drugs used for multiple sclerosis).

Feinstein A, Freeman J, Lo AC. Treatment of progressive multiple sclerosis: what works, what does not, and what is needed. Lancet Neurol 2015; 14: 194-207. PMID: 25772898

(Commentary on management of progressive multiple sclerosis in which most of the newer disease modifying agents have little effect, mentions that major attention should be paid to management and relief of symptoms such as fatigue, bladder dysfunction, spasticity, pain, depression and cognitive dysfunction; no discussion of liver related adverse effects).

O'Connor P, Comi G, Freedman MS, Miller AE, Kappos L, Bouchard JP, Lebrun-Frenay C, et al.; Teriflunomide Multiple Sclerosis Oral (TEMSO) Trial Group and the MRI-AC in Houston, Texas. Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study. Neurology 2016; 86: 920-30. PMID: 26865517

(Among 742 patients with multiple sclerosis treated with teriflunomide for up to 9 years in an extension study after a controlled trial [O'Connor 2011], 25 patients [2.8% to 3.8%] developed ALT elevations above 3 times the ULN and discontinued therapy and 2 had concurrent increases in bilirubin, although other causes were found in both).

Ancello S, Goliel T, Reddy S. Toxicity in the treatment: the first reported case of DILI induced by multiple sclerosis drug teriflunomide. Am J Gastro 2017;112:S1279-80. Not in PubMed.

(37 year old woman with multiple sclerosis developed fatigue and jaundice 6 months after starting teriflunomide [bilirubin 9.0 mg/dL, ALT 1498 U/L, Alk P 159 U/L] resolving after discontinuation).

Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA. Multiple sclerosis. Nat Rev Dis Primers. 2018;4:43. PMID: 30410033 .

(Review of the pathogenesis, clinical features, natural history, management and therapy of multiple sclerosis).

Antonazzo IC, Poluzzi E, Forcesi E, Riise T, Bjornevik K, Baldin E, Muratori L, et al . Liver injury with drugs used for multiple sclerosis: a contemporary analysis of the FDA Adverse Event Reporting System. Mult Scler. 2019;25:1633-1640. PMID: 30230957.

( Analysis of reports of liver injury to the FDA Adverse Events Reporting System between 2004 and 2016 suggested that the disease modifying agents for multiple sclerosis that appear to have hepatotoxic potential include interferon beta, teriflunomide, fingolimod, mitoxantrone and alemtuzumab, whereas glatiramer, dimethyl fumarate , and natalizumab do no t ).

LeSaint KT, Waksman J, Smolin CG. A case of teriflunomide-induced hepatic injury: assessing causality using available rules. Toxicol Communications 2020;4:62-66. Not in PubMed

( 48 year old man with multiple sclerosis developed fever and jaundice shortly after starting teriflunomide [bilirubin 6.2 mg/dL, ALT 478 U/L, Alk P 236 U/L] with rapid improvement on stopping and treatment with cholestyramine ).

Choudhary R, Ashraf R, Thakur V , Kumaran MS . Teriflunomide-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Clin Exp Dermatol. 2021;46:166-169. PMID: 32557734.

( 27 year old woman with multiple sclerosis developed fever, rash , and facial edema 3 weeks after starting teriflunomide [ALT 3827 U/L, bilirubin and Alk P not given , eosinophils 1600/ μ L ], with improvement on stopping and prednisolone and cholestyramine therapy but severe relapse when she stopped corticosteroid therapy and subsequent death from refractory septic shock).

Kingwell E, Zhang T, Zhu F, Walld R, Carruthers R, Evans C, Marrie RA, et al. Short-term laboratory and related safety outcomes for the multiple sclerosis oral disease-modifying therapies: an observational study. Expert Opin Drug Saf. 2021;20:481-487. PMID: 33342303.

(Among 1,140 patients placed on a disease modifying drug for multiple sclerosis between 2011 and 2016 in two Canadian provinces , de novo elevations in ALT arose in 12% of those on teriflunomide compared to 13% on dimethyl fumarate and 30% on fingolimod ).

Nehzat N, Mirmosayyeb O, Barzegar M, Vosoughi R, Fazeli E, Shaygannejad V. Comparable Efficacy and safety of teriflunomide versus dimethyl fumarate for the treatment of relapsing-remitting multiple sclerosis. Neurol Res Int. 2021;2021:6679197. PMID: 34336283.

(Among 159 Iranian patients with relapsing-remitting multiple sclerosis treated with either teriflunomide or dimethyl fumarate the matched cohorts had similar annualized relapse rates and adverse event rates [81% vs 88%] and “liver dysfunction” rates [15% vs 15%] while only 1 patient taking teriflunomide discontinued therapy because of “abnormal liver function” ).

Mian P, van Haaften WT, Assink M, van Drie-Pierik RJHM. Acute teriflunomide overdose with relatively mild symptoms: A case report. J Clin Pharm Ther. 2021;46:1784-1786. PMID: 33421160.

( 37 year old man with multiple sclerosis took an overdose of teriflunomide [672 mg: 48 tablets] along with cocaine and alcohol but suffered only mild headache and polyuria and blood testing revealed normal complete blood counts as well as liver and kidney tests ).

Kappos L, Fox RJ, Burcklen M, Freedman MS, Havrdová EK, Hennessy B, Hohlfeld R, et al. Ponesimod compared with teriflunomide in patients with relapsing multiple sclerosis in the active-comparator phase 3 OPTIMUM Study: a randomized clinical trial. JAMA Neurol. 2021;78:558–67. PMID: 33779698.

( Among 1133 adults with relapsing multiple sclerosis treated with oral ponesimod [20 mg] or teriflunomide [14 mg] once daily for up to 2 years, the annualized relapse rate was lower with ponesimod [0.2 vs 0.3] and overall adverse event rates were similar [89% vs 88%], while ALT elevations were more frequent with ponesimod [any elevation 20% vs 9%, elevation above 3 times ULN in 17% vs 8%, and resulting in discontinuation in 9% vs 6%], yet no patient developed clinically apparent acute liver injury with jaundice).

Drugs for multiple sclerosis. Med Lett Drugs Ther. 2021;63(1620):42–8.  PMID: 33976089.

(Concise review of the relative clinical efficacy, safety and costs of drugs for relapsing multiple sclerosis including parenteral agents [such as interferon-beta, glatiramer acetate, natalizumab, alemtuzumab, ocrelizumab, ofatumumab, rituximab and mitoxantrone] and the oral agents [such as the S1P receptor modulators, cladribine, fumarates, and teriflunomide], many of which are associated with serum ALT elevations and several have been reported to cause clinically apparent liver injury or reactivation of hepatitis B).

Biolato M, Bianco A, Lucchini M, Gasbarrini A, Mirabella M, Grieco A. The disease-modifying therapies of relapsing-remitting multiple sclerosis and liver injury: a narrative review. CNS Drugs. 2021;35:861-880. PMID: 34319570.

(Extensive review of the frequency and characteristics of hepatic injury associated with different disease modifying drugs for multiple sclerosis, mentions that in controlled trials, teriflunomide therapy was associated with ALT elevations in 31 % of patients that were above 5 times ULN in 2 %, while discontinuations for liver injury were uncommon [ 3% to 4 %], and since approval there have been no published cases of teriflunomide induced liver injury).

Ferreira CM, Vasconcelos-Pereira EF, Oliveira VM, Salgado PR, Domingos JA, Monreal MTFD, Guerra-Shinohara EM, et al. Hepatotoxicity associated with the use of teriflunomide in a patient with multiple sclerosis: A case report. Medicine (Baltimore). 2021;100:e28246. PMID: 34941096.

( 44 year old Brazilian woman with multiple sclerosis developed abdominal pain and nausea 48 days after starting teriflunomide [bilirubin 1.2 mg/dL, ALT 1384 U/L, GGT 690 U/L], with prompt improvement on discontinuation, later tolerating glatiramer ).

Wurzburger R. A case of delayed hepatic injury associated with teriflunomide use as assessed for causality using the updated RUCAM. Case Reports Hepatol. 2022;2022:6331923. PMID: 35756947.

( 60 year old woman with multiple sclerosis developed jaundice 9 months after starting teriflunomide [bilirubin 2.5 rising to 10.9 mg/dL, ALT 777 U/L, Alk P 478 rising to 972 U/L] with resolution of jaundice within a month of stopping but Alk P was still elevated [355 U/L] ).

Montalban X, Vermersch P, Arnold DL, Bar-Or A, Cree BAC, Cross AH, Kubala Havrdova E, et al.; evolution RMS investigators. Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials. Lancet Neurol. 2024;23:1119-1132. PMID: 39307151.

(Among 2290 adults with relapsing multiple sclerosis treated in two control trials of evobrutinib vs teriflunomide, the annualized relapse rate was similar in both arms [15% vs 14%] as were adverse event rates [86% vs 87%], including elevated ALT rates [15% vs 18%] although elevations above 5 times ULN within 12 weeks was higher with evobrutinib [5% vs <1%] as were combined elevations of bilirubin and ALT levels [in 3 vs 1 patient] ).

Ng HS, Zhu F, Zhao Y, Yao S, Lu X, Ekuma O, Evans C, Fisk JD, Marrie RA, Tremlett H. Adverse Events associated with disease-modifying drugs for multiple sclerosis: a multiregional population-based study. Neurology. 2024;102:e208006. PMID: 38181306.

(Among 35,894 people from 4 Canadian provinces with multiple sclerosis and available health data there was an increased risk for incident chronic liver disease in patients on teriflunomide and acute liver injury in those on dimethyl fumarate).

Dumitru-Martoiu MM, Petrescu S, Panea CA. Etiopathogenic and therapeutic considerations in a multiple sclerosis case with acute toxic hepatitis. Reports (MDPI). 2025;8:38. PMID: 40710829.

(39 year old woman with multiple sclerosis on long-term natalizumab [7 years] and ashwagandha for weight loss [1 month] took 4 to 5 tablets of acetaminophen [unknown dose] for 5 days for a upper respiratory infection and presented with jaundice and ecchymoses [bilirubin 7.6 mg/dL, ALT 2120 U/L, Alk P 247 U/L, R~25] with rapid recovery and normal ALT one week later).

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