Teriflunomide is an oral pyrimidine synthesis inhibitor, and an active metabolite of leflunomide. Teriflunomide is indicated for the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. Teriflunomide inhibits dihydroorotate dehydrogenase, which is a mitochondrial enzyme involved in de novo pyrimidine synthesis. In clinical trials of up to 40 months duration in patients with relapsing forms of multiple sclerosis, teriflunomide consistently demonstrated statistically significant reductions in annual relapse rates and the relative risk of disability progression compared to placebo. Changes in total lesion volume of T2 and hypointense T1 lesions were also significantly lower with teriflunomide compared to placebo. The drug labeling carries boxed warnings regarding the risk for hepatotoxicity and a risk for teratogenicity. Due to the long half-life, an accelerated drug elimination procedure should be used when there is a need to lower the teriflunomide concentration due to potential adverse effects. Teriflunomide was FDA-approved in 2012.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-May be taken with or without food.
An increased risk of malignancy, including lymphoproliferative disorders, is associated with some immunosuppressive medications. During clinical trials with teriflunomide, there was no apparent increase in the risk of malignancy. Larger, long-term controlled clinical or epidemiologic study is needed to further clarify the risk of malignancy or lymphoproliferative disorders with teriflunomide treatment.
Clinically significant and potentially life-threatening hepatotoxicity, including acute hepatic failure requiring transplant, has been reported in patients treated with teriflunomide during postmarketing experience. The concurrent use of other drugs which may be hepatotoxic may increase risk for liver injury. Baseline liver function tests (LFTs) including serum transaminase and bilirubin concentrations should be measured within 6 months before starting treatment. Monitor ALT concentrations at least monthly for 6 months after treatment initiation and consider additional monitoring when teriflunomide is given with other potentially hepatotoxic drugs or if the patient develops signs and symptoms consistent with potential liver injury. ALT and bilirubin monitoring should occur in patients presenting with unexplained potential symptoms of liver dysfunction including nausea, vomiting, fatigue, anorexia, or jaundice with or without dark urine. Consider drug discontinuation with serum transaminase increases greater than 3 times the upper level of normal (ULN). If liver injury is suspected to be teriflunomide-induced, discontinue the drug and start an accelerated elimination procedure and monitor LFTs weekly until normalized. Elevated hepatic enzymes have occurred during clinical trials with teriflunomide, mostly within the first year of treatment, and some patients have experienced jaundice. An ALT greater than 3 times the ULN occurred in 5.8% and 6.2% of patients taking teriflunomide 7 mg and 14 mg, respectively, compared to 3.8% of patients taking placebo. When treatment was discontinued or an accelerated elimination procedure was performed, half of the patients' elevations returned to normal or near normal values within 2 months. One patient developed ALT elevations greater than 32-times the ULN with jaundice following 5 months of daily treatment with teriflunomide 14 mg; the patient recovered following plasmapheresis and an accelerated elimination procedure. ALT elevations of any magnitude occurred in 13% to 15% of patients taking either 7 mg or 14 mg of teriflunomide, compared to 9% of patients taking placebo. During an open-label long-term safety trial, AST elevations more than 2-times the ULN were reported in 12.3% to 22.7% of patients. Three cases of elevations in total bilirubin more than 2-times the ULN with ALT elevations more than 3-times the ULN have been observed with teriflunomide treatment; however, all patients had comorbidities that may have contributed to hyperbilirubinemia. Elevations in GGT have also been reported.
Teriflunomide is associated with immunomodulation and bone marrow suppression. During clinical trials, patients taking either teriflunomide 7 mg or 14 mg experienced mean decreases in white blood cell count (WBC) and platelet counts of 15% and 10%, respectively. Decreases mainly occurred during the first 6 weeks of treatment and were sustained over the course of treatment. Neutropenia occurred in 4% to 6% of patients, with neutrophil counts less than 1.5 x 109/L occurring in 12% to 16% of patients. Lymphopenia with leukocyte counts of less than 0.8 x 109/L occurred in 10% to 12% of patients. Rare cases of thrombocytopenia with a platelet count less than 50,000/mm3 have been observed in the postmarketing setting. Pancytopenia and agranulocytosis have been reported during postmarketing observation with leflunomide. Teriflunomide is an active metabolite of leflunomide; both drugs produce similar blood concentrations of teriflunomide. Therefore, similar hematologic risks with teriflunomide are expected. Complete blood cell (CBC) counts and symptoms of bone marrow or immunosuppression should be monitored during therapy.
Several infectious complications have been reported during teriflunomide treatment. Infections across clinical trials with incidence rates include naso-pharyngitis (21% to 53%), influenza (9.2% to 34.8%), upper respiratory infection (18% to 43.9%), cystitis (7.3% to 23.5%), and oral herpes (1.2% to 12.1%). Rare cases of tuberculosis infection were observed during trials. The risk of serious infection with teriflunomide appears to be no greater than that of placebo, as 2.2% and 2.7% of patients who received teriflunomide 7 mg or 14 mg experienced these infections compared to 2.2% of those that received placebo. A fatal case of Klebsiella pneumonia sepsis was reported in a patient who took teriflunomide 14 mg for 1.7 years. Cytomegalovirus hepatitis reactivation has occurred. Fatal infections including Pneumocystitis jiroveci pneumonia and aspergillosis have been reported during postmarketing observation with leflunomide. Teriflunomide is an active metabolite of leflunomide, and both drugs produce similar blood concentrations of teriflunomide. Therefore, similar infectious risks may be expected. If a patient develops a serious infection consider suspending treatment with teriflunomide and using an accelerated elimination procedure. Reassess the benefits and risks prior to the resumption of therapy. Instruct patients to report any symptoms of infection to a physician.
During clinical trials, peripheral neuropathy, including polyneuropathy and mononeuropathy (i.e., carpal tunnel syndrome) confirmed by nerve conduction studies, occurred in 1.4% and 1.9% of patients with multiple sclerosis taking teriflunomide 7 mg and 14 mg, respectively, compared to 0.4% of those taking placebo. Following drug discontinuation in 8 patients with confirmed peripheral neuropathy, 5 patients recovered. Older adult patients 60 years or more of age, patients with diabetes mellitus, or those who are taking concomitant neurotoxic medications may be at increased risk for peripheral neuropathy. If a patient taking teriflunomide develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing therapy and performing an accelerated elimination procedure. Paresthesias (8% to 9 %), hypoesthesia (48.1% to 50%), pallanesthesia (30.3% to 33.3%), hyperreflexia (21.2% to 23.5%), and dizziness (21.2% to 22.2%) also occurred with teriflunomide use. Headache is commonly reported, occurring in 16% to 18% of patients. Insomnia (9% to 34.6%) and fatigue (10% to 48.5%) have also been observed during clinical trials.
Teriflunomide is contraindicated for use in patients with a history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any of the inactive ingredients. Teriflunomide is an active metabolite of leflunomide; both drugs produce similar blood concentrations of teriflunomide. Therefore, similar risks for hypersensitivity reactions are expected. Teriflunomide may cause anaphylactoid reactions such as anaphylaxis and other severe allergic reactions such as angioedema. Dyspnea and urticaria have occurred. Cases of Stevens-Johnson syndrome (SJS) and a case of fatal toxic epidermal necrolysis (TEN) have been reported. Rare cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported with teriflunomide. One fatal case of DRESS occurred in close temporal association (34 days) with the initiation of teriflunomide treatment. Educate patients about the signs and symptoms of anaphylaxis and angioedema as well as symptoms of severe skin reactions (e.g., rash, lymphadenopathy, or hepatic dysfunction, with or without fever). Patients should discontinue teriflunomide and seek immediate medical attention if hypersensitivity symptoms occur. Discontinue teriflunomide if a clear, alternative etiology for the reaction cannot be established, and do not re-expose the patient. Begin an accelerated elimination procedure. Other dermatologic reactions have been reported with teriflunomide use. Alopecia is common with teriflunomide, occurring in 10% to 13% of patients during clinical trials. Pruritus (2.8% to 3.5%), urticaria (0.8% to 1.1%), and erythema multiforme have also been observed. Psoriasis or worsening of psoriasis (including pustular psoriasis) has been observed with teriflunomide during postmarketing experience. Rash (unspecified) was observed in 16.7% to 22.2% of patients during a long-term follow-up trial of 8.5 years.
Hypophosphatemia has been noted during teriflunomide use. Mild hypophosphatemia (0.6 mmol/L or more but less than the lower limit of normal) was reported in 18%, and moderate hypophosphatemia (above 0.3 mmol/L but less than 0.6 mmol/L) in 4% of teriflunomide-treated patients compared to 7% and 0.8% of placebo-treated patients, respectively. Serum phosphorus concentrations less than 0.3 mmol/L have not been reported.
Renal failure (unspecified) may occur in patients receiving teriflunomide. Serum creatinine values increased from baseline by 100% or more in 0.6% to 0.8% of teriflunomide-treated patients. These elevations were transient, and some were accompanied by hyperkalemia. Teriflunomide may cause acute uric acid nephropathy with transient hyperuricemia and transient acute renal failure (unspecified) because the drug increases renal uric acid clearance.
Cardiovascular adverse events observed in some teriflunomide-treated patients include increases in systolic and diastolic blood pressure and hypertension. Mean increases of 2.3 to 2.7 mmHg (systolic) and 1.4 to 1.9 mmHg (diastolic) blood pressures occurred, with hypertension occurring in 3.1% to 4.3% of teriflunomide patients. Comparatively, hypertension occurred in 1.8% of placebo-treated patients. Blood pressure should be monitored prior to and during teriflunomide treatment. Appropriate clinical management should occur if needed. During clinical trials, 3 sudden deaths and 1 case of myocardial infarction occurred in patients taking teriflunomide over 1 to 9 years. Drug causality has not been established in these 4 cases.
Teriflunomide frequently causes diarrhea and nausea, with observed incidence rates of 13% to 14% and 8% to 11%, respectively. Upper abdominal pain and dyspepsia have also been reported. Pancreatitis and colitis have been observed in the postmarketing setting in adults. If pancreatitis is suspected, discontinue teriflunomide and start an accelerated elimination procedure. Pancreatitis appears to occur at an increased incidence in teriflunomide-treated pediatric patients vs. observations noted in adults, and was observed in 1.8% (2/109) of pediatric patients ages 10 to 17 years who received teriflunomide during a clinical trial vs. 0% of patients who received placebo (n = 57). All patients in the pediatric trial recovered or were recovering after treatment discontinuation and accelerated elimination procedure. Elevated or abnormal blood creatine phosphokinase was reported in 6.4% of pediatric patients who received teriflunomide compared to 0% of patients in the placebo group. The safety and efficacy of teriflunomide for the treatment of relapsing form of multiple sclerosis in pediatric patients was not established in the trial.
Adverse effects affecting the musculoskeletal system reported during teriflunomide therapy include arthralgia (6% to 8% of patients). Extremity pain (7.1% to 45.7%), back pain (8% to 36.4%), and muscle weakness or myasthenia (37.9% to 42%) have also been observed.
Interstitial lung disease, including acute interstitial pneumonitis, has been reported with teriflunomide during post-marketing experience. Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported with leflunomide. Teriflunomide is an active metabolite of leflunomide and both drugs produce similar concentrations of teriflunomide, and thus similar pulmonary risks may occur. Types of lung disease may include, but are not limited to, bronchiolitis, eosinophilic pneumonia, hypersensitivity pneumonitis, interstitial pneumonia, pneumoconiosis, pulmonary fibrosis, or sarcoidosis of the lung. Monitor patients for signs of new or worsening pulmonary disease. Clinical presentations may vary greatly among patients. 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.
Based on animal studies, teriflunomide may increase the risk of teratogenesis and/or fetal death when administered to a pregnant woman. All patients must be fully counseled on the potential for serious risk to the fetus. Proper contraception is required for females of reproductive potential and recommended for men. Teriflunomide has been detected in human semen; the risk of male-mediated fetal toxicity is not known. Early detection and reporting of potential pregnancy is important. Should pregnancy occur, rapidly lowering the plasma concentration of teriflunomide by instituting an accelerated elimination procedure may decrease the risk to the fetus. Females who wish to become pregnant or males who wish to father a child must discontinue the drug and undergo an accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk to the fetus. Advise all patients that teriflunomide may stay in the blood for up to 2 years after the last dose and that an accelerated elimination procedure may be used if needed.
Teriflunomide is contraindicated for use in patients with a history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any of the inactive ingredients in teriflunomide. Teriflunomide may cause serious hypersensitivity reactions or anaphylaxis. Reported reactions have included anaphylaxis, angioedema, and serious skin reactions. Cases of serious rash, including Stevens-Johnson syndrome (SJS) and a case of fatal toxic epidermal necrolysis (TEN) have been reported. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with teriflunomide. One fatal case of DRESS occurred in close temporal association (34 days) with the initiation of teriflunomide treatment. Educate patients about the signs and symptoms of anaphylaxis and angioedema as well as symptoms of severe skin reactions (e.g., rash, lymphadenopathy, or hepatic dysfunction). Patients should discontinue teriflunomide and seek immediate medical attention if these symptoms occur. Discontinue teriflunomide if a clear, alternative etiology for the reaction cannot be established, and do not re-expose the patient. Begin an accelerated elimination procedure.
Teriflunomide is contraindicated for use in patients with severe hepatic disease, as these patients may be at risk for further hepatic injury or development of elevated serum transaminases. Clinically significant and potentially life-threatening hepatotoxicity, including acute liver failure requiring transplant, has been reported in patients treated with teriflunomide during postmarketing experience. Patients with pre-existing acute or chronic hepatic impairment, such as hepatitis, jaundice, or those with serum ALT concentrations more than 2 times the upper level of normal (ULN) should usually not be treated with teriflunomide. Baseline liver function tests (LFTs) including serum transaminase and bilirubin concentrations should be measured within the 6 months before starting treatment. Monitor ALT concentrations at least monthly for 6 months after therapy initiation; additional monitoring may be necessary when teriflunomide is given with other hepatotoxic drugs. ALT and bilirubin monitoring should occur in patients presenting with unexplained potential symptoms of liver dysfunction including nausea, vomiting, fatigue, anorexia, or jaundice with or without dark urine. Consider drug discontinuation with serum transaminase increases more than 3 times the ULN. If liver injury is suspected, discontinue and begin an accelerated elimination procedure. Monitor weekly LFTs until normalization. If teriflunomide-induced liver injury is not suspected, therapy may be resumed.
Teriflunomide may cause immunosuppression and is therefore not recommended for use in patients with severe immunodeficiency or existing bone marrow suppression. Decreases in white blood cell (WBC) concentrations of approximately 15% and platelet concentrations of approximately 10% were experienced by patients taking teriflunomide during clinical trials. Rare cases of thrombocytopenia with platelet counts less than 50,000/mm3 have been reported. Pancytopenia and agranulocytosis have been reported with leflunomide, the parent compound of teriflunomide. Obtain a baseline complete blood count (CBC) within 6 months prior to treatment initiation; during therapy continue to monitor based on signs or symptoms of bone marrow suppression, including neutropenia. Concomitant use of teriflunomide with chemotherapy, or immunosuppressive therapies used for the treatment of multiple sclerosis has not been evaluated. Safety studies in which teriflunomide was concomitantly administered with other immune-modulating therapies for up to 1 year (interferon beta or glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations has not been established. In any situation in which the decision is made to switch from teriflunomide 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. Use of an accelerated elimination procedure may decrease this risk, but may also result in return of disease activity if the patient had been responding to teriflunomide treatment. Patients taking teriflunomide may be more susceptible to infections, including bacterial, fungal, or viral infection or opportunistic infections. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops serious infection, consider interrupting teriflunomide therapy and using an accelerated elimination procedure. Patients should report any signs or symptoms of infection, such as fever, chills, sore throat or other symptoms to their prescriber while taking teriflunomide. A fatal case of Klebsiella pneumonia sepsis has been reported in a patient taking teriflunomide 14 mg for a duration of 1.7 years. Fatal infections have been reported in the postmarketing setting in patients receiving leflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which may predispose patients to infection. In clinical studies with teriflunomide, cytomegalovirus hepatitis reactivation has been observed. Cases of tuberculosis were also reported. Screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for Mycobacterium tuberculosis infection before teriflunomide initiation. Teriflunomide has not been studied in patients with a positive tuberculosis screen, and the safety of using teriflunomide in individuals with latent tuberculosis infection is unknown.
Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the drug elimination procedure has not been performed. Advise patients that the use of some vaccines should be avoided during treatment and for at least 6 months after discontinuation.
Interstitial lung disease, including acute interstitial pneumonitis, has been reported with teriflunomide in the post-marketing setting. Worsening of pre-existing interstitial lung disease or pulmonary disease has been reported with the use of leflunomide, of which teriflunomide is an active metabolite. Interstitial lung disease may include, but is not limited to, bronchiolitis, eosinophilic pneumonia, hypersensitivity pneumonitis, interstitial pneumonia, pneumoconiosis, pulmonary fibrosis, or sarcoidosis of the lung. 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 teriflunomide elimination procedure.
Caution should be used during teriflunomide therapy in patients with pre-existing hypertension as increases in blood pressure (systolic and/or diastolic) were reported in clinical trials. Hypertension occurred in some individuals. Blood pressure should be monitored prior to treatment initiation and periodically during treatment. Elevated blood pressure during treatment should be appropriately managed according to current clinical guidelines.
Teriflunomide was associated with the development of peripheral neuropathy during clinical trials. Older and geriatric adults more than 60 years of age, patients using concomitant neurotoxic medications, and patients with diabetes mellitus may have an increased risk for peripheral neuropathy. Patients with pre-existing peripheral neuropathy may develop a worsening of symptoms. Drug discontinuation or the use of an accelerated elimination procedure should be considered if a patient develops symptoms of peripheral neuropathy, such as tingling of the hands or feet or bilateral numbness. Geriatric patients were not enrolled in pre-approval clinical trials of teriflunomide for the treatment of multiple sclerosis.
Teriflunomide is contraindicated for use during pregnancy. Animal studies indicate that teriflunomide may cause major birth defects and/or intrauterine fetal death during human pregnancy. Prospectively collected human data (from pregnancy registries, clinical trials, pharmacovigilance cases, and published literature) of more than 150 pregnancies exposed to teriflunomide and more than 300 pregnancies exposed to leflunomide do not indicate increased birth defects or miscarriage with inadvertent teriflunomide exposure in the early first trimester followed by an accelerated elimination procedure; however, data are too limited to be conclusive. There are no data about exposures later in the first trimester and beyond. In animal reproduction studies, high incidences of fetal malformations (primarily craniofacial, and axial and appendicular skeletal defects) and embryolethality were reported at plasma exposures (AUC) lower than that at the maximum human recommended dose of 14 mg/day. No well-controlled trials in humans are available. Women who wish to become pregnant should discontinue teriflunomide and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL); the patient should use effective contraception until it is verified that the plasma concentration has been lowered to this level. Human plasma concentrations of teriflunomide less than 0.02 mg/L are expected to have minimal risk to the fetus. The patient should be counseled to immediately contact their health care provider if pregnancy is suspected (e.g., a delay in menses) during treatment or anytime within the 2 years after discontinuing the drug, since teriflunomide may stay in the blood for up to 2 years following the last dose. Perform a pregnancy test if pregnancy is suspected. An accelerated teriflunomide elimination procedure should be used to rapidly lower teriflunomide concentration, which may decrease risk to the fetus. Refer the patient to an obstetrician or gynecologist, preferably experienced in reproductive toxicity, for further evaluation and management. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to terflunomide; information about the registry can be obtained at mothertobaby.org/ongoing-study/aubagio or by calling 1-800-745-4447, option 2 or 1-877-311-8972.
All patients, both male and female, should be advised of the reproductive risk for teriflunomide. Teriflunomide may increase the risk of major birth defects, and it is contraindicated for use in females of reproductive potential not using effective contraception. A woman of reproductive potential must not begin treatment with teriflunomide until pregnancy is ruled out; perform pregnancy testing prior to treatment initiation. Risks associated with fetal exposure to teriflunomide during pregnancy should be discussed. An accelerated drug elimination procedure is recommended in all women of reproductive age who discontinue teriflunomide. Women receiving teriflunomide who wish to become pregnant must discontinue the drug and undergo an accelerated drug elimination procedure, which includes verification that the plasma concentration of teriflunomide is less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L are expected to have minimal risk to the fetus. Contraceptives should be continued during an accelerated drug elimination procedure in all females of reproductive age until it is verified that the plasma concentration of teriflunomide is less than 0.02 mg/L (0.02 mcg/mL). Contraception requirements have also been advised for males. Teriflunomide is detected in human semen; studies evaluating male-induced fetal risk are not available. Male-mediated teratogenicity is a potential concern; male patients should use adequate contraception, and males wishing to father a child should discontinue the drug and undergo an accelerated elimination procedure or wait until verification that the plasma concentration of teriflunomide is less than 0.02 mg/L (0.02 mcg/mL). Advise all patients that teriflunomide may stay in the blood for up to 2 years after the last dose and that an accelerated elimination procedure may be used if needed. Patients should be counseled to immediately contact their health care provider if pregnancy is suspected. If a pregnancy is confirmed in a treated female, an accelerated teriflunomide elimination procedure may be considered to rapidly lower the teriflunomide concentration, which may decrease risk to the fetus. It is not clear if teriflunomide affects male fertility. Oral administration of teriflunomide (0, 1, 3, 10 mg/kg/day) to male rats prior to and during mating (to untreated females) resulted in no adverse effects on fertility; however, a reduced epididymal sperm count was observed at the mid and high doses tested. The no-effect dose for reproductive toxicity in male rats (1 mg/kg) is less than the MRHD on a BSA basis.
Teriflunomide should be avoided during breast-feeding. It is not known if teriflunomide is excreted in human milk. The extensive half-life and GI absorption of the drug suggest that it could be present in human milk. Serious adverse reactions associated with teriflunomide may occur in the breast-fed infant. All disease-modifying multiple sclerosis agents are usually avoided during breast-feeding, particularly in the early post-partum period, when exclusive breast-feeding of the infant is often encouraged.
The safety and efficacy of teriflunomide for the treatment of relapsing form of multiple sclerosis (MS) was not established in a placebo controlled trial in children and adolescent patients 10 to 17 years. This well-controlled clinical study included 166 pediatric patients with MS (109 patients received once-daily doses of teriflunomide and 57 patients received placebo) for up to 96 weeks and failed to establish effectiveness of teriflunomide. Additionally, there were some safety concerns. Pancreatitis has been reported in adults in the postmarketing setting, but appears to occur at higher frequency in the pediatric population. In this pediatric study, cases of pancreatitis were reported in 1.8% (2/109) of patients who received teriflunomide compared to 0% of patients in the placebo group. All patients in the pediatric trial recovered or were recovering after treatment discontinuation and accelerated elimination procedure. Additionally, elevated or abnormal blood creatine phosphokinase (CPK) was reported in 6.4% of pediatric patients who received drug treatment vs. 0% of those patients in the placebo group.
For the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease:
Oral dosage:
Adults: 7 or 14 mg PO once daily.
Therapeutic Drug Monitoring:
Prior to therapy initiation and during maintenance treatment
Measure serum transaminases, bilirubin, and a CBC within the 6 months prior to starting teriflunomide. Perform tuberculin skin testing or other tests to rule out tuberculosis. Once on treatment, measure ALT at least monthly for 6 months; check CBC if signs or symptoms of infection are present. Exclude pregnancy in females of reproductive potential before treatment initiation. Monitor blood pressure before starting treatment and periodically thereafter. Consider an accelerated elimination procedure if liver injury or pregnancy is suspected.
Drug Elimination Procedure for suspected drug-induced liver injury, cases of pregnancy, women of childbearing age, men who wish to father a child, hypersensitivity, significant overdose or toxicity, or other circumstances that require rapid lowering of teriflunomide plasma concentrations
After stopping treatment for teriflunomide, a drug elimination procedure with cholestyramine or activated charcoal is recommended if it is desirable to rapidly obtain plasma concentrations less than 0.02 mg/L. The procedure can achieve a 98% or greater lowering of serum teriflunomide concentrations within 11 days. Without the procedure, it may take up to 2 years for concentrations to decrease to this level.
-Stop treatment with teriflunomide.
-Administer cholestyramine 8 grams PO 3 times per day or activated charcoal powder 50 grams PO every 12 hours for 11 days. The dose of cholestyramine can be reduced to 4 grams PO 3 times per day if the 8 gram dose is not tolerated. Also, the 11 days do not need to be consecutive unless there is a need to rapidly lower teriflunomide concentrations.
-At 11 days, both procedures led to more than 98% decrease in teriflunomide plasma concentrations.
-Accelerated elimination may cause the return of disease activity if the patient had previously responded to teriflunomide treatment.
Maximum Dosage Limits:
-Adults
14 mg/day PO.
-Geriatric
14 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Teriflunomide is contraindicated in patients with severe hepatic impairment. No dosage adjustment is needed in patients with mild or moderate hepatic impairment.
Patients with Renal Impairment Dosing
No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment.
*non-FDA-approved indication
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Zidovudine, ZDV should be used cautiously with other drugs that can cause bone marrow suppression including teriflunomide because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage or discontinuation of zidovudine may be warranted. Teriflunomide, an organic anion transporter OAT3 renal updake inhibitor, may cause elevated concentrations of zidovudine, an OAT3 substrate.
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Acetaminophen; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Acetaminophen; Caffeine; Dihydrocodeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Acetaminophen; Caffeine; Pyrilamine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Alemtuzumab: (Major) Concomitant use of teriflunomide with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
Alogliptin; Pioglitazone: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as pioglitazone. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Alosetron: (Moderate) Use caution when administering teriflunomide and alosetron concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as alosetron, may decrease alosetron exposure and lead to a reduction in efficacy.
Alpelisib: (Major) Avoid coadministration of alpelisib with teriflunomide due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and teriflunomide is a BCRP inhibitor.
Amlodipine; Atorvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Anagrelide: (Moderate) Use caution when administering teriflunomide and anagrelide concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as anagrelide, may decrease anagrelide exposure and lead to a reduction in efficacy. Monitor platelet counts.
Aspirin, ASA; Butalbital; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Aspirin, ASA; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily for episodic migraine or 30 mg PO once daily for chronic migraine if coadministered with teriflunomide. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of OATP1B1 and OATP1B3 and teriflunomide is an OATP inhibitor. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Atorvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Baricitinib: (Moderate) Monitor for increased baricitinib effects if administered with teriflunomide as baricitinib exposure may increase; a baricitinib dose reduction may be necessary. Baricitinib is an OAT3 substrate; teriflunomide is an OAT3 inhibitor.
Bendamustine: (Major) Consider the use of an alternative therapy if teriflunomide treatment is needed in patients receiving bendamustine. Teriflunomide may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and teriflunomide is a CYP1A2 inducer.
Brincidofovir: (Moderate) Postpone the administration of teriflunomide for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and teriflunomide is necessary. Brincidofovir is an OATP1B1/3 substrate and teriflunomide is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Bupivacaine; Lidocaine: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to lidocaine, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, lidocaine doses may need adjustment if teriflunomide treatment is discontinued.
Butalbital; Acetaminophen; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Butalbital; Acetaminophen; Caffeine; Codeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Butalbital; Aspirin; Caffeine; Codeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Caffeine; Sodium Benzoate: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Cefaclor: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with cefaclor, a substrate of OAT3, may increase cefaclor plasma concentrations. Monitor for increased adverse effects from cefaclor, such as diarrhea, nausea, or abdominal pain. Adjust the dose of cefaclor as necessary and clinically appropriate.
Charcoal: (Major) Activated charcoal can bind with teriflunomide and enhance its clearance from the systemic circulation via intestinal trapping. Because teriflunomide has a prolonged half-life, staggering the administration times of each agent will not prevent this drug interaction. After 11 days of activated charcoal administration, teriflunomide concentrations are reduced by approximately 98%. Activated charcoal is used to facilitate teriflunomide elmination from the body when clinically necessary.
Chikungunya Vaccine, Live: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cholestyramine: (Major) Cholestyramine can bind with teriflunomide and enhance its clearance from the systemic circulation via intestinal trapping. Because teriflunomide has a prolonged half-life, staggering the administration times of each agent will not prevent this drug interaction. After 11 days of cholestyramine administration, teriflunomide concentrations are reduced by approximately 98%. Cholestyramine is used to facilitate teriflunomide elmination from the body when clinically necessary.
Cimetidine: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with cimetidine, a substrate of OAT3, may increase cimetidine plasma concentrations. Monitor for increased adverse effects from cimetidine, such as dose-related elevations in hepatic enzymes. Adjust the dose of cimetidine as necessary and clinically appropriate.
Ciprofloxacin: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with ciprofloxacin, a substrate of OAT3, may increase ciprofloxacin plasma concentrations. Monitor for increased adverse effects from ciprofloxacin, such as nausea, vomiting, diarrhea, or abdominal pain. Adjust the dose of ciprofloxacin as necessary and clinically appropriate.
Clofarabine: (Moderate) Concomitant use of clofarabine, a substrate of OAT1 and OAT3, and teriflunomide, an inhibitor of OAT protein (OATP), may result in increased clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g., hand and foot syndrome, rash, pruritus) in patients also receiving OATP inhibitors.
Clozapine: (Moderate) Caution is advisable during concurrent use of teriflunomide with clozapine. Teriflunomide induces CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Patients receiving clozapine in combination with a CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions and consider reducing the clozapine dose if necessary.
Cycloserine: (Moderate) In vitro studies indicate that teriflunomide is a substrate of ABCG2 (breast cancer resistance protein, BCRP). Drugs that are inhibitors of BCRP, such as cyclosporine, may cause increases in teriflunomide plasma concentrations. Monitor patients for adverse effects, including symptoms serious liver injury and immunosuppression.
Daprodustat: (Major) Reduce the initial daprodustat dose by half during concomitant use of teriflunomide unless the daprodustat dose is already 1 mg. Monitor hemoglobin and further adjust the daprodustat dose as appropriate. Concomitant use may increase daprodustat exposure and the risk for daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and teriflunomide is a moderate CYP2C8 inhibitor. Concomitant use with a moderate CYP2C8 inhibitor is expected to increase daprodustat overall exposure by approximately 4-fold.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desogestrel; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Dichlorphenamide: (Moderate) Monitor for increased toxicity of dichlorphenamide, including hypokalemia and hyperchloremic metabolic acidosis, if teriflunomide and dichlorphenamide are coadministered. Dichlorphenamide is a substrate for OAT3. Teriflunomide may increase exposure to dichlorphenamide through OAT3 inhibition. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
Dienogest; Estradiol valerate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Diphenhydramine; Naproxen: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as naproxen. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects, including additive hepatotoxicity.
Drospirenone: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Drospirenone; Estetrol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Drospirenone; Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Drospirenone; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Duloxetine: (Moderate) Use caution when administering teriflunomide and duloxetine concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as duloxetine, may decrease duloxetine exposure and lead to a reduction in efficacy.
Elagolix: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as teriflunomide is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Teriflunomide inhibits OATP1B1 in vivo and is expected to increase concentrations of drugs that are substrates for OATP1B1. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as teriflunomide is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Teriflunomide inhibits OATP1B1 in vivo and is expected to increase concentrations of drugs that are substrates for OATP1B1. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density. (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of grazoprevir with teriflunomide is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Grazoprevir is a substrate of the organic anion-transporting peptide (OATP1B1/1B3); teriflunomide is an in vitro inhibitor of OATP.
Eltrombopag: (Moderate) In vitro studies indicate that teriflunomide is a substrate of ABCG2 (breast cancer resistance protein, BCRP). Drugs that are inhibitors of BCRP, such as eltrombopag, may cause increases in teriflunomide plasma concentrations. Monitor patients for adverse effects, including symptoms serious liver injury and immunosuppression.
Eluxadoline: (Major) When administered concurrently with teriflunomide, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); teriflunomide is an in vitro inhibitor of OATP.
Ergotamine; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Estradiol; Levonorgestrel: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Estradiol; Norethindrone: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Estradiol; Norgestimate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Ethinyl Estradiol; Norelgestromin: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Ethinyl Estradiol; Norgestrel: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Etonogestrel; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Etrasimod: (Major) Avoid concomitant use of etrasimod and teriflunomide in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Etrasimod is a CYP2C9 and CYP2C8 substrate and teriflunomide is a moderate CYP2C8 inhibitor.
Ezetimibe; Simvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Fluvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Furosemide: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with furosemide, a substrate of OAT3, may increase furosemide plasma concentrations. Monitor for increased adverse effects from furosemide, such as excessive fluid loss or hypotension.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and teriflunomide as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of organic anion transporting polypeptide (OATP) 1B1/3 and breast cancer resistance protein (BCRP); teriflunomide is an inhibitor of these drug transporters. (Moderate) Caution is advised with the coadministration of pibrentasvir and teriflunomide as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of breast cancer resistance protein (BCRP); teriflunomide is an inhibitor of BCRP.
HMG-CoA reductase inhibitors: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Intranasal Influenza Vaccine: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Concurrent use of teriflunomide, an inhibitor of the hepatic uptake organic anion transporting polypeptides OATP1B1/1B3, with rifampin, an OATP substrate, may increase exposure to rifampin. Consider reducing the dosage of rifampin as necessary and clinically appropriate, and monitor patients closely. Additive hepatotoxicity or hematologic toxicity may occur. The potential for additive adverse effects should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
Isoniazid, INH; Rifampin: (Moderate) Concurrent use of teriflunomide, an inhibitor of the hepatic uptake organic anion transporting polypeptides OATP1B1/1B3, with rifampin, an OATP substrate, may increase exposure to rifampin. Consider reducing the dosage of rifampin as necessary and clinically appropriate, and monitor patients closely. Additive hepatotoxicity or hematologic toxicity may occur. The potential for additive adverse effects should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
Ketoprofen: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with ketoprofen, a substrate of OAT3, may increase ketoprofen plasma concentrations. Monitor for increased adverse effects from ketoprofen, such as nausea, vomiting, diarrhea, or decreased urine output. Adjust the ketoprofen dose as necessary and clinically appropriate.
Lamivudine, 3TC; Zidovudine, ZDV: (Major) Zidovudine, ZDV should be used cautiously with other drugs that can cause bone marrow suppression including teriflunomide because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage or discontinuation of zidovudine may be warranted. Teriflunomide, an organic anion transporter OAT3 renal updake inhibitor, may cause elevated concentrations of zidovudine, an OAT3 substrate.
Leflunomide: (Contraindicated) Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Leflunomide treatment is contraindicated in those patients currently receiving teriflunomide treatment. Duplicate treatment can lead to toxicity, including hepatic toxicity, bone marrow suppression, and infection risks. Overdose has caused diarrhea, abdominal pain, leukopenia, anemia, and elevated liver function tests.
Letermovir: (Moderate) Closely monitor for letermovir-related adverse events (i.e., tachycardia, atrial fibrillation, and gastrointestinal events) if administered with teriflunomide, as use of these drugs together may result in elevated letermovir plasma concentration. Letermovir is a substrate of the organic anion-transporting polypeptides (OATP1B1/3); teriflunomide is an inhibitor of OATP1B1/3.
Leuprolide; Norethindrone: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Levonorgestrel: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Lidocaine: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to lidocaine, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, lidocaine doses may need adjustment if teriflunomide treatment is discontinued.
Lidocaine; Epinephrine: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to lidocaine, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, lidocaine doses may need adjustment if teriflunomide treatment is discontinued.
Lidocaine; Prilocaine: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to lidocaine, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, lidocaine doses may need adjustment if teriflunomide treatment is discontinued.
Live Vaccines: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Lovastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Maraviroc: (Moderate) Use caution and closely monitor for increased adverse effects during concurrent administration of maraviroc and teriflunomide as increased maraviroc concentrations may occur. Maraviroc is a substrate of organic anion-transporting polypeptide (OATP1B1); teriflunomide is an inhibitor of OATP1B1. The effects of this transporter on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Measles/Mumps/Rubella Vaccines, MMR: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Metformin; Repaglinide: (Moderate) Closely monitor for hypoglycemia and for repaglinide-induced side effects when these drugs are used together. In some patients, a dosage reduction of repaglinide may be required. In vivo data suggest that teriflunomide is an inhibitor of CYP2C8, as increases in Cmax and AUC were observed following concurrent use of repaglinide, a CYP2C8 substrate. Repaglinide Cmax and AUC increased 1.7- and 2.4-fold, respectively, following a single dose of repaglinide 0.25 mg with repeated dosing of teriflunomide.
Methotrexate: (Major) Teriflunomide is an inhibitor of the hepatic uptake transporter organic anion transporting polypeptide OATP1B1 and the renal uptake organic anion transporter OAT3, while methotrexate is a substrate of both of these transporters. Concomitant use may produce greater potential for hepatotoxicity. The potential for hepatotoxicity should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
Mexiletine: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to mexiletine, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, mexiletine doses may need adjustment if teriflunomide treatment is discontinued.
Mitoxantrone: (Moderate) Concurrent use of teriflunomide, an inhibitor of the breast cancer resistance protein (BCRP), with mitoxantrone, a substrate of BCRP, may increase exposure to mitoxantrone. Consider reducing the dosage of mitoxantrone as necessary and clinically appropriate, and monitor patients closely. Additive hepatotoxicity or hematologic toxicity may occur. The potential for additive effects should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
Momelotinib: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with teriflunomide is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; teriflunomide is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with teriflunomide is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP2C8 substrate and teriflunomide is a moderate CYP2C8 inhibitor. In vitro, the metabolism of paclitaxel to 6-alpha-hydroxypaclitaxel was inhibited by another inhibitor of CYP2C8.
Naproxen: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as naproxen. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects, including additive hepatotoxicity.
Naproxen; Esomeprazole: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as naproxen. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects, including additive hepatotoxicity.
Naproxen; Pseudoephedrine: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as naproxen. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects, including additive hepatotoxicity.
Nateglinide: (Moderate) Closely monitor for hypoglycemia and for nateglinide-induced side effects when these drugs are used together. In some patients, a dosage reduction of nateglinide may be required. Concurrent use of teriflunomide, an inhibitor of the organic anion transporting polypeptides OATP1B1/1B3, may increase exposure to nateglinide, an OATP substrate. Consider reducing the dosage of nateglinide as necessary and clinically appropriate. Monitor patients for increases in adverse effects, which may include hypoglycemia.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Norethindrone: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Norethindrone; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Norgestimate; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Norgestrel: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Ocrelizumab: (Moderate) Ocrelizumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis. Concomitant use of ocrelizumab with any of these therapies may increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects such as teriflunomide. The median half-life of teriflunomide is 18 to 19 days, and teriflunomide may remain in plasma for up to 2 years after discontinuation.
Ofatumumab: (Moderate) Concomitant use of ofatumumab with teriflunomide may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as teriflunomide. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients. The median half-life of teriflunomide is 18 to 19 days, and teriflunomide may remain in plasma for up to 2 years following discontinuation.
Oral Contraceptives: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Paclitaxel: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as paclitaxel. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Penicillin G Benzathine: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with penicillin G, a substrate of OAT3, may increase penicillin G plasma concentrations. Monitor for increased adverse effects from penicillin G, such as nausea, vomiting, diarrhea, or seizures. Adjust the dose of penicillin G as necessary and clinically appropriate.
Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with penicillin G, a substrate of OAT3, may increase penicillin G plasma concentrations. Monitor for increased adverse effects from penicillin G, such as nausea, vomiting, diarrhea, or seizures. Adjust the dose of penicillin G as necessary and clinically appropriate.
Penicillin G Procaine: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with penicillin G, a substrate of OAT3, may increase penicillin G plasma concentrations. Monitor for increased adverse effects from penicillin G, such as nausea, vomiting, diarrhea, or seizures. Adjust the dose of penicillin G as necessary and clinically appropriate.
Penicillin G: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with penicillin G, a substrate of OAT3, may increase penicillin G plasma concentrations. Monitor for increased adverse effects from penicillin G, such as nausea, vomiting, diarrhea, or seizures. Adjust the dose of penicillin G as necessary and clinically appropriate.
Pioglitazone: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as pioglitazone. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Pioglitazone; Glimepiride: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as pioglitazone. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Pioglitazone; Metformin: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as pioglitazone. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Pitavastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Pravastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Propafenone: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to propafenone, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, propafenone doses may need adjustment if teriflunomide treatment is discontinued.
Quinine: (Moderate) Use caution when administering teriflunomide and quinine concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2 and an inhibitor of CYP2C8. Coadministration of teriflunomide with CYP1A2 and CYP2C8 substrates, such as quinine, may lead to increases in adverse effects or possible efficacy reduction.
Rasagiline: (Moderate) Use caution when administering teriflunomide with rasagiline. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as rasagiline, may decrease rasagiline exposure and lead to efficacy reduction. If teriflunomide is discontinued in a patient taking either rasagiline, serum concentrations may increase. Monitor patients for increases in adverse effects, such as dyskinesia, hallucinations, or nausea. Dose adjustments may be required.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Repaglinide: (Moderate) Closely monitor for hypoglycemia and for repaglinide-induced side effects when these drugs are used together. In some patients, a dosage reduction of repaglinide may be required. In vivo data suggest that teriflunomide is an inhibitor of CYP2C8, as increases in Cmax and AUC were observed following concurrent use of repaglinide, a CYP2C8 substrate. Repaglinide Cmax and AUC increased 1.7- and 2.4-fold, respectively, following a single dose of repaglinide 0.25 mg with repeated dosing of teriflunomide.
Resmetirom: (Major) Avoid concomitant use of resmetirom and teriflunomide due to the risk for increased resmetirom exposure which may increase the risk for resmetirom-related adverse effects. While use is not recommended, if concomitant use is necessary, consider a resmetirom dosage reduction. For patients with an actual body weight less than 100 kg, reduce the resmetirom dosage to 60 mg once daily. For patients with an actual body weight of 100 kg or more, reduce the resmetirom dosage to 80 mg once daily. Resmetirom is a CYP2C8 and OATP1B1/3 substrate and teriflunomide is a moderate CYP2C8 and OATP1B1/3 inhibitor. Concomitant use with another moderate CYP2C8 inhibitor increased resmetirom overall exposure by 1.7-fold.
Revefenacin: (Major) Coadministration of revefenacin is not recommended with teriflunomide because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; teriflunomide is an inhibitor of OATP1B1 and OATP1B3.
Rifampin: (Moderate) Concurrent use of teriflunomide, an inhibitor of the hepatic uptake organic anion transporting polypeptides OATP1B1/1B3, with rifampin, an OATP substrate, may increase exposure to rifampin. Consider reducing the dosage of rifampin as necessary and clinically appropriate, and monitor patients closely. Additive hepatotoxicity or hematologic toxicity may occur. The potential for additive adverse effects should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
Riluzole: (Moderate) Coadministration of riluzole with teriflunomide may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and teriflunomide is a CYP1A2 inducer.
Ropinirole: (Moderate) Teriflunomide is a weak inducer of CYP1A2, which may lead to decreased plasma concentrations of ropinirole, a CYP1A2 substrate. If these drugs are coadministered, adjustment of ropinirole dosage may be required.
Rosiglitazone: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as rosiglitazone. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Rosuvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Rosuvastatin; Ezetimibe: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Rotavirus Vaccine: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Selexipag: (Major) Reduce selexipag dose to once daily when coadministered with teriflunomide due to increased exposure to the active metabolite of selexipag, which may cause side effects. Selexipag is a substrate of CYP2C8 and teriflunomide is a moderate CYP2C8 inhibitor.
Simvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Smallpox Vaccine, Vaccinia Vaccine: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and teriflunomide. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and teriflunomide is an OATP1B3 inhibitor.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with teriflunomide. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the Breast Cancer Resistance Protein (BCRP); teriflunomide is an inhibitor of BCRP. Teriflunomide is also an inhibitor of the hepatic enzyme CYP2C8. Velpatasvir is a CYP2C8 substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir and teriflunomide. Taking these medications together may increase voxilaprevir plasma concentrations, potentially increasing the risk for adverse events. Voxilaprevir is a substrate for the drug transporter Organic Anion Transporting Polypeptides 1B1/1B3 (OATP1B1/1B3). Teriflunomide is an OATP1B1/1B3 inhibitor. (Moderate) Use caution when administering velpatasvir with teriflunomide. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the Breast Cancer Resistance Protein (BCRP); teriflunomide is an inhibitor of BCRP. Teriflunomide is also an inhibitor of the hepatic enzyme CYP2C8. Velpatasvir is a CYP2C8 substrate.
Sumatriptan; Naproxen: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as naproxen. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects, including additive hepatotoxicity.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of teriflunomide is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a BCRP substrate and teriflunomide is a BCRP inhibitor.
Terbinafine: (Moderate) Caution is advised when administering terbinafine with teriflunomide. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP1A2 and CYP2C8; teriflunomide is an inducer of CYP1A2 and an inhibitor of CYP2C8. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered.
Theophylline, Aminophylline: (Moderate) Use caution when administering teriflunomide and theophylline; aminophylline concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as theophylline; aminophylline, may decrease theophylline exposure and lead to a reduction in efficacy.
Tizanidine: (Moderate) Use caution when administering teriflunomide and tizanidine concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as tizanidine, may decrease tizanidine exposure and lead to a reduction in efficacy.
Topotecan: (Major) Avoid coadministration of teriflunomide with oral topotecan due to increased topotecan exposure; teriflunomide may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and teriflunomide is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
Tucatinib: (Moderate) Closely monitor for tucatinib-related adverse reactions if coadministration with teriflunomide is necessary due to the risk of increased tucatinib exposure. Tucatinib is a CYP2C8 substrate and teriflunomide is a moderate CYP2C8 inhibitor.
Typhoid Vaccine: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with teriflunomide. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP drug transporter; teriflunomide is a BCRP inhibitor.
Varicella-Zoster Virus Vaccine, Live: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with teriflunomide is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP1A2 substrate and teriflunomide is CYP1A2 inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. Teriflunomide may decrease peak INR by approximately 25%. The mechanism is uncertain but, during pharmacokinetic studies, teriflunomide did not affect the pharmacokinetics of S-warfarin (a CYP2C9 substrate).
Yellow Fever Vaccine, Live: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Zavegepant: (Major) Avoid concomitant use of zavegepant and teriflunomide. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and teriflunomide is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Zidovudine, ZDV: (Major) Zidovudine, ZDV should be used cautiously with other drugs that can cause bone marrow suppression including teriflunomide because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage or discontinuation of zidovudine may be warranted. Teriflunomide, an organic anion transporter OAT3 renal updake inhibitor, may cause elevated concentrations of zidovudine, an OAT3 substrate.
Teriflunomide is a selective, non-competitive, and reversible inhibitor of dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. This inhibition results in antiproliferative effects among peripheral T-and B-lymphocytes, leading to a reduced concentration of activated lymphocytes in the CNS. A lower concentration of activated lymphocytes may reduce the inflammatory demyelination that occurs in multiple sclerosis. Reduced phospholipid synthesis and protein glycosylation in immune cells may also take place due to lower pyrimidine availability, which can prevent lipid messenger generation and impair the function of immune cell surface molecules.
Teriflunomide is administered orally and is widely distributed in plasma with protein binding greater than 99%. Approximately 3 months of use must occur before steady-state concentrations are achieved. Teriflunomide undergoes primary hydrolysis and oxidation to form minor metabolites; however, teriflunomide itself is the principal active moiety found in plasma. Secondary pathways of metabolism include oxidation, N-acetylation, and sulfate conjugation. Teriflunomide is excreted unchanged through biliary excretion and its metabolites are excreted renally. Approximately 60.1% of a dose is recovered in the feces (37.5%) or urine (22.6%) over 3 weeks; following an accelerated elimination procedure using cholestyramine, an additional 23.1% can be recovered (mostly in feces). The median half-life in healthy patients following repeated doses of 7 mg or 14 mg is approximately 18 and 19 days, respectively. Total body clearance of teriflunomide is 30.5 mL/hour following a single IV dose.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2C8, CYP1A2, and OAT3; BCRP and OATP1B1/1B3
Teriflunomide is an inhibitor of CYP2C8 in vivo, and may increase the concentrations and exposures of known CYP2C8 substrates. Teriflunomide may also be a weak inducer of CYP1A2 in vivo, and the exposure of drugs metabolized by CYP1A2 may be reduced. Teriflunomide inhibits the activity of the drug transporter OAT3 in vivo and may increase the exposure of drugs which are OAT3 substrates. Monitor these patients and adjust the dose of the concomitant drug(s) which are substrates for these enzymes or OAT3 as required. Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. Consider reducing the dose of drugs that are substrates of these drug transporters and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking teriflunomide.
-Route-Specific Pharmacokinetics
Oral Route
Maximum concentrations of teriflunomide are attained within 1 to 4 hours following oral administration. After repeated doses of 7 mg or 14 mg, the AUC accumulation ratio is approximately 30. Food has no clinically relevant effect on teriflunomide oral absorption.
-Special Populations
Hepatic Impairment
Teriflunomide pharmacokinetics were not altered in patients with mild to moderate hepatic impairment. The pharmacokinetics of teriflunomide in patients with severe hepatic impairment have not been studied.
Renal Impairment
Teriflunomide pharmacokinetics were not altered in patients with mild, moderate, or severe renal impairment.
Gender Differences
In a population-based analysis, females experienced a 23% decrease in teriflunomide clearance compared to males.