OVERVIEW

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CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Teriflunomide	163451-81-8	C12-H9-F3-N2-O

ANNOTATED BIBLIOGRAPHY

References updated: 15 January 2017

• 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, Bennett WM, Vincenti F. A case study: immunotherapy for multiple sclerosis. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1025-7.

  (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. [PubMed: 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.

  (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. [PubMed: 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. [PubMed: 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. [PMC free article: PMC3573681] [PubMed: 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. [PubMed: 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. [PubMed: 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. [PubMed: 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. [PubMed: 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. [PubMed: 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. [PubMed: 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. [PubMed: 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. [PubMed: 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. [PubMed: 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. [PMC free article: PMC4446235] [PubMed: 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. [PubMed: 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. [PMC free article: PMC4782117] [PubMed: 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).