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  • CLASSES

    MS Agents
    Pyrimidine Synthesis Inhibitors

    BOXED WARNING

    Hepatic disease, hepatitis, hepatotoxicity, jaundice

    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.

    Intrauterine fetal death, pregnancy

    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.[51794] [61642]

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    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.[51794] 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.[51794]

    DEA CLASS

    Rx

    DESCRIPTION

    Oral pyrimidine synthesis inhibitor; an active metabolite of leflunomide
    Used in adults with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
    Boxed warnings regarding risk for hepatotoxicity and for teratogenicity

    COMMON BRAND NAMES

    AUBAGIO

    HOW SUPPLIED

    AUBAGIO Oral Tab: 7mg, 14mg

    DOSAGE & INDICATIONS

    For the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
    Oral dosage
    Adults

    7 mg or 14 mg PO once daily.

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Teriflunomide is contraindicated in patients with severe hepatic impairment. No dosage adjustment is needed in patients with mild or moderate hepatic impairment.

    Renal Impairment

    No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    May be taken with or without food.

    STORAGE

    AUBAGIO:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Angioedema, serious hypersensitivity reactions or anaphylaxis, serious rash

    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.

    Hepatic disease, hepatitis, hepatotoxicity, jaundice

    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.

    Agranulocytosis, bone marrow suppression, chemotherapy, immunosuppression, infection, thrombocytopenia, tuberculosis

    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.

    Vaccination

    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.

    Eosinophilic pneumonia, pneumonitis, pulmonary disease, pulmonary fibrosis, sarcoidosis

    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.

    Hypertension

    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.

    Diabetes mellitus, geriatric, peripheral neuropathy

    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.

    Intrauterine fetal death, pregnancy

    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.[51794] [61642]

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    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.[51794] 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.[51794]

    Breast-feeding

    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.

    Children

    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.

    ADVERSE REACTIONS

    Severe

    renal failure (unspecified) / Delayed / 0-0.8
    hepatotoxicity / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    eosinophilic pneumonia / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    myasthenia / Delayed / 37.9-42.0
    cystitis / Delayed / 7.3-23.5
    hyperreflexia / Delayed / 21.2-23.5
    elevated hepatic enzymes / Delayed / 5.8-22.7
    hypophosphatemia / Delayed / 4.0-18.0
    lymphopenia / Delayed / 10.0-12.0
    neutropenia / Delayed / 4.0-6.0
    hypertension / Early / 3.1-4.3
    peripheral neuropathy / Delayed / 1.4-1.9
    hyperbilirubinemia / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    immunosuppression / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    psoriasis / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    dyspnea / Early / Incidence not known

    Mild

    infection / Delayed / 1.2-53.0
    pharyngitis / Delayed / 21.0-53.0
    hypoesthesia / Delayed / 48.1-50.0
    fatigue / Early / 10.0-48.5
    back pain / Delayed / 8.0-36.4
    influenza / Delayed / 9.2-34.8
    insomnia / Early / 9.0-34.6
    dizziness / Early / 21.2-22.2
    rash / Early / 16.7-22.2
    headache / Early / 16.0-18.0
    diarrhea / Early / 13.0-14.0
    alopecia / Delayed / 10.0-13.0
    nausea / Early / 8.0-11.0
    paresthesias / Delayed / 8.0-9.0
    arthralgia / Delayed / 6.0-8.0
    pruritus / Rapid / 2.8-3.5
    urticaria / Rapid / 0.8-1.1
    carpal tunnel syndrome / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    dyspepsia / Early / Incidence not known

    DRUG INTERACTIONS

    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; 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; Magnesium Salicylate; Phenyltoloxamine: (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; Phenyltoloxamine; Salicylamide: (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; Butalbital; 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.
    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; 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.
    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.
    Aspirin, ASA; 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.
    Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily 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 OATP inhibitor resulted in a 2.85-fold increase in atogepant 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.
    Atorvastatin; 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.
    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.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking teriflunomide. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a BCRP substrate and teriflunomide is a BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%.
    Bosentan: (Moderate) Concomitant use of bosentan and teriflunomide may result in elevated bosentan plasma concentrations. Teriflunomide is an inhibitor of the hepatic uptake transporter of the organic anion transporting polypeptide OATP1B1, while bosentan is a substrate. Monitor patients for increases in adverse effects, such as headache, flushing, hypotension, elevated hepatic enzymes, or lower limb edema.
    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.
    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.
    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.
    Cinacalcet: (Moderate) Use caution when administering teriflunomide and cinacalcet concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as cinacalcet, may decrease cinacalcet exposure and lead to a reduction in efficacy. Monitor serum calcium concentrations.
    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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of ombitasvir may result in elevated plasma concentrations ombitasvir. Ombitasvir is a substrate of BCRP, and teriflunomide is a BRCP inhibitor. The degree of increase in the plasma concentrations of the antivirals has not been defined. Close monitoring is advised if these drugs are administered together. (Moderate) Concurrent administration of teriflunomide with paritaprevir may result in elevated plasma concentrations of paritaprevir. Paritaprevir are substrates of BCRP, and teriflunomide is a BRCP inhibitor. In addition, paritaprevir is a substrate of the organic anion transporting polypeptides (OATP1B1 and OATP1B3), and teriflunomide is an OATP inhibitor. When these drugs are coadministered, the degree of increase in the plasma concentrations of the antivirals has not been defined. Close monitoring is advised if these drugs are administered together. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with teriflunomide. Concurrent use may increase dasabuvir exposure. Dasabuvir is a CYP2C8 and BCRP substrate and teriflunomide is a moderate CYP2C8 and BCRP inhibitor.
    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: (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; Levonorgestrel; Folic Acid; 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.
    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.
    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.
    Glimepiride; 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.
    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.
    Lansoprazole; 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.
    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.
    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.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP2C8 substrate, may be increased when administered concurrently with teriflunomide, a CYP2C8 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP2C8 substrate, may be increased when administered concurrently with teriflunomide, a CYP2C8 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    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.
    Lovastatin; Niacin: (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.
    Mestranol; 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.
    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.
    Metformin; 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.
    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.
    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.
    Niacin; 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.
    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.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of ombitasvir may result in elevated plasma concentrations ombitasvir. Ombitasvir is a substrate of BCRP, and teriflunomide is a BRCP inhibitor. The degree of increase in the plasma concentrations of the antivirals has not been defined. Close monitoring is advised if these drugs are administered together. (Moderate) Concurrent administration of teriflunomide with paritaprevir may result in elevated plasma concentrations of paritaprevir. Paritaprevir are substrates of BCRP, and teriflunomide is a BRCP inhibitor. In addition, paritaprevir is a substrate of the organic anion transporting polypeptides (OATP1B1 and OATP1B3), and teriflunomide is an OATP inhibitor. When these drugs are coadministered, the degree of increase in the plasma concentrations of the antivirals has not been defined. Close monitoring is advised if these drugs are administered together.
    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.
    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.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, an organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with teriflunomide, an OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, an OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively.
    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.
    Rubella 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.
    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.
    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.
    Simeprevir: (Minor) Use caution with concurrent use of simeprevir and teriflunomide. Teriflunomide is an inhibitor of OAT1B1, which may increase the plasma concentrations of simeprevir, a substrate of OATP1B1/3 in vitro, resulting in adverse effects, such as rash.
    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.
    Simvastatin; Sitagliptin: (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.
    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: (Major) Avoid coadministration of teriflunomide with talazoparib due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a BCRP substrate and teriflunomide is a BCRP inhibitor. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure.
    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. Teriflunomide is a CYP1A2 inducer and the R-enantiomer of warfarin is a CYP1A2 substrate. 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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.[51794] [61642]

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    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.