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Teriflunomide: A Once-daily Oral Medication for the Treatment of Relapsing Forms of Multiple Sclerosis

  • Aaron E. Miller
    Correspondence
    Address correspondence to: Aaron E. Miller, MD, Icahn School of Medicine at Mount Sinai and the Corinne Goldsmith Dickinson Center of Multiple Sclerosis, 5 East 98th, Box 1138, New York, NY 10029.
    Affiliations
    Icahn School of Medicine at Mount Sinai, New York, New York
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Open AccessPublished:September 10, 2015DOI:https://doi.org/10.1016/j.clinthera.2015.08.003

      Abstract

      Purpose

      The purpose was to summarize US prescribing information for teriflunomide in the treatment of patients with relapsing forms of multiple sclerosis (RMS), with reference to clinical efficacy and safety outcomes.

      Methods

      In September 2012, the US Food and Drug Administration granted approval for the use of teriflunomide, 14 mg and 7 mg once daily, to treat RMS on the basis of the results of a Phase II study and the Phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) trial. After recent updates to the prescribing information (October 2014), key findings from these and 2 other Phase III clinical trials, TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis) and TOPIC (Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis), and practical considerations for physicians are summarized.

      Findings

      Teriflunomide, 14 mg and 7 mg, significantly reduced mean number of unique active lesions on magnetic resonance imaging (MRI; P < 0.05 for both doses) in the Phase II study. In the TEMSO and TOWER studies, the 14-mg dose of teriflunomide significantly reduced annualized relapse rate (31% and 36% relative risk reduction compared with placebo, respectively; both P < 0.001) and risk of disability progression sustained for 12 weeks (hazard ratio vs placebo 0.70 and 0.69, respectively; both P < 0.05). The 7-mg dose significantly (P < 0.02) reduced annualized relapse rate in both studies, although the reduction in risk of disability progression was not statistically significant. Teriflunomide treatment was also associated with significant efficacy on MRI measures of disease activity in TEMSO; both doses significantly reduced total lesion volume and number of gadolinium-enhancing T1 lesions. TOPIC evaluated patients with a first clinical event consistent with acute demyelination and brain MRI lesions characteristic of multiple sclerosis. More patients were free of relapse in the teriflunomide 14-mg and 7-mg groups than in the placebo group (P < 0.05 for both comparisons). In safety data pooled from the 4 studies, adverse events occurring in ≥2% of patients and ≥2% higher than in the placebo group were headache, alanine aminotransferase increase, diarrhea, alopecia (hair thinning), nausea, paresthesia, arthralgia, neutropenia, and hypertension. Routine monitoring procedures before and on treatment are recommended to assess potential safety issues. Women of childbearing potential must use effective contraception and, in the event of pregnancy, undergo an accelerated elimination procedure to reduce plasma concentrations of teriflunomide.

      Implications

      Clinical evidence suggests that teriflunomide is an effective therapeutic choice for patients with RMS, both as an initial treatment and as an alternative for patients who may have experienced intolerance or inadequate response to a previous or current disease-modifying therapy.

      Key words

      Introduction

      Teriflunomide
      Trademark: Aubagio® (Genzyme, Cambridge, Massachusetts).
      is a once-daily oral immunomodulator with anti-inflammatory properties, licensed for the treatment of patients with relapsing forms of multiple sclerosis (RMS).
      Aubagio tablets [US prescribing information].
      Teriflunomide received US Food and Drug Administration (FDA) approval in September 2012 and was the second oral disease-modifying therapy to be licensed for RMS. Three oral agents are now available, including fingolimod†
      Trademark: Gilenya® (Novartis, East Hanover, New Jersey).
      ,
      Gilenya (fingolimod) capsules [US prescribing information].
      and dimethyl fumarate
      Trademark: Tecfidera® (Biogen Idec, Cambridge, Massachusetts).
      ,
      Tecfidera capsules [US prescribing information].
      which provide an alternative to the injectable therapies, interferon-β and glatiramer acetate, that have some limitations for tolerability, efficacy, and patient acceptability.
      The exact mechanism by which teriflunomide exerts its therapeutic effect in MS is not fully understood, but it likely involves a reduction in the number of activated lymphocytes that enter the central nervous system. Teriflunomide selectively and reversibly inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme in de novo pyrimidine synthesis that is required by rapidly dividing lymphocytes. Blocking dihydroorotate dehydrogenase results in a reversible cytostatic effect that limits the expansion of stimulated T and B cells thought to be responsible for the damaging inflammatory process associated with MS. In contrast, resting and slowly dividing cells, including lymphocytes and nonlymphoid cells, rely on the pyrimidine salvage pathway to meet their pyrimidine demand. Because this pathway is not affected by teriflunomide, basic homeostatic functions of resting and slowly dividing cells appear to be preserved, and immune cells remain available for immune surveillance.
      • Gold R.
      • Wolinsky J.S.
      Pathophysiology of multiple sclerosis and the place of teriflunomide.
      • Bar-Or A.
      • Pachner A.
      • Menguy-Vacheron F.
      • et al.
      Teriflunomide and its mechanism of action in multiple sclerosis.
      Teriflunomide is the active metabolite of leflunomide
      Trademark: Arava® (sanofi-aventis, Bridgewater, New Jersey).
      , a drug licensed for the treatment of active rheumatoid arthritis since 1998.
      Arava tablets [US prescribing information].
      The extensive clinical experience with leflunomide (>2.58 million patient-years of cumulative exposure) has informed the teriflunomide US prescribing information about its safety profile. However, note that leflunomide was only evaluated in patients with rheumatoid arthritis, whose condition is often confounded by comorbidities and concomitant medications.
      Teriflunomide is approved in >50 countries and, as of August 2014, ~30,000 patients were treated with teriflunomide in clinical trials and postmarketing settings worldwide.
      This review summarizes key data that supported FDA approval of teriflunomide, 14 mg and 7 mg, and informed recommendations in the US prescribing information. The prescribing recommendations are also reviewed, with the aim of providing a practical summary for US clinicians who wish to prescribe teriflunomide for patients with RMS.

      Key Findings from Clinical Trials

      The FDA approval of teriflunomide in September 2012 was based primarily on safety and efficacy data from 2 randomized, placebo-controlled clinical trials that evaluated the teriflunomide 14-mg and 7-mg once-daily doses in patients with RMS: the 108-week Phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) study (Study 1; NCT00134563
      • O׳Connor P.
      • Wolinsky J.S.
      • Confavreux C.
      • et al.
      Randomized trial of oral teriflunomide for relapsing multiple sclerosis.
      ) and a 36-week Phase II study (Study 4; NCT01487096
      • O׳Connor P.W.
      • Li D.
      • Freedman M.S.
      • et al.
      A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses.
      ). In October 2014, the teriflunomide prescribing information was updated to include data from 2 additional randomized, placebo-controlled Phase III trials: TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis; Study 2; NCT00751881
      • Confavreux C.
      • O׳Connor P.
      • Comi G.
      • et al.
      Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ) in patients with RMS, and TOPIC (Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis; Study 3; NCT00622700
      • Miller A.E.
      • Wolinsky J.S.
      • Kappos L.
      • et al.
      Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ) in patients with a first demyelinating event consistent with MS (Table I).
      Table IOverview of placebo-controlled trials of teriflunomide
      StudyStudy PopulationStudy DesignTreatment Arms
      All randomized patients who received one or more dose of study medication.
      Main End Points
      Phase IIClinically definite MSRandomized (1:1:1), double-blind, placebo-controlledTeriflunomide 14 mg/d (n = 57)Primary
      Aged 18–65 yearsDuration 36 weeksTeriflunomide 7 mg/d (n = 61)Number of combined unique active lesions per MRI scan
      EDSS score ≤6Placebo (n = 61)Secondary
      2 relapses in past 3 years; 1 relapse in past yearOther MRI measures
      Other MRI outcomes measured were the number of T1 enhancing lesions and T2 active lesions, the number patients with combined unique active lesions, and the percentage change from baseline in total lesion volume.
      Annualized relapse rateDisability progression
      TEMSO (Phase III)McDonald criteria (2001) for MS with relapsing course ± progressionRandomized (1:1:1), double-blind, placebo-controlledTeriflunomide 14 mg/d (n = 358)Primary
      Aged 18–55 yearsDuration 108 weeksTeriflunomide 7 mg/d (n = 365)Annualized relapse rate
      EDSS score ≤5.5Placebo (n = 363)Secondary
      ≥2 clinical relapses in previous 2 years or ≥1 relapse in past yearConfirmed disability progression sustained ≥12 weeks
      No relapse in 60 days before random assignmentMRI total lesion volume
      Number of Gd-enhancing lesions on T1-weighted images
      TOWER (Phase III)McDonald criteria (2005) for MS with relapsing course ± progressionRandomized (1:1:1), double-blind, placebo-controlledTeriflunomide 14 mg/d (n = 370)Primary
      Aged 18–55 yearsDuration up to 40 monthsTeriflunomide 7 mg/d (n = 407)Annualized relapse rate
      EDSS score ≤5.5Placebo (n = 388)Secondary
      ≥2 clinical relapses in previous 2 years or ≥1 relapse in past yearConfirmed disability progression sustained ≥12 weeks
      No relapse in 30 days before random assignment
      TOPIC (Phase III)Aged 18–55 yearsRandomized (1:1:1), double-blind, placebo-controlledTeriflunomide 14 mg/d (n = 214)Primary
      First clinical event consistent with acute demyelination ≤90 days before random assignmentDuration up to 108 weeksTeriflunomide 7 mg/d (n = 203)Time to relapse
      ≥2 T2-weighted MRI lesions ≥3 mm in diameterPlacebo (n = 197)Secondary
      Time to relapse or new MRI lesion
      EDSS = Expanded Disability Status Scale; Gd = gadolinium; MRI = magnetic resonance imaging; MS = multiple sclerosis.
      low asterisk All randomized patients who received one or more dose of study medication.
      Other MRI outcomes measured were the number of T1 enhancing lesions and T2 active lesions, the number patients with combined unique active lesions, and the percentage change from baseline in total lesion volume.

      Clinical and Magnetic Resonance Imaging Outcomes

      Phase II Study

      The 36-week Phase II study of 179 patients with clinically confirmed MS
      • Poser C.M.
      • Paty D.W.
      • Scheinberg L.
      • et al.
      New diagnostic criteria for multiple sclerosis: guidelines for research protocols.
      and a history of relapse reported positive outcomes with teriflunomide on magnetic resonance imaging (MRI) variables. The mean number of unique active lesions per scan was significantly lower in the teriflunomide 14-mg and 7-mg groups (0.98 and 1.06 lesions/scan, respectively) than in the placebo group (2.69 lesions/scan; P = 0.0052 and P = 0.0234, respectively) (Figure 1).
      Aubagio tablets [US prescribing information].
      • O׳Connor P.W.
      • Li D.
      • Freedman M.S.
      • et al.
      A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses.
      Figure thumbnail gr1
      Figure 1Effect of teriflunomide treatment on MRI-defined unique active lesions in the Phase II study of teriflunomide. MRI = magnetic resonance imaging.

      TEMSO

      TEMSO
      Aubagio tablets [US prescribing information].
      • O׳Connor P.
      • Wolinsky J.S.
      • Confavreux C.
      • et al.
      Randomized trial of oral teriflunomide for relapsing multiple sclerosis.
      enrolled 1088 patients with active disease (baseline Expanded Disability Status Scale [EDSS] scores ≤5.5, and at least 2 clinical relapses in the previous 2 years or 1 relapse during the preceding year) who met the McDonald 2001 criteria
      • McDonald W.I.
      • Compston A.
      • Edan G.
      • et al.
      Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.
      for MS and had a relapsing clinical course with or without progression. The majority of patients enrolled (91%) had relapsing-remitting MS, with the remainder having a progressive form of MS with relapses. Teriflunomide 14 mg significantly reduced the risk of confirmed disability progression sustained for 12 weeks compared with placebo (as measured by ≥1-point increase from baseline EDSS score ≤5.5 or a 0.5-point increase for those with a baseline EDSS score >5.5; P = 0.028; hazard ratio = 0.70) (Figure 2). At week 108, the estimated percentage of patients with 12-week sustained disability progression with the use of the Kaplan-Meier method was 20.2% and 27.3%, in the teriflunomide 14-mg and placebo groups, respectively. The 14-mg dose also significantly reduced annualized relapse rate (ARR) by 31% (P = 0.0005) compared with placebo (Figure 3), and the majority of patients (56.5%) remained relapse-free at week 108 compared with the 45.6% of patients that received placebo (Table II).
      Aubagio tablets [US prescribing information].
      Figure thumbnail gr2
      Figure 2Time to disability progression sustained for 12 weeks during the TEMSO (A) and TOWER (B) studies. Modified intent-to-treat population. Kaplan-Meier estimates for time-to-event data. HR was estimated with the use of a Cox proportional hazards model; P value was determined with the log-rank test. HR = hazard ratio. Adapted with permission.
      • O׳Connor P.
      • Wolinsky J.S.
      • Confavreux C.
      • et al.
      Randomized trial of oral teriflunomide for relapsing multiple sclerosis.
      • Confavreux C.
      • O׳Connor P.
      • Comi G.
      • et al.
      Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial.
      Figure thumbnail gr3
      Figure 3Annualized relapse rates in the TEMSO (A) and TOWER (B) studies. Modified intent-to-treat population. Adapted with permission.
      • O׳Connor P.
      • Wolinsky J.S.
      • Confavreux C.
      • et al.
      Randomized trial of oral teriflunomide for relapsing multiple sclerosis.
      Table IIClinical and MRI outcomes from the TEMSO and TOWER studies
      TEMSOTOWER
      Teriflunomide 14 mg (n = 358)Teriflunomide 7 mg (n = 365)Placebo (n = 363)Teriflunomide 14 mg (n = 370)Teriflunomide 7 mg (n = 407)Placebo (n = 388)
      Clinical results
       Annualized relapse rate (primary end point)0.3690.3700.5390.3190.3890.501
        P value0.00050.0002<0.00010.0183
        Relative risk reduction vs placebo, %31313622
       Patients remaining relapse-free at week 108, %56.553.745.657.158.246.8
       Patients with disability progression at week 108, %20.221.727.315.821.119.7
        P value0.0280.0840.0440.762
        Hazard ratio0.700.760.690.96
      MRI results
       Median change from baseline in total lesion volume
      Total lesion volume: sum of total volume of T2 lesion component and T1-hypointense lesion component measured by MRI.
      (mL) at week 108
      0.3450.7551.127
        P value0.0003
      Determined with cubic root-transformed data for total lesion volume.
      0.0317
      Determined with cubic root-transformed data for total lesion volume.
       Mean number of Gd-enhancing T1 lesions per scan0.2610.5701.331
        P value<0.0001<0.001
      Gd = gadolinium; MRI = magnetic resonance imaging.
      low asterisk Total lesion volume: sum of total volume of T2 lesion component and T1-hypointense lesion component measured by MRI.
      Determined with cubic root-transformed data for total lesion volume.
      Teriflunomide 7 mg also significantly reduced ARR by 31% (P = 0.0002) with 53.7% of patients remaining relapse free (Figure 3). However, the 7-mg dose did not have a significant effect on the risk of disability progression (P = 0.084) compared with placebo (Table II, Figure 2).
      The effect of teriflunomide on MRI variables was also assessed in TEMSO.
      Aubagio tablets [US prescribing information].
      • O׳Connor P.
      • Wolinsky J.S.
      • Confavreux C.
      • et al.
      Randomized trial of oral teriflunomide for relapsing multiple sclerosis.
      • Wolinsky J.S.
      • Narayana P.A.
      • Nelson F.
      • et al.
      Magnetic resonance imaging outcomes from a phase III trial of teriflunomide.
      Significant dose-dependent improvements with teriflunomide over placebo were seen in change from baseline in total lesion volume (the key MRI end point) and number of gadolinium-enhancing T1 lesions per scan (Table II and Figure 4).
      Figure thumbnail gr4
      Figure 4Key MRI outcomes from the TEMSO study. (A) Median change in total lesion volume from baseline. (B) Mean number of Gd-enhancing lesions per T1-weighted scan. Gd = gadolinium; TEMSO = Teriflunomide Multiple Sclerosis Oral.
      A post hoc analysis of TEMSO found that the efficacy of teriflunomide on ARR was consistent across a range of prespecified patient subgroups defined by sex, age, prior MS therapy, and baseline disease activity.
      Aubagio tablets [US prescribing information].
      • Miller A.E.
      • O׳Connor P.
      • Wolinsky J.S.
      • et al.
      Pre-specified subgroup analyses of a placebo-controlled Phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis.

      TOWER

      TOWER
      Aubagio tablets [US prescribing information].
      • Confavreux C.
      • O׳Connor P.
      • Comi G.
      • et al.
      Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial.
      included 1165 patients who met the McDonald 2005 criteria
      • Polman C.H.
      • Reingold S.C.
      • Edan G.
      • et al.
      Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”.
      for MS and had a relapsing clinical course (with or without progression). Most (98%) patients had relapsing-remitting MS, and the remaining 2% had a progressive form of MS with relapses.
      A significant reduction in the risk of disability progression sustained for 12 weeks (P = 0.044; hazard ratio = 0.69) was observed in the teriflunomide 14-mg group compared with placebo; at week 108, an estimated 15.8% of patients in the teriflunomide 14-mg group had 12-week sustained disability progression, compared with 19.7% in the placebo group (Figure 2). Teriflunomide 14 mg significantly reduced ARR by 36% (P = 0.0001) (Figure 3), and at week 108, 57.1% of patients treated with teriflunomide 14 mg were free from relapse, compared with 46.8% of patients given placebo (Table II). Teriflunomide 7 mg significantly reduced ARR by 22% compared with placebo (P = 0.0183) (Figure 3), but it had no significant effect on 12-week sustained disability progression (Table II). Teriflunomide treatment reduced ARR in a post hoc analysis of prespecified patient subgroups defined by sex, age, prior MS therapy, and baseline disease activity.
      Aubagio tablets [US prescribing information].

      TOPIC

      In the TOPIC study, patients (N = 614) had a first acute or subacute clinical event consistent with demyelination that occurred within 90 days of being randomly assigned, with ≥2 T2 lesions ≥3 mm in diameter on MRI, and were treated for up to 108 weeks. The proportion of patients free of relapse was greater in the teriflunomide 14-mg (72.2%; P < 0.05) and 7-mg (70.5%; P < 0.05) groups than in the placebo group (61.7%).
      Aubagio tablets [US prescribing information].
      • Miller A.E.
      • Wolinsky J.S.
      • Kappos L.
      • et al.
      Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial.

      Safety Profile and Tolerability

      Safety profile and tolerability data included in the US prescribing information are based on a pooled analysis of data from 2047 patients treated with teriflunomide in the studies discussed in the sections above. The most frequent adverse events in patients receiving teriflunomide (occurring in ≥2% of patients and ≥2% above the rate in patients receiving placebo) were headache, alanine aminotransferase (ALT) increase, diarrhea, alopecia (hair thinning), nausea, paresthesia, arthralgia, neutropenia, and hypertension (Table III).
      Aubagio tablets [US prescribing information].
      ALT increase was the event most frequently associated with treatment discontinuation in the pooled clinical studies, with 2.6 % and 3.3 % of patients discontinuing in the teriflunomide 14-mg and 7-mg groups, respectively, compared with 2.3% of patients in the placebo group.
      Aubagio tablets [US prescribing information].
      Table IIIAdverse events during placebo-controlled teriflunomide trials
      Reported in ≥2% of patients in at least 1 teriflunomide arm, and reported for teriflunomide 14 mg or 7 mg at ≥2% higher than the placebo group, in the Phase II, TEMSO, TOWER, and TOPIC studies.
      Adverse Event (% of patients)Teriflunomide 14 mg (N = 1002)Teriflunomide 7 mg (N = 1045)Placebo (N = 997)
      Headache161815
      ALT increase15139
      Diarrhea14138
      Alopecia13105
      Nausea1187
      Paresthesia987
      Arthralgia685
      Neutropenia642
      Hypertension432
      ALT = alanine aminotransferase.
      low asterisk Reported in ≥2% of patients in at least 1 teriflunomide arm, and reported for teriflunomide 14 mg or 7 mg at ≥2% higher than the placebo group, in the Phase II, TEMSO, TOWER, and TOPIC studies.

      Hepatic Events

      In clinical trials, if ALT increase was >3 times the upper limit of normal on 2 consecutive tests, teriflunomide treatment was to be discontinued and patients to undergo an accelerated elimination procedure. ALT >3 times the upper limit of normal occurred in 6.2% and 5.8% of patients receiving teriflunomide 14 mg and 7 mg, respectively, and 3.8% of patients receiving placebo. Most elevations occurred within the first year of treatment, and one-half of the cases returned to normal levels without stopping teriflunomide treatment.
      Aubagio tablets [US prescribing information].

      Pregnancy

      On the basis of animal studies, teriflunomide may be associated with teratogenicity. Fetal malformations were observed in pregnant rats and rabbits administered oral teriflunomide during organogenesis. In studies in which teriflunomide was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and incidences of limb malformations were observed. Teriflunomide is therefore contraindicated in pregnant women and women of childbearing potential who are not using reliable contraception. Although teriflunomide was positive in vitro in a chromosomal aberration assay in human lymphocytes at concentrations higher than exposure in clinical studies, other nonclinical studies found no evidence of genotoxicity, mutagenesis, or carcinogenesis.
      Aubagio tablets [US prescribing information].

      White Blood Cells

      Mean reductions in white blood cell counts (mainly lymphocytes and neutrophils) of ~15% were observed in a pooled analysis of placebo-controlled trials. These decreases occurred during the first 6 weeks of teriflunomide initiation and persisted during treatment, although mean absolute counts remained within the normal range for most patients.
      Aubagio tablets [US prescribing information].

      Infections and Malignancies

      No overall increase in the risk of serious infections was observed in patients treated with teriflunomide 14 mg (2.7%) or teriflunomide 7 mg (2.2%) compared with placebo (2.2%), and no increase in the incidence of malignancies and lymphoproliferative disorders was reported in the clinical studies.
      Aubagio tablets [US prescribing information].
      Because cases of tuberculosis were observed in clinical studies with teriflunomide, patients should be screened for latent tuberculosis infection and should be treated in case of a positive result, before initiation of teriflunomide treatment.

      Blood Pressure

      Increases in blood pressure were observed in patients who received teriflunomide in clinical studies, with mean increases of 2.7 mm Hg (teriflunomide 14 mg) and 2.3 mm Hg (teriflunomide 7 mg) in systolic blood pressure and <2 mm Hg in diastolic blood pressure in either group; the mean changes from baseline in the placebo group were –0.6 mm Hg (systolic) and –0.3 mm Hg (diastolic). Hypertension was reported as an adverse event in 4.3% and 3.1% of patients treated with teriflunomide 14 mg or 7 mg, respectively, compared with 1.8% for placebo.
      Aubagio tablets [US prescribing information].
      Four cardiovascular deaths (3 sudden deaths and 1 myocardial infarction in a patient with a history of hyperlipidemia and hypertension) were reported among ~2600 patients exposed to teriflunomide in the clinical development program. These deaths occurred during open-label extension studies, 1 to 9 years after initiation of teriflunomide treatment, and no relation between teriflunomide and cardiovascular death was established. In addition, no evidence was found that teriflunomide caused clinically significant prolongation in the QT interval in an ECG study performed in healthy subjects.
      Aubagio tablets [US prescribing information].
      • Menguy-Vacheron F.
      • Msihid J.
      • Poitiers F.
      • et al.
      Lack of effect on cardiac repolarisation with teriflunomide compared with placebo: a thorough ECG study.

      Peripheral Neuropathy

      Peripheral neuropathy, including both polyneuropathy and mononeuropathy (eg, carpal tunnel syndrome), occurred more frequently in patients treated with teriflunomide than in patients taking placebo. The incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.9% (17 patients) and 1.4% (13 patients) in patients receiving teriflunomide 14 mg and 7 mg, respectively, compared with 0.4% (4 patients) receiving placebo. Treatment was discontinued in 5 patients receiving the 14-mg dose and 3 patients receiving the 7-mg dose; 5 patients recovered after treatment discontinuation.

      Practical Considerations for Clinicians Prescribing Teriflunomide

      Clinicians wishing to initiate teriflunomide therapy in patients with RMS need to be aware of certain requirements for routine assessment of patients before initiation of therapy and for further monitoring during treatment. These requirements are discussed in more detail in the sections below and are summarized in Table IV.
      Table IVRoutine monitoring and counseling recommended before initiation of teriflunomide and during therapy
      Before Initiation of TeriflunomideDuring Teriflunomide Treatment
      Measure transaminase and bilirubin concentrations (within 6 months before starting therapy)Monitor ALT concentrations at least monthly (for 6 months)
      Exclude pregnancy and confirm use of reliable contraception; counsel patients on potential for serious fetal riskCheck blood pressure periodically
      Obtain complete blood count (within 6 months before starting therapy)Counsel patients to continue use of reliable contraception during therapy
      Screen for latent tuberculosis infection
      Check baseline blood pressure
      ALT = alanine aminotransferase.
      Teriflunomide safety assessments and recommendations in the US prescribing information were informed by leflunomide postmarketing experience, data from teriflunomide preclinical studies and clinical trials, and from implications of the known immunomodulatory mechanism of action of teriflunomide.

      Routine Measures before Initiation of Teriflunomide Therapy

      Rare cases of severe liver injury in the postmarketing setting were documented in patients treated with leflunomide, and monitoring requirements for hepatic enzymes were included in the teriflunomide prescribing information. Measurements of serum transaminase and bilirubin concentrations should be obtained within 6 months of starting teriflunomide treatment. Teriflunomide should not normally be given to patients with pre-existing acute or chronic liver disease or patients with a serum ALT concentration >2 times the upper limit of normal before treatment initiation.
      Data from animal studies suggest that teriflunomide may be associated with teratogenicity. Pregnancy must be avoided in women of childbearing potential who are taking teriflunomide, and the use of reliable contraception should be confirmed with the patient. Before treatment, pregnancy should be excluded, and patients should be counseled fully on the potential for serious fetal risk. Men not wishing to father a child and their female partners should use reliable contraception.
      Rare cases of pancytopenia, agranulocytosis, and thrombocytopenia were reported in the postmarketing setting with leflunomide, although no case of severe pancytopenia was reported for teriflunomide. On the basis of observed reductions in lymphocytes and neutrophils in clinical trials with teriflunomide, a complete blood count should be obtained within 6 months of starting treatment with teriflunomide.
      Patients with active infection should not start teriflunomide treatment until resolution of the infection. Cases of tuberculosis were observed in clinical studies with teriflunomide. Before initiating teriflunomide therapy, patients should be screened with a tuberculin skin test or blood test for latent tuberculosis infection, and patients with a positive result should be treated according to standard medical practice before teriflunomide treatment is initiated.
      Small increases in blood pressure were observed in teriflunomide studies. Blood pressure should be checked before the start of teriflunomide treatment and monitored thereafter.

      Routine Measures during Teriflunomide Therapy

      Serum ALT concentrations should be monitored at least monthly for 6 months after treatment initiation; additional monitoring should be considered if teriflunomide is administered with other potentially hepatotoxic drugs or if a patient develops symptoms suggestive of hepatic dysfunction.
      Male and female patients should be counseled to continue use of reliable contraception during therapy. If pregnancy does occur during treatment, teriflunomide should be discontinued immediately, and the accelerated elimination procedure described in the next section should be initiated until teriflunomide plasma concentrations are <0.02 μg/mL, a concentration at which minimal risk to the fetus is expected. For male patients who wish to father a child after commencing therapy, teriflunomide should be discontinued, and the accelerated drug elimination procedure should be implemented.
      Blood pressure should be checked periodically, and any cases of elevated blood pressure should be managed appropriately.

      Accelerated Elimination Procedure

      Teriflunomide is eliminated slowly from plasma, taking an average of 8 months to decline to plasma concentrations <0.02 µg/mL. Elimination of teriflunomide from plasma can be accelerated by the administration of cholestyramine (8 g or 4 g TID) or activated charcoal (50 g BID), which results in a >98% decrease in teriflunomide plasma concentration over 11 days (Figure 5). The recommended elimination procedure with the use of 8 g cholestyramine is more efficient than the lower dose; however, in cases of poor tolerability, the 4-g dose may be considered.

      Miller A, Turpault S, Menguy-Vacheron F. Rapid elimination procedure of teriflunomide with cholestyramine or activated charcoal. Presented at the Fourth Cooperative Meeting of CMSC and ACTRIMS, 30 May–2 June 2012, San Diego, CA. P10.

      Dosing does not need to take place on consecutive days unless an urgent lowering of teriflunomide plasma concentration is desired. Situations in which accelerated elimination of teriflunomide should also be considered are listed in Table V.
      Figure thumbnail gr5
      Figure 5Teriflunomide plasma concentrations after an accelerated elimination procedure. A loading dose of teriflunomide (70 mg/d for 3–4 days) was administered to achieve steady state rapidly; this was followed by a maintenance dose of teriflunomide 14 mg/d for 8 to 11 days. Cholestyramine (8 g or 4 g, TID) or activated charcoal (50 g, BID) was administered orally for 11 days after teriflunomide treatment. Adapted with permission.
      • Freedman M.S.
      Teriflunomide in relapsing multiple sclerosis: therapeutic utility.
      Table VTeriflunomide contraindications, warnings, and precautions in US prescribing information
      Warnings and PrecautionsRationale
       Severe hepatic impairmentLeflunomide/teriflunomide clinical trials
       Patients who are pregnant or women of childbearing potential not using reliable contraception (pregnancy category X)Leflunomide/teriflunomide preclinical toxicology
       Co-administration of leflunomideLeflunomide/immunomodulation
      Warnings and precautionsRationaleRecommendations While on Teriflunomide
       Hepatotoxicity
      The US prescribing information contains a Boxed Warning for hepatotoxicity and risk of teratogenicity.
      Leflunomide/teriflunomide clinical trialsDiscontinue teriflunomide if drug-induced liver injury is suspected; start accelerated elimination procedure, and monitor liver tests weekly until normalized
       Risk of teratogenicity
      The US prescribing information contains a Boxed Warning for hepatotoxicity and risk of teratogenicity.
      /use in women of childbearing potential
      Leflunomide/teriflunomide preclinical toxicologyIn patients who become pregnant/wish to become pregnant, discontinue teriflunomide immediately; start accelerated drug elimination until plasma concentration <0.02 μg/mL reached
      Because it is not known whether teriflunomide is present in breast milk, counsel patients on whether to continue teriflunomide or breastfeed; they should not do both
       Concomitant use with immunosuppressive or immunomodulating therapiesLeflunomide/immunomodulationIf decision is made to switch from teriflunomide to another DMT, monitor for hematologic toxicity and potential rebound of disease
       Accelerated elimination procedureLeflunomide/teriflunomide clinical trialsAccelerated elimination of teriflunomide should be implemented after discontinuation of teriflunomide in cases in which: (1) pregnancy occurs during teriflunomide therapy, (2) a patient taking teriflunomide wishes to become pregnant or father a child, (3) drug-induced liver injury is suspected, or (4) clinically significant toxicity emerges
       Bone marrow effects/immunosuppression potential/infectionsLeflunomide/teriflunomide immunomodulationCheck complete blood count within 6 months before starting therapy; base further monitoring on symptoms of bone marrow suppression
       Peripheral neuropathyLeflunomide/teriflunomide clinical trialsIf peripheral neuropathy is suspected, consider discontinuing teriflunomide and implementing accelerated elimination
       Skin reactionsLeflunomide
      Reported only in patients with rheumatoid arthritis receiving leflunomide. A similar risk would be expected for teriflunomide.
      In cases of Stevens-Johnson syndrome or toxic epidermal necrolysis, discontinue teriflunomide and implement accelerated elimination
       Blood pressure increaseLeflunomide/teriflunomide clinical trialsManage elevated blood pressure appropriately
       Respiratory effectsLeflunomide
      Reported only in patients with rheumatoid arthritis receiving leflunomide. A similar risk would be expected for teriflunomide.
      Consider teriflunomide discontinuation in cases of new onset or worsening pulmonary symptoms such as cough and dyspnea (± fever); if discontinuation is necessary, consider implementing accelerated elimination
      DMT = disease-modifying therapy.
      low asterisk The US prescribing information contains a Boxed Warning for hepatotoxicity and risk of teratogenicity.
      Reported only in patients with rheumatoid arthritis receiving leflunomide. A similar risk would be expected for teriflunomide.

      Pharmacokinetics

      A population pharmacokinetic (PK) analysis in healthy volunteers and patients with MS found that the median half-life of teriflunomide after repeated oral dosing of 14 mg and 7 mg is ~19 and 18 days, respectively. With daily dosing, steady-state concentrations are reached after ~3 months. No clinically significant impact of food was found on the PK profile of teriflunomide; therefore, teriflunomide can be taken with or without food.
      Moreover, mild and moderate hepatic impairment and severe renal impairment had no impact on the PK profile of teriflunomide. Consequently, no dose adjustment is necessary in patients with these conditions.
      Aubagio tablets [US prescribing information].
      • Turpault S.
      • Menguy-Vacheron F.
      • Limsakun T.
      Evaluation of pharmacokinetics and tolerability of oral teriflunomide in subjects with mild and moderate hepatic impairment.
      • Menguy-Vacheron F.
      • Clot P.-F.
      • Cai L.
      • et al.
      Effect of severe renal impairment on the pharmacokinetics and tolerability of teriflunomide.

      Drug–Drug Interactions

      In vitro studies found that teriflunomide is not metabolized by cytochrome P450 (CYP) or flavin monoamine oxidase enzymes, thereby limiting the potential for interactions with many co-administered drugs. However, teriflunomide may affect the exposure to concomitantly administered drugs metabolized by CYP2C8, CYP1A2, and organic anion transporter (OAT) 3. Teriflunomide also inhibits the action of breast cancer resistance protein and OAT peptides B1 and B3 (OATP1B1/B3) in vivo. Recommendations for patients receiving teriflunomide and agents metabolized by these agents and for patients receiving warfarin or ethinylestradiol and levonorgestrel are summarized in Table VI.
      Table VICo-administration of teriflunomide with other drugs
      Drug Category (Examples)EffectRecommendation While on Teriflunomide
      CYP1A2 substrates (caffeine, duloxetine, alosetron, theophylline, tizanidine)18% decrease in caffeine CmaxMonitor patients receiving a concomitant CYP1A2 substrate
      55% decrease in caffeine AUC
      CYP2C8 substrates (repaglinide, paclitaxel, pioglitazone, rosiglitazone)
      • 1.7-fold increase in repaglinide Cmax
      • 2.4-fold increase in repaglinide AUC
      Monitor patients receiving a concomitant CYP2C8 substrate
      CYP2C9 substrate (warfarin)25% decrease in peak INRMonitor INR closely
      Combined oral contraceptives (ethinylestradiol/levonorgestrel)Increase in ethinylestradiol Cmax and AUC0–24 (1.58-fold increase and 1.54-fold increase, respectively)Consider type or dose of oral contraceptive
      Increase in levonorgestrel Cmax and AUC0–24 (1.33-fold increase and 1.41-fold increase, respectively)
      OAT3 substrates (cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine)Inhibition of OAT3 by teriflunomide in vivoMonitor patients receiving a concomitant OAT3 substrate
      Adjust dose of OAT3 substrate if required
      OATP family (atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin, methotrexate, rifampin)Inhibition of OATP1B1/1B3 by teriflunomide in vivoMonitor patients closely for signs and symptoms of increased exposures to concomitant OATP1B1/1B3 substrates
      Consider reducing dose of OATP family drugs
      Dose of rosuvastatin should not exceed 10 mg once daily
      BCRP substrates (mitoxantrone)Inhibition of BCRP by teriflunomide in vivoMonitor patients closely for signs and symptoms of increased exposures to concomitant BCRP substrates
      Consider reducing dose of BRCP substrates
      BCRP = breast cancer resistance protein; CYP = cytochrome P450; INR = international normalized ratio; OAT = organic anion transporter; OATP = organic anion transporting peptide.
      The effects of co-administration of teriflunomide with antineoplastic or immunosuppressive MS therapies are not yet evaluated. No safety concerns were revealed during concomitant administration of teriflunomide with other immunomodulating therapies in Phase II combination studies for up to 1 year (interferon-β, glatiramer acetate), but the long-term safety profile of these combinations in the treatment of MS is not established.
      Aubagio tablets [US prescribing information].
      • Freedman M.S.
      • Wolinsky J.S.
      • Wamil B.
      • et al.
      Teriflunomide added to interferon-β in relapsing multiple sclerosis: a randomized phase II trial.
      • Freedman M.S.
      • Wolinsky J.S.
      • Wamil B.
      • et al.
      Oral teriflunomide plus glatiramer acetate in relapsing multiple sclerosis.
      Co-administration of teriflunomide with leflunomide is contraindicated.
      Aubagio tablets [US prescribing information].

      Summary

      Teriflunomide is a once-daily oral treatment option for adults with RMS, and data from 4 placebo-controlled, randomized trials support its use in these patients. The 14-mg dose had a significant impact on 3 key measures of MS disease activity: risk of sustained disability progression, ARR, and various MRI measures. The 7-mg dose also exhibited significant improvements on relapse rate and MRI outcomes and a numerical improvement on the risk of disability progression compared with placebo. Both teriflunomide doses had a similar safety profile and tolerability. Pretreatment clinical and laboratory evaluations and on-treatment monitoring will facilitate timely identification of any potential safety profile concerns that arise in patients treated with teriflunomide. In conclusion, these data suggest that teriflunomide is an effective treatment option for patients with RMS with a favorable benefit–risk profile and a therapeutic alternative for those patients unable to tolerate their past or current disease-modifying therapy.

      Conflicts of Interest

      AEM received research support from Biogen Idec, Genentech, Novartis, Questcor, Roche, and Sanofi and consulting fees from Accordant Health Services, Acorda Therapeutics, Alkermes, Biogen Idec, EMD Serono, Genentech, Genzyme, GSK, Mallinckrodt Pharmaceuticals [Questcor], Novartis, Roche, and Teva. The author has indicated that he has no other conflicts of interest regarding the content of this article.

      Acknowledgments

      The clinical trials reported in this review were sponsored by Genzyme, a Sanofi company. This manuscript was reviewed by Stephanie Jurgensen, MPH, of Genzyme. Editorial assistance was provided by Veronica Porkess, PhD, Fishawack Communications, also funded by Genzyme.
      Aaron Miller contributed to the selection of pre-clinical and clinical study data to be included in the review, the interpretation of data, the drafting of the manuscript, the review of all drafts, and final approval of the manuscript.

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