Teriflunomide Drug Information

Hepatotoxicity

Clinically significant and potentially life-threatening liver injury, including acute liver failure requiring transplant, has been reported in patients treated with teriflunomide tablets in the postmarketing setting. Patients with pre-existing liver disease and patients taking other hepatotoxic drugs may be at increased risk for developing liver injury when taking teriflunomide tablets. Clinically significant liver injury can occur at any time during treatment with teriflunomide tablets.

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 tablets. Teriflunomide tablets are contraindicated in patients with severe hepatic impairment. In placebo-controlled trials in adult patients, ALT greater than three times the ULN occurred in of patients receiving teriflunomide tablets 7 mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period.

These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, teriflunomide tablets were discontinued and patients underwent an accelerated elimination procedure.

Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months. One patient in the controlled trials in adult patients developed ALT 32 times the ULN and jaundice 5 months after initiation of teriflunomide tablets 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure.

Teriflunomide tablets-induced liver injury in this patient could not be ruled out. Obtain serum transaminase and bilirubin levels within 6 months before initiation of teriflunomide tablets therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide tablets.

Consider additional monitoring when teriflunomide tablets are given with other potentially hepatotoxic drugs. Consider discontinuing teriflunomide tablets if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on teriflunomide tablets 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 tablets-induced, discontinue teriflunomide tablets and start an accelerated elimination procedure and monitor liver tests weekly until normalized. If teriflunomide tablets-induced liver injury is unlikely because some other probable cause has been found, resumption of teriflunomide tablets therapy may be considered.

Embryofetal Toxicity

Teriflunomide tablets may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryofetal lethality occurred in animal reproduction studies in multiple animal species at plasma teriflunomide exposures similar to or lower than that in humans at the maximum recommended human dose (MRHD) of 14 mg/day. Teriflunomide tablets are contraindicated for use in pregnant women and in females of reproductive potential not using effective contraception.

Exclude pregnancy before starting treatment with teriflunomide tablets in females of reproductive potential. Advise females of reproductive potential to use effective contraception during teriflunomide tablets treatment and during an accelerated drug elimination procedure after teriflunomide tablets treatment. If a woman becomes pregnant while taking teriflunomide tablets, stop treatment with teriflunomide tablets, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve a plasma teriflunomide concentration of less than 0.02 mg/L.

Upon discontinuing teriflunomide tablets, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving teriflunomide tablets treatment who wish to become pregnant must discontinue teriflunomide tablets and undergo an accelerated drug elimination procedure, which includes verification that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL). Men wishing to father a child should also discontinue use of teriflunomide tablets and either undergo an accelerated elimination procedure or wait until verification that the plasma teriflunomide concentration is less than 0.02 mg/L (0.02 mcg/mL).

Based on animal data, human plasma concentrations of teriflunomide of less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryofetal risk.

Procedure for Accelerated Elimination of Teriflunomide 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, although because of 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 teriflunomide tablets.

Elimination can be accelerated by either of the following procedures: • Administration of cholestyramine 8 g every 8 hours for 11 days. If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly. At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations.

Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to teriflunomide tablets treatment.

Bone Marrow Effects/Immunosuppression Potential/Infections Bone Marrow Effects A mean decrease compared to baseline in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo-controlled trials in adult patients with 7 mg and 14 mg of teriflunomide tablets. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. No cases of serious pancytopenia were reported in premarketing clinical trials of teriflunomide tablets but rare cases of pancytopenia and agranulocytosis have been reported in the postmarketing setting with leflunomide.

A similar risk would be expected for teriflunomide tablets. Cases of thrombocytopenia with teriflunomide tablets, including rare cases with platelet counts less than 50,000/mm 3, have been reported in the postmarketing setting. Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with teriflunomide tablets.

Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression. Risk of Infection/Tuberculosis Screening Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection consider suspending treatment with teriflunomide tablets and using an accelerated elimination procedure.

Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving teriflunomide tablets to report symptoms of infections to a physician. Teriflunomide tablets are not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections.

Medications like teriflunomide tablets that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections. In placebo-controlled studies of teriflunomide tablets in adult patients, no overall increase in the risk of serious infections was observed with teriflunomide tablets compared to placebo (2.2%). However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking teriflunomide tablets 14 mg for 1.7 years.

Fatal infections have been reported in the postmarketing setting in patients receiving leflunomide, especially Pneumocystis jirovecii pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. In clinical studies with teriflunomide tablets, cytomegalovirus hepatitis reactivation has been observed.

In clinical studies with teriflunomide tablets in adult patients, cases of tuberculosis have been observed. Prior to initiating teriflunomide tablets, screen patients for latent tuberculosis infection with a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection. Teriflunomide tablets have not been studied in patients with a positive tuberculosis screen, and the safety of teriflunomide tablets in individuals with latent tuberculosis infection is unknown.

For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with teriflunomide tablets. Vaccination: No clinical data are available on the efficacy and safety of live vaccinations in patients taking teriflunomide tablets. Vaccination with live vaccines is not recommended.

The long half-life of teriflunomide tablets should be considered when contemplating administration of a live vaccine after stopping teriflunomide tablets. Malignancy The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with teriflunomide tablets.

No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the teriflunomide tablets clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with teriflunomide tablets.

Hypersensitivity Reactions

Teriflunomide tablets can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included dyspnea, urticaria, and angioedema including lips, eyes, throat, and tongue. Inform patients of the signs and symptoms of anaphylaxis and angioedema.

Serious Skin Reactions Cases of serious skin reactions, sometimes fatal, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with teriflunomide tablets. Fatal outcomes were reported in one case of TEN and one case of DRESS. Inform patients of the signs and symptoms that may signal a serious skin reaction.

Instruct patients to discontinue teriflunomide tablets and seek immediate medical care should these signs and symptoms occur. Unless the reaction is clearly not drug related, discontinue teriflunomide tablets and begin an accelerated elimination procedure immediately. In such cases, patients should not be re-exposed to teriflunomide.

Drug Reaction with Eosinophilia and Systemic Symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with teriflunomide tablets. One fatal case of DRESS that occurred in close temporal association (34 days) with the initiation of teriflunomide tablets treatment has been reported in the postmarketing setting. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.

Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident.

If such signs or symptoms are present, the patient should be evaluated immediately. Discontinue teriflunomide tablets, unless an alternative etiology for signs or symptoms is established, and begin an accelerated elimination procedure immediately.

Peripheral Neuropathy

In placebo-controlled studies in adult patients, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), occurred more frequently in patients taking teriflunomide tablets than in patients taking placebo. Five of them recovered following treatment discontinuation. Not all cases of peripheral neuropathy resolved with continued treatment.

Peripheral neuropathy also occurred in patients receiving leflunomide. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking teriflunomide tablets develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing teriflunomide tablets therapy and performing an accelerated elimination procedure.

Increased Blood Pressure

In placebo-controlled studies in adult patients, the mean change from baseline to the end of study in systolic blood pressure was +2.3 mmHg and +2.7 mmHg for teriflunomide tablets 7 mg and 14 mg, respectively, and -0.6 mmHg for placebo. Check blood pressure before start of teriflunomide tablets treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with teriflunomide tablets.

Respiratory Effects

Interstitial lung disease, including acute interstitial pneumonitis, has been reported with teriflunomide tablets in the postmarketing setting. Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. Interstitial lung disease may be fatal and may occur acutely at any time during therapy with a variable clinical presentation.

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

Pancreatitis in Pediatric Patients

Teriflunomide tablets are not approved for use in pediatric patients. In the pediatric clinical trial, cases of pancreatitis were observed in 1.8% (2/109) of patients receiving teriflunomide tablets; one of these cases was serious.

Concomitant Use with Immunosuppressive or Immunomodulating Therapies Coadministration with antineoplastic or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated. Safety studies in which teriflunomide tablets were concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations in the treatment of multiple sclerosis has not been established.

In any situation in which the decision is made to switch from teriflunomide tablets to another agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds.