Teriflunomide

Introduction Overview

Generic Name

teriflunomide

Brand Name

Aubagio

Dosage Form

Tablets (7 mg, 14 mg)

Drug Class

Selective immunosuppressants

Pharmacokinetics

Absorption

Teriflunomide is well absorbed from the gastrointestinal tract, with peak plasma concentrations reached approximately 1 to 4 hours following oral administration. The absolute bioavailability is high, and absorption is not significantly affected by food ingestion, allowing flexibility in dosing with or without meals. The drug demonstrates linear pharmacokinetics over the therapeutic dose range. Due to its long half-life, steady state plasma concentrations are reached after several weeks to months of continuous dosing. Food does not substantially alter the extent or rate of absorption, ensuring consistent drug exposure regardless of meal timing or content.

Distribution

Following absorption, teriflunomide is extensively distributed throughout body tissues and is highly bound to plasma proteins, primarily albumin, with plasma protein binding estimated to be greater than 99%. This high protein binding influences its volume of distribution, estimated at approximately 70 liters, indicating extensive distribution beyond the plasma compartment. Teriflunomide crosses biological membranes but has limited penetration into the central nervous system, which is relevant for its mechanism in multiple sclerosis. The drug also partitions into erythrocytes to some extent, contributing to its overall distribution profile.

Metabolism

Teriflunomide undergoes minimal metabolism, with the major route of elimination being unchanged drug. It is neither extensively metabolized by hepatic enzymes nor does it undergo significant cytochrome P450–mediated metabolism, reducing potential for metabolic drug interactions. Minor metabolic pathways may involve hydrolysis and conjugation, but these represent a very small fraction of elimination. The drug's pharmacokinetics are not significantly affected by polymorphisms in liver enzymes, consistent with its non-reliance on hepatic metabolism for clearance.

Elimination

Teriflunomide demonstrates a notably long terminal half-life of approximately 18 to 19 days, due primarily to extensive enterohepatic recirculation and slow clearance mechanisms. Excretion occurs mainly via biliary elimination into feces, with a smaller amount eliminated in urine as unchanged drug. The prolonged elimination necessitates consideration of drug elimination procedures in cases of toxicity or pregnancy. Because of this prolonged half-life, teriflunomide may remain in systemic circulation for up to two years post-treatment, and accelerated elimination protocols utilizing cholestyramine or activated charcoal are sometimes employed to enhance drug clearance.

Dosage Forms

Adults

For adult patients with relapsing forms of multiple sclerosis, teriflunomide is administered orally as tablets at dosages of either 7 mg or 14 mg once daily. The choice of dose depends on patient-specific factors including tolerability and clinical response. The medication can be taken with or without food, which enhances patient adherence and convenience. Regular monitoring via liver function tests and blood counts is recommended while under therapy.

Adolescents

While specific pediatric usage data for teriflunomide in adolescents is limited and its safety and efficacy have not been firmly established in individuals under 18 years of age, use in this population requires careful clinical judgment, weighing potential benefits and risks. Dosing, if considered, should be individualized and closely monitored under specialist supervision in multiple sclerosis clinics. There are no currently approved teriflunomide formulations specifically indicated for pediatric patients.

Special Populations

Special populations such as patients with hepatic impairment should avoid teriflunomide due to the risk of exacerbated liver toxicity. Renal impairment does not significantly alter teriflunomide pharmacokinetics, but caution is advised. The drug is contraindicated in pregnancy due to teratogenicity risks and requires effective contraception during and for an extended period after discontinuation. Elderly patients should be evaluated individually, as no specific dosing adjustments have been established. Additionally, an accelerated elimination procedure is recommended when rapid removal of the drug is necessary, notably in cases of pregnancy or severe adverse effects. The elimination procedure typically involves administration of cholestyramine or activated charcoal to interrupt enterohepatic recirculation and hasten drug clearance.

Mechanism Of Action

Teriflunomide acts as a selective immunomodulatory agent by inhibiting dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme critical for de novo pyrimidine synthesis. In proliferating activated lymphocytes, which require increased nucleotide synthesis, DHODH inhibition results in reduced production of uridine monophosphate, leading to decreased DNA and RNA synthesis. This effect selectively impairs the proliferation of rapidly dividing autoreactive T and B lymphocytes without substantially affecting resting or slowly dividing cells, thereby limiting pathological immune responses implicated in multiple sclerosis.

At the cellular level, by suppressing lymphocyte proliferation, teriflunomide reduces the infiltration of these immune cells into the central nervous system. This attenuates inflammation, decreases myelin damage, and slows disease progression. The drug does not cause broad immunosuppression but modulates the immune system sufficiently to reduce autoimmune attacks on neural tissue. Importantly, teriflunomide maintains the immune system's capacity to respond to pathogens, reducing infection risk compared to broader immunosuppressants.

Additionally, teriflunomide may exert anti-inflammatory effects beyond DHODH inhibition, including modulation of cytokine production, inhibition of tyrosine kinase signaling pathways, and reduction of pro-inflammatory mediators. These secondary effects contribute to its clinical efficacy in relapsing-remitting multiple sclerosis.

Clinical studies support teriflunomide’s capability to slow relapse rates, reduce lesion burden, and delay disability progression in MS patients. Comparatively, teriflunomide’s mechanism is distinct from injectable interferons or monoclonal antibodies targeting immune cell adhesion molecules; its oral route and selective action offer benefits in terms of convenience and safety profile. Ongoing research is investigating additional molecular targets and broader immunological effects of teriflunomide in neuroinflammatory diseases.

Pharmacological Actions

Selective inhibition of dihydroorotate dehydrogenase leading to impaired pyrimidine synthesis in rapidly dividing lymphocytes
Immunomodulatory effect reducing autoreactive T and B lymphocyte proliferation
Anti-inflammatory action by suppression of cytokine release and reduction of immune-mediated nerve inflammation
Reduction of lymphocyte infiltration into the central nervous system
Slowing progression of demyelination and neurodegeneration in multiple sclerosis
Modulation of immune system activity without broad immunosuppression
Oral immunosuppressant action with favorable safety profile
Prolonged pharmacodynamic effect due to long half-life

Therapeutic Clinical Uses

Treatment of relapsing forms of multiple sclerosis (including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS) in adults
Reduction of relapse rate in patients with relapsing multiple sclerosis
Slowing of disability progression associated with multiple sclerosis
Reduction in formation and growth of MRI-detectable brain lesions in MS patients
Management of autoimmune neuroinflammation through selective immunosuppression
Adjunct therapy to modulate immune response in demyelinating diseases
Treatment alternative to injectable MS therapies to improve patient adherence
Potential use in MS patients contraindicated for other immunomodulatory agents

Side Or Adverse Effects

Headache, frequently reported during treatment
Nausea and gastrointestinal disturbances such as diarrhea
Hair thinning or alopecia as a common cosmetic adverse effect
Elevations in liver enzymes indicating hepatotoxicity risk
Fatigue and weakness, occasionally impacting quality of life
Infections due to immunosuppression, including upper respiratory infections
Allergic reactions including rash, urticaria, and rarely severe skin reactions such as Stevens-Johnson syndrome
Peripheral neuropathy manifesting as numbness or tingling distinct from MS symptoms
Hypertension due to possible vascular effects requiring monitoring
Weight loss reported in some patients during therapy
Rare cases of interstitial lung disease or pneumonitis
Transient neutropenia and leucopenia
Elevated risk of tuberculosis reactivation in predisposed individuals
Potential teratogenicity causing severe fetal harm if used during pregnancy
Rare hypersensitivity reactions with systemic impact

Precautions

Perform baseline and periodic monitoring of liver function tests to detect hepatotoxicity early
Screen for active infections and latent tuberculosis prior to initiation
Avoid use in patients with severe hepatic impairment or history of significant liver disease
Use effective contraception during treatment and for up to two years after cessation due to teratogenic risk
Monitor blood pressure regularly as hypertension may develop during use
Educate patients to report signs of infection promptly due to immunosuppressive effect
Avoid concomitant use with leflunomide as they share active metabolites and toxicity risk
Use caution in patients with pre-existing neuropathy or peripheral nerve disorders
Suspend treatment if severe skin reactions occur and provide urgent medical evaluation
Regularly assess blood cell counts to monitor for neutropenia or leukopenia
Advise patients against receiving live vaccines during and for at least 6 months after treatment cessation
Evaluate renal function, although dose adjustment not clearly required, caution is prudent
Be alert for signs of allergic or hypersensitivity reactions
Discourage use in breastfeeding due to potential drug excretion in milk
Ensure adherence to specified drug elimination procedures in cases of pregnancy or toxicity

Warnings

Contraindicated during pregnancy and in women of childbearing potential not using effective contraception
Pregnancy requires immediate discontinuation and implementation of accelerated drug elimination
Severe hepatotoxicity including fatal liver injury may occur; discontinue if liver injury suspected
Risk of serious infections due to immunosuppression; avoid live vaccines during therapy
Potential for severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
May cause peripheral neuropathy that may require drug discontinuation
Cautiously monitor for hypertension and treat as needed to avoid complications
Drug persists in body for prolonged periods; special elimination procedures required to expedite clearance
Avoid use in combination with leflunomide due to increased toxicity risk
Increased susceptibility to tuberculosis and other opportunistic infections
Immunosuppressive effects may mask symptoms of infection
Potential hematological abnormalities necessitate hematologic monitoring
Do not initiate in patients with severe liver impairment
Risk of fetal harm mandates strict pregnancy prevention measures
Patients should be informed of risks and benefits prior to therapy initiation

Contraindications

Known hypersensitivity to teriflunomide or leflunomide
Severe hepatic impairment or active liver disease
Pregnancy or planned pregnancy without appropriate drug elimination protocol
Concomitant use with leflunomide-containing products
Patients with severe immunodeficiency or uncontrolled infections
History of serious hypersensitivity to teriflunomide components
Breastfeeding due to potential for infant exposure
Use in pediatric populations not established and generally not recommended
Patients unable to comply with contraception or monitoring requirements
Concomitant live vaccinations during treatment
Active pulmonary tuberculosis without adequate treatment
Patients with severe uncontrolled hypertension
Known hypersensitivity to any inactive tablet ingredients (e.g., lactose intolerance)

Drug Interactions

Concomitant use with leflunomide is contraindicated due to additive toxicity
Drugs that suppress the immune system (e.g., chemotherapy agents, biologic immunosuppressants) may increase infection risk when combined
Rifampin and other CYP inducers may increase teriflunomide clearance, reducing efficacy
Warfarin: Teriflunomide may influence INR values, requiring monitoring and potential dose adjustment
Cholestyramine and activated charcoal increase teriflunomide elimination and may reduce its plasma levels if coadministered
Medications metabolized by CYP enzymes generally have low interaction risk but caution should be exercised
Vaccines: Live vaccines should be avoided during treatment and up to 6 months after stopping therapy
Contraceptives: Teriflunomide does not significantly reduce hormonal contraceptive effectiveness, but additional contraception is advised due to teratogenicity
Drugs causing hepatic toxicity may increase risk when combined with teriflunomide
Antihypertensive agents require monitoring as teriflunomide may raise blood pressure
Herbal supplements affecting immune function or liver enzymes should be used cautiously
Over-the-counter drugs such as NSAIDs may require special consideration in liver-impaired patients
Drugs interfering with enterohepatic circulation can alter teriflunomide pharmacokinetics
Potential interaction with agents affecting blood cell counts requiring hematologic monitoring
Attention to concurrent use of neurotoxic drugs to avoid additive neuropathic effects

Preparations Of The Drug

Oral tablets available in 7 mg strength
Oral tablets available in 14 mg strength
Tablets contain inactive ingredients including lactose monohydrate, corn starch, hydroxypropyl cellulose, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, talc, polyethylene glycol, and indigo carmine aluminum lake
The 7 mg tablets also contain iron oxide yellow as an inactive colorant
Packaged in blister packs for oral administration
Supplied as film-coated tablets for ease of swallowing and stability
Stored at controlled room temperature away from moisture and heat
Commercially available from Sanofi Genzyme with FDA approval
Available as brand-name Aubagio and in generic teriflunomide formulations