INDICATION

NAT-TERIFLUNOMIDE is indicated as monotherapy for the treatment of patients with relapsing remitting multiple sclerosis (RRMS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

WARNINGS
HEPATOTOXICITY
Severe liver injury including fatal liver failure occurred rarely in the post marketing setting. Concomitant use of NAT-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 NAT-TERIFLUNOMIDE therapy. Monitor ALT levels at least monthly for six months after starting NAT-TERIFLUNOMIDE. If drug induced liver injury is suspected, discontinue NAT-TRIFLUNOMIDE and start an accelerated elimination procedure with cholestyramine or charcoal. Teriflunomide is contraindicated in patients with severe hepatic impairment. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking NAT-TERIFLUNOMIDE.

RISK OF TERATOGENICITY
Based on animal data, teriflunomide may cause major birth defects if used during pregnancy. Pregnancy must be excluded before starting NAT-TERIFLUNOMIDE. Teriflunomide is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during NAT-TERIFLUNOMIDE treatment or prior to the completion of an accelerated elimination procedure after NAT-TERIFLUNOMIDE treatment.

Physicians are encouraged to enroll pregnant women in the Enhanced Pharmacovigilance Pregnancy Active Surveillance Program, or pregnant women may enroll themselves in the Teriflunomide Enhanced Pharmacovigilance Pregnancy Active Surveillance Program by calling 1-800-296-9329.

If you are a man whose partner plans to become pregnant, you should stop taking NAT-TERIFLUNOMIDE and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L. If your partner does not plan to become pregnant, use effective birth control while taking NAT-TERIFLUNOMIDE.

CONTRAINDICATIONS
Teriflunomide is contraindicated in patients:

• with known hypersensitivity to teriflunomide, leflunomide (the parent compound) or to any of the nonmedicinal ingredients in the formulation
• who are currently treated with leflunomide
• Co-administration of teriflunomide with leflunomide is contraindicated.
• with severe hepatic impairment
• who are pregnant or women of childbearing potential not using reliable contraception. NAT-TERIFLUNOMIDE may cause fetal harm when administered to a pregnant woman. Pregnancy must be excluded before start of treatment.
• with immunodeficiency states (e.g. AIDS)
• with impaired bone marrow function or significant anemias, leucopenia, neutropenia or thrombocytopenia
• with serious active infections

WARNINGS AND PRECAUTIONS

Accelerated Elimination Procedure

Teriflunomide is eliminated slowly from the plasma.

Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, however, due to individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of NAT-TERIFLUNOMIDE.

Elimination can be accelerated by either of the following procedures:

• Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used.
• Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.

Hematologic
The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained at the decreased level during treatment.

The majority of patients recovered from decreased neutrophils and/or lymphocyte cell counts in less than 8 weeks, whether continuing on teriflunomide or after discontinuation.

Rare cases of pancytopenia, agranulocytosis and thrombocytopenia have been reported in the postmarketing setting with leflunomide. A similar risk is expected for teriflunomide.

Obtain a complete blood cell count (CBC) within 6 months before initiating treatment with NAT-TERIFLUNOMIDE. Further monitoring should be based on signs and symptoms suggestive of infection.

In any situation in which the decision is made to switch to or from teriflunomide, from or to another agent with a known potential for hematologic suppression, monitoring for hematologic toxicity is recommended, because there will be overlap of systemic exposure to both compounds, due to the slow elimination from plasma of teriflunomide and some of the other therapies (eg, natalizumab, fingolimod). Use of an accelerated elimination procedure may decrease this risk when switching to another therapy, but may also potentially result in return of disease activity if the patient had been responding to NAT-TERIFLUNOMIDE treatment. (Please see product monograph for ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics; WARNINGS AND PRECAUTIONS, Accelerated Elimination Procedure).

In patients with pre-existing anemia, leucopenia, and/or thrombocytopenia as well as in patients with impaired bone marrow function or those at risk of bone marrow suppression, the risk of hematological disorders is increased. If such effects occur, the accelerated elimination procedure should be considered.

Hepatic
Liver function abnormalities have been reported in some patients treated with teriflunomide in clinical trials. Severe liver injury including fatal liver failure occurred rarely in the post marketing setting. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking teriflunomide. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with teriflunomide. Teriflunomide is contraindicated in patients with severe hepatic impairment (please see product monograph for CONTRAINDICATIONS).

Elevations of liver enzymes have been observed in patients receiving teriflunomide.

For all patients, obtain serum transaminase and bilirubin levels within 6 months before initiating treatment with teriflunomide. Monitor ALT levels at least monthly for six months after starting NAT-TERIFLUNOMIDE. Consider additional monitoring when NAT-TERIFLUNOMIDE is given with other potentially hepatotoxic drugs. Consider discontinuing NAT-TERIFLUNOMIDE if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on NAT-TERIFLUNOMIDE therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be teriflunomide-induced, discontinue NAT-TERIFLUNOMIDE and start an accelerated elimination procedure and monitor liver tests weekly until normalized. If teriflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of teriflunomide therapy may be considered.

Due to a potential for additive hepatotoxic effects, alcohol consumption should be avoided during treatment with NAT-TERIFLUNOMIDE.

Hypoproteinemia
Since teriflunomide is highly protein bound and as the binding is dependent upon the concentrations of albumin, unbound plasma teriflunomide concentrations are expected to be increased in patients with hypoproteinemia, e.g. in nephrotic syndrome. Teriflunomide is not recommended in patients with conditions of severe hypoproteinemia.

Infections
Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection during treatment, consider suspending treatment with NAT-TERIFLUNOMIDE and using an accelerated elimination procedure. Benefits and risks should be reassessed prior to resumption of therapy. Patients receiving NAT-TERIFLUNOMIDE should report symptoms of infections to a physician.

Teriflunomide is contraindicated in patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections (please see product monograph for CONTRAINDICATIONS). Medications like teriflunomide that have immunomodulatory potential may cause patients to be more susceptible to infections, including opportunistic infections. Prior to initiating NAT-TERIFLUNOMIDE, screen patients for latent tuberculosis infection. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to initiating treatment with NAT-TERIFLUNOMIDE.

Hypersensitivity
Cases of hypersensitivity, angioedema and anaphylactic reaction have been reported during the post-marketing period. Advise the patient to discontinue NAT-TERIFLUNOMIDE and seek immediate medical care if any signs or symptoms of anaphylaxis or angioedema occurs.

Concomitant use of Immunosuppressive or Immunomodulating Therapies

As leflunomide is the parent compound of teriflunomide, co-administration of NAT-TERIFLUNOMIDE with leflunomide is contraindicated.

Co-administration with antineoplastic or immunosuppressive therapies has not been evaluated and is not recommended due to the potential risk of additive immune system effects.

Vaccination
Two clinical studies have shown that teriflunomide treated patients mounted appropriate immune responses when vaccinated with inactivated neoantigen (first vaccination), or recall antigen (reexposure). No clinical data are available on the efficacy and safety of live vaccinations in patients taking teriflunomide. Vaccination with live vaccines is, however, not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping NAT-TERIFLUNOMIDE.

Peripheral Neuropathy
Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking NAT-TERIFLUNOMIDE develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing NAT-TERIFLUNOMIDE therapy and performing an accelerated elimination procedure.

Respiratory
Interstitial lung disease (ILD), including acute interstitial pneumonitis, has been reported with teriflunomide in the post marketing setting.

ILD and worsening of interstitial lung disease have been reported during treatment with leflunomide, the parent compound of teriflunomide. ILD is a potentially fatal disorder and may occur acutely at any time during treatment with a variable clinical presentation. The risk is increased in patients with a history of ILD.

New onset or worsening of pulmonary symptoms, such as persistent cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy and for further investigation, as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure.

Use in Women of Childbearing Potential
Teriflunomide is contraindicated in women who are pregnant or women of child bearing potential not using reliable contraception. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, the drug should be immediately discontinued and an accelerated elimination procedure should be initiated. Under these conditions, the patient should be referred to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling.

There are no adequate and well-controlled studies of teriflunomide in pregnant women.

However, based on animal studies, teriflunomide may increase the risk of fetal death or teratogenic effects when administered to pregnant women. In animal studies, teriflunomide has been shown to be selectively teratogenic and embryolethal in multiple species when administered during pregnancy at doses less than those used clinically.

Women of childbearing potential must not be started on NAT-TERIFLUNOMIDE until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with NAT-TERIFLUNOMIDE, patients must be fully counseled on the potential for serious risk to the fetus. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the fetus.

Upon discontinuing NAT-TERIFLUNOMIDE, it is recommended that all women of childbearing potential not using reliable contraception undergo an accelerated elimination procedure. Women receiving NAT-TERIFLUNOMIDE treatment who wish to become pregnant must discontinue NAT-TERIFLUNOMIDE and undergo an accelerated elimination procedure, which includes verification that teriflunomide plasma concentrations decreases to at least 0.02 mg/L. Human plasma concentrations of teriflunomide less than 0.02 mg/L are expected to have minimal risk.

Teriflunomide can increase the plasma concentration of oral contraceptives 1.54-fold, therefore consideration should be given to the type or dose of oral contraceptives used (please see product monograph for DRUG INTERACTIONS).

Use in males
Teriflunomide is detected in human semen. Animal studies to specifically evaluate the risk of male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of NAT-TERIFLUNOMIDE and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L.

Last Revised: February 18, 2022