Teriflunomide (Aubagio®): A Comprehensive Pharmacological and Clinical Review for the Management of Relapsing Multiple Sclerosis

Executive Summary

Teriflunomide is an oral, once-daily, first-line disease-modifying therapy (DMT) approved for the treatment of relapsing forms of multiple sclerosis (MS). As a small molecule drug, it represents a significant evolution from the injectable platform therapies that once dominated MS management. Its primary mechanism of action is the selective and reversible inhibition of dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway. This action exerts a cytostatic effect on rapidly proliferating, activated T and B lymphocytes, which are central to the autoimmune pathogenesis of MS, thereby reducing neuroinflammation. The clinical efficacy of teriflunomide has been robustly established in pivotal Phase III trials, including TEMSO and TOWER, which demonstrated significant reductions in annualized relapse rates and a slowing of disability progression compared to placebo.

A defining characteristic of teriflunomide is its unique pharmacokinetic profile, marked by an exceptionally long elimination half-life of approximately two weeks, which is attributable to extensive enterohepatic recycling. This property necessitates a prolonged period to reach steady-state concentrations and means the drug can persist in the body for up to two years after discontinuation. This long half-life directly informs the drug's most critical safety considerations, which are codified in U.S. Food and Drug Administration (FDA) Boxed Warnings for hepatotoxicity and embryofetal toxicity. The risk of severe liver injury requires rigorous baseline and ongoing liver function monitoring, while the teratogenic potential contraindicates its use in pregnancy and mandates comprehensive contraceptive counseling for both female and male patients. An accelerated elimination procedure using cholestyramine or activated charcoal is a critical component of its management, required in cases of severe toxicity or planned pregnancy. Within the competitive MS therapeutic landscape, teriflunomide is positioned as an established oral option whose convenience is counterbalanced by a significant need for careful patient selection and diligent safety monitoring.

Introduction: The Evolution of Oral Disease-Modifying Therapies in Multiple Sclerosis

For decades, the therapeutic landscape for multiple sclerosis (MS) was defined by injectable disease-modifying therapies (DMTs). Agents such as interferon beta-1a, interferon beta-1b, and glatiramer acetate formed the cornerstone of treatment for relapsing forms of the disease.[1] While these platform therapies represented a monumental advance in reducing relapse frequency and mitigating disease activity, their parenteral route of administration imposed a significant treatment burden, often leading to injection-site reactions, flu-like symptoms, and challenges with long-term adherence. This created a clear and persistent unmet need within the MS community for effective treatments with more convenient administration routes.[4]

The paradigm of MS management underwent a fundamental shift beginning in 2010 with the approval of the first oral DMTs. This innovation heralded a new era of treatment, offering patients freedom from injections and a significant improvement in quality of life. Teriflunomide, marketed as Aubagio®, was a key agent in this therapeutic revolution, becoming the second oral tablet approved by the FDA for MS in 2012.[7] Its development was uniquely informed by its lineage as the principal active metabolite of leflunomide (Arava®), a drug with a long and well-characterized history in the treatment of rheumatoid arthritis since its approval in 1998.[7] This relationship provided a substantial foundation of safety and pharmacokinetic data, positioning teriflunomide as a well-understood molecule poised to address the need for effective and convenient oral MS therapy.

Drug Profile and Physicochemical Characteristics

Teriflunomide is a synthetic, small molecule compound with a well-defined chemical structure and distinct physical properties that influence its formulation and biological activity.

Chemical Identity

Teriflunomide is chemically classified as an enamide, derived from the formal condensation of the carboxy group of (2Z)-2-cyano-3-hydroxybut-2-enoic acid with the anilino group of 4-(trifluoromethyl)aniline.[13] This structure places it within several chemical classes, including nitriles, enols, aromatic amides, and (trifluoromethyl)benzenes.[13]

• Generic Name: Teriflunomide [1]
• IUPAC Name: (Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide [9]

Key Identifiers

The compound is uniquely identified by several standard chemical and drug registry numbers, ensuring its precise identification across scientific literature, regulatory databases, and commercial products.

• CAS Number: 163451-81-8 [9]
• DrugBank ID: DB08880 [9]
• Other Key Identifiers:
• UNII: 1C058IKG3B [9]
• ChEBI ID: CHEBI:68540 [9]
• ChEMBL ID: CHEMBL973 [9]
• KEGG ID: D10172 [9]

Molecular and Physical Properties

The physicochemical properties of teriflunomide are summarized in Table 1. It is a white to off-white crystalline powder with a molecular weight of approximately 270.21 g/mol.[14] A critical property is its solubility; it is practically insoluble in water but soluble in organic solvents like dimethyl sulfoxide (DMSO).[13] This low aqueous solubility is pH-dependent and is a key factor in its formulation as an oral solid dosage form.[23]

Table 1: Key Identifiers and Physicochemical Properties of Teriflunomide

Property	Value	Source(s)
IUPAC Name	(Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide	9
CAS Number	163451-81-8	9
DrugBank ID	DB08880	9
Molecular Formula	C12​H9​F3​N2​O2​	9
Molecular Weight	270.21 g/mol	9
Appearance	White to off-white crystalline powder	14
Solubility	Practically insoluble in water; Soluble in DMSO	13
Melting Point	227–232 °C	14
pKa	3.1	23
BCS Class	Class 2	23

Pharmaceutical Formulation

Teriflunomide is marketed for oral administration as film-coated tablets. It is available in two dosage strengths: 7 mg and 14 mg.[13] The tablets are distinguished by their appearance: the 7 mg tablet is a very light greenish-bluish grey to pale greenish-blue hexagonal tablet, while the 14 mg tablet is a pale blue to pastel blue pentagonal tablet.[28]

Developmental History and Regulatory Milestones

The development of teriflunomide for multiple sclerosis is a notable example of a "metabolite-as-drug" strategy, which leveraged decades of prior clinical experience to de-risk and streamline its path to approval.

The Leflunomide Connection

Teriflunomide is not a new chemical entity in terms of human exposure; it is the sole, principal active metabolite of leflunomide (Arava®), a drug approved in 1998 for the treatment of rheumatoid arthritis.[7] Upon oral administration, leflunomide undergoes rapid and near-complete conversion to teriflunomide through the opening of its isoxazole ring in the intestinal wall and liver.[6] Approximately 70% of an administered leflunomide dose is converted to teriflunomide, which is entirely responsible for the therapeutic effects observed.[9]

This pre-existing relationship was a profound advantage for the development of teriflunomide for MS. By the time clinical trials for MS began, a vast repository of human safety, tolerability, and pharmacokinetic data had already been accumulated from over a decade of leflunomide's use in a large population of patients with rheumatoid arthritis.[11] This extensive prior experience reduced the uncertainty typically associated with a new drug's behavior in the human body. It allowed developers to focus more intently on establishing efficacy in the new indication (MS) and provided regulatory agencies with a higher degree of confidence regarding the drug's long-term safety profile, particularly for known risks such as hepatotoxicity and teratogenicity, which were already well-characterized for leflunomide. This strategic leveraging of existing pharmacological knowledge likely shortened the development timeline and facilitated a more focused and efficient clinical trial program.

Clinical Development for Multiple Sclerosis

The rationale for investigating teriflunomide in MS stemmed directly from its known immunomodulatory effects and the extensive safety database from leflunomide.[6] The clinical development program was marked by several key trials:

• Phase II Study (NCT00228163): This initial trial provided the essential proof-of-concept, demonstrating that oral teriflunomide was effective in reducing MRI lesions and was well-tolerated in patients with relapsing MS, thereby justifying the move to larger, pivotal studies.[37]
• Phase III TEMSO Trial (NCT00134563): Completed in July 2010, the Teriflunomide Multiple Sclerosis Oral trial was the first pivotal study. It robustly demonstrated the efficacy of both 7 mg and 14 mg doses in reducing relapse rates and disability progression compared to placebo over two years. The positive results of TEMSO formed the core of the initial regulatory submissions.[6]
• Phase III TOWER Trial (NCT00751881): This second large-scale Phase III trial further substantiated the findings of TEMSO, confirming the significant efficacy of teriflunomide in reducing relapse rates and, for the 14 mg dose, delaying the progression of physical disability.[4]

Regulatory Approvals

Based on the strength of its clinical development program, teriflunomide gained approvals from major regulatory bodies worldwide.

• U.S. Food and Drug Administration (FDA):
• Teriflunomide was first approved in the United States on September 12, 2012, under the brand name Aubagio® (manufactured by Sanofi/Genzyme) for the treatment of relapsing forms of MS in adults.[7]
• In June 2021, the FDA issued a Complete Response Letter regarding the application for a pediatric indication, citing that the data from the TERIKIDS study were insufficient to support approval at that time.[43] The agency's review highlighted that the study failed to meet its primary endpoint, potentially due to study design elements and lower drug exposure in the pediatric cohort than in the adult population that established efficacy.[43]
• European Medicines Agency (EMA):
• The EMA's Committee for Medicinal Products for Human Use (CHMP) recommended marketing authorization on March 21, 2013.[45] Full marketing authorization valid throughout the European Union was granted on August 26, 2013, for the treatment of adult patients with RRMS.[46]
• In a significant divergence from the FDA's decision, the EMA approved teriflunomide for the treatment of pediatric patients aged 10 years and older with RRMS on June 18, 2021. This made it the first oral MS therapy available for this younger population in the EU.[47]

This discrepancy in pediatric approval between the two major regulatory bodies underscores the inherent challenges of conducting clinical trials in rare disease populations. The differing outcomes suggest that the EMA and FDA may have applied different risk-benefit assessments, with the EMA possibly placing greater weight on the unmet need for an oral therapy in pediatric MS or interpreting the totality of the evidence from the TERIKIDS study differently. This divergence has significant implications for global drug development strategies and highlights the complexities of achieving harmonized regulatory outcomes, particularly for pediatric indications.

• Generic Availability: Following the expiration of patents, generic versions of teriflunomide began receiving approval from regulatory agencies around 2018-2019, increasing market competition and access to the therapy.[49]

Comprehensive Pharmacological Profile

5.1 Mechanism of Action (MOA)

The therapeutic effect of teriflunomide in multiple sclerosis is primarily attributed to its targeted immunomodulatory activity.

• Primary Mechanism: Teriflunomide is a selective and reversible inhibitor of dihydroorotate dehydrogenase (DHODH), a critical enzyme located in the mitochondria.[1] DHODH catalyzes a key rate-limiting step in the de novo synthesis pathway of pyrimidines (uridine and cytidine), which are essential building blocks for DNA and RNA.[6]
• Immunomodulatory Outcome: In the context of MS, peripherally activated T and B lymphocytes undergo rapid proliferation, a process that places high demand on pyrimidine synthesis. By inhibiting DHODH, teriflunomide effectively deprives these rapidly dividing lymphocytes of the necessary pyrimidines, leading to a cytostatic (antiproliferative) effect.[6] This is a crucial distinction from cytotoxic agents, as teriflunomide does not directly kill the cells. Instead, it reduces the clonal expansion of pathogenic lymphocytes, thereby diminishing the pool of activated immune cells available to cross the blood-brain barrier and mediate inflammatory damage within the central nervous system (CNS).[13]
• Selective Action: The mechanism of teriflunomide confers a degree of selectivity. While activated lymphocytes are highly dependent on the de novo pathway, resting or homeostatically proliferating cells can utilize an alternative, DHODH-independent "salvage pathway" to recycle pyrimidines from degraded nucleic acids.[6] This allows teriflunomide to preferentially target the pathogenic, proliferating immune cells while having a more limited impact on the broader immune system. This targeted cytostatic approach underpins its safety profile, distinguishing it from older, broadly immunosuppressive or cytotoxic drugs and explaining why its primary risks are organ-specific toxicities rather than profound myelosuppression.[1]
• Secondary Mechanisms: While DHODH inhibition is the principal mechanism, other actions may contribute to teriflunomide's overall effect. These include the inhibition of tyrosine kinase enzymes, although this effect is observed at concentrations higher than those used clinically, and the modulation of the pro-inflammatory transcription factor NF-κB.[6]

5.2 Pharmacokinetics (ADME)

The absorption, distribution, metabolism, and excretion (ADME) profile of teriflunomide is defined by several key features, most notably its exceptionally long elimination half-life.

• Absorption: Following oral administration, teriflunomide is well absorbed, with a high bioavailability of nearly 100%. Peak plasma concentrations (Cmax​) are typically reached within 1 to 4 hours post-dose. The presence of food may delay the time to peak concentration (Tmax​) but does not have a clinically meaningful impact on the overall extent of absorption (AUC).[6]
• Distribution: Teriflunomide is extensively bound to plasma proteins, primarily albumin, with a binding percentage greater than 99%. This high degree of protein binding restricts its distribution to the plasma compartment, resulting in a low apparent volume of distribution of approximately 11 L.[6]
• Metabolism: Teriflunomide is only moderately metabolized, and the parent drug is the predominant component found circulating in the plasma. The primary metabolic pathway is hydrolysis, with oxidation, N-acetylation, and sulfate conjugation representing minor pathways. Importantly, teriflunomide is not significantly metabolized by cytochrome P450 (CYP450) enzymes.[23]
• Excretion: The most defining pharmacokinetic feature of teriflunomide is its very slow elimination, characterized by a median terminal half-life of 18 to 19 days.[6] This is a direct consequence of extensive enterohepatic recycling, a process where the drug is excreted via the bile into the gastrointestinal tract and is then substantially reabsorbed back into circulation.[34] This recycling loop dramatically prolongs the drug's presence in the body. Due to this slow elimination, it takes approximately 3.5 months to reach 95% of steady-state concentrations, and teriflunomide can remain detectable in the plasma for up to two years after the last dose.[23] Final elimination occurs through both feces (approximately 38%) and urine (approximately 23%).[9]

This single pharmacokinetic trait—extensive enterohepatic recycling leading to a very long half-life—is the central concept that dictates the entire clinical management strategy for teriflunomide. It elevates the significance of the drug's major toxicities from acute concerns to long-term risks. For a short-acting teratogen, contraception is required only during active treatment. For teriflunomide, its persistence for up to two years necessitates complex, long-term family planning for both women and men, and makes an active "washout" procedure essential for those who wish to conceive.[6] Similarly, in the event of severe hepatotoxicity, simply discontinuing the drug is insufficient to halt ongoing liver damage due to its prolonged presence; the accelerated elimination procedure becomes a mandatory emergency intervention.[59] This property fundamentally transforms teriflunomide from a simple once-daily oral medication into a therapy requiring a comprehensive, long-term management plan that includes extensive pre-treatment counseling, post-treatment planning, and a clear protocol for rapid elimination.

5.3 The Accelerated Elimination Procedure

Given the profound clinical implications of teriflunomide's long half-life, a specific procedure to rapidly clear the drug from the body is an integral part of its prescribing information and clinical management.

• Rationale: The accelerated elimination procedure is indicated in any situation where rapid removal of teriflunomide is desired. This includes cases of severe adverse events (e.g., liver injury, severe infection), in patients who become pregnant while on therapy, or in female or male patients who discontinue the drug and wish to conceive.[6]
• Methodology: The procedure works by interrupting the enterohepatic recycling of teriflunomide. Oral administration of a binding agent sequesters the drug in the gastrointestinal tract, preventing its reabsorption and promoting its fecal excretion. Two standard regimens are used:
• Cholestyramine: 8 grams administered every 8 hours (three times daily) for 11 days. A lower dose of 4 grams three times daily can be used if the standard dose is not well tolerated.[6]
• Activated Charcoal: 50 grams of oral powder administered every 12 hours (twice daily) for 11 days.[28]
• Efficacy: This 11-day procedure is highly effective, reducing plasma teriflunomide concentrations by over 98% and shortening the effective elimination half-life from weeks to approximately 1-2 days.[33] After completion, plasma concentrations should be verified to be below the target of 0.02 mg/L.

Clinical Efficacy in Relapsing Multiple Sclerosis

The efficacy of teriflunomide as a treatment for relapsing forms of MS has been established through a comprehensive clinical development program, including large, randomized, placebo-controlled Phase III trials.

6.1 Evidence from Phase III Placebo-Controlled Trials (TEMSO & TOWER)

The TEMSO and TOWER trials were the pivotal studies that formed the basis for teriflunomide's approval. They evaluated two doses, 7 mg and 14 mg daily, against placebo in patients with relapsing-remitting MS. The key efficacy findings are summarized in Table 2.

• Annualized Relapse Rate (ARR): Both trials consistently demonstrated that teriflunomide significantly reduced the ARR compared to placebo. The 14 mg dose produced a relative risk reduction of 31.5% in TEMSO and 36.3% in TOWER.[4] The 7 mg dose also provided a statistically significant reduction in ARR in both studies.[4]
• Disability Progression: A key secondary endpoint was the time to 12-week confirmed disability progression, a measure of sustained worsening of neurological function. In both TEMSO and TOWER, the 14 mg dose significantly reduced the risk of disability progression by approximately 30% compared to placebo.[4] In contrast, the 7 mg dose did not demonstrate a statistically significant effect on this outcome, establishing the 14 mg dose as superior for mitigating long-term disability accumulation.[65]
• MRI Outcomes: Teriflunomide demonstrated a potent effect on radiological markers of disease activity. Both the 7 mg and 14 mg doses led to significant reductions in the number of gadolinium-enhancing (Gd+) T1 lesions (a marker of active inflammation) and the burden of disease as measured by the volume of new or enlarging T2 lesions on brain MRI scans, compared to placebo.[6]

Table 2: Summary of Efficacy Endpoints from Pivotal Phase III Clinical Trials (TEMSO & TOWER)

Trial	Treatment Arm	Annualized Relapse Rate (ARR)	Risk Reduction in 12-Week Confirmed Disability Progression	Key MRI Outcome	Source(s)
TEMSO	Placebo	0.54	Baseline	Baseline	6
	Teriflunomide 7 mg	0.37 (31.2% reduction vs. placebo, p<0.001)	23.7% reduction (p=0.08)	Significant reduction in Gd+ lesions & T2 lesion volume	6
	Teriflunomide 14 mg	0.37 (31.5% reduction vs. placebo, p<0.001)	29.8% reduction (p=0.03)	Significant reduction in Gd+ lesions & T2 lesion volume	6
TOWER	Placebo	0.50	Baseline	Not a primary outcome	10
	Teriflunomide 7 mg	0.39 (22.3% reduction vs. placebo, p=0.02)	No significant effect	Not a primary outcome	10
	Teriflunomide 14 mg	0.32 (36.3% reduction vs. placebo, p<0.001)	31.5% reduction (p=0.04)	Not a primary outcome	10

6.2 Evidence in Early MS (TOPIC Trial)

The TOPIC trial (NCT00622700) was designed to evaluate the efficacy of teriflunomide in the earliest stages of MS, specifically in patients presenting with a first clinical demyelinating event, also known as clinically isolated syndrome (CIS).[45] The primary endpoint of the study was the time to a second clinical event, which would confirm a diagnosis of clinically definite MS (CDMS). The results demonstrated that both the 7 mg and 14 mg doses of teriflunomide significantly delayed the time to conversion to CDMS compared with placebo, supporting its use as an early intervention to slow the disease course.[67]

6.3 Long-Term Extension Studies and Real-World Evidence

The durability of teriflunomide's efficacy has been demonstrated in long-term extension studies of the pivotal trials. Data from the TEMSO extension, with follow-up extending up to 9-12 years, have shown that the treatment effect is maintained over time, with patients continuing to exhibit low rates of disease activity and a consistent safety and tolerability profile.[37]

Furthermore, real-world evidence from observational studies, such as the Teri-PRO (NCT01895335) and TAURUS-MS I studies, has provided valuable insights into the effectiveness and patient experience with teriflunomide in routine clinical practice. These studies have generally confirmed the efficacy findings from the randomized controlled trials and have highlighted high levels of treatment satisfaction among patients, likely attributable to the convenience of its once-daily oral administration.[70]

Clinical Application: Dosing, Administration, and Patient Management

The effective and safe use of teriflunomide in clinical practice requires adherence to specific guidelines regarding its indications, dosing, and a comprehensive monitoring plan.

7.1 Approved Indications

Teriflunomide is indicated for the treatment of relapsing forms of multiple sclerosis. This broad indication encompasses:

• Clinically Isolated Syndrome (CIS): The first episode of neurologic symptoms caused by inflammation and demyelination in the CNS.[28]
• Relapsing-Remitting Multiple Sclerosis (RRMS): The most common form of MS, characterized by clearly defined attacks of new or increasing neurologic symptoms.[10]
• Active Secondary Progressive Multiple Sclerosis (SPMS): A stage of MS that follows RRMS, characterized by progressive worsening of neurologic function with or without superimposed relapses.[28]

In the European Union, the indication is extended to include pediatric patients aged 10 years and older with RRMS.[13]

7.2 Dosing Regimens and Administration

• Adults: The recommended dose is either 7 mg or 14 mg, taken orally once daily.[27] The choice between the two doses may be guided by the balance of efficacy and tolerability for the individual patient, although the 14 mg dose has demonstrated superior efficacy in preventing disability progression.[6] The tablets can be administered with or without food.[28]
• Pediatric Population (EU only): The dosage is based on body weight to achieve exposures comparable to the adult 14 mg dose.
• Patients with body weight >40 kg: 14 mg once daily.[33]
• Patients with body weight ≤40 kg: 7 mg once daily.[33]

7.3 Mandatory Pre-Treatment Screening and Ongoing Monitoring

Due to its specific safety profile, a structured approach to screening and monitoring is essential for all patients initiating teriflunomide.

• Liver Function:
• Baseline: Transaminase (specifically ALT) and bilirubin levels must be obtained within 6 months before starting therapy.[28]
• Monitoring: ALT levels must be monitored at least monthly for the first six months of treatment.[28]
• Pregnancy Status:
• Baseline: Pregnancy must be excluded in females of reproductive potential before treatment initiation.[28]
• Counseling: All patients (both female and male) of reproductive potential must be counseled on the teratogenic risk and the need for effective contraception during and for a period after treatment.[40]
• Hematology:
• Baseline: A complete blood cell count (CBC) with differential should be obtained within 6 months before starting therapy.[28]
• Monitoring: Further monitoring should be based on clinical signs and symptoms of infection or bone marrow suppression.[28]
• Tuberculosis Screening:
• Baseline: Patients should be screened for latent tuberculosis (TB) infection with either a tuberculin skin test or an interferon-gamma release assay before initiation of therapy.[28]
• Blood Pressure:
• Baseline: Blood pressure should be checked before starting treatment.[28]
• Monitoring: Blood pressure should be monitored periodically throughout treatment.[28]

Safety and Tolerability Profile

The safety profile of teriflunomide is well-characterized, dominated by two major risks that have led to FDA Boxed Warnings. Adherence to monitoring guidelines is critical to mitigate these and other potential adverse events.

8.1 FDA Boxed Warnings

The prescribing information for teriflunomide includes boxed warnings for two significant risks:

• Hepatotoxicity: Teriflunomide carries a risk of severe and potentially life-threatening liver injury, including cases of acute liver failure requiring transplantation that have been reported in the postmarketing setting.[7] The risk is elevated in patients with pre-existing liver disease and in those taking other hepatotoxic medications concomitantly.[60] Consequently, teriflunomide is contraindicated in patients with severe hepatic impairment.[28]
• Embryofetal Toxicity (Teratogenicity): Based on data from animal reproduction studies, teriflunomide may cause major birth defects when administered during pregnancy.[7] Teratogenic effects were observed in multiple animal species at plasma exposures similar to or even lower than those achieved with the recommended human dose. As a result, teriflunomide is contraindicated for use in pregnant women and in females of reproductive potential who are not using effective contraception.[9] Due to the drug's long half-life and presence in semen, men wishing to father a child must also discontinue therapy and undergo the accelerated elimination procedure.[44]

8.2 Common and Serious Adverse Events

Beyond the boxed warnings, teriflunomide is associated with a range of other adverse events, summarized in Table 3.

• Common Adverse Events: The most frequently reported adverse reactions (occurring in ≥10% of patients and at a rate at least 2% greater than placebo in clinical trials) are an increase in alanine aminotransferase (ALT), alopecia (hair thinning or loss), diarrhea, nausea, and headache.[6]
• Serious and Clinically Significant Adverse Events:
• Bone Marrow Effects: Teriflunomide can cause a decrease in white blood cell counts (leukopenia) and neutrophil counts (neutropenia), which may increase the risk of infection.[6]
• Infections: Patients may have an increased susceptibility to infections, including serious and opportunistic infections.[33]
• Peripheral Neuropathy: Cases of peripheral neuropathy, manifesting as numbness, tingling, or pain in the hands and feet that is distinct from MS-related sensory symptoms, have been reported.[40]
• Hypersensitivity and Severe Skin Reactions: Rare but severe reactions, including anaphylaxis, angioedema, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been observed.[58]
• Increased Blood Pressure: Treatment can lead to new-onset or worsening of pre-existing hypertension.[28]
• Respiratory Effects: Rare cases of interstitial lung disease (ILD), which can be fatal, have been reported.[33]
• Pancreatitis: Cases of pancreatitis, some serious, have been reported, particularly in the pediatric population.[48]

Table 3: Summary of Common (≥10%) and Clinically Significant Serious Adverse Events

System Organ Class	Adverse Event	Frequency	Clinical Description/Management Note	Source(s)
Hepatobiliary	Increase in Alanine Aminotransferase (ALT)	Very Common	Can be a sign of liver injury. Requires monthly monitoring for first 6 months. Discontinue if liver injury is suspected.	28
	Severe Liver Injury / Liver Failure	Rare	Boxed Warning. Potentially life-threatening. Requires immediate discontinuation and accelerated elimination.	61
Skin & Subcutaneous	Alopecia (Hair Thinning/Loss)	Very Common	Generally mild to moderate, often occurs early in treatment and may improve over time.	28
	Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN)	Rare	Severe, life-threatening mucocutaneous reactions. Requires immediate discontinuation and medical intervention.	72
Gastrointestinal	Diarrhea	Very Common	Typically mild to moderate and self-limiting.	28
	Nausea	Very Common	Typically mild to moderate and self-limiting.	28
	Pancreatitis	Rare	Severe upper abdominal pain. Reported in pediatric patients. Requires discontinuation.	48
Nervous System	Headache	Very Common	Generally mild to moderate.	28
	Peripheral Neuropathy	Uncommon	Numbness or tingling different from MS symptoms. Consider discontinuation if it occurs.	40
Blood & Lymphatic	Neutropenia / Leukopenia	Common	Decrease in white blood cell counts. Increases risk of infection. Requires baseline CBC.	28
Vascular	Hypertension	Common	May cause or worsen high blood pressure. Requires baseline and periodic monitoring.	28
Respiratory	Interstitial Lung Disease (ILD)	Very Rare	New or worsening cough and dyspnea. Can be fatal. Requires investigation and discontinuation.	33

8.3 Contraindications

The use of teriflunomide is absolutely contraindicated in several specific situations due to the high risk of severe adverse outcomes. These are summarized in Table 4.

8.4 Clinically Significant Drug-Drug Interactions

Teriflunomide has the potential to interact with several other medications through various mechanisms, requiring careful management and monitoring. Key interactions are also detailed in Table 4.

Table 4: Key Contraindications and Major Drug Interactions

Category	Specific Agent/Condition	Clinical Consequence	Management Recommendation	Source(s)
Contraindications	Severe Hepatic Impairment	Increased risk of fatal hepatotoxicity.	Contraindicated.	28
	Pregnancy / Females of reproductive potential not using effective contraception	Boxed Warning for embryofetal toxicity.	Contraindicated.	77
	Hypersensitivity to Teriflunomide or Leflunomide	Risk of severe allergic reactions (e.g., anaphylaxis, SJS).	Contraindicated.	77
	Co-administration with Leflunomide	Substantially increases teriflunomide exposure and risk of toxicity.	Contraindicated.	61
Drug Interactions	CYP2C8 Substrates (e.g., amiodarone, diclofenac)	Teriflunomide is a weak inhibitor of CYP2C8, increasing exposure of substrates.	Use with caution; monitor for adverse effects of the co-administered drug.	27
	CYP1A2 Substrates (e.g., duloxetine, caffeine, erlotinib)	Teriflunomide is a weak inducer of CYP1A2, decreasing exposure and potentially efficacy of substrates.	Use with caution; monitor for reduced efficacy of the co-administered drug.	27
	BCRP and OATP1B1/B3 Substrates (e.g., rosuvastatin)	Teriflunomide inhibits these transporters, increasing exposure of substrates.	Monitor for adverse effects. Dose of rosuvastatin should not exceed 10 mg daily.	77
	Warfarin	Teriflunomide may decrease the International Normalized Ratio (INR).	Monitor INR closely upon initiation of teriflunomide.	77
	Other Immunosuppressants (e.g., adalimumab)	Additive immunosuppressive effects and increased risk of infection.	Avoid combination or use with extreme caution.	27
	Live Vaccines	Potential for vaccine-induced infection due to immunomodulatory effect.	Avoid co-administration.	60

Comparative Analysis and Therapeutic Positioning

The role of teriflunomide in MS management is best understood by comparing its efficacy, safety, and cost-effectiveness against other available DMTs. This comparison defines its therapeutic niche in a crowded and evolving treatment landscape.

9.1 Comparison with First-Line Oral DMTs

Teriflunomide is often compared to the other primary oral DMTs, dimethyl fumarate and fingolimod. A summary of their comparative profiles is presented in Table 5.

• vs. Dimethyl Fumarate (Tecfidera®): A substantial body of real-world and observational evidence has compared these two agents, with results often showing a slight advantage for dimethyl fumarate. Several studies have reported that treatment with dimethyl fumarate is associated with better clinical outcomes, including a longer time to first relapse and a lower risk of disability worsening.[84] Other analyses have found similar efficacy on clinical endpoints but superior performance for dimethyl fumarate on MRI outcomes, with a greater reduction in new lesion formation.[86] A consistent finding across studies is the difference in discontinuation patterns: patients are more likely to stop teriflunomide due to a perceived lack of efficacy, whereas discontinuation of dimethyl fumarate is more often driven by tolerability issues, particularly gastrointestinal side effects.[87]
• vs. Fingolimod (Gilenya®): Comparative observational studies consistently suggest that fingolimod may offer superior efficacy in reducing annualized relapse rates compared to teriflunomide.[88] However, the effect of the two drugs on disability progression appears to be similar, at least in the short-to-medium term of 2.5 years. An important differentiator is treatment persistence; studies have shown that patients are more likely to remain on fingolimod long-term compared to teriflunomide.[90]

Table 5: Comparative Profile of Teriflunomide vs. Other Key Oral DMTs for MS

Feature	Teriflunomide (Aubagio®)	Dimethyl Fumarate (Tecfidera®)	Fingolimod (Gilenya®)
Mechanism of Action	Reversible inhibition of dihydroorotate dehydrogenase (DHODH), blocking de novo pyrimidine synthesis.	Activation of the Nrf2 antioxidant pathway; immunomodulatory effects.	Sphingosine 1-phosphate (S1P) receptor modulator; sequesters lymphocytes in lymph nodes.
Dosing Frequency	Once daily	Twice daily	Once daily
Efficacy vs. Placebo (ARR Reduction)	~31-36%	~44-53%	~54%
Key Safety Concerns / Boxed Warnings	Hepatotoxicity, Embryofetal Toxicity	Lymphopenia, Progressive Multifocal Leukoencephalopathy (PML), flushing, GI events.	Bradycardia/AV block at initiation, macular edema, lymphopenia, PML, liver injury.
Required Monitoring	LFTs (monthly x 6 mo), BP, CBC, TB screen, Pregnancy test	CBC at baseline and periodically	First-dose observation (ECG, vitals), LFTs, ophthalmologic exam, CBC.
Patient Persistence / Discontinuation	Higher discontinuation for lack of efficacy.	Higher discontinuation for adverse events (GI, flushing).	Higher persistence compared to teriflunomide and dimethyl fumarate.

9.2 Comparison with Injectable DMTs

• vs. Interferon Beta-1a (Rebif®): The TENERE trial (NCT00883337) was a pivotal head-to-head study comparing teriflunomide with subcutaneous interferon beta-1a. The trial found that the 14 mg dose of teriflunomide demonstrated comparable efficacy to interferon beta-1a on the primary endpoint of time to treatment failure and on the secondary endpoint of ARR.[10] A key finding was that patients treated with oral teriflunomide reported significantly higher treatment satisfaction compared to those on the injectable interferon, highlighting the value of its convenient administration route.[65]
• vs. Glatiramer Acetate (Copaxone®): While no direct, head-to-head randomized trials have compared teriflunomide to glatiramer acetate, some real-world database analyses exist. One such study suggested that peginterferon beta-1a was associated with lower ARRs than both glatiramer acetate and teriflunomide, providing an indirect comparison.[96] Teriflunomide has been studied as a potential add-on therapy to glatiramer acetate, where it was found to have an acceptable safety profile and provided some additional reduction in MRI activity.[97]

9.3 Cost-Effectiveness Analysis

The economic burden of MS is substantial, with the high cost of DMTs being a major contributor.[99] The cost-effectiveness of teriflunomide varies depending on the comparator and the healthcare system being analyzed.

• In some economic models, particularly in European settings, dimethyl fumarate has been found to be a dominant strategy over teriflunomide, meaning it provides greater health benefits (in Quality-Adjusted Life Years, or QALYs) at a lower overall cost.[103]
• Newer, often higher-efficacy therapies like ofatumumab and ozanimod have also been shown in analyses to be more cost-effective or even dominant compared to teriflunomide.[99]
• Conversely, when compared to older injectable therapies, teriflunomide has demonstrated a favorable economic profile in certain markets. For instance, a study from the Chinese healthcare perspective found teriflunomide to be dominant over interferon beta-1b, providing higher QALYs at a lower total cost.[69]

The collective evidence positions teriflunomide in a specific therapeutic niche. Its initial value was as a convenient oral alternative to injectables with comparable efficacy to interferon beta-1a.[65] However, the emergence of other oral and high-efficacy therapies has refined its role. Real-world data suggest its efficacy may be moderately lower than that of dimethyl fumarate and fingolimod [84], while newer agents offer superior efficacy profiles.[99] Therefore, teriflunomide is often considered a suitable first-line oral option for patients who prioritize once-daily convenience, have moderate disease activity, and for whom the specific safety profile—particularly the contraindications related to pregnancy and liver disease—is acceptable. Its place in the treatment algorithm is increasingly challenged, reflecting the dynamic and rapidly advancing nature of MS therapeutics.

Future Directions and Emerging Research

Research involving teriflunomide continues to evolve, focusing on its potential use in earlier stages of the disease and its role as a benchmark for novel therapies.

New Indications

• Radiologically Isolated Syndrome (RIS): A significant recent advance has been the investigation of teriflunomide in RIS, a condition where individuals have MRI findings suggestive of MS but have not yet experienced clinical symptoms. The Phase 3 TERIS trial (NCT03122652) was designed to determine if early treatment with teriflunomide could delay the onset of a first clinical event. The trial yielded positive results, demonstrating that teriflunomide led to a significant risk reduction of 63% to 72% in preventing conversion to clinically definite MS compared to placebo.[110] These findings suggest a promising future role for teriflunomide as a preventive therapy in the preclinical phase of MS, potentially altering the disease course before clinical disability emerges.

Role as an Active Comparator

A key indicator of a drug's establishment as a standard of care is its use as an active comparator in clinical trials for new, investigational agents. Teriflunomide has now achieved this status. For example, the Phase III FREXALT trial (NCT04260711) is evaluating the efficacy and safety of frexalimab, a novel CD40L antibody, directly against teriflunomide in patients with relapsing MS.[112]

This transition into the role of an active comparator is a dual-edged sword. On one hand, it validates teriflunomide as an effective and ethically sound benchmark for MS treatment, confirming its important contribution to the field. On the other hand, the primary goal of such trials is for the new investigational drug to demonstrate superiority over the established one. This positioning signifies that while teriflunomide is a current standard, it is also the standard to be surpassed by the next generation of therapies. Its future role may increasingly be that of a yardstick against which innovation is measured, even as its own position as a first-line therapy is challenged by the very drugs being tested against it.

Mechanism of Action Research

While the primary MOA is well-established, research continues to explore the more nuanced effects of teriflunomide on the immune system. Studies are ongoing to better characterize its impact on different immune cell subsets, such as its capacity to modify B-cell activation and alter B-cell cytokine secretion profiles, providing a more complete picture of its immunomodulatory effects beyond its antiproliferative action on T-cells.[114]

Conclusion and Expert Insights

Teriflunomide has secured a firm and important position within the therapeutic armamentarium for relapsing forms of multiple sclerosis. As one of the first oral disease-modifying therapies, it offered a transformative improvement in convenience and treatment satisfaction over the long-standing injectable agents. Its efficacy, characterized by a moderate but consistent reduction in relapse rates and a delay in disability progression, is well-supported by a robust program of randomized controlled trials and long-term real-world evidence.

However, the clinical utility of teriflunomide is fundamentally defined by the interplay between its benefits and its unique safety and pharmacokinetic profile. Its exceptionally long elimination half-life, a direct result of enterohepatic recycling, amplifies the gravity of its two most significant risks: hepatotoxicity and embryofetal toxicity. These risks are not merely potential side effects but are central, management-defining characteristics that necessitate a rigorous framework of patient selection, comprehensive pre-treatment counseling for both women and men, mandatory safety monitoring, and a clear protocol for accelerated elimination.

In the current, highly competitive MS landscape, teriflunomide is situated as a valuable, albeit not the most potent, oral option. While newer agents may offer higher efficacy, teriflunomide remains a relevant choice, particularly for treatment-naïve patients with moderate disease activity who are not planning a family and have no underlying liver disease. Its recent success in delaying disease onset in radiologically isolated syndrome may open a new frontier for its use in preclinical MS. Ultimately, the decision to initiate teriflunomide must be a highly individualized one, carefully balancing its proven efficacy and oral convenience against its specific and significant risk profile in the context of a growing number of alternative therapies.

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