Aubagio
Hepatotoxicity: Clinically significant and potentially life-threatening liver injury, including acute liver failure requiring transplant, has been reported in patients treated with teriflunomide in the post-marketing setting. Concomitant use with other hepatotoxic drugs may increase the risk. Obtain transaminase and bilirubin levels within 6 months before initiation and monitor ALT at least monthly for 6 months after starting therapy.
Embryofetal toxicity: Teriflunomide may cause major birth defects if used during pregnancy. Teratogenicity and embryofetal lethality have been demonstrated in animal reproduction studies at plasma exposures lower than the maximum recommended human dose. Teriflunomide is contraindicated in pregnant women and in females of reproductive potential not using effective contraception. Pregnancy must be excluded before initiation; if pregnancy occurs, discontinue immediately and start an accelerated elimination procedure.
Indications
Teriflunomide is an oral, once-daily immunomodulator approved for the treatment of relapsing forms of multiple sclerosis. It is the principal active metabolite of leflunomide and exerts its effect through selective and reversible inhibition of dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo synthesis of pyrimidines required by rapidly dividing lymphocytes. Slow-dividing or resting lymphocytes, which rely on the salvage pathway, are largely spared, helping to preserve general immune competence. Teriflunomide was the second oral disease-modifying therapy approved for MS in the United States and remains a moderate-efficacy option in the modern DMT landscape, particularly valued for its convenience, well-characterised long-term safety profile, and broad real-world experience exceeding 100,000 patients and approximately 285,800 patient-years as of 2019.
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Relapsing forms of multiple sclerosis (RMS) — including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease | Adults (FDA, EMA) | Monotherapy | FDA & EMA Approved |
| Relapsing-remitting multiple sclerosis | Paediatric patients aged 10–17 years (EMA only) | Monotherapy | EMA Approved (2021) |
Teriflunomide is approved as monotherapy and is not indicated for primary progressive multiple sclerosis. The European Commission extended the approval to include children aged 10–17 years with relapsing-remitting MS in 2021 based on the TERIKIDS trial. The FDA has not approved paediatric use; the current US prescribing information explicitly states that effectiveness in patients aged 10–17 was not established in TERIKIDS, and notes that cases of pancreatitis were observed in this paediatric trial. Although the TOPIC study demonstrated significant reduction in conversion to clinically definite MS in patients with a first clinical demyelinating event, the FDA umbrella indication of “relapsing forms” already encompasses clinically isolated syndrome under the 2017 McDonald criteria.
Radiologically isolated syndrome (RIS) — the TERIS randomised trial (n=89) reported a 63% unadjusted risk reduction in time to a first clinical demyelinating event with teriflunomide 14 mg versus placebo over 96 weeks. Evidence quality: moderate (single phase 3 trial; small sample).
Paediatric MS in jurisdictions outside the EU — TERIKIDS missed its primary endpoint (time to relapse) but met key secondary MRI endpoints (T2 lesions reduced 55%, gadolinium-enhancing lesions reduced 75%). EMA-approved for ages 10–17; FDA has not approved this indication. Evidence quality: moderate.
Off-label use should follow shared decision-making and ideally be coordinated through neuroimmunology specialists.
Dosing
Teriflunomide is administered orally as a single daily tablet. No loading dose, dose titration, or weight-based adjustment is required. Both 7 mg and 14 mg doses are clinically active, but the 14 mg dose has shown more consistent benefit on disability progression in pivotal trials and is the preferred maintenance dose for most patients. Steady-state plasma concentrations are not reached for approximately 20 weeks, and the long terminal half-life (about 18–19 days) has important implications for adverse-event management, drug interactions, and pregnancy planning.
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Daily Dose | Notes |
|---|---|---|---|---|
| Relapsing MS — standard adult dosing | — | 14 mg PO once daily | 14 mg/day | Preferred dose; greater effect on confirmed disability progression in pivotal trials Take with or without food; food has no clinically relevant effect on absorption |
| Relapsing MS — alternative dose (tolerability concerns) | — | 7 mg PO once daily | 7 mg/day | Reasonable option for patients intolerant of 14 mg; both doses reduce annualised relapse rate, but the 7 mg dose did not consistently slow disability progression |
| Missed dose | — | Take the dose as soon as remembered on the same day | — | If close to the next scheduled dose, skip the missed dose and resume the next day Do not double-dose |
Accelerated Elimination Procedure
Teriflunomide undergoes extensive enterohepatic recycling and is eliminated slowly, taking approximately 8 months on average for plasma concentrations to fall below the recommended threshold of 0.02 mg/L (0.02 µg/mL); individual variation may extend this to 2 years. When rapid clearance is needed — suspected drug-induced liver injury, planned pregnancy or unintended pregnancy, severe adverse reaction, switch to another high-efficacy DMT, or overdose — an accelerated elimination procedure is performed.
- Cholestyramine 8 g orally every 8 hours for 11 days (preferred regimen). If 8 g is not tolerated, 4 g every 8 hours may be used, but the elimination is somewhat less complete.
- Activated charcoal 50 g orally every 12 hours for 11 days as an alternative when cholestyramine is poorly tolerated or contraindicated.
- Dosing days do not need to be consecutive unless plasma concentrations need to be lowered rapidly (e.g., toxicity, confirmed pregnancy).
- Both regimens reduce plasma concentrations by more than 98% over 11 days. Verify two separate plasma concentrations <0.02 mg/L at least 14 days apart before clearing the patient (e.g., for conception or for switching to another therapy with overlapping immunosuppression).
- Haemodialysis is not effective at removing teriflunomide because of its >99% plasma protein binding.
Special Populations
- Renal impairment: no dose adjustment required for any degree of impairment, including dialysis-dependent patients. Free fraction may rise modestly in severe impairment but did not require dose change.
- Mild–moderate hepatic impairment (Child-Pugh A or B): no dose adjustment.
- Severe hepatic impairment (Child-Pugh C): contraindicated. Pharmacokinetics not evaluated.
- Elderly (≥65 years): not specifically studied; pivotal trials enrolled patients up to 55 years. Use the standard 14 mg dose with closer monitoring of liver function and infection risk.
- Pregnancy: contraindicated. Effective contraception is required during therapy and until plasma teriflunomide is verified <0.02 mg/L (either after spontaneous elimination over ~8 months or after an accelerated elimination procedure).
- Lactation: avoid (contraindicated during breastfeeding per EMA SmPC). Teriflunomide is detected in rat milk; human data are insufficient. The long half-life means infant exposure could be prolonged.
- Paediatric patients (10–17 years): EMA-approved (2021) at 7 mg or 14 mg once daily based on TERIKIDS; the FDA has not approved paediatric use. Cases of pancreatitis were observed in the TERIKIDS trial.
- Males planning conception: teriflunomide is detected in human semen, but plasma concentrations in male partners are very low. Risk of male-mediated fetal toxicity is considered low; nevertheless, men wishing to father a child have the option to undergo an accelerated elimination procedure to reduce plasma teriflunomide to <0.02 mg/L before attempting conception.
Because of teriflunomide’s long half-life and its position as a moderate-efficacy DMT, clinicians frequently encounter switching scenarios. When switching to teriflunomide from injectable platform therapies, no washout is needed. When switching from teriflunomide to a higher-efficacy agent (e.g., natalizumab, ocrelizumab, ofatumumab, cladribine, S1P modulators), an accelerated elimination procedure is generally recommended to reduce the risk of additive immunosuppression — even in the absence of a documented adverse interaction. After elimination is verified (plasma <0.02 mg/L confirmed twice, ≥14 days apart), the new DMT can be initiated without further delay.
Pharmacology
Mechanism of Action
Teriflunomide is the principal active metabolite of leflunomide and exerts its therapeutic effect through selective, reversible, non-competitive inhibition of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme essential to the de novo synthesis of pyrimidines. Because activated, rapidly proliferating B and T lymphocytes are heavily dependent on de novo pyrimidine synthesis, teriflunomide reduces their expansion and effector function while leaving most other cell populations relatively unaffected. Resting and slow-dividing lymphocytes use the salvage pathway and are not significantly suppressed, helping to preserve baseline immune surveillance.
The clinical consequence in multiple sclerosis is a sustained reduction in the number of activated lymphocytes available to traffic to the central nervous system, fewer new and gadolinium-enhancing MRI lesions, lower annualised relapse rates, and — at the 14 mg dose — slower confirmed disability progression. A mean decrease of approximately 15% in white blood cell count (mainly neutrophils and lymphocytes) and approximately 10% in platelet count develops within the first 6 weeks and stabilises during ongoing therapy; most patients remain within normal laboratory ranges.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral bioavailability approximately 100%; Tmax 1–4 hours; food does not affect absorption to a clinically relevant extent. Linear pharmacokinetics across the dose range of 5–25 mg/day; AUC accumulation ratio at steady state is approximately 30 after repeated 7 or 14 mg doses | Tablets may be taken with or without food at any time of day; predictable systemic exposure across the licensed dose range |
| Distribution | Volume of distribution approximately 11 L after a single intravenous dose; plasma protein binding >99% (predominantly albumin); largely confined to plasma | Extensive protein binding contributes to the long residence time and explains why dialysis does not effectively remove the drug |
| Metabolism | Primary biotransformation is hydrolysis to minor metabolites; secondary pathways include oxidation, N-acetylation, and sulfate conjugation. CYP450 plays a minor role in elimination. Teriflunomide itself is an inhibitor of CYP2C8, BCRP, and OATP1B1/OATP1B3 in vivo, and a weak inducer of CYP1A2 | Limited cytochrome-mediated drug interactions as a victim; the most clinically relevant pharmacokinetic interactions arise from teriflunomide’s effects on transporters and CYP2C8 (e.g., rosuvastatin, repaglinide) |
| Elimination | Median terminal half-life approximately 19 days at 14 mg and 18 days at 7 mg; steady state reached in ~20 weeks. Over 21 days, 60.1% of an administered dose is excreted: 37.5% via faeces (primarily as unchanged drug through biliary secretion) and 22.6% via urine (mostly metabolites). Extensive enterohepatic recycling mediated by ABCG2 prolongs the half-life. Without intervention, plasma concentrations take an average of 8 months (up to 2 years in some individuals) to fall below 0.02 mg/L | Long half-life means therapeutic effect — and adverse effects — persist for many months after discontinuation; rapid clearance requires the accelerated elimination procedure with cholestyramine or activated charcoal, which reduces concentrations by >98% over 11 days |
Teriflunomide is the major circulating moiety detected in plasma after oral administration of the parent drug; minor metabolites are present at concentrations more than 1,000-fold lower than the parent drug. Anti-drug immunogenicity is not a feature, given that teriflunomide is a small molecule rather than a protein.
Side Effects
The safety profile of teriflunomide is well-characterised across more than 2,000 patients in placebo-controlled trials and over 285,800 patient-years of real-world exposure. Most adverse reactions are mild to moderate, occur early in therapy, and are self-limited. Frequencies below are drawn primarily from FDA prescribing information Table 1 (pooled placebo-controlled studies of approximately 2,047 teriflunomide-treated patients), the EMA Summary of Product Characteristics, and the long-term TEMSO and TOWER extension studies.
| Adverse Effect | Incidence (14 mg / 7 mg / placebo) | Clinical Note |
|---|---|---|
| Headache | 16% / 18% / 15% | Usually mild; standard analgesics and reassurance are typically sufficient. The placebo rate of 15% is also high — much of this is background |
| ALT increased | 15% / 13% / 9% | Mostly <3 × ULN; transient and often resolves with continued therapy. ALT >3 × ULN occurred in 6.2% (14 mg), 5.8% (7 mg), and 3.8% (placebo) of patients; half normalised without discontinuation |
| Diarrhoea | 14% / 13% / 8% | Generally mild to moderate; usually self-limited within the first few weeks. Symptomatic management is sufficient in most cases |
| Alopecia (hair thinning / decreased hair density) | 13% / 10% / 5% | Median onset 99 days; usually mild–moderate, reversible, and improves while remaining on therapy. Important early counselling point because of cosmetic concern |
| Nausea | 11% / 8% / 7% | Mild to moderate; typically resolves with continued therapy. Taking with food may improve tolerability |
| Mild neutropenia (lab finding: neutrophils <1.5 × 10⁹/L) | 16% / 12% / 7% | Lab abnormality, not a clinical AE; mean WBC drop of ~15% develops in the first 6 weeks and stabilises. Severe neutropenia is rare |
| Mild lymphopenia (lab finding: lymphocytes <0.8 × 10⁹/L) | 12% / 10% / placebo not specified | Lab abnormality; mean lymphocyte count typically remains around 1.5 × 10⁹/L. Severe lymphopenia is uncommon |
| Mild hypophosphataemia (lab finding: phosphorus ≥0.6 mmol/L) | 18% (pooled teriflunomide) / 7% placebo | Lab abnormality; clinically asymptomatic in essentially all patients. No serum phosphorus levels <0.3 mmol/L observed in trials |
| Adverse Effect | Incidence (14 mg / placebo) | Clinical Note |
|---|---|---|
| Hypertension | 4.3% / 1.8% | Mean systolic BP rise +2.7 mmHg; mean diastolic +1.9 mmHg. Usually responsive to lifestyle measures or standard antihypertensive therapy |
| Peripheral neuropathy (NCS-confirmed, pooled placebo-controlled trials) | 1.9% / 0.4% | Often improves after discontinuation but may persist; consider nerve conduction studies if suspected. Discontinuation usually warranted if confirmed |
| Influenza, upper and lower respiratory tract infections, urinary tract infection (per EMA SmPC: ≥1/100 to <1/10) | Common (1–10%) | Includes nasopharyngitis, bronchitis, sinusitis, pharyngitis, and cystitis. Mostly viral and self-limited; encourage seasonal vaccination |
| Paresthesia, sciatica, carpal tunnel syndrome (per EMA SmPC) | Common (1–10%) | Distinguish paresthesia from a possible MS relapse; monitor for evolving peripheral neuropathy |
| Acne, rash | Common (1–10%) | Usually mild and amenable to standard topical therapy |
| Arthralgia, myalgia, musculoskeletal pain, back pain | Common (1–10%) | Typically mild; standard analgesics |
| Anxiety, palpitations, vomiting, abdominal pain, toothache, weight decrease | Common (1–10%) | Per EMA SmPC; usually mild and self-limited |
| GGT and AST increased, blood creatine phosphokinase increased | Common (1–10%) | Lab findings; investigate clinically significant elevations; CPK rises rarely indicate myositis |
| Pollakiuria, menorrhagia | Common (1–10%) | Per EMA SmPC; symptomatic management |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Acute liver failure / severe hepatotoxicity (boxed warning) | Rare; post-marketing reports of cases requiring transplant | Any time, but the highest-risk monitoring window is the first 6 months | Discontinue immediately; start accelerated elimination with cholestyramine; refer to hepatology; investigate competing causes |
| Fetal harm (boxed warning) | Class effect based on animal data | First-trimester exposure of greatest concern | Confirm pregnancy with quantitative β-hCG; discontinue immediately; perform accelerated elimination; refer to maternal-fetal medicine; report to the Aubagio Pregnancy Registry (1-800-745-4447, option 2) |
| Bone marrow suppression (severe leukopenia, thrombocytopenia, pancytopenia) | Rare (post-marketing) | Variable; most often within the first months | Discontinue therapy; perform accelerated elimination; obtain haematology input |
| Serious infections (bacterial, viral, opportunistic) | 14 mg 2.7%; 7 mg 2.2%; placebo 2.2% (no overall increase in pooled trials) | Any time during therapy | Hold further dosing during severe infection; consider accelerated elimination if infection is opportunistic or fails to respond |
| Tuberculosis reactivation | Rare | Variable | Screen for latent TB before initiation; treat latent TB before starting; coordinate with infectious diseases for active disease |
| Severe skin reactions — Stevens–Johnson syndrome, toxic epidermal necrolysis (including a fatal case), DRESS (including a fatal case) | Rare (post-marketing) | Days to weeks after initiation | Discontinue immediately; perform accelerated elimination; refer for urgent dermatology and inpatient care if mucosal involvement or systemic features |
| Hypersensitivity / anaphylaxis / angioedema | Rare | Minutes to days | Discontinue permanently; perform accelerated elimination; manage acute reaction with epinephrine, antihistamines, and corticosteroids as indicated |
| Interstitial lung disease (acute interstitial pneumonitis) | Rare (post-marketing; class effect with leflunomide) | Variable, may be acute; can be fatal | Investigate new or worsening dyspnoea/cough with chest imaging; discontinue if confirmed; perform accelerated elimination |
| Hyperkalaemia and acute uric acid nephropathy with transient acute renal failure | Uncommon (per FDA PI; some elevations transient) | Variable | Monitor electrolytes and renal function as clinically indicated; manage acutely; consider accelerated elimination |
| Hypertensive crisis | Uncommon | Variable | Manage acutely; consider continuation of teriflunomide with antihypertensive therapy if no other contributing cause |
| Severe peripheral neuropathy (within the broader 1.9% NCS-confirmed neuropathy rate) | Rare | Variable | Discontinue; perform accelerated elimination if symptoms are progressive or disabling; consult neurology |
| Pancreatitis (paediatric trial finding) | Reported in TERIKIDS | Variable | If pancreatitis is suspected, discontinue teriflunomide and start accelerated elimination per FDA labelling |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| ALT elevation | 7 mg 3.3%; 14 mg 2.6%; placebo 2.3% | Most common reason for treatment discontinuation in pivotal trials. Most events are reversible after discontinuation and accelerated elimination |
| Hair thinning / alopecia (patient choice) | ~1–2% | Cosmetic concerns; counselling about reversibility may improve persistence |
| Diarrhoea or nausea | ~1–2% | Usually resolves with continued therapy; rarely warrants discontinuation alone |
| Pregnancy planning | ~1–2% | Long half-life requires either an 8-month spontaneous washout or an accelerated elimination procedure |
| Lack of efficacy / breakthrough disease activity | ~3–5% over long-term follow-up | Triggers escalation to higher-efficacy DMTs, often with accelerated elimination during the switch |
| Other adverse events / patient choice | ~3–5% | Includes peripheral neuropathy, hypertension, infections |
Hepatotoxicity is the most clinically important risk. Obtain transaminases and bilirubin within the 6 months before initiation, then check ALT at least monthly for the first 6 months of therapy, and every 6–12 weeks thereafter (or sooner if symptoms develop). If ALT exceeds 3 × ULN on a confirmed repeat measurement, discontinue teriflunomide and start an accelerated elimination procedure. Monitor LFTs weekly until normalisation. If liver injury is judged unrelated to teriflunomide after evaluation, resumption may be considered.
Drug Interactions
Teriflunomide is metabolised primarily by hydrolysis with minor CYP involvement, so it is a “victim” in relatively few interactions. As a “perpetrator,” it inhibits CYP2C8, BCRP, OATP1B1/1B3, and OAT3, and weakly induces CYP1A2. The most clinically important interactions are pharmacodynamic (additive immunosuppression, hepatotoxicity), the absolute contraindication with leflunomide, and the substrate-level effects on rosuvastatin, repaglinide, and warfarin.
Monitoring
Monitoring centres on the boxed warnings — hepatotoxicity and embryofetal toxicity — and on a structured pre-treatment workup that screens for infection, blood pressure, pregnancy, and baseline haematology. Most adverse events declare themselves within the first 6 months, so the monitoring schedule is most intensive during this window.
-
ALT (and AST, ALP, bilirubin)
Within 6 mo before initiation, then monthly × 6 months, then periodically (3–6-monthly) thereafter
Routine Cornerstone of safety monitoring (boxed warning). If ALT >3 × ULN is confirmed on repeat testing, discontinue teriflunomide and initiate accelerated elimination. Investigate symptoms of hepatic dysfunction (unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine) urgently regardless of recent normal LFTs. -
Pregnancy test
Before initiation in all patients of reproductive potential; rapid retest if any clinical suspicion
Routine Confirm a negative pregnancy test before starting therapy. Counsel about effective contraception during therapy and until plasma teriflunomide is verified <0.02 mg/L after discontinuation. Refer all suspected pregnancies for accelerated elimination and to maternal-fetal medicine; report to the Aubagio Pregnancy Registry (1-800-745-4447, option 2). -
Complete blood count with differential
Within 6 months before initiation, then periodically based on signs and symptoms of infection or marrow suppression
Routine Mild reductions in lymphocytes and neutrophils are expected. Severe cytopenia is rare but warrants discontinuation and accelerated elimination. -
Blood pressure
Baseline; periodically thereafter
Routine Hypertension occurs in 4.3% of 14 mg patients vs 1.8% on placebo. Manage with lifestyle measures or standard antihypertensive therapy; teriflunomide rarely requires discontinuation for hypertension alone. -
Tuberculosis screening
Before initiation
Routine Tuberculin skin test or interferon-gamma release assay; treat latent tuberculosis before starting therapy in line with local infection-control guidance. -
Hepatitis B and C screening
Before initiation
Routine Identify patients with chronic viral hepatitis who may require hepatology input and antiviral prophylaxis to limit hepatotoxicity risk. -
Vaccination review
Before initiation; annual seasonal vaccines on therapy
Routine Complete required live vaccines before starting; inactivated vaccines (influenza, pneumococcal, COVID-19, hepatitis B) generate adequate responses on therapy and are recommended. -
Symptom review
Every visit; safety-net all patients between visits
Routine Specifically ask about peripheral neuropathy symptoms (numbness, tingling, weakness), dyspnoea or new cough (interstitial lung disease), unexplained fever or skin rash, and new GI or hepatic symptoms. -
Brain MRI
Annually or per institutional MS protocol
Routine Assess MS disease activity (new T2 or gadolinium-enhancing lesions). Breakthrough activity may indicate need for escalation to a higher-efficacy DMT. -
Plasma teriflunomide concentration
After accelerated elimination procedure or when clearance must be verified
Trigger-based Confirm two separate plasma concentrations <0.02 mg/L at least 14 days apart before allowing pregnancy or before initiating another DMT with overlapping immunosuppression. -
Nerve conduction studies
If new sensory or motor symptoms suggest peripheral neuropathy
Trigger-based Confirmed peripheral neuropathy may warrant discontinuation; symptoms can persist after stopping therapy and may be slower to resolve without accelerated elimination. -
Chest imaging / pulmonary review
If new dyspnoea, persistent cough, or unexplained hypoxia
Trigger-based Investigate promptly for interstitial lung disease (a leflunomide-class effect); discontinue teriflunomide and start accelerated elimination if confirmed. -
Pancreatic enzymes (lipase, amylase)
If new severe abdominal pain (especially in paediatric patients)
Trigger-based Pancreatitis was observed in the TERIKIDS paediatric trial. Per current FDA labelling, if pancreatitis is suspected, discontinue teriflunomide and start an accelerated elimination procedure.
Contraindications & Cautions
Absolute Contraindications
- Severe hepatic impairment (Child-Pugh C). Pharmacokinetics not evaluated and risk of further hepatotoxicity is unacceptable.
- Pregnancy. Confirm a negative pregnancy test before initiation; teriflunomide is teratogenic and embryolethal in animals at exposures lower than the maximum recommended human dose.
- Females of reproductive potential not using effective contraception. Effective contraception must be in place before therapy begins and continued until plasma teriflunomide is verified <0.02 mg/L after discontinuation.
- Hypersensitivity to teriflunomide, leflunomide, or any inactive ingredient. Reactions have included anaphylaxis, angioedema, and serious skin reactions.
- Coadministration with leflunomide. Combined exposure produces additive teriflunomide toxicity.
Relative Contraindications (Specialist Input Recommended)
- Pre-existing acute or chronic liver disease, or baseline ALT >2 × ULN — generally avoid; if unavoidable, hepatology co-management and intensified LFT monitoring.
- Severe immunodeficiency, severe bone marrow disease, or severe uncontrolled infection — defer therapy until resolved or stabilised.
- Active or untreated latent tuberculosis — treat latent TB before initiation.
- Active hepatitis B or C — manage in conjunction with hepatology before initiation.
- Significant bone marrow suppression or recent treatment with myelosuppressive agents — avoid until haematology recovers.
- Concomitant use of strong hepatotoxins — avoid where possible; if unavoidable, intensify LFT monitoring.
Use with Caution
- Pre-existing peripheral neuropathy — monitor for worsening; consider alternative DMT.
- Significant cardiovascular disease or pre-existing hypertension — control blood pressure before initiation and monitor on therapy.
- Pre-existing interstitial lung disease — increased risk of recurrence or worsening (class effect with leflunomide).
- History of pancreatitis — consider given the paediatric TERIKIDS finding; monitor for new abdominal symptoms.
- Older adults (≥65 years) — limited trial data; use with closer monitoring.
- Patients with poor treatment adherence or unable to attend monthly LFT monitoring — adherence to safety monitoring is essential given the boxed warning for hepatotoxicity.
Clinically significant and potentially life-threatening liver injury, including acute liver failure requiring transplant, has been reported in patients treated with teriflunomide in the post-marketing setting. A similar risk was identified earlier with leflunomide because both drugs achieve similar plasma teriflunomide concentrations. Concomitant hepatotoxic drugs increase the risk. Obtain transaminases and bilirubin within 6 months before initiation and monitor ALT at least monthly for 6 months after starting therapy. Discontinue and start accelerated elimination if ALT >3 × ULN is confirmed.
Teriflunomide may cause major birth defects if used during pregnancy. Animal reproduction studies in rats and rabbits show teratogenicity and embryolethality at plasma teriflunomide exposures lower than the maximum recommended human dose of 14 mg/day. Teriflunomide is contraindicated in pregnant women and in females of reproductive potential not using effective contraception. Exclude pregnancy before initiation; if pregnancy occurs during therapy, discontinue immediately and perform an accelerated elimination procedure.
Mild reductions in white blood cell count and platelets occur during therapy; rarely, severe pancytopenia, agranulocytosis, or thrombocytopenia have been reported. Serious infections, including tuberculosis reactivation and opportunistic infections, may occur. Stevens–Johnson syndrome, toxic epidermal necrolysis (including a fatal case), and DRESS (including a fatal case) have been reported in the post-marketing setting. Cases of pancreatitis were observed in the paediatric clinical trial (TERIKIDS); discontinue teriflunomide and start an accelerated elimination procedure if pancreatitis is suspected.
Patient Counselling
Purpose of Therapy
Teriflunomide is a once-daily tablet that lowers the activity of certain immune cells (lymphocytes) that contribute to multiple sclerosis. It reduces relapses and slows the development of new MRI lesions; the 14 mg dose also slows the build-up of disability. It does not cure MS, and it may take several months to reach its full effect.
How to Take
Swallow one tablet (7 mg or 14 mg) by mouth once a day. The tablet may be taken with or without food, at any time of day, but consistency helps with adherence. Do not stop teriflunomide without speaking to a clinician — because the medication remains in the body for up to 8 months (occasionally up to 2 years), sudden discontinuation does not provide rapid clearance. If a more rapid removal is needed (for example, for pregnancy planning, suspected liver injury, or before starting another medication), a clinician will prescribe an “accelerated elimination procedure” using cholestyramine or activated charcoal for 11 days.
Sources
- Sanofi-Genzyme. AUBAGIO (teriflunomide) tablets — Full Prescribing Information. https://products.sanofi.us/aubagio/aubagio.pdf Primary US labelling; authoritative source for indications, dosing, boxed warnings, contraindications, drug interactions, monitoring, and adverse reaction tables (Table 1).
- US Food and Drug Administration. AUBAGIO (teriflunomide) — Approved Labelling, NDA 202992 (s017). 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/202992s017lbl.pdf Most recent FDA-approved label revision; reflects the current wording of the boxed warning (HEPATOTOXICITY and EMBRYOFETAL TOXICITY) and the paediatric pancreatitis precaution.
- European Medicines Agency. Aubagio: EPAR — Product Information. https://www.ema.europa.eu/en/documents/product-information/aubagio-epar-product-information_en.pdf European Summary of Product Characteristics; primary source for the EMA paediatric (10–17 years) approval and the EMA frequency tables for adverse reactions.
- National Library of Medicine. AUBAGIO — DailyMed Drug Label. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4650d12c-b9c8-4525-b07f-a2d773eca155 Continuously updated repository of the latest FDA-approved labelling text for clinician reference.
- O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293–1303. https://doi.org/10.1056/NEJMoa1014656 TEMSO pivotal phase 3 trial (n=1,088) establishing efficacy of teriflunomide 7 mg and 14 mg vs placebo over 108 weeks; primary source for ARR (0.37 vs 0.54), confirmed disability progression, and adverse-event rates.
- 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. Lancet Neurol. 2014;13(3):247–256. https://doi.org/10.1016/S1474-4422(13)70308-9 Second pivotal phase 3 trial confirming reduction in ARR (36% relative reduction at 14 mg vs placebo) and disability progression in 1,169 patients.
- Vermersch P, Czlonkowska A, Grimaldi LM, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014;20(6):705–716. https://doi.org/10.1177/1352458513507821 TENERE active-comparator trial; teriflunomide 14 mg achieved annualised relapse rate similar to subcutaneous IFN beta-1a, supporting its place as a moderate-efficacy oral alternative.
- Miller AE, Wolinsky JS, 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. Lancet Neurol. 2014;13(10):977–986. https://doi.org/10.1016/S1474-4422(14)70191-7 Phase 3 trial in 618 clinically isolated syndrome patients; demonstrated reduction in conversion to clinically definite MS.
- O’Connor P, Comi G, Freedman MS, et al. Long-term safety and efficacy of teriflunomide: nine-year follow-up of the randomized TEMSO study. Neurology. 2016;86(10):920–930. https://doi.org/10.1212/WNL.0000000000002441 Long-term TEMSO extension; supports cumulative AE-related discontinuation rates and durable efficacy on relapses and MRI activity.
- Comi G, Freedman MS, Kappos L, et al. Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions. Mult Scler Relat Disord. 2016;5:97–104. PMID 26856952. Pooled safety analysis from phase 2, TEMSO, TOWER, and TOPIC; primary source for very common adverse events at incidence ≥10% and ≥2% above placebo: ALT increase, headache, diarrhoea, hair thinning, nausea.
- Chitnis T, Banwell B, Kappos L, et al. Safety and efficacy of teriflunomide in paediatric multiple sclerosis (TERIKIDS): a multicentre, double-blind, phase 3, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(12):1001–1011. https://doi.org/10.1016/S1474-4422(21)00364-1 Phase 3 paediatric trial (n=166; 109 teriflunomide, 57 placebo) supporting EMA paediatric approval; primary endpoint not met but T2 lesion burden reduced 55% and gadolinium-enhancing lesions reduced 75%.
- Lebrun-Frénay C, Siva A, Sormani MP, et al. Teriflunomide and time to clinical multiple sclerosis in patients with radiologically isolated syndrome: the TERIS randomized clinical trial. JAMA Neurol. 2023;80(10):1080–1088. https://doi.org/10.1001/jamaneurol.2023.2815 Phase 3 trial (n=89) in radiologically isolated syndrome; teriflunomide 14 mg reduced the risk of a first clinical demyelinating event by 63% (unadjusted) versus placebo.
- Bar-Or A, Pachner A, Menguy-Vacheron F, Kaplan J, Wiendl H. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs. 2014;74(6):659–674. https://doi.org/10.1007/s40265-014-0212-x Comprehensive mechanism review; underpins the DHODH inhibition / pyrimidine de novo synthesis description in the Pharmacology section.
- National Institutes of Health, LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Teriflunomide. https://www.ncbi.nlm.nih.gov/books/NBK548525/ Authoritative summary of teriflunomide hepatotoxicity, supporting the boxed warning narrative and monitoring recommendations.
- Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis. Neurology. 2018;90(17):777–788. https://doi.org/10.1212/WNL.0000000000005347 American Academy of Neurology guideline (reaffirmed 2024) positioning teriflunomide among DMT options for active relapsing MS.
- Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Eur J Neurol. 2018;25(2):215–237. https://doi.org/10.1111/ene.13536 European treatment guideline informing positioning of teriflunomide as a moderate-efficacy first-line oral DMT.
- Vukusic S, Carra-Dalliere C, Ciron J, et al. Pregnancy and multiple sclerosis: 2022 recommendations from the French multiple sclerosis society. Mult Scler J. 2023;29(1):11–36. https://doi.org/10.1177/13524585221129472 Practical guidance on managing DMTs around conception and lactation; informs the contraindications, monitoring, and counselling sections.