Teriflunomide

Teriflunomide is a prescription medication used to treat the symptoms of relapsing forms of multiple sclerosis (MS).

• Teriflunomide is available under the following different brand names: Aubagio

Adult dosage

Tablet

• 7mg
• 14mg

Multiple Sclerosis

Adult dosage

• 7 mg or 14 mg orally once a day

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

Common side effects of Teriflunomide include:

• liver problems,
• influenza,
• hair loss or thinning hair,
• nausea,
• diarrhea,
• burning or prickly feeling in your skin, or
• numbness or tingling in the hands or feet different from the MS symptoms.

Serious side effects of Teriflunomide include:

• fever,
• chills,
• body aches,
• flu symptoms,
• sores in the mouth and throat,
• itching,
• tired feeling,
• loss of appetite,
• dark urine,
• clay-colored stools,
• yellowing of the skin or eyes,
• fast or racing heartbeats,
• confusion,
• little or no urinating,
• chest pain,
• dry cough,
• wheezing,
• feeling short of breath,
• skin redness or peeling,
• swelling,
• rapid weight gain

Rare side effects of Teriflunomide include:

• none 

This is not a complete list of side effects and other serious side effects or health problems that may occur as a result of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Teriflunomide has no noted severe interactions with any other drugs
• Teriflunomide has serious interactions with the following drugs:
  • axicabtagene ciloleucel
  • brexucabtagene autoleucel
  • ciltacabtagene autoleucel
  • idecabtagene vicleucel
  • lisocabtagene maraleucel
  • tisagenlecleucel
  • tucatinib
• Teriflunomide has moderate interactions with at least 62 other drugs.
• Teriflunomide has no noted severe interactions with any other drugs

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all your products. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions or concerns.

Contraindications

• History of hypersensitivity reaction to teriflunomide, leflunomide, or excipients
• Severe hepatic impairment
• Pregnancy
• Current leflunomide treatment 

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Teriflunomide?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Teriflunomide?”

Cautions

• The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications; there is potential for immunosuppression with this drug; no apparent increase in the incidence of malignancies and lymphoproliferative disorders reported in 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 therapy
• No clinical data is available on the efficacy and safety of live vaccinations in patients receiving therapy; vaccination with live vaccines is not recommended; the long half-life of the drug should be considered when contemplating administration of a live vaccine after stopping therapy
• It May take an average of 8 months to clear the drug from plasma; consider accelerated elimination with cholestyramine or activated charcoal
• Decreases in white blood cell count and platelet count have been observed; a recent CBC should be available before starting teriflunomide; monitor for signs and symptoms of an infection; consider suspending treatment with teriflunomide in case of serious infection; do not start teriflunomide in patients with active infections
• Not recommended for patients with serious immunodeficiency; do not initiate treatment in patients with active acute or chronic infections
• Peripheral neuropathy, including polyneuropathy and mononeuropathy, has been reported; evaluate the patient and consider discontinuing therapy; if a patient taking a drug develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing therapy and performing accelerated elimination procedure
• May cause an increase in renal uric acid clearance and decreases in serum uric acid
• Use caution in hyperkalemia
  • Anaphylaxis and severe allergic reactions were reported; signs and symptoms have included dyspnea, urticaria, and angioedema including lips, eyes, throat, and tongue; inform patients of signs and symptoms of anaphylaxis and angioedema
  • May increase blood pressure; measure blood pressure at treatment initiation and monitor blood pressure during treatment; elevated blood pressure should be appropriately managed during treatment
  • 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, maybe a reason for discontinuation of therapy and further investigation as appropriate; if discontinuation of the drug is necessary, consider initiation of the accelerated elimination procedure
  • Pancreatitis reported; if pancreatitis is suspected, discontinue teriflunomide and start an accelerated elimination procedure
  • Cases of tuberculosis reported; before initiating therapy, screen patients for latent tuberculosis infection with a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection
• Hepatotoxicity
  • Clinically significant and potentially life-threatening liver injury, including acute liver failure requiring transplant, was reported in patients receiving therapy 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 this drug; clinically significant liver injury can occur at any time during therapy
  • 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 this drug
  • Obtain serum transaminase and bilirubin levels within 6 months before initiation of therapy; monitor ALT levels at least monthly for six months after starting treatment; consider additional monitoring when therapy administered with other potentially hepatotoxic drugs
  • Consider discontinuing therapy if serum transaminase increase (above 3x ULN) is confirmed; monitor serum transaminase and bilirubin, 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 therapy-induced, discontinue the drug and start an accelerated elimination procedure and monitor liver tests weekly until normalized; if drug-induced liver injury is unlikely because some other probable cause is found, resumption of therapy may be considered
• Accelerated elimination of teriflunomide
  • This drug is eliminated slowly from plasma; without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations below 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 treatment; elimination can be accelerated by either of the following procedures:
    • Administration of cholestyramine 8 g every 8hour 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
    • 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 end of 11 days, both regimens successfully have accelerated teriflunomide elimination, leading to a more than 98% decrease in teriflunomide plasma concentrations; the use of the accelerated elimination procedure may potentially result in the return of disease activity if the patient had been responding to treatment
• Skin reactions
  • Cases of serious skin reactions, including cases of Stevens-Johnson syndrome (SJS) and a fatal case of toxic epidermal necrolysis (TEN), reported
  • Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with therapy; 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 (.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
  • Inform patients of signs and symptoms that may signal a serious skin reaction; instruct patients to discontinue therapy and seek immediate medical care should these signs and symptoms occur
  • Unless the reaction is not drug-related, discontinue therapy and begin an accelerated elimination procedure immediately; in such cases, patients should not be re-exposed to drug
  • Early manifestations of hypersensitivity (.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 therapy unless an alternative etiology for the signs or symptoms is established, and begin an accelerated elimination procedure immediately; in such cases, patients should not be re-exposed to drug
  • Bone Marrow Effects / Immunosuppression Potential
  • Cases of thrombocytopenia, including rare cases with platelet, counts below 50,000/mm3, reported in postmarketing setting; obtain a complete blood cell count (CBC) within 6 months before initiation of treatment; further monitoring should be based on signs and symptoms suggestive of bone marrow suppression
  • A mean decrease compared to baseline in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and platelet count of approximately 10% observed
  • Most reports are confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection
• Risk of infection
  • 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 and using an accelerated elimination procedure; reassess benefits and risks before the resumption of therapy; instruct patients to report symptoms of infections to a physician
  • Therapy is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections; medications that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections
  • One fatal case of Klebsiella pneumonia sepsis was reported in a patient taking this medication (14 mg) for 1.7 years; fatal infections were reported in the postmarketing setting in patients receiving this drug, especially Pneumocystis jirovecii pneumonia and aspergillosis
  • Most 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, cytomegalovirus hepatitis reactivation has been observed
  • In clinical trials in adult patients, cases of tuberculosis are observed; before initiating treatment, screen patients for latent tuberculosis infection with a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection
  • This drug has not been studied in patients with a positive tuberculosis screen, and safety in individuals with latent tuberculosis infection is unknown; for patients testing positive in tuberculosis screening, treat by standard medical practice before administering therapy
• Drug interaction overview
  • Teriflunomide is a CYP2C8 inhibitor, weak CYP1A2 inducer, organic anion transporter 3 (OAT3) inhibitor; BCRP and organic anion transporting polypeptide B1 and B3 (OATP1B1/1B3) inhibitor
  • Coadministration with CYP2C8 substrates (.g, paclitaxel, pioglitazone, repaglinide, rosiglitazone) may increase exposure to the CYP2C8 substrates
  • Coadministration with warfarin requires close monitoring of INR because teriflunomide may decrease peak INR by ~25%
  • Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel; consider the type or dose of contraceptives used in combination with teriflunomide
  • Coadministration with OAT3 substrates may increase the exposure of the OAT3 substrates
  • Concomitant use with CYP1A2 substrates and teriflunomide may reduce exposure of the CYP1A2 substrates
  • Immunosuppressive or immunomodulating therapies
    • Coadministration with antineoplastic or immunosuppressive therapies used for the treatment of multiple sclerosis has not been evaluated
    • When switching from teriflunomide to another agent with a known potential for hematologic suppression, monitor for hematologic toxicity, because there will be an overlap of systemic exposure to both compounds
    • The use of an accelerated elimination procedure may decrease this risk, but may also potentially result in the return of disease activity if the patient had been responding to treatment

Pregnancy and Lactation

• Contraindicated for use in pregnant women and females of reproductive potential not using effective contraception because of potential for fetal harm based on animal data
• Exclude pregnancy before initiating treatment in females of reproductive potential; advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment
• Discontinue treatment in a female who wishes to become pregnant and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL); use effective contraception until is verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL), which are expected to have minimal embryofoetal risk
• If the patient becomes pregnant during therapy, stop treatment, inform the patient of the potential risk to the fetus, and perform an accelerated drug elimination procedure to achieve plasma concentrations of less than 0.02 mg/L (0.02 mcg/mL); refer the patient to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling
• Pregnancy exposure registry
  • Registry monitors pregnancy outcomes in women exposed to therapy during pregnancy; healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2
• Males
  • The drug 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 effective contraception
  • Discontinue therapy in men wishing to father a child 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)
  • To minimize any possible risk, men not wishing to father a child and their female partners should use effective contraception
• Lactation
  • Not known whether a drug is excreted in human milk; or detected in rat milk following a single oral dose; because of the potential for adverse reactions in a breastfed infant from therapy, women should not breastfeed during treatment
  • Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for therapy and any potential adverse effects on the breastfed infant from the drugs or the underlying maternal condition