Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Leflunomide Tablets howsupplied; Princilap Display Panel NDC 10702- 277 -03 Leflunomide Tablets, USP 10 mg Rx Only 30 Tablets KVK-Tech containerlabel10mg; Principal Display Panel NDC 10702- 278 -03 Leflunomide Tablets, USP 20 mg Rx Only 30 Tablets KVK-Tech containerlabel20mg
- 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Leflunomide Tablets howsupplied
- Princilap Display Panel NDC 10702- 277 -03 Leflunomide Tablets, USP 10 mg Rx Only 30 Tablets KVK-Tech containerlabel10mg
- Principal Display Panel NDC 10702- 278 -03 Leflunomide Tablets, USP 20 mg Rx Only 30 Tablets KVK-Tech containerlabel20mg
Overview
Leflunomide is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is 4-Isoxazolecarboxamide, 5-methyl-N-[4-(trifluoromethyl)-phenyl]-. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.21 and the following structural formula: Leflunomide tablets are available for oral administration as film coated tablets containing 10, or 20 mg of active drug. Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, corn starch, talc, titanium dioxide, and yellow ferric oxide (20 mg tablet only). chemicalstructure
Indications & Usage
Leflunomide tablets are indicated for the treatment of adults with active rheumatoid arthritis (RA). Leflunomide tablets are a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis. (1)
Dosage & Administration
Loading dosage for patients at low risk for leflunomide tablets-associated hepatotoxicity and leflunomide tablets-associated myelosuppression: 100 mg daily for 3 days. (2.1) Maintenance dosage: 20 mg daily. (2.1) Maximum recommended daily dosage: 20 mg once daily. (2.1) If 20 mg once daily is not tolerated, may decrease dosage to 10 mg once daily. (2.1) Screen patients for active and latent tuberculosis, pregnancy test (females), blood pressure, and laboratory tests before starting leflunomide tablets. (2.2) 2.1 Recommended Dosage The recommended dosage of leflunomide tablets are 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient’s risk of leflunomide tablets-associated hepatotoxicity and leflunomide tablets-associated myelosuppression. The loading dosage provides steady-state concentrations more rapidly. For patients who are at low risk for leflunomide tablets-associated hepatotoxicity and leflunomide tablets- associated myelosuppression the recommended leflunomide tablets loading dosage is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily. For patients at high risk for leflunomide tablets-associated hepatotoxicity (e.g., those taking concomitant methotrexate) or leflunomide tablets-associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended leflunomide tablets dosage is 20 mg once daily without a loading dose [ see Warnings and Precautions (5.2, 5.4) ]. The maximum recommended daily dosage is 20 mg once per day. Consider dosage reduction to 10 mg once daily for patients who are not able to tolerate 20 mg daily (i.e., for patients who experience any adverse events listed in Table 1). Monitor patients carefully after dosage reduction and after stopping therapy with leflunomide tablets, since the active metabolite of leflunomide, teriflunomide, is slowly eliminated from the plasma [ see Clinical Pharmacology (12.3) ]. After stopping leflunomide tablets treatment, an accelerated drug elimination procedure is recommended to reduce the plasma concentrations of the active metabolite, teriflunomide [ see Warnings and Precautions (5.3 )]. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach undetectable plasma teriflunomide concentrations after stopping leflunomide tablets [ see Clinical Pharmacology (12.3) ]. 2.2 Evaluation and Testing Prior to Starting Leflunomide Tablets Prior to starting leflunomide tablets treatment the following evaluations and tests are recommended: Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection [ see Warnings and Precautions (5.4) ] Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts [ see Warnings and Precautions (5.2, 5.4) ] For females of reproductive potential, pregnancy testing [ see Warnings and Precautions (5.1) ] Check blood pressure [ see Warnings and Precautions (5.10) ]
Warnings & Precautions
After stopping leflunomide tablets, it is recommended that an accelerated drug elimination procedure be used to reduce the plasma concentrations of the active metabolite, teriflunomide. (5.3) Severe infections (including sepsis), pancytopenia, agranulocytosis and thrombocytopenia: Stop leflunomide tablets and use accelerated elimination procedure. Do not start leflunomide tablets in patients with active infection. Monitor CBCs during treatment with leflunomide tablets. (5.4) Stevens-Johnson syndrome and toxic epidermal necrolysis: Stop leflunomide tablets and use accelerated elimination procedure. (5.5) Peripheral neuropathy: If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing leflunomide tablets. (5.7) Interstitial lung disease: May be fatal. New onset or worsening symptoms may necessitate discontinuation of leflunomide tablets and initiation of accelerated elimination procedure. (5.8) Increased blood pressure: Monitor and treat. (5.10) 5.1 Embryo-Fetal Toxicity Leflunomide tablets may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryo-lethality occurred in animal reproduction studies with leflunomide at doses lower than the human exposure level [ see Use in Specific Populations (8.1) ]. Leflunomide tablets are contraindicated for use in pregnant women [ see Contraindications (4) ]. Exclude pregnancy before starting treatment with leflunomide tablets in females of reproductive potential [ see Dosage and Administration (2.2) ]. Advise females of reproductive potential to use effective contraception during leflunomide tablets treatment and during an accelerated drug elimination procedure after leflunomide tablets treatment [ see Use in Specific Populations (8.3) ]. If a woman becomes pregnant while taking leflunomide tablets, stop treatment with leflunomide tablets, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve non-detectable plasma concentrations of teriflunomide, the active metabolite of leflunomide [ see Warnings and Precautions (5.3) ]. Upon discontinuing leflunomide tablets, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving leflunomide tablets treatment who wish to become pregnant must discontinue leflunomide tablets and undergo an accelerated drug elimination procedure, which includes verification that plasma concentrations of the active metabolite of leflunomide, teriflunomide, are less than 0.02 mg/L (0.02 mcg/mL). Based on animal data, human plasma concentrations of teriflunomide of less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryo-fetal risk [ see Contraindications (4), Warnings and Precautions (5.3), and Use in Specific Populations (8.1) ]. 5.2 Hepatotoxicity Severe liver injury, including fatal liver failure, has been reported in some patients treated with leflunomide tablets. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) of greater than twice the upper limits of normal (>2xULN) before initiating treatment, should not be treated with leflunomide tablets. Use caution when leflunomide tablets are given with other potentially hepatotoxic drugs. Monitoring of ALT levels is recommended at least monthly for six months after starting leflunomide tablets, and thereafter every 6-8 weeks. If ALT elevation > 3 fold ULN occurs, interrupt leflunomide tablets therapy and investigate the cause. If likely leflunomide tablets- induced, perform the accelerated drug elimination procedure and monitor liver tests weekly until normalized [ see Warnings and Precautions (5.3) ]. If leflunomide tablets-induced liver injury is unlikely because some other cause has been found, resumption of leflunomide tablets therapy may be considered. If leflunomide tablets and methotrexate are given concomitantly, follow the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity with ALT, AST, and serum albumin testing. 5.3 Procedure for Accelerated Elimination of Leflunomide Tablets and its Active Metabolite The active metabolite of leflunomide, teriflunomide, is eliminated slowly from the plasma [ see Clinical Pharmacology (12.3) ]. Use of an accelerated drug elimination procedure will rapidly reduce plasma concentrations of leflunomide and its active metabolite, teriflunomide. Therefore, an accelerated elimination procedure should be considered at any time after discontinuation of leflunomide tablets, and in particular, when a patient has experienced a severe adverse reaction (e.g., hepatotoxicity, serious infection, bone marrow suppression, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral neuropathy, interstitial lung disease), suspected hypersensitivity, or has become pregnant. It is recommended that all women of childbearing potential undergo an accelerated elimination procedure after stopping leflunomide tablets treatment. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations of less than 0.02 mg/L, the plasma concentration not associated with embryo-fetal toxicity in animals. Elimination can be accelerated by the following procedures: Administer cholestyramine 8 grams orally 3 times daily for 11 days. Alternatively, administer 50 grams of activated charcoal powder (made into a suspension) orally every 12 hours for 11 days. Verify plasma teriflunomide concentrations of less than 0.02 mg/L (0.02 µg/mL) by two separate tests at least 14 days apart. If plasma teriflunomide concentrations are higher than 0.02 mg/L, repeat cholestyramine and/or activated charcoal treatment. The duration of accelerated drug elimination treatment may be modified based on the clinical status and tolerability of the elimination procedure. The procedure may be repeated as needed, based on teriflunomide concentrations and clinical status. Use of the accelerated drug elimination procedure may potentially result in return of disease activity if the patient had been responding to leflunomide tablets treatment. 5.4 Immunosuppression, Bone Marrow Suppression, and Risk of Serious Infections Leflunomide tablets are not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. If a serious infection occurs, consider interrupting leflunomide tablets therapy and initiating the accelerated drug elimination procedure [ see Warnings and Precautions (5.3) ]. Medications like leflunomide tablets that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis. Severe infections including sepsis, which may be fatal, have been reported in patients receiving Leflunomide tablets, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid arthritis, may predispose patients to infection. Cases of tuberculosis were observed in clinical studies with teriflunomide, the metabolite of leflunomide tablets. Prior to initiating leflunomide tablets, all patients should be screened for active and inactive (“latent”) tuberculosis infection as per commonly used diagnostic tests. Leflunomide tablets have not been studied in patients with a positive tuberculosis screen, and the safety of leflunomide tablets in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with leflunomide tablets and monitored carefully during leflunomide tablets treatment for possible reactivation of the infection. Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving leflunomide tablets alone. These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality. Patients taking leflunomide tablets should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6 to 8 weeks thereafter. If used with concomitant methotrexate and/or other potential immunosuppressive agents, chronic monitoring should be monthly. If evidence of bone marrow suppression occurs in a patient taking leflunomide tablets, stop treatment with leflunomide tablets, and perform an accelerated drug elimination procedure to reduce the plasma concentration of the leflunomide tablets active metabolite, teriflunomide [ see Warnings and Precautions (5.3) ]. In any situation in which the decision is made to switch from leflunomide tablets to another anti-rheumatic 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. 5.5 Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and Drug Reactions with Eosinophilia and Systemic Symptoms Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving leflunomide tablets. If a patient taking leflunomide tablets develops any of these conditions, stop leflunomide tablets treatment and perform an accelerated drug elimination procedure [ see Warnings and Precautions (5.3) ]. 5.6 Malignancy and Lymphoproliferative Disorders The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppression medications. There is a potential for immunosuppression with leflunomide tablets. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the clinical trials of leflunomide tablets, but larger dosages and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with leflunomide tablets. 5.7 Peripheral Neuropathy Cases of peripheral neuropathy have been reported in patients receiving leflunomide tablets and in clinical studies with teriflunomide, the active metabolite of leflunomide. Most patients recovered after discontinuation of treatment, but some patients had persistent symptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking leflunomide tablets develops a peripheral neuropathy, consider discontinuing leflunomide tablets therapy and performing an accelerated drug elimination procedure [ see Warning and Precautions (5.3) ]. 5.8 Interstitial Lung Disease Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide tablets and has been associated with fatal outcomes [ see Adverse Reactions (6.2) ]. The risk of leflunomide tablets-associated interstitial lung disease is increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder that may occur acutely at any time during therapy and has 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 leflunomide tablets therapy and for further investigation as appropriate. If discontinuation of leflunomide tablets are necessary, consider performing an accelerated drug elimination procedure [ see Warnings and Precautions (5.3) ]. 5.9 Vaccinations No clinical data are available on the efficacy and safety of vaccinations during leflunomide tablets treatment. Vaccination with live vaccines is, however, not recommended. The long half-life of the active metabolite of leflunomide tablets should be considered when contemplating administration of a live vaccine after stopping leflunomide tablets. 5.10 Blood Pressure Monitoring In placebo-controlled studies with the active metabolite of leflunomide tablets, teriflunomide, elevations in blood pressure were observed in some subjects. Blood pressure should be checked before starting treatment with leflunomide tablets and monitored periodically thereafter [ See Adverse Reactions (6.1) ].
Boxed Warning
EMBRYO-FETAL TOXICITY and HEPATOTOXICITY WARNING: EMBRYO-FETAL TOXICITY and HEPATOTOXICITY Embryo-Fetal Toxicity Leflunomide tablets are contraindicated for use in pregnant women because of the potential for fetal harm. Teratogenicity and embryo-lethality occurred in animals administered leflunomide at doses lower than the human exposure level. Exclude pregnancy before the start of treatment with leflunomide tablets in females of reproductive potential. Advise females of reproductive potential to use effective contraception during leflunomide tablets treatment and during an accelerated drug elimination procedure after leflunomide tablets treatment. Stop leflunomide tablets and use an accelerated drug elimination procedure if the patient becomes pregnant. [ see Contraindications (4), Warnings and Precautions (5.1, 5.3), Use in Special Populations (8.1, 8.3)], and Clinical Pharmacology (12.3). Hepatotoxicity Severe liver injury, including fatal liver failure, has been reported in patients treated with leflunomide tablets. Leflunomide tablets are contraindicated in patients with severe hepatic impairment. Concomitant use of leflunomide tablets with other potentially hepatotoxic drugs may increase the risk of liver injury. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2xULN before initiating treatment, are at increased risk and should not be treated with leflunomide tablets. Monitor ALT levels at least monthly for six months after starting leflunomide tablets, and thereafter every 6-8 weeks. If leflunomide-induced liver injury is suspected, stop leflunomide tablets treatment, start an accelerated drug elimination procedure, and monitor liver tests weekly until normalized. [ see Contraindications (4), Warnings and Precautions (5.2, 5.3), Use in Special Populations (8.6) ]. WARNING: EMBRYO-FETAL TOXICITY and HEPATOTOXICITY See full prescribing information for complete boxed warning. Embryo-Fetal Toxicity Teratogenicity and embryo-lethality occurred in animals administered leflunomide. (5.1, 8.1) Exclude pregnancy prior to initiating leflunomide tablets therapy. (5.1, 8.3) Advise use of effective contraception in females of reproductive potential during treatment and during a drug elimination procedure. (5.1, 5.3, 8.3) Stop leflunomide tablets and use an accelerated drug elimination procedure if the patient becomes pregnant. (5.1, 5.3, 8.1) Hepatotoxicity Severe liver injury and fatal liver failure have been reported. (5.2) Avoid leflunomide tablets use in patients with pre-existing liver disease, or those with serum alanine aminotransferase (ALT) >2xULN. (5.2, 8.6) Use caution when leflunomide tablets are given with other potentially hepatotoxic drugs. (5.2) Monitor ALT levels. Interrupt leflunomide tablets treatment if ALT elevation > 3 fold ULN. If likely leflunomide-induced, start accelerated drug elimination procedure and monitor liver tests weekly until normalized. (5.2, 5.3)
Contraindications
Leflunomide Tablets are contraindicated in: Pregnant women. Leflunomide tablets may cause fetal harm. If a woman becomes pregnant while taking this drug, stop leflunomide tablets, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure [ see Warnings and Precautions (5.1 and 5.3) and Use in Specific Populations (8.1 )]. Patients with severe hepatic impairment [ see Warnings and Precautions (5.2) ]. Patients with known hypersensitivity to leflunomide or any of the other components of leflunomide tablets. Known reactions include anaphylaxis [ see Adverse Reactions (6.1) ]. Patients being treated with teriflunomide [ see Drug Interactions (7) ]. Pregnancy. (4, 5.1, 8.1) Severe hepatic impairment. (4, 5.2) Hypersensitivity to leflunomide tablets or any of its inactive components. (4) Current teriflunomide treatment. (4)
Adverse Reactions
The following serious adverse reactions are described elsewhere in the labeling: Hepatotoxicity [ see Warnings and Precautions (5.2) ] Immunosuppression [ see Warnings and Precautions (5.4) ] Bone marrow suppression [ see Warnings and Precautions (5.4) ] Stevens-Johnson syndrome and toxic epidermal necrolysis [ see Warnings and Precautions (5.5) ] Peripheral neuropathy [ see Warnings and Precautions (5.7) ] Interstitial lung disease [ see Warnings and Precautions (5.8) ] The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide tablets treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, dyspepsia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact KVK-Tech, Inc. at 1-215-579-1842 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with leflunomide tablets administered as either monotherapy or in combination with methotrexate or sulfasalazine. Patients ranged in age from 19 to 85 years, with an overall median age of 58 years. The mean duration of RA was 6 years ranging from 0 to 45 years. Elevation of Liver Enzymes Treatment with leflunomide tablets were associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤ 2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial 1 and Trial 2. It was notable that the absence of folate use in Trial 3 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate. In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide tablets were administered to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo. Most Common Adverse Reactions The most common adverse reactions in leflunomide tablets-treated patients with RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. Table 2 displays the most common adverse reactions in the controlled studies in patients with RA at one year (> 5% in any leflunomide tablets treatment group). Adverse events during a second year of treatment with leflunomide tablets in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence. Less Common Adverse Reactions In addition, in controlled clinical trials, the following adverse events in the leflunomide tablets treatment group occurred at a higher incidence than in the placebo group. These adverse events were deemed possibly related to the study drug. Blood and Lymphatic System: leukocytosis, thrombocytopenia; Cardiovascular: chest pain, palpitation, thrombophlebitis of the leg, varicose vein; Eye: blurred vision, eye disorder, papilledema, retinal disorder, retinal hemorrhage; Gastrointestinal: alkaline phosphatase increased, anorexia, bilirubinemia, flatulence, gamma-GT increased, salivary gland enlarged, sore throat, vomiting, dry mouth; General Disorders: malaise; Immune System: anaphylactic reaction; Infection: abscess, flu syndrome, vaginal moniliasis; Nervous System: dizziness, headache, somnolence; Respiratory System: dyspnea; table1 table2 6.2 Post Marketing Experience The following additional adverse reactions have been identified during post approval use of leflunomide tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System: agranulocytosis, leukopenia, neutropenia, pancytopenia; Infection: opportunistic infections, severe infections including sepsis; Gastrointestinal: acute hepatic necrosis, colitis, including microscopic colitis, hepatitis, jaundice/cholestasis, pancreatitis; severe liver injury such as hepatic failure; Immune System: angioedema; Nervous system: peripheral neuropathy; Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal; pulmonary hypertension; Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis, skin ulcer
Drug Interactions
Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide’s in vivo activity. Drug interaction studies have been conducted with both leflunomide tablets (leflunomide) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects. Effect of potent CYP and transporter inducers Leflunomide is metabolized by CYP450 metabolizing enzymes. Concomitant use of leflunomide tablets and rifampin, a potent inducer of CYP and transporters, increased the plasma concentration of teriflunomide by 40%. However, when co-administered with the metabolite, teriflunomide, rifampin did not affect its pharmacokinetics. No dosage adjustment is recommended for leflunomide tablets when coadministered with rifampin. Because of the potential for leflunomide tablets concentrations to continue to increase with multiple dosing, caution should be used if patients are to be receiving both leflunomide tablets and rifampin [ see Clinical Pharmacology (12.3) ]. Effect on CYP2C8 substrates Teriflunomide is an inhibitor of CYP2C8 in vivo . In patients taking leflunomide tablets, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required [ see Clinical Pharmacology (12.3) ]. Effect on warfarin Coadministration of leflunomide tablets with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of leflunomide tablets, may decrease peak INR by approximately 25%. Effect on oral contraceptives Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with leflunomide tablets [ see Clinical Pharmacology (12.3) ]. Effect on CYP1A2 substrates Teriflunomide, the active metabolite of leflunomide tablets, may be a weak inducer of CYP1A2 in vivo . In patients taking leflunomide tablets, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required [ see Clinical Pharmacology (12.3) ]. Effect on organic anion transporter 3 (OAT3) substrates Teriflunomide inhibits the activity of OAT3 in vivo . In patients taking leflunomide tablets, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required [ see Clinical Pharmacology (12.3) ]. Effect on BCRP and organic anion transporting polypeptide B1 and B3 (OATP1B1/1B3) substrates Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking leflunomide tablets, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking leflunomide tablets [ see Clinical Pharmacology (12.3) ]. Drugs metabolized by CYP2C8 and OAT3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. (7) Teriflunomide may increase exposure of ethinylestradiol and levonorgestrel. Choose an appropriate oral contraceptive. (7) Drugs metabolized by CYP1A2: Monitor patients because teriflunomide may decrease exposure of these drugs. (7) Warfarin: Monitor INR as teriflunomide may decrease INR. (7) Drugs metabolized by BCRP and OATP1B1/B3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. (7) Rosuvastatin: The dose of rosuvastatin should not exceed 10 mg once daily in patients taking leflunomide tablets. (7)
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