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Teriflunomide

Medically reviewed by Drugs.com. Last updated on Jul 12, 2019.

Pronunciation

(ter i FLOO noh mide)

Index Terms

  • A771726
  • HMR1726

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Aubagio: 7 mg, 14 mg [contains corn starch, fd&c blue #2 aluminum lake]

Brand Names: U.S.

  • Aubagio

Pharmacologic Category

  • Pyrimidine Synthesis Inhibitor

Pharmacology

Teriflunomide is an immunomodulatory agent that inhibits pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects. It may reduce the number of activated lymphocytes in the CNS.

Distribution

Vd: IV: 11 L

Metabolism

Primarily by hydrolysis to minor metabolites; secondary pathways include oxidation, conjugation, and N-acetylation

Excretion

Feces (~38%); urine (~23%)

Time to Peak

Plasma: 1-4 hours

Half-Life Elimination

Median: 18-19 days; enterohepatic recycling appears to contribute to the long half-life of this agent, since activated charcoal and cholestyramine substantially reduce plasma half-life

Protein Binding

>99%

Special Populations: Gender

There was a 23% decrease in Cl in females compared with males.

Use: Labeled Indications

Multiple sclerosis, relapsing: Treatment of patients with relapsing forms of multiple sclerosis.

Off Label Uses

Multiple sclerosis, clinically isolated syndrome

Data from a randomized, double-blind, placebo-controlled trial supports the use of teriflunomide for delaying the conversion to multiple sclerosis in patients with clinically isolated syndrome, a first symptomatic episode consistent with a demyelinating event [Miller 2014].

Based on the American Academy of Neurology practice guidelines for disease-modifying therapies for adults with multiple sclerosis, teriflunomide is probably effective at decreasing the risk of conversion to multiple sclerosis in patients with clinically isolated syndrome.

Contraindications

Hypersensitivity to teriflunomide, leflunomide, or any component of the formulation; severe hepatic impairment; coadministration with leflunomide; pregnant women; females of reproductive potential not using effective contraception.

Canadian labeling: Additional contraindications (not in US labeling): Immunodeficiency states (eg, AIDS); impaired bone marrow function or significant anemias, leucopenia, neutropenia, or thrombocytopenia; serious active infections

Dosing: Adult

Multiple sclerosis, relapsing: Adults: Oral: 7 mg or 14 mg once daily.

Multiple sclerosis, clinically isolated syndrome (off-label use): Adults: Oral: 7 mg or 14 mg once daily (Miller 2014).

Dosing: Adjustment for Toxicity

ALT elevations >3 times ULN: Discontinue teriflunomide and initiate cholestyramine or activated charcoal to enhance elimination

Drug elimination procedure: To achieve nondetectable serum concentrations (<0.02 mg/L) of teriflunomide administer either of the following:

Cholestyramine: 8 g every 8 hours for 11 days. If not tolerated, may decrease to 4 g every 8 hours for 11 days. The 11 days do not need to be consecutive unless plasma concentrations need to be lowered rapidly.

or

Activated charcoal: 50 g every 12 hours for 11 days. The 11 days do not need to be consecutive unless plasma concentrations need to be lowered rapidly.

Note: Both treatments have successfully lead to >98% decrease in teriflunomide concentrations.

Administration

Administer without regard to meals.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Consider therapy modification

Amodiaquine: CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Amodiaquine. Avoid combination

Asunaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCRP/ABCG2 Substrates: Teriflunomide may increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Bendamustine: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Bendamustine. Concentrations of active metabolites may be increased. Monitor therapy

Bile Acid Sequestrants: May decrease the serum concentration of Teriflunomide. Management: Unless using this combination to intentionally enhance teriflunomide elimination, consider an alternative to the bile acid sequestrants when possible. Separating drug administration is unlikely to be effective at avoiding the interaction. Consider therapy modification

Caffeine and Caffeine Containing Products: Teriflunomide may decrease the serum concentration of Caffeine and Caffeine Containing Products. Monitor therapy

Charcoal, Activated: May decrease the serum concentration of Teriflunomide. Management: Unless using this combination to intentionally enhance teriflunomide elimination, consider an alternative to charcoal when possible. Separating drug administration is not likely to be effective at avoiding this interaction. Consider therapy modification

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

CloZAPine: CYP1A2 Inducers may decrease the serum concentration of CloZAPine. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CYP1A2 Substrates (High risk with Inducers): Teriflunomide may decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Monitor therapy

CYP2C8 Substrates (High risk with Inhibitors): CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates (High risk with Inhibitors). Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Desloratadine: CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Desloratadine. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. Avoid combination

Erlotinib: Teriflunomide may decrease the serum concentration of Erlotinib. Management: Avoid the concomitant use of erlotinib and teriflunomide if possible. If concomitant use is unavoidable, increase the erlotinib dose by 50 mg increments at 2-week intervals to a maximum of 300 mg. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Grazoprevir. Avoid combination

Leflunomide: May enhance the adverse/toxic effect of Teriflunomide. Leflunomide may increase the serum concentration of Teriflunomide. Avoid combination

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

OAT1/3 Substrates: Teriflunomide may increase the serum concentration of OAT1/3 Substrates. Monitor therapy

OATP1B1/1B3 (SLCO1B1/1B3) Substrates: Teriflunomide may increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Monitor therapy

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pirfenidone: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Pirfenidone. Monitor therapy

Repaglinide: Teriflunomide may increase the serum concentration of Repaglinide. Monitor therapy

Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Avoid combination

Riluzole: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Riluzole. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Rosuvastatin: Teriflunomide may increase the serum concentration of Rosuvastatin. Management: Limit the maximum adult rosuvastatin dose to 10 mg/day in patients receiving teriflunomide, and monitor for evidence of rosuvastatin toxicity (eg, muscle toxicity, elevated transaminase concentrations). Consider therapy modification

Selexipag: CYP2C8 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Selexipag. Management: Reduce the selexipag dose to once daily when combined with moderate CYP2C8 inhibitors. Revert back to twice daily selexipag dosing upon stopping the moderate CYP2C8 inhibitor. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Avoid combination

Warfarin: Teriflunomide may decrease the serum concentration of Warfarin. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Headache (16% to 18%)

Dermatologic: Alopecia (10% to 13%)

Endocrine & metabolic: Hypophosphatemia (18%)

Gastrointestinal: Diarrhea (13% to 14%), nausea (8% to 11%)

Hematologic & oncologic: Lymphocytopenia (10% to 12%)

Hepatic: Increased serum alanine aminotransferase (13% to 15%)

1% to 10%:

Cardiovascular: Hypertension (3% to 4%)

Central nervous system: Paresthesia (8% to 9%)

Hematologic & oncologic: Neutropenia (4% to 6%)

Neuromuscular & skeletal: Arthralgia (6% to 8%), peripheral neuropathy (including carpal tunnel syndrome; 1% to 2%)

<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, cytomegalovirus disease (reactivation), hypersensitivity reaction, increased serum creatinine, interstitial pulmonary disease, jaundice, pancreatitis, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, uric acid nephropathy

ALERT: U.S. Boxed Warning

Hepatotoxicity:

Severe liver injury, including fatal liver failure, has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Concomitant use of teriflunomide with other potentially hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of teriflunomide therapy. Monitor ALT levels at least monthly for 6 months after starting teriflunomide. If drug-induced liver injury is suspected, discontinue teriflunomide and start an accelerated elimination procedure with cholestyramine or charcoal. Teriflunomide is contraindicated in patients with severe hepatic impairment. Patients with preexisting liver disease may be at an increased risk of developing elevated serum transaminases when taking teriflunomide.

Embryofetal toxicity:

Teriflunomide is contraindicated for use in pregnant women and in women of reproductive potential who are not using effective contraception because of the potential for fetal harm. Teratogenicity and embryolethality occurred in animals at plasma teriflunomide exposures lower than that in humans. Exclude pregnancy before the start of treatment with teriflunomide in females of reproductive potential. Advise females of reproductive potential to use effective contraception during teriflunomide treatment and during an accelerated drug elimination procedure after teriflunomide treatment. Stop teriflunomide and use an accelerated drug elimination procedure if the patient becomes pregnant.

Warnings/Precautions

Concerns related to adverse effects:

• Dermatologic reactions: Cases of serious skin reactions, including cases of Stevens-Johnson syndrome and fatal toxic epidermal necrolysis have been reported with teriflunomide; very rare cases of drug reaction with eosinophilia and systemic symptoms have been reported with leflunomide. Discontinue if evidence of severe dermatologic reactions occurs and begin an accelerated drug elimination procedure (eg, cholestyramine, activated charcoal) immediately; in such cases, patients should not be re-exposed to teriflunomide.

• Hepatotoxicity: [US Boxed Warning]: Use of leflunomide has been associated with reports of hepatotoxicity, hepatic failure, and death, therefore, a similar risk is expected with teriflunomide. Patients with preexisting liver disease (acute or chronic liver disease or ALT >2 x ULN) may be at an increased risk of developing elevated transaminases during therapy; use is contraindicated in patients with severe impairment. Use in patients with concurrent exposure to potentially hepatotoxic drugs may increase the risk of hepatotoxicity. Obtain transaminase and bilirubin levels within 6 months prior to initiation of treatment. Monitor ALT levels at least monthly for first 6 months during therapy; if hepatotoxicity is likely teriflunomide-induced, start drug elimination procedures (eg, cholestyramine, activated charcoal) and monitor liver function tests weekly until normalized. Discontinuation of therapy may be considered if transaminases increase >3 x ULN.

• Hypersensitivity reactions: Anaphylaxis and severe allergic reactions may occur; discontinue if any signs or symptoms of hypersensitivity reaction occur and begin an accelerated drug elimination procedure (eg, cholestyramine, activated charcoal) immediately; in such cases, patients should not be re-exposed to teriflunomide.

• Hypertension: Increases in blood pressure have been reported; monitor at initiation of therapy and periodically thereafter.

• Infections: May increase susceptibility to infection, including opportunistic pathogens. Severe infections, sepsis, and fatalities have been reported with leflunomide. One case of fatal sepsis has been reported with teriflunomide. Not recommended in patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. Caution should be exercised when considering the use in patients with a history of new/recurrent infections, with conditions that predispose them to infections, or with chronic, latent, or localized infections. Patients who develop a new infection while undergoing treatment should be monitored closely; consider suspension or discontinuation of therapy and drug elimination procedures (eg, cholestyramine, activated charcoal) if infection is serious.

• Interstitial lung disease: Interstitial lung disease, including acute interstitial pneumonitis, has been reported; may be fatal and occur at any time during therapy. Consider treatment discontinuation in patients who develop new onset or worsening of pulmonary symptoms. Drug elimination procedures (eg, cholestyramine, activated charcoal) should be considered if evidence of interstitial lung disease.

• Malignancy: Use may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. As compared to the general population, an increased risk of lymphoma has been noted in clinical trials with use of some immunosuppressive medications.

• Pancreatitis: Very rare cases of pancreatitis have been reported (Aubagio Canadian product monograph 2015); discontinue therapy in patients with symptoms of acute pancreatitis suspected to be drug-induced and begin drug elimination procedures (eg, cholestyramine, activated charcoal).

• Peripheral neuropathy: Cases of peripheral neuropathy (including polyneuropathy and mononeuropathy) have been reported; use with caution in patients >60 years, receiving concomitant neurotoxic medications or patients with diabetes; discontinue if evidence of peripheral neuropathy occurs and begin drug elimination procedures (eg, cholestyramine, activated charcoal).

• Renal effects: Transient acute renal failure, most likely due to acute uric acid nephropathy, has been reported.

Disease-related concerns:

• Hematologic disorders: Use with caution in patients with a prior history of significant hematologic abnormalities; avoid use with bone marrow dysplasia. Neutropenia, leukopenia, and thrombocytopenia (including rare cases of platelet counts <50,000/mm3) have been reported in clinical trials. Use of leflunomide has been associated with rare pancytopenia, agranulocytosis, and thrombocytopenia, therefore, a similar risk may be expected with teriflunomide. Monitoring of hematologic function is required.

• Tuberculosis: Safety has not been established in patients with latent tuberculosis infection. Patients should be screened for tuberculosis and if necessary, treated prior to initiating therapy.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy/women of childbearing potential: [US Boxed Warning]: Teriflunomide is contraindicated in pregnant women or women of childbearing potential who are not using effective contraception. Pregnancy must be excluded prior to initiating treatment in females of reproductive potential.

Other warnings/precautions:

• Drug elimination procedure: Due to variations in clearance, it may take up to 2 years to reach low levels of teriflunomide metabolite serum concentrations. A drug elimination procedure using cholestyramine or activated charcoal is recommended when a more rapid elimination is needed. If a response to teriflunomide had already been observed, the use of a rapid elimination procedure may result in the return of disease activity.

• Immunizations: Patients should be brought up to date with all immunizations before initiating therapy. Live vaccines should not be given concurrently; there are no data available concerning secondary transmission of live vaccines in patients receiving therapy.

Monitoring Parameters

CBC within 6 months of initiation and periodically thereafter based on signs/symptoms of infection; serum creatinine; serum transaminase and bilirubin within 6 months of initiation of therapy and monthly during the initial 6 months of treatment. In addition, monitor for signs/symptoms of severe infection, abnormalities in hepatic function tests, symptoms of hepatotoxicity, hypophosphatemia, and blood pressure (baseline and periodically thereafter). Monitor hepatic function tests weekly until normalized in patients with suspected teriflunomide-induced hepatotoxicity. Screen for tuberculosis prior to therapy. Evaluate pregnancy status in females of reproductive potential before treatment initiation.

Pregnancy Considerations

[US Boxed Warning]: Teriflunomide is contraindicated in pregnant women and in females of reproductive potential who are not using effective contraception because of the potential for fetal harm. Teratogenicity and embryolethality occurred in animals at plasma teriflunomide exposures lower than that in humans. Stop teriflunomide and use an accelerated drug elimination procedure if the patient becomes pregnant. Pregnancy outcome information following maternal use during pregnancy or following use in male patients who fathered a child are limited (Andersen 2018; Kieseier 2014).

[US Boxed Warning]: Exclude pregnancy before the start of treatment with teriflunomide in females of reproductive potential. Women of childbearing potential should not receive therapy until pregnancy has been excluded, they have been counseled concerning fetal risk, and reliable contraceptive measures have been confirmed.

[US Boxed Warning]: Advise females of reproductive potential to use effective contraception during teriflunomide treatment and during an accelerated drug elimination procedure after teriflunomide treatment. Women who wish to become pregnant, as well as all females of reproductive potential, should undergo the accelerated drug elimination procedure when teriflunomide is discontinued. Pregnancy should be avoided until undetectable serum concentrations (<0.02 mg/L) are verified.

Teriflunomide is found in semen. Males and their female partners should use reliable contraception during therapy. Males who wish to father a child should discontinue teriflunomide and undergo the accelerated drug elimination procedure or wait until plasma teriflunomide concentrations are <0.02 mg/L.

In general, disease-modifying therapies for multiple sclerosis (MS) are stopped prior to a planned pregnancy, and not initiated during pregnancy, except in females at high risk of MS activity (AAN [Rae-Grant 2018]). Consider use of agents other than teriflunomide for females at high risk of disease reactivation who are planning a pregnancy. Delaying pregnancy is recommended for females with persistent high disease activity; when disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/EAN [Montalban 2018]).

Data collection to monitor pregnancy and infant outcomes following exposure to teriflunomide is ongoing. Health care providers are encouraged to enroll females exposed to teriflunomide during pregnancy in the pregnancy registry (800-745-4447, option 2).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, diarrhea, hair thinning or loss, or joint pain. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), severe headache, severe dizziness, passing out, vision changes, bruising, bleeding, severe loss of strength and energy, swollen glands, burning or numbness feeling, signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), or signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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