Teriflunomide (Monograph)

Brand name: Aubagio
Drug class: Antimetabolites

Medically reviewed by Drugs.com on Oct 10, 2024. Written by ASHP.

Introduction

Pyrimidine synthesis inhibitor with immunomodulatory and disease-modifying activity in multiple sclerosis (MS).

Uses for Teriflunomide

Multiple Sclerosis

Treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Teriflunomide is one of several disease-modifying therapies used in the management of relapsing forms of MS. Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing MRI lesions, and disability progression.

The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with relapsing forms of MS who have had recent relapses and/or MRI lesion activity. Clinicians should consider adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate therapy.

Teriflunomide Dosage and Administration

General

Pretreatment Screening

• Obtain transaminase and bilirubin levels within 6 months prior to initiating teriflunomide therapy.

• Obtain CBC within 6 months prior to initiating teriflunomide therapy.

• Screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for mycobacterium tuberculosis infection. Do not initiate teriflunomide in patients with active infections.

• Check blood pressure prior to initiating teriflunomide therapy.

• Exclude pregnancy prior to initiation of treatment in females of reproductive potential.

Patient Monitoring

• Monitor ALT concentrations at least monthly for 6 months after starting teriflunomide therapy.

• Monitor CBC during therapy based on signs and symptoms of infection.

• Monitor BP periodically during treatment.

Administration

Oral Administration

Administer orally once daily without regard to food.

Dosage

Adults

Multiple Sclerosis

Oral

7 or 14 mg once daily.

Accelerated Elimination Procedures

• Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes an average of 8 months to reach plasma concentrations <0.02 mg/L and, because of individual variations in clearance, may take up to 2 years. An accelerated elimination procedure may be used at any time following teriflunomide discontinuance.

• May accelerate elimination of teriflunomide from plasma by using either an oral cholestyramine or activated charcoal procedure.

• Cholestyramine regimen: Cholestyramine 8 g orally every 8 hours for 11 days. If this dosage is not well tolerated, may administer 4 g orally 3 times daily instead.

• Activated charcoal regimen: Activated charcoal 50 g orally as suspension every 12 hours for 11 days.

• If either elimination procedure is poorly tolerated, the treatment days do not need to be consecutive unless teriflunomide plasma concentrations need to be reduced rapidly.

• Following completion of the 11-day accelerated elimination procedures, both regimens successfully accelerated teriflunomide elimination, resulting in >98% decrease in plasma concentrations of the drug.

• Use of an accelerated elimination procedure may potentially result in a return of disease activity if the patient had been responding to teriflunomide therapy.

Special Populations

Hepatic Impairment

No dosage adjustment necessary in patients with mild or moderate hepatic impairment. Not studied in patients with severe hepatic impairment; use is contraindicated.

Renal Impairment

No dosage adjustment necessary for patients with mild, moderate, or severe renal impairment. Dose supplementation following hemodialysis or peritoneal dialysis unlikely to be necessary.

Geriatric Patients

No specific dosage recommendations.

Cautions for Teriflunomide

Contraindications

• Severe hepatic impairment.

• Women who are pregnant and females of reproductive potential not using reliable contraception.

• Concomitant leflunomide therapy.

• History of hypersensitivity reaction to teriflunomide, leflunomide, or any ingredient in the formulations.

Warnings/Precautions

Warnings

Hepatotoxicity

Severe and potentially life-threatening liver injury, including liver failure requiring transplant, reported during postmarketing surveillance. (See Boxed Warning.) Increased risk of elevated serum transaminases in patients with preexisting liver disease.

ALT increases reported, usually during first year of therapy. In half of the cases, ALT concentrations returned to normal despite continued use of the drug.

Clinically important liver injury may occur at any time during therapy.

Patients with preexisting acute or chronic liver disease and those with ALT concentrations >2 times the ULN generally should not be treated with teriflunomide. Contraindicated in patients with severe hepatic impairment.

Obtain transaminase and bilirubin concentrations within 6 months prior to initiation of teriflunomide. Monitor ALT at least monthly during the initial 6 months of therapy. Consider additional liver function monitoring in patients concurrently receiving other potentially hepatotoxic drugs. If transaminase concentrations increase to >3 times the ULN, consider discontinuance of teriflunomide.

Monitor serum transaminases and bilirubin during teriflunomide therapy, particularly in patients who develop signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine).

If drug-induced liver injury is suspected, discontinue teriflunomide, initiate an accelerated elimination procedure, and monitor liver function tests weekly until values return to normal. If teriflunomide is considered an unlikely cause of ALT elevation because another probable cause is found, may consider resuming the drug.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. (See Boxed Warning.) Teratogenicity (e.g., skeletal variations and other malformations) and embryolethality observed in animals.

Contraindicated in pregnant women and in females of reproductive potential who are not using reliable contraception.

Pregnancy must be avoided during teriflunomide therapy and prior to completion of the drug-elimination procedure following discontinuance of the drug.

Teriflunomide is present in human semen; animal studies to evaluate risk of male-mediated fetal toxicity not conducted to date.

Other Warnings and Precautions

Accelerated Elimination Procedures

Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it may take an average of 8 months or up to 2 years for plasma concentrations to decrease to undetectable levels (<0.02 mg/L) following discontinuance of teriflunomide. Manufacturer recommends an accelerated elimination procedure when more rapid elimination is required or desirable.

An accelerated elimination procedure is recommended in all females of reproductive potential upon teriflunomide discontinuance and in men who wish to father a child after discontinuance of the drug.

An accelerated elimination procedure is also recommended in patients with potentially serious drug-related adverse effects (e.g., suspected liver injury, serious infection, peripheral neuropathy, severe dermatologic reactions, new onset or worsening pulmonary symptoms, pancreatitis).

If the patient responded to teriflunomide treatment, an accelerated elimination procedure may result in return of disease activity.

Hematologic Effects

Decreases in WBC and platelet counts reported; WBC decreases generally occurred during first 6 weeks of therapy and remained low during treatment.

No cases of serious pancytopenia reported with teriflunomide. Rare cases of pancytopenia and agranulocytosis reported during postmarketing experience with leflunomide; similar risk expected for teriflunomide. Thrombocytopenia (with platelet counts decreasing to <50,000/mm³ in rare cases) reported during postmarketing experience with teriflunomide.

Obtain CBC within 6 months prior to initiation of treatment. Additional hematologic monitoring should be based on signs and symptoms suggestive of bone marrow suppression.

Risk of Infection/Tuberculosis Screening

Do not initiate teriflunomide in patients with active acute or chronic infections until the infection is resolved. If a serious infection develops, consider interruption of therapy and initiation of an accelerated elimination procedure. Reassess risks and benefits of teriflunomide prior to reinitiating the drug.

No overall increase in risk of serious infection was observed in teriflunomide-treated patients in clinical studies; however, one fatal case of Klebsiella pneumoniae sepsis occurred in a patient receiving teriflunomide 14 mg daily for 1.7 years. Reactivation of cytomegalovirus hepatitis also reported. Fatal infections, including Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia and aspergillosis, reported with leflunomide; most were confounded by concomitant immunosuppressant therapy and/or comorbidities, in addition to rheumatoid disease, that may predispose patients to infection.

Not recommended in patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Drugs with an immunosuppressive potential, including teriflunomide, may increase susceptibility to infection, including opportunistic infections.

Cases of tuberculosis observed. Not evaluated in patients with latent tuberculosis infection; safety of the drug in such patients is unknown. Screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for mycobacterium tuberculosis infection prior to initiation of therapy. When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection.

Vaccination

Limited clinical data available regarding efficacy and safety of vaccination in patients receiving teriflunomide. Vaccination with live vaccines not recommended. Consider the long half-life of teriflunomide when contemplating administration of a live vaccine after discontinuing the drug.

Malignancy

Increased risk of malignancy, particularly lymphoproliferative disorders, in patients receiving some immunosuppressant drugs. While an increased incidence of malignancies and lymphoproliferative disorders has not been observed in patients receiving teriflunomide in clinical studies, larger and longer-term studies are needed to determine whether there is an increased risk of malignancy with the drug.

Peripheral Neuropathy

Peripheral neuropathy, including polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), reported; most cases were mild or moderate in severity.

Possible increased risk for peripheral neuropathy in patients ≥60 years of age, patients concomitantly receiving other neurotoxic medications, and those with diabetes. Consider discontinuance of teriflunomide and use of an accelerated elimination procedure if a patient develops symptoms consistent with peripheral neuropathy (e.g., bilateral numbness or tingling of hands or feet).

Blood Pressure Increases

Elevated BP and hypertension reported.

Measure BP at baseline and monitor periodically during therapy. Manage elevated BP appropriately.

Interstitial Lung Disease

Interstitial lung disease, including acute interstitial pneumonitis, reported during postmarketing experience with teriflunomide.

Interstitial lung disease and worsening of preexisting interstitial lung disease, sometimes fatal, also reported in patients receiving leflunomide.

May occur acutely at any time during therapy, with a variable clinical presentation.

In patients experiencing new or worsening pulmonary symptoms (e.g., cough, dyspnea) with or without fever, consider discontinuing teriflunomide. If discontinuance is warranted, consider use of an accelerated elimination procedure.

Pancreatitis

Pancreatitis reported in 1.8% (2 patients) of pediatric patients in a clinical study; one case was serious. Both patients recovered following drug discontinuance and an accelerated elimination procedure. Teriflunomide is not approved for use in pediatric patients.

Pancreatitis also reported in adults.

If pancreatitis is suspected, discontinue teriflunomide and initiate an accelerated elimination procedure.

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis and angioedema, reported.

If manifestations of anaphylaxis or angioedema occur, immediately discontinue drug and perform an accelerated elimination procedure (unless the reaction is clearly not drug related). Do not re-expose patient to the drug.

Serious Skin Reactions

Serious and potentially fatal skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, reported; at least 1 fatality occurred.

If a serious skin reaction occurs, immediately discontinue drug and perform an accelerated elimination procedure (unless the reaction is clearly not drug related). Do not re-expose patient to the drug.

Drug Reaction with Eosinophilia and Systemic Symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS; also known as multi-organ hypersensitivity), a serious and potentially fatal reaction, reported; one fatality occurred during postmarketing experience. Clinical presentation typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis) sometimes resembling an acute viral infection. Early manifestations (e.g., fever, lymphadenopathy) may be present with or without rash.

If manifestations of DRESS occur, immediately discontinue drug and perform an accelerated elimination procedure (unless the reaction is clearly not drug related). Do not re-expose patient to the drug.

Specific Populations

Pregnancy

May cause fetal harm; teratogenicity and embryolethality reported in animals.

Exclude pregnancy prior to initiating therapy.

If pregnancy occurs, immediately discontinue therapy and perform an accelerated elimination procedure.

Pregnancy registry has been established for teriflunomide. Report exposure occurring during pregnancy, or if a patient becomes pregnant within 2 years following the last teriflunomide dose, to the registry by calling 800-745-4447, option 2.

Lactation

Distributes into milk in rats; not known whether distributed into human milk. Potential effects on nursing infants or on milk production not known. Breastfeeding not recommended during therapy.

Females and Males of Reproductive Potential

Exclude pregnancy prior to initiating teriflunomide in females of reproductive potential. Advise such females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment.

Females of reproductive potential should use effective contraception during and following discontinuance of therapy (until plasma concentrations of the drug are <0.02 mg/L since such concentrations are expected to have minimal embryofetal risk).

Females of reproductive potential who wish to become pregnant should discontinue the drug and undergo an accelerated elimination procedure; effective contraceptive methods should be used until it is verified that plasma teriflunomide concentrations are <0.02 mg/L.

Men receiving teriflunomide who do not wish to father a child and their female partners should use reliable contraception. Men treated with teriflunomide who wish to father a child should discontinue the drug and either undergo an accelerated elimination procedure or wait until it is verified that plasma concentrations are <0.02 mg/L.

Pediatric Use

Safety and efficacy not established.

In a controlled clinical study, efficacy not established in pediatric patients 10–17 years of age with MS. Pancreatitis reported at higher rate in pediatric patients compared to adults. Increased or abnormal blood creatine phosphokinase also reported in pediatric patients.

Geriatric Use

Clinical studies did not include patients >65 years of age.

Hepatic Impairment

Mild and moderate hepatic impairment had no impact on pharmacokinetics. Pharmacokinetics not studied in patients with severe hepatic impairment.

Because of possible increased risk of hepatotoxicity, use not normally recommended in patients with preexisting acute or chronic liver disease or baseline serum ALT concentrations >2 times the ULN. Contraindicated in patients with severe hepatic impairment.

Renal Impairment

Severe renal impairment had no clinically important effect on pharmacokinetics.

Common Adverse Effects

Common adverse effects (≥10%): headache, diarrhea, nausea, alopecia, increased ALT concentrations.

Drug Interactions

Not metabolized by CYP or flavin monoamine oxidase enzymes.

Inhibits CYP2C8 and weakly induces CYP1A2.

Inhibitor of the efflux transporter breast cancer resistant protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and organic anion transporter 3 (OAT3).

Drug interactions may continue to occur after patient no longer is receiving teriflunomide. May reduce risk by using an accelerated elimination procedure after discontinuance of therapy.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Possible increased AUC and peak plasma concentrations of CYP2C8 substrates; monitor patients during concurrent therapy.

Possible reduced AUC and peak plasma concentrations of CYP1A2 substrates resulting in reduced efficacy; monitor patients during concurrent therapy.

Drugs Transported by Organic Anion Transporters and Organic Anion-Transporting Polypeptide

Systemic exposure of OAT3 substrates or OATP substrates may be increased when administered concomitantly with teriflunomide. Monitor patients closely for signs of increased exposure; adjust dosage of substrate drug accordingly.

Drugs Transported by Breast Cancer Resistance Protein

Systemic exposure of BCRP substrates may be increased when administered concomitantly with teriflunomide. Monitor patients closely for signs of increased exposure; adjust dosage of substrate drug accordingly.

Hepatotoxic Agents

Possible increased risk of serious hepatotoxicity during concurrent use. Consider additional monitoring of liver function.

Neurotoxic Agents

Possible increased risk of peripheral neuropathy.

Specific Drugs

Teriflunomide Pharmacokinetics

Absorption

Bioavailability

Median time to peak plasma teriflunomide concentrations ranged from 1–4 hours after oral administration.

Steady-state concentrations achieved in approximately 3 months.

Food

No clinically relevant effect on pharmacokinetics.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

Highly bound (>99%) to plasma proteins and mainly distributed in plasma.

Elimination

Metabolism

Teriflunomide is the major circulating moiety in plasma. Primary biotransformation pathway to minor metabolites is hydrolysis; oxidation is a minor pathway. Secondary pathways include oxidation, N-acetylation, and sulfate conjugation.

Elimination Route

Eliminated in feces (37.5%; mainly through direct biliary excretion of unchanged drug) and in urine (22.6%; mainly as metabolites) within 21 days.

Half-life

Median half-life of 18 and 19 days after chronic dosing of 7 and 14 mg daily, respectively.

Special Populations

Mild and moderate hepatic impairment: No effect on pharmacokinetics. Severe hepatic impairment: Pharmacokinetics not evaluated.

Severe renal impairment had no clinically important effect on pharmacokinetics. Appears to be negligibly removed by peritoneal dialysis and hemodialysis.

In a population analysis, clearance was decreased by 23% in females compared with males.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

• Teriflunomide is the principal active metabolite of leflunomide (an antirheumatic agent) and is responsible for essentially all of leflunomide's pharmacologic activity in vivo.

• Exact mechanism of action of teriflunomide in MS is unknown; may involve, at least in part, a reduction in the number of activated lymphocytes in the CNS.

• Inhibits pyrimidine synthesis through reversible inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase.

Advice to Patients

• Provide a copy of the teriflunomide medication guide to the patient each time the drug is dispensed; stress importance of patients reading the medication guide.

• Inform patients of the potential for hepatotoxic effects and the need for monitoring of liver enzymes prior to initiating teriflunomide and at least monthly for at least 6 months while they are receiving the drug. Stress importance of reporting possible signs or symptoms of liver injury (e.g., unexplained nausea, vomiting, fatigue, anorexia, jaundice, dark urine) to their clinician.

• Risk of fetal harm. Advise women of childbearing potential of the need for effective contraception during teriflunomide treatment and until teriflunomide plasma concentrations are verified to be <0.02 mg/L. Advise women of childbearing potential to notify their clinician immediately if pregnancy occurs or is suspected. Stress importance of informing women who become pregnant while taking teriflunomide, or within 2 years following the last dose, about the existence of a pregnancy registry. Instruct men who wish to father a child to discontinue teriflunomide and use an accelerated elimination procedure. Instruct men taking teriflunomide who do not wish to father a child to use reliable contraception to minimize any possible risk to the fetus; their female partners should also use effective contraception.

• Advise women to avoid breast-feeding while taking teriflunomide.

• Inform patients that teriflunomide may stay in the blood for up to 2 years following the last dose and that an accelerated elimination procedure may be used if needed.

• Possible increased risk of infections. Inform patients that teriflunomide may decrease WBCs and that their clinician may check their blood counts before initiating teriflunomide therapy. Advise patients to contact their clinician if they develop any symptoms of infection (e.g., fever, tiredness, body aches, chills, nausea, vomiting), particularly if they develop fever.

• Advise patients that some vaccines should be avoided during treatment with teriflunomide and for at least 6 months after discontinuing the drug.

• Risk of peripheral neuropathy. Advise patients to contact their clinician if they develop symptoms of peripheral neuropathy (e.g., numbness or tingling of the hands or feet) that are different from their MS symptoms.

• Risk of serious allergic reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS); advise patients to immediately discontinue the drug and seek medical attention if any manifestations of hypersensitivity reactions (e.g., dyspnea, urticaria, angioedema, skin rash, hives) or DRESS (e.g., fever, rash, lymphadenopathy, hepatic dysfunction, muscle pain) occur.

• Risk of serious skin reactions; advise patients to immediately discontinue the drug and seek medical attention if any manifestations of serious skin reactions occur (e.g., rash, mouth sores, blisters, peeling skin).

• Inform patients that teriflunomide may increase BP.

• Stress importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Teriflunomide is available through a specialty pharmacy network.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Reload page with references included

Frequently asked questions

• What are the new drugs used for multiple sclerosis (MS)?
• Ocrevus vs Aubagio: How do they compare for MS?
• Does Aubagio suppress the immune system?
• How long do Aubagio side effects last?
• Can Aubagio cause PML as a side effect?
• Does Aubagio work in multiple sclerosis (MS)?

View more FAQ

Medical Disclaimer