Leflunomide is the first isoxazol derivative approved for the treatment of rheumatoid arthritis (RA). Leflunomide was also the first agent for rheumatoid arthritis indicated for both symptomatic improvement and retardation of structural joint damage based on radiographic evidence of its disease modifying activity. After 52 weeks of treatment in clinical trials, leflunomide showed similar improvements in tender and swollen joint counts, pain, and other symptoms when compared to methotrexate or sulfasalazine. Leflunomide was significantly superior to placebo in time to progression of structural disease as evidenced by Sharp X-ray scores. Sharp scores were not consistently different between leflunomide and methotrexate. Analysis of long-term studies will define whether or not leflunomide prevents RA-induced disability, but data are available to show that leflunomide subjectively improves functional daily activity and quality of life. Due to its unique mechanism of action, leflunomide efficacy may be additive to other antirheumatic agents, but certain drugs are not recommended for concurrent use (e.g., methotrexate). Leflunomide has a fast onset of action (4 weeks) relative to other disease-modifying agents. However, the long half-life of the drug (14-15 days) is problematic should adverse events like hepatotoxicity occur, and a drug elimination procedure is required for cases of pregnancy or significant overdose or toxicity to rapidly lower drug plasma levels (see Dosage). Leflunomide is being evaluated for the treatment of systemic lupus erythematosus and for efficacy as an immunosupressant in organ transplantation. Leflunomide received priority review and FDA approval in September 1998; at that time it was the first disease-modifying agent for RA approved in more than a decade. In June 2003, leflunomide received an expanded indication for the improvement of physical function (e.g., ability to perform daily activities) in patients with rheumatoid arthritis.
General Administration Information
For storage information, see specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.
Route-Specific Administration
Oral Administration
-Administer tablets with or without food. Give the daily dose at approximately the same time each day.
Leflunomide has a unique pharmacokinetic profile and mechanism of action. The long elimination half-life should be considered in the treatment of severe adverse reactions. Some side effects may be prolonged after discontinuation of the medication. For some patients, the leflunomide drug elimination protocol will be warranted.
An increased risk of malignancy, including lymphoproliferative disorders, is associated with some immunosuppressive medications. During clinical trials with leflunomide, there was no apparent increase in the risk of malignancy. Larger, long-term trials are needed to further clarify the risk of malignancy or lymphoproliferative disorders.
Of 816 patients who received leflunomide in controlled clinical trials, 3-4% experienced paresthesias. In all controlled and uncontrolled trials, 2% of patients who received leflunomide (n = 1339) for up to 12 months reported paraesthesias. Peripheral neuropathy also appears to be a drug-related adverse event. Between September 1998 and September 2002, the FDA received 80 case reports of peripheral neuropathy associated with leflunomide usage. The onset of peripheral numbness, tingling, burning, severe pain, cold sensation in the distal extremities, or extremity weakness, ranged from 3-1126 days (mean of 180 days) after leflunomide initiation. Statistically significantly more patients that stopped leflunomide within 30 days of symptom onset had improvement or resolution of peripheral neuropathy symptoms as compared with patients that stopped leflunomide beyond 30 days of neuropathy onset. The median time until symptom improvement or resolution was 135 days as compared with greater than 755 days for patients that did not stop leflunomide within 30 days of symptom onset. With the exception of 1 patient that took gabapentin for peripheral neuropathy symptoms, patients who continued taking leflunomide for more than 30 days after symptom onset did not experience improvement or recovery unless they discontinued leflunomide.
Adverse GI effects may occur during leflunomide therapy and are the most likely to cause medication intolerance. Of 1339 patients who received leflunomide in clinical trials, 17% developed diarrhea; in controlled trials only (n = 816), diarrhea was reported in 22-27% of patients. Abdominal pain and dyspepsia occurred in 6-8% and 6-10% of patients during controlled trials, respectively, and 5% of patients across all trials. Nausea was reported in up to 13% of patients during clinical trials, while vomiting and mouth ulcers occurred in up to 5%. Gastroenteritis was noted in 1-3% of patients in controlled and uncontrolled trials, and anorexia in 3%. Weight loss can be significant, and was reported in 2% of patients during controlled trials and 4% of patients in all rheumatoid arthritis trials. Over the first 6 months of leflunomide receipt as determined by meta-analyses, 10% of all patients enrolled in phase II and III studies lost 10-19 pounds and 2% lost 20 or more pounds. For 4% of patients, the weight loss represented 10% of their baseline weight. During controlled trials, the following adverse events were reported in 1 to < 3% of patients: stomatitis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, xerostomia, enlarged salivary gland, tooth disorder. Pancreatitis has been observed during post-marketing surveillance. Of 74 patients between 3 and 17 years of age, GI adverse events were abdominal pain, diarrhea, nausea, vomiting, weight loss, and oral ulceration.
In clinical trials with adults, leflunomide treatment was associated with elevated hepatic enzymes, primarily ALT and AST. Most elevations in liver transaminases were mild ( 2-fold or less the upper limit of normal (ULN)) and resolved while continuing treatment. Approximately 6% to 10% of patients receiving leflunomide in controlled clinical trials developed LFT elevations; in all rheumatoid arthritis trials, 5% of patients developed elevations. Elevations > 3-fold ULN occurred in 1.5% to 4.4% of patients in controlled trials. Reversal of elevations greater than 3-fold ULN usually occurred with either dose reduction or with discontinuation of treatment. Increased risk occurs with coadministration of other known hepatotoxic drugs. In a small clinical trial with concurrent methotrexate, clinically significant increases (more than 2-fold ULN) in hepatic enzymes were seen in 33% of patients. All patients had resolution of elevations after dose reductions or drug discontinuations, and several patients were able to continue concomitant treatment. It should be noted that 3 patients required liver biopsy to assess status. In a study of 101 adults that initiated treatment with leflunomide, 9 had grade 2 or 3 elevations of ALT, AST, alkaline phosphatase, or gamma-glutamyl transpeptidase (GGT); 4 of the 9 patients had elevations in ALT. Six of the 9 patients were followed for a year. The other 3 were followed for 2 to 3 months. Eight of the 9 patients' elevation(s) occurred within the first 6 months, none had a history of hepatic disease or excessive alcohol consumption, and 8 concomitantly used potential hepatotoxic medicines. Of the 101 adults, 8 used both leflunomide and methotrexate. Only 1 of the 8 developed grade 2 elevations in alkaline phosphatase and GGT, which reverted to normal without drug alterations. Grade 2 elevations were defined as more than 2.5- to 5-times ULN whereas grade 3 elevations were defined as more than 5- to 20-times ULN. Of 74 children between 3 to 17 years of age, 9 developed elevations of ALT and/or AST between 1.2- and 3-fold of the ULN and 5 patients had elevations between 3- and 8-fold ULN. Hepatotoxicity, including cases of jaundice, cholestasis, acute hepatic necrosis, cirrhosis, hepatitis, and hepatic failure, has been reported in Europe and in the U.S. during postmarketing surveillance; most cases occur within 6 months of beginning therapy and have been associated with confounding patient factors, including the presence of other medications that are potentially hepatotoxic. On occasion, death has occurred (e.g., 12 of 130 cases of serious liver problems). Also, cholelithiasis occurred in 1% to 2.9% of patients who received leflunomide in controlled clinical trials. Death has also been reported in 14 of 49 patients with severe liver injury; the cases were reported to the FDA between August 2002 and May 2009. Other outcomes included liver transplantation in 5 patients and a life-threatening event in 9 patients. Twenty-three reports described jaundice at the time of diagnosis, 11 reported coagulopathy, and 5 reported encephalopathy. Other presenting symptoms included vomiting, rash and or itching, abdominal pain, and pyrexia. Seventeen cases reported normal hepatic enzymes before starting leflunomide. The estimated duration of treatment before the occurrence of severe liver injury ranged from 9 days to 6 years; most developed severe liver injury within the first 6 to 12 months of treatment. Among these patients, the greatest risk for liver injury was seen in patients taking other drugs known to cause liver injury and in patients with pre-existing liver disease. Before the first dose, determine the patient's serum ALT concentration. Check hepatic enzymes at least monthly for 6 months after starting leflunomide and at least every 6 to 8 weeks thereafter. If the ALT rises to greater than 3-times the ULN and leflunomide is suspected, stop treatment and begin a cholestyramine washout to speed the removal of leflunomide from the body. Conduct follow-up liver function tests at least weekly until the ALT value is within normal range.
Leflunomide frequently causes reactions of the skin and hair. Alopecia occurred in 10% of 1339 patients on leflunomide during all trials for rheumatoid arthritis, and 9-17% in controlled trials; it appears to be reversible with drug discontinuation. Some patients may experience hair discoloration (1-2.9%) as well. In most cases hair loss is not severe. Skin reactions may frequently consist of rash (unspecified) (10-12%) and pruritus (4-6%). Urticaria occurs < 1%. Skin rash typically resolves on drug discontinuation. Children 3-17 years of age had alopecia and rash. In clinical trials, anaphylactoid reactions were rare (< 1%). One case occurred in the phase II studies following rechallenge after leflunomide had been withdrawn due to rash. Overall, allergic reactions occurred in approximately 1-5% of patients during various clinical trials. Adverse dermatologic reactions reported in 1-2.9% of patients during controlled trials include acne vulgaris, contact dermatitis, hematoma, ecchymosis, maculopapular rash, nail disorder, skin discoloration, skin or subcutaneous nodules, or skin ulcer. In post-marketing experience, rare cases of angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), erythema multiforme, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis and worsening psoriasis have been reported. If any of these conditions occur, discontinue treatment and initiate a drug elimination procedure.
Hypertension was reported as a side effect in 9-10% of patients treated with leflunomide in phase III clinical trials. However, hypertension as a pre-existing condition was over-represented in the leflunomide treatment arms of all trials. Of 315 patients who received leflunomide, 1% developed new-onset hypertension whereas < 1% of 210 patients who received placebo had the event. Also, hypertension was noted among some of the 74 patients 3-17 years of age with polyarticular course juvenile rheumatoid arthritis. No quantitative or qualitative data are available. Determine blood pressure before leflunomide initiation and periodically during drug receipt. Chest pain (unspecified) was also reported in 1-4% of patients. Adverse cardiovascular effects reported in 1-2.9% of patients include angina, migraine, palpitations, sinus tachycardia, varicose vein, and vasodilation.
Adverse reactions associated with the use of leflunomide in rheumatoid arthritis (RA) controlled trials at one year include nervous system reactions. Headache was reported at an overall rate of 7%, with reports up to 13% in placebo controlled trials. Dizziness was reported at an overall rate of 4%, with reports up to 7% in active controlled trials. Other reactions reported in 1% to < 3% of patients include anxiety, depression, insomnia, neuropathic pain, neuritis, sleep disorder, sweating increased (hyperhidrosis), and vertigo.
Despite its mechanism of action, significant immunosuppression appears to be rare. Leflunomide may cause patients to be more susceptible to infection including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis including extra-pulmonary tuberculosis, and aspergillosis. Opportunistic infections and severe infections including sepsis that may be fatal have been reported during the post-marketing period. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. In clinical trials, infection rates and other signs or symptoms of immunosuppression were similar in leflunomide, placebo, or other treatment groups. The following infections were reported among 1339 patients who received leflunomide in all rheumatoid arthritis clinical trials, and among 816 patients specifically in controlled trials: respiratory infection (15%, 21-27%); upper respiratory infection (4%, 0%); bronchitis (7%, 5-8%); rhinitis (2%, 2-5%); sinusitis (2%, 1-5%); pharyngitis (3%, 2-3%); pneumonia (2%, 2-3%); influenza (2%, 0-4%); and urinary tract infection (5% in all trials). Children 3-17 years of age also commonly had upper respiratory infections; however, the likelihood of the adverse event as compared with placebo is unavailable. Other infections occurring in 1-2.9% of patients included oral or vaginal candidiasis, herpes simplex, herpes zoster, and fungal dermatitis. If a serious infection occurs, leflunomide therapy may need to be interrupted and a drug elimination procedure initiated.
Anemia including iron deficiency anemia occurred in 1-2.9% of patients who received leflunomide in clinical trials. Rare reports of pancytopenia, agranulocytosis, neutropenia, and thrombocytopenia in patients receiving leflunomide have been received. Most patients received or had recently discontinued concomitant methotrexate or other immunosuppressive drugs. In some cases, patients had a prior history of a significant hematologic abnormality. In a few cases, transient thrombocytopenia or leukopenia (< 2000/mm3) occurred. A causal relationship of leflunomide to these hematologic events has not been established. Because of the potential severity of these problems, patients should receive routine CBC monitoring. Baseline and monthly values for platelet, white blood cell count, and hemoglobin or hematocrit are needed. Six months after leflunomide initiation if concomitant methotrexate or another immunosuppressant is not used, monitoring may be decreased to every 6-8 weeks. Patients should be instructed to promptly report any signs of hematologic toxicity or infection including unusual bleeding, pyrexia, pharyngitis, chills, or bruising. If evidence of bone marrow suppression occurs, leflunomide therapy should be discontinued and a drug elimination procedure initiated.
Teratogenesis is a serious concern with leflunomide, and the drug is contraindicated for use during pregnancy due to the potential for serious fetal harm. In animals, leflunomide was teratogenic during organogenesis. Anophthalmia and hydrocephalus were the most common teratogenic effects. Leflunomide also increased embryolethality (intrauterine fetal death) and decreased maternal body weight throughout gestation. Surviving fetuses showed decreased birth weights and a marked decrease in postnatal survival. If a woman becomes pregnant while taking leflunomide, she should stop the medication, be apprised of the potential fetal risks, and undergo an accelerated drug elimination procedure to achieve non-detectable plasma concentrations of teriflunomide, the active metabolite of leflunomide. Instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from leflunomide. The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L (0.02 mcg/mL).
Interstitial lung disease has been reported during leflunomide treatment; some cases have been fatal. The clinical presentation is variable. Patients present acutely with new or worsening pulmonary symptoms such as cough or dyspnea. A fever may be present. Of 1339 patients who received leflunomide in clinical trials, 3% had a cough; in 816 in controlled trials, cough occurred in 4-5%. Although rare, reports of interstitial pneumonitis and pulmonary fibrosis have been received during the post-marketing period. Interstitial lung disease may occur at any time during drug receipt. If pulmonary symptoms develop, leflunomide therapy may need to be interrupted and a drug elimination procedure initiated. Adverse reactions reported in 1-2.9% of patients include asthma, dyspnea, epistaxis, and other unspecified lung disorders.
Genitourinary effects reported in 1-2.9% of patients during controlled clinical trials of leflunomide include proteinuria, cystitis, dysuria, hematuria, hyperuricosuria, menstrual irregularity/disorder, prostate disorder, and increased urinary frequency. Leflunomide has a specific effect on the brush border of the renal proximal tubule that causes a uricosuric effect. Some patients may have a separate effect of hypophosphaturia. These effects have not been seen together nor have there been alterations in renal function.
Adverse metabolic or endocrine reactions associated with leflunomide in 1-2.9% of patients during controlled clinical trials include hyperglycemia, hyperlipidemia, peripheral edema, diabetes mellitus, elevations of creatine phosphokinase, and hyperthyroidism. Hypokalemia was noted in 1-3% of patients.
Musculoskeletal adverse effects with leflunomide are infrequent. The following reactions were reported among 1339 patients who received leflunomide in all rheumatoid arthritis clinical trials, and among 816 patients specifically in controlled trials: arthralgia (1%, < 1-4%), muscle cramps (1%, 0-4%), joint disorders (4%, 2-8%), synovitis (2%, < 1-4%), and tenosynovitis (3%, 2-5%). Arthrosis, bone necrosis, bone pain, bursitis, myalgia, and tendon rupture occurred in 1-2.9% of patients.
Sensory adverse reactions to leflunomide noted in up to 2.9% of patients during controlled clinical trials include blurred vision, cataracts, conjunctivitis, dysgeusia, and other unspecified ocular disorders.
In 1339 leflunomide recipients across all rheumatoid arthritis trials, asthenia, pain, and back pain were reported in 3%, 2%, and 5% of patients, respectively; in controlled trials (n = 816), asthenia was reported in 3-6% of patients, pain in 1-4%, and back pain in 6-8%. Other reactions noted in up to 2.9% of leflunomide-treated patients in controlled trials include fever, hernia, malaise, neck pain, pelvic pain, abscess, and cyst.
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.
Leflunomide is contraindicated in patients with known leflunomide hypersensitivity, teriflunomide hypersensitivity, or any of the product components. Leflunomide causes a risk of serious hypersensitivity reactions or anaphylaxis and other severe allergic reactions such as angioedema. Rare cases of serious rash, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving leflunomide. Educate patients about the signs and symptoms of serious hypersensitivity or severe skin reactions (e.g., anaphylaxis, rash, lymphadenopathy, or hepatic dysfunction). Patients should discontinue leflunomide and seek immediate medical attention if these symptoms occur. If a patient taking leflonomide develops any of these conditions, stop treatment and perform an accelerated drug elimination procedure.
Leflunomide treatment should only be considered when the anticipated therapeutic benefit outweighs the risk of hepatotoxicity and severe liver injury. Severe liver injury, including fatal hepatic failure, has been reported in some patients treated with leflunomide. Treatment is not recommended in any patient with preexisting acute or chronic hepatic disease (including acute or chronic hepatitis B or C virus infection), as there is an increased risk for acute or chronic hepatotoxicity. Do not initiate treatment in any patient who has elevated liver enzymes defined as an alanine aminotransferase (ALT) greater than 2 times the upper limit of normal (ULN). Coadminister any other hepatotoxic medication with caution, including alcohol. Initiate treatment with caution in the presence of alcoholism or heavy alcohol consumption. Monitoring of ALT levels is recommended at baseline, and at least monthly for 6 months after starting the drug, and thereafter every 6 to 8 weeks. If an ALT elevation more than 3-fold ULN occurs, interrupt leflunomide therapy and investigate the cause. If the liver enzyme elevation is likely leflunomide-induced, perform the accelerated drug elimination procedure and monitor liver function tests (LFTs) weekly until normalized. If leflunomide-induced liver injury is unlikely because some other cause has been found, resumption of therapy may be considered. Instruct patients to immediately contact their health care professional if signs and symptoms of liver disease develop (e.g., jaundice). When methotrexate is given concomitantly, follow the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity (i.e., ALT, AST, and serum albumin testing monthly).
Leflunomide is not recommended for patients with severe immunosuppression, bone marrow dysplasia, or severe uncontrolled infections. If a serious infection occurs, consider interrupting leflunomide therapy and initiating the accelerated drug elimination procedure. Medications like leflunomide 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, 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. Prior to initiating leflunomide, all patients should be screened for active and inactive ("latent") tuberculosis infection as per commonly used diagnostic tests. Leflunomide has not been studied in patients with a positive tuberculosis screen, and the safety of leflunomide 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 and monitored carefully during leflunomide treatment for possible reactivation of the infection. Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving leflunomide 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. Chemotherapy may also increase these risks. Patients taking leflunomide should have a complete blood count (CBC) [or platelets and white blood cell count (WBC)], and a hemoglobin or hematocrit monitored at baseline and monthly for 6 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, stop treatment with leflunomide, and perform an accelerated drug elimination procedure to reduce the plasma concentration of the leflunomide active metabolite, teriflunomide. In any situation in which the decision is made to switch from leflunomide 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.
Due to the lack of clinical information related to the safety and efficacy of vaccine administration during leflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of leflunomide 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.
Cases of peripheral neuropathy have been reported in patients receiving leflunomide and in clinical studies with teriflunomide, the active metabolite of leflunomide. Most patients recovered after discontinuation of treatment, but some patients had persistent symptoms. Geriatric or older adults more than 60 years of age, the use of concomitant neurotoxic medications, and the presence of diabetes mellitus may increase the risk for peripheral neuropathy. If a patient taking leflunomide develops a peripheral neuropathy, consider discontinuing leflunomide therapy and performing an accelerated drug elimination procedure.
Interstitial lung disease, including acute interstitial pneumonitis, has been reported with leflunomide. Worsening of pre-existing interstitial lung disease or pulmonary disease has been reported with the use of leflunomide, and pre-existing interstitial lung disease is a risk factor for these events. Some of these cases have been associated with fatal outcomes. 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 elimination procedure.
Leflunomide has not been adequately studied in patients with renal impairment or renal failure. Single-dose studies in patients on dialysis have shown a doubling of the free (active) fraction of the M1 metabolite. Because of the role of the kidney in leflunomide elimination and no clinical experience in this patient population, leflunomide should be used with caution in the presence of renal dysfunction. Leflunomide is not removed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).
Caution should be used during leflunomide therapy in patients with pre-existing hypertension. In placebo-controlled studies with the active metabolite, teriflunomide, elevations in blood pressure were observed in some subjects. Hypertension occurred in some individuals. Blood pressure should be monitored prior to leflunomide initiation and periodically during treatment. Elevated blood pressure during treatment should be appropriately managed according to current clinical guidelines.
Leflunomide is contraindicated for use during pregnancy due to the potential for serious fetal harm. Exclude the possibility of pregnancy prior to treatment. A woman of reproductive potential must use adequate contraception during treatment and for the time of drug elimination following completion of treatment. If a woman becomes pregnant while taking leflunomide, she should stop the medication and be apprised of the potential fetal risks. Begin the accelerated drug elimination procedure. Lowering the plasma concentration of the active metabolite, teriflunomide, as soon as pregnancy is detected may decrease the risk to the fetus. The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L. Pregnancy exposure registry data are not available at this time to inform the presence or absence of drug-associated risk with the use of leflunomide during human pregnancy. Leflunomide has been shown to be embryotoxic in rabbits and rats at systemic concentrations 1/10 to 1/100 the normal human exposure level based on AUC. Leflunomide was teratogenic during organogenesis. Anophthalmia and hydrocephalus were the most common teratogenic effects. The drug also increased embryo-lethality (intrauterine fetal death) and decreased maternal body weight throughout gestation. Surviving fetuses showed decreased birth weights and a marked decrease in postnatal survival. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to leflunomide; information about the registry can be obtained at www.pregnancystudies.org/participate-in-a-study or mothertobaby.org/ongoing-study/arava or by calling 1-877-311-8972.
Counsel patients about the reproductive risk during leflunomide treatment. Do not initiate therapy in females of reproductive potential until pregnancy testing is performed with confirmed negative results. Contraception requirements for females are established. Females of reproductive potential should use effective contraception during treatment and during the time of the accelerated drug elimination procedure after leflunomide treatment is complete. If a woman becomes pregnant while taking leflunomide, she should stop the medication, be apprised of the potential fetal risks, and undergo an accelerated drug elimination procedure to achieve non-detectable plasma concentrations of teriflunomide, the active metabolite of leflunomide. A woman who wishes to become pregnant after starting treatment should not pursue pregnancy until the medication has been discontinued AND the proper drug elimination procedure for leflunomide has been completed to achieve plasma teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL). Administration of the drug elimination procedure after leflunomide discontinuation is recommended for all women of childbearing potential. Female 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 drug elimination procedure may be considered, which may decrease risk to the fetus. Male-mediated teratogenicity is a potential concern with leflunomide treatment. Teriflunomide, the active metabolite of leflunomide, is detected in human semen; studies evaluating male-induced fetal risk are not available. To minimize any possible risk, men not wishing to father a child and their female partners should use effective contraception. Men wishing to father a child should undergo an accelerated elimination procedure or wait until verification that the plasma teriflunomide concentration is less than 0.02 mg/L (0.02 mcg/mL). Advise all patients that the drug 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.
Data are not available to determine if leflunomide is present in human milk, the effects of leflunomide on the breast-fed infant, or the effects of lefunomide on milk production. Due to the potential for serious adverse reactions in a breast-fed infant, lactating women should discontinue breast-feeding during treatment with leflunomide.
The safety and effectiveness of leflunomide in children and adolescents less than 18 years of age have not been established. A single multicenter, double-blind, active-controlled trial was conducted in 94 pediatric patients (1:1 randomization) with polyarticular course juvenile idiopathic arthritis (JIA) as defined by the American College of Rheumatology (ACR). In this trial, leflunomide treatment was not effective in these patients. The safety of leflunomide was studied in 74 patients with polyarticular course JIA (age 3 to 17 years). The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. Less common adverse events included anemia, hypertension, and weight loss. Fourteen pediatric patients experienced ALT and/or AST elevations, 9 patients had elevations between 1.2 and 3-fold the upper limit of normal (ULN), 5 patients had elevations between 3- and 8-fold the ULN.
For the treatment of rheumatoid arthritis:
Oral dosage:
Adults: 100 mg PO once daily for 3 days, then give 20 mg PO once daily. Do not administer a loading dose in persons at high risk for hepatotoxicity or myelosuppression. May reduce dose to 10 mg PO once daily for persons unable to tolerate 20 mg/day.
For the treatment of juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA)*:
NOTE: The safety and efficacy of leflunomide for pediatric patients with polyarticular course JRA has not been fully evaluated.
Oral dosage:
Children and Adolescents: Based on population analyses, dose simulation testing, and M1 concentration analyses, 10 mg PO once daily for children 10 to 19.9 kg, 15 mg PO once daily for children 20 to 40 kg, and 20 mg PO once daily for children weighing more than 40 kg are recommended. Of 94 patients aged 3 to 17 years who received either leflunomide or methotrexate in a double-blinded fashion, 68% had at least a 30% improvement (JRA Definition of Improvement) with leflunomide (loading dose of 100 mg PO for 1 to 3 days, maintenance dose of 10 mg PO every other day to 20 mg PO once daily based on weight). In contrast, 89% of patients treated with methotrexate 0.5 mg/kg/week PO up to 25 mg/week met the study endpoint. Most (91%) patients were disease-modifying antirheumatic drug naive, and at least 89% of patients in both groups completed the 16 weeks of treatment. In another study, 14 of 27 patients aged 3 to 17 years who were either refractory or intolerant to methotrexate had a treatment response with leflunomide (dose not specified). Response was defined as at least a 30% improvement and was based on the intention-to-treat principle; 66.7% of patients completed the 26 weeks of therapy.
For the treatment of sarcoidosis*:
Oral dosage:
Adults: 10 to 20 mg PO once daily.
Therapeutic Drug Monitoring:
Prior to therapy initiation and during maintenance treatment
Measure serum hepatic transaminases (e.g., serum alanine aminotransferase or ALT), bilirubin, and a CBC (including white blood cell count, platelet count, hemoglobin/hematocrit) prior to treatment. Exclude pregnancy via pregnancy testing in females of reproductive potential before treatment initiation. Perform tuberculin skin testing or other tests to rule out tuberculosis; consider periodic testing once on therapy. Once on treatment, measure ALT at least monthly for 6 months and then every 6 to 8 weeks thereafter. Monitor platelet, WBC and hemoglobin/hematocrit monthly for 6 months following initiation of therapy and every 6 to 8 weeks thereafter (or monthly if on methotrexate or other immunosuppressive agents). Monitor blood pressure before starting treatment and periodically thereafter.
Drug Elimination Procedure for suspected drug-induced liver injury, cases of pregnancy, women of childbearing age, men who wish to father a child, hypersensitivity, significant overdose or drug-induced toxicity or severe adverse reaction, or other circumstances that require rapid lowering of leflunomide (teriflunomide) plasma concentrations
The active metabolite of leflunomide is teriflunomide, and thus, laboratories measure teriflunomide concentrations.
-Stop treatment with leflunomide.
-Use of an accelerated drug elimination procedure will rapidly reduce plasma concentrations of leflunomide and its active metabolite, teriflunomide. Without the drug elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations less than 0.02 mg/L due to individual variation in drug clearance.
-Elimination can be accelerated by the following procedures:-Administer cholestyramine 8 grams PO 3 times daily for 11 days.
-Alternatively, administer 50 grams of activated charcoal (made into a suspension) PO every 12 hours for 11 days.
-Verify plasma teriflunomide concentration of less than 0.02 mg/L (0.02 mcg/mL) by 2 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 also 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 treatment.
Maximum Dosage Limits:
-Adults
20 mg/day PO for maintenance dose.
-Elderly
20 mg/day PO for maintenance dose.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Initiation in patients with hepatic impairment is not recommended; patients with severe hepatic impairment are contraindicated to receive leflunomide. Do not initiate leflunomide in patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) more than 2 times the upper limit of normal (ULN) before initiating treatment.
During treatment: If ALT elevation more than 3-fold the ULN occurs while the patient is receiving leflunomide, then interrupt leflunomide therapy and investigate the cause. If likely drug-induced, perform the accelerated drug elimination procedure and monitor liver function tests (LFTs) weekly until normalized. If leflunomide-induced liver injury is unlikely because some other cause has been found, resumption of leflunomide therapy may be considered. If leflunomide 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.
Patients with Renal Impairment Dosing
No specific guidelines for dosage adjustment in renal impairment are available. Caution is recommended, as the renal route is important in drug elimination.
Intermittent hemodialysis
Leflunomide is not removed during hemodialysis.
Peritoneal dialysis
Leflunomide is not dialyzed by chronic ambulatory peritoneal dialysis (CAPD) procedures.
*non-FDA-approved indication
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Closely monitor for zidovudine-induced side effects such as hematologic toxicity when these drugs are used together. In some patients, a dosage reduction of zidovudine may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with zidovudine, a substrate of OAT3, may increase zidovudine plasma concentrations.
Acetaminophen; Ibuprofen: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Alogliptin; Pioglitazone: (Moderate) Closely monitor for hypoglycemia and for pioglitazone-induced side effects when these drugs are used together. In some patients, a dosage reduction of pioglitazone may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Pioglitazone is a substrate for CYP2C8. In vivo data suggest that teriflunomide is an inhibitor of CYP2C8, as Cmax and AUC increased 1.7- and 4.2-fold, respectively, following concurrent use of another CYP2C8 substrate.
Alosetron: (Moderate) Closely monitor for reduced efficacy of alosetron if coadministered with leflunomide. An adjustment of the alosetron dose may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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 leflunomide 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 leflunomide 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 leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, 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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Amlodipine; Celecoxib: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily for episodic migraine or 30 mg PO once daily for chronic migraine if coadministered with leflunomide. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of OATP1B1 and OATP1B3 and leflunomide is an OATP inhibitor. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Atorvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, 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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Azathioprine: (Major) Concomitant use of azathioprine with leflunomide may increase the risk for hepatotoxicity. Caution and close monitoring are advised if these drugs are used together.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Baricitinib: (Moderate) Monitor for increased baricitinib effects if administered with leflunomide as baricitinib exposure may increase; a baricitinib dose reduction may be necessary. Baricitinib is an OAT3 substrate; leflunomide is an OAT3 inhibitor.
Bendamustine: (Major) Consider the use of an alternative therapy if leflunomide treatment is needed in patients receiving bendamustine. Leflunomide may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and leflunomide is a CYP1A2 inducer.
Brincidofovir: (Moderate) Postpone the administration of leflunomide for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and leflunomide is necessary. Brincidofovir is an OATP1B1/3 substrate and leflunomide is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Bupivacaine; Meloxicam: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Cefaclor: (Moderate) Closely monitor for cefaclor-induced side effects such as nausea, diarrhea, or abdominal pain when these drugs are used together. In some patients, a dosage reduction of cefaclor may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Celecoxib: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Celecoxib; Tramadol: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Charcoal: (Major) Activated charcoal can bind with leflunomide and enhance its clearance from the systemic circulation via intestinal trapping. Because the active metabolite of leflunomide, M1, has a prolonged half-life, staggering the administration times of each agent will not prevent this drug interaction. After 24 hours of activated charcoal administration, the levels of M1, the active metabolite of leflunomide, are reduced by approximately 37%. This effective means of gastrointestinal dialysis has actually been used therapeutically in patients with leflunomide toxicity. Charcoal is used as an alternative to cholestyramine in the drug elimination procedure for leflunomide.
Chikungunya Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
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 leflunomide and enhance its clearance from the systemic circulation via intestinal trapping. Because the active metabolite of leflunomide, M1, has a prolonged half-life, staggering the administration times of each agent will not prevent this drug interaction. After 24 hours of cholestyramine administration, the levels of M1, the active metabolite of leflunomide, are reduced by approximately 40%. This effective means of 'gastrointestinal dialysis' has actually been used therapeutically in patients with leflunomide toxicity. Cholestyramine is the key agent in the drug elimination procedure for leflunomide.
Cimetidine: (Moderate) Closely monitor for cimetidine-induced side effects when these drugs are used together. In some patients, a dosage reduction of cimetidine may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Ciprofloxacin: (Moderate) Closely monitor for ciprofloxacin-induced side effects such as nausea, vomiting, diarrhea, or abdominal pain when these drugs are used together. In some patients, a dosage reduction of ciprofloxacin may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Daprodustat: (Major) Reduce the initial daprodustat dose by half during concomitant use of leflunomide unless the daprodustat dose is already 1 mg. Monitor hemoglobin and further adjust the daprodustat dose as appropriate. Concomitant use may increase daprodustat exposure and the risk for daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and leflunomide is a moderate CYP2C8 inhibitor. Concomitant use with a moderate CYP2C8 inhibitor is expected to increase daprodustat overall exposure by approximately 4-fold.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desogestrel; Ethinyl Estradiol: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Dichlorphenamide: (Moderate) Monitor for increased toxicity of dichlorphenamide, including hypokalemia and hyperchloremic metabolic acidosis, if leflunomide and dichlorphenamide are coadministered. Dichlorphenamide is a substrate for OAT3. Teriflunomide, the active metabolite of leflunomide, 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.
Diclofenac: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Diclofenac; Misoprostol: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Dienogest; Estradiol valerate: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Diflunisal: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Diphenhydramine; Ibuprofen: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Diphenhydramine; Naproxen: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as leflunomide, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
Dronabinol: (Major) Use caution if coadministration of dronabinol with leflunomide is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; leflunomide is a moderate inhibitor of CYP2C9 in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
Drospirenone: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Drospirenone; Estetrol: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Drospirenone; Estradiol: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Drospirenone; Ethinyl Estradiol: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Duloxetine: (Moderate) Closely monitor for reduced efficacy of duloxetine if coadministered with leflunomide. An adjustment of the duloxetine dose may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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 leflunomide 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. The active metabolite of leflunomide, which is responsible for virtually all of its activity, 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 leflunomide 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. The active metabolite of leflunomide, which is responsible for virtually all of its activity, 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) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Eluxadoline: (Major) Reduce the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with leflunomide. Coadministration may increase exposure of eluxadoline. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is an OATP1B1 substrate and leflunomide is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
Estradiol; Levonorgestrel: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Estradiol; Norethindrone: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Estradiol; Norgestimate: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Ethinyl Estradiol; Norelgestromin: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Ethinyl Estradiol; Norgestrel: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Etodolac: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Etonogestrel; Ethinyl Estradiol: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Etrasimod: (Major) Avoid concomitant use of etrasimod and leflunomide in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Etrasimod is a CYP2C9 and CYP2C8 substrate and leflunomide is a moderate CYP2C8 inhibitor.
Ezetimibe; Simvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, 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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Fenoprofen: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Flurbiprofen: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Fluvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, 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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Fosphenytoin: (Minor) It is unknown whether other medications that are significantly metabolized by the cytochrome P450 2C9 enzyme, such as fosphenytoin, will have drug interactions with leflunomide. Clinical and/or therapeutic drug monitoring of these potentially interacting drugs may be warranted on initiation of leflunomide therapy.
Furosemide: (Moderate) Closely monitor for furosemide-induced side effects such as excessive fluid loss or hypotension when these drugs are used together. In some patients, a dosage reduction of furosemide may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
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 leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, 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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Hydrocodone; Ibuprofen: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Ibuprofen: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Ibuprofen; Famotidine: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Ibuprofen; Oxycodone: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Ibuprofen; Pseudoephedrine: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Indomethacin: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Isoniazid, INH: (Major) Concomitant use of isonazid with leflunomide may increase the risk for hepatotoxicity. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concomitant use of isonazid with leflunomide may increase the risk for hepatotoxicity. Caution and close monitoring are advised if these drugs are used together. (Moderate) No dosage adjustment is recommended for leflunomide when coadministered with rifampin. Because of the potential for leflunomide concentrations to increase with multiple dosing, caution should be used if rifampin is added to therapy. Concomitant use of leflunomide and rifampin, a potent inducer of CYP and transporters, increased the plasma concentration of teriflunomide by 40%, probably via induction of metabolism of leflunomide to the active metabolite. However, rifampin administration with the metabolite alone ( teriflunomide) did not alter the pharmacokinetics of the drug.
Isoniazid, INH; Rifampin: (Major) Concomitant use of isonazid with leflunomide may increase the risk for hepatotoxicity. Caution and close monitoring are advised if these drugs are used together. (Moderate) No dosage adjustment is recommended for leflunomide when coadministered with rifampin. Because of the potential for leflunomide concentrations to increase with multiple dosing, caution should be used if rifampin is added to therapy. Concomitant use of leflunomide and rifampin, a potent inducer of CYP and transporters, increased the plasma concentration of teriflunomide by 40%, probably via induction of metabolism of leflunomide to the active metabolite. However, rifampin administration with the metabolite alone ( teriflunomide) did not alter the pharmacokinetics of the drug.
Itraconazole: (Moderate) A pharmacodynamic interaction may occur when leflunomide is given concomitantly with other hepatotoxic drugs including itraconazole. The potential for hepatotoxicity should also be considered when such medications would be prescribed after leflunomide administration has ceased, if the patient has not received the leflunomide elimination procedure.
Ketoconazole: (Moderate) A pharmacodynamic interaction may occur when leflunomide is given concomitantly with other hepatotoxic drugs, such as ketoconazole, The potential for hepatotoxicity should also be considered when ketoconazole would be prescribed after leflunomide administration has ceased, if the patient has not received the leflunomide elimination procedure.
Ketoprofen: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Ketorolac: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Closely monitor for zidovudine-induced side effects such as hematologic toxicity when these drugs are used together. In some patients, a dosage reduction of zidovudine may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with zidovudine, a substrate of OAT3, may increase zidovudine plasma concentrations.
Leuprolide; Norethindrone: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Levoketoconazole: (Moderate) A pharmacodynamic interaction may occur when leflunomide is given concomitantly with other hepatotoxic drugs, such as ketoconazole, The potential for hepatotoxicity should also be considered when ketoconazole would be prescribed after leflunomide administration has ceased, if the patient has not received the leflunomide elimination procedure.
Levonorgestrel: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Lovastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, 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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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 leflunomide as increased maraviroc concentrations may occur. Maraviroc is a substrate of organic anion-transporting polypeptide (OATP1B1); leflunomide 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: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Meclofenamate Sodium: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Mefenamic Acid: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Meloxicam: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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 leflunomide's active metabolite.
Methotrexate: (Major) A pharmacodynamic interaction may occur when leflunomide is given concomitantly with other hepatotoxic drugs. The potential for hepatotoxicity should also be considered when such medications would be prescribed after leflunomide administration has ceased, if the patient has not received the leflunomide elimination procedure. In a small phase III study of leflunomide with methotrexate, 33% of the patients had LFT enzyme elevations of 2-fold the upper limit of normal (ULN) or greater. All of these resolved with either continuation of the medications with dosage adjustment or leflunomide discontinuation. Furthermore, 3.8% of 133 patients with normal LFTs on methotrexate had an ALT serum concentration at least 3 times the ULN with leflunomide addition. In contrast, 0.8% of 130 patients with placebo addition met the criteria. If leflunomide and methotrexate are used concomitantly, the American College of Rheumatology guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly. Also, laboratory monitoring for leflunomide needs to be conducted.
Mitoxantrone: (Moderate) Closely monitor for mitoxantrone-induced side effects such as hepatotoxicity or hematologic toxicity when these drugs are used together. In some patients, a dosage reduction of mitoxantrone may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the Breast Cancer Resistance Protein (BCRP). Use of teriflunomide with mitoxantrone, a substrate of BCRP, may increase mitoxantrone plasma concentrations.
Momelotinib: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with leflunomide is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; leflunomide is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Nabumetone: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with leflunomide is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP2C8 substrate and leflunomide is a moderate CYP2C8 inhibitor. In vitro, the metabolism of paclitaxel to 6-alpha-hydroxypaclitaxel was inhibited by another inhibitor of CYP2C8.
Naproxen: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Naproxen; Esomeprazole: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Naproxen; Pseudoephedrine: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the organic anion transporting polypeptides OATP1B1/1B3 and may increase exposure to nateglinide, an OATP substrate.
Nonsteroidal antiinflammatory drugs: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Norethindrone: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Norethindrone; Ethinyl Estradiol: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Norgestimate; Ethinyl Estradiol: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Norgestrel: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Oral Contraceptives: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Oxaprozin: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Paclitaxel: (Moderate) Closely monitor for for paclitaxel-induced side effects when these drugs are used together. In some patients, a dosage reduction of paclitaxel may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Paclitaxel is a substrate for CYP2C8. In vivo data suggest that teriflunomide is an inhibitor of CYP2C8, as Cmax and AUC increased 1.7- and 4.2-fold, respectively, following concurrent use of another CYP2C8 substrate.
Penicillin G Benzathine: (Moderate) Closely monitor for penicillin G-induced side effects such as nausea, vomiting, diarrhea, or seizures when these drugs are used together. In some patients, a dosage reduction of penicillin G may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Closely monitor for penicillin G-induced side effects such as nausea, vomiting, diarrhea, or seizures when these drugs are used together. In some patients, a dosage reduction of penicillin G may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Penicillin G Procaine: (Moderate) Closely monitor for penicillin G-induced side effects such as nausea, vomiting, diarrhea, or seizures when these drugs are used together. In some patients, a dosage reduction of penicillin G may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Penicillin G: (Moderate) Closely monitor for penicillin G-induced side effects such as nausea, vomiting, diarrhea, or seizures when these drugs are used together. In some patients, a dosage reduction of penicillin G may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Phenytoin: (Minor) Phenytoin clearance can be decreased by drugs that inhibit hepatic microsomal enzymes, particularly those drugs that significantly inhibit the cytochrome P450 2C subset of isoenzymes including leflunomide. Clinical and/or therapeutic drug monitoring of phenytoin may be warranted on initiation of leflunomide therapy.
Pioglitazone: (Moderate) Closely monitor for hypoglycemia and for pioglitazone-induced side effects when these drugs are used together. In some patients, a dosage reduction of pioglitazone may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Pioglitazone is a substrate for CYP2C8. In vivo data suggest that teriflunomide is an inhibitor of CYP2C8, as Cmax and AUC increased 1.7- and 4.2-fold, respectively, following concurrent use of another CYP2C8 substrate.
Pioglitazone; Glimepiride: (Moderate) Closely monitor for hypoglycemia and for pioglitazone-induced side effects when these drugs are used together. In some patients, a dosage reduction of pioglitazone may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Pioglitazone is a substrate for CYP2C8. In vivo data suggest that teriflunomide is an inhibitor of CYP2C8, as Cmax and AUC increased 1.7- and 4.2-fold, respectively, following concurrent use of another CYP2C8 substrate.
Pioglitazone; Metformin: (Moderate) Closely monitor for hypoglycemia and for pioglitazone-induced side effects when these drugs are used together. In some patients, a dosage reduction of pioglitazone may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Pioglitazone is a substrate for CYP2C8. In vivo data suggest that teriflunomide is an inhibitor of CYP2C8, as Cmax and AUC increased 1.7- and 4.2-fold, respectively, following concurrent use of another CYP2C8 substrate.
Piroxicam: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Pitavastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, 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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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 leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, 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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP2C9, such as leflunomide, may lead to increases in the serum concentrations of ramelteon.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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 leflunomide's active metabolite.
Resmetirom: (Major) Avoid concomitant use of resmetirom and leflunomide due to the risk for increased resmetirom exposure which may increase the risk for resmetirom-related adverse effects. While use is not recommended, if concomitant use is necessary, consider a resmetirom dosage reduction. For patients with an actual body weight less than 100 kg, reduce the resmetirom dosage to 60 mg once daily. For patients with an actual body weight of 100 kg or more, reduce the resmetirom dosage to 80 mg once daily. Resmetirom is a CYP2C8 and OATP1B1/3 substrate and leflunomide is a moderate CYP2C8 and OATP1B1/3 inhibitor. Concomitant use with another moderate CYP2C8 inhibitor increased resmetirom overall exposure by 1.7-fold.
Revefenacin: (Major) Coadministration of revefenacin is not recommended with leflunomide 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; leflunomide is an inhibitor of OATP1B1 and OATP1B3.
Rifampin: (Moderate) No dosage adjustment is recommended for leflunomide when coadministered with rifampin. Because of the potential for leflunomide concentrations to increase with multiple dosing, caution should be used if rifampin is added to therapy. Concomitant use of leflunomide and rifampin, a potent inducer of CYP and transporters, increased the plasma concentration of teriflunomide by 40%, probably via induction of metabolism of leflunomide to the active metabolite. However, rifampin administration with the metabolite alone ( teriflunomide) did not alter the pharmacokinetics of the drug.
Riluzole: (Moderate) Coadministration of riluzole with leflunomide may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and leflunomide is a CYP1A2 inducer.
Rituximab: (Moderate) Coadministration may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs and symptoms of infection.
Rituximab; Hyaluronidase: (Moderate) Coadministration may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs and symptoms of infection.
Rosiglitazone: (Moderate) Closely monitor for hypoglycemia and for rosiglitazone-induced side effects when these drugs are used together. In some patients, a dosage reduction of rosiglitazone may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Rosiglitazone is a substrate for CYP2C8. In vivo data suggest that teriflunomide is an inhibitor of CYP2C8, as Cmax and AUC increased 1.7- and 4.2-fold, respectively, following concurrent use of another CYP2C8 substrate.
Rosuvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, 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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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 leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, 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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide. Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration.
Selexipag: (Major) Reduce selexipag dose to once daily when coadministered with leflunomide due to increased exposure to the active metabolite of selexipag, which may cause side effects. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Selexipag is a CYP2C8 substrate. Teriflunomide is an inhibitor of CYP2C8.
Simvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, 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. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and leflunomide. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and leflunomide is an OATP1B3 inhibitor.
Sulfasalazine: (Moderate) An additive effect may occur when leflunomide is given concomitantly with other hepatotoxic drugs. Sulfasalazine has caused elevations in liver enzymes and concomitant therapy with leflunomide may warrant caution.
Sulindac: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Sumatriptan; Naproxen: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of leflunomide is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a BCRP substrate and leflunomide is a BCRP inhibitor.
Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering leflunomide. 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 increase 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 CYP2C9; leflunomide is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
Teriflunomide: (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.
Theophylline, Aminophylline: (Moderate) Closely monitor for reduced efficacy of theophylline if coadministered with leflunomide. An adjustment of the theophylline dose may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as theophylline, may decrease theophylline exposure and lead to a reduction in efficacy.
Tizanidine: (Moderate) Closely monitor for reduced efficacy of tizanidine if coadministered with leflunomide. An adjustment of the tizanidine dose may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
Tolmetin: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Topotecan: (Major) Avoid coadministration of leflunomide with oral topotecan due to increased topotecan exposure; leflunomide may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and leflunomide 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 leflunomide is necessary due to the risk of increased tucatinib exposure. Tucatinib is a CYP2C8 substrate and leflunomide is a moderate CYP2C8 inhibitor.
Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with leflunomide. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP drug transporter; leflunomide is a BCRP inhibitor.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with leflunomide is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Leflunomide is metabolized to teriflunomide, which is responsible for almost all of leflunomide's activity in vivo. 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: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Zavegepant: (Major) Avoid concomitant use of zavegepant and leflunomide. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and leflunomide is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Zidovudine, ZDV: (Moderate) Closely monitor for zidovudine-induced side effects such as hematologic toxicity when these drugs are used together. In some patients, a dosage reduction of zidovudine may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with zidovudine, a substrate of OAT3, may increase zidovudine plasma concentrations.
Leflunomide exhibits essentially all of its pharmacologic activity via its active primary metabolite A77 1726 (M1). M1 is chemically classified as a malonitrilamide. The in vitro and in vivo mechanisms of malonitrilamides are not completely defined at this time. M1 inhibits dihydroorotate dehydrogenase (DHODH), an enzyme located in cell mitochondria that catalyzes a key step in de novo pyrimidine synthesis. A secondary mechanism of action is inhibition of cytokine and growth factor receptor associated tyrosine kinase activity. The inhibition of DHODH occurs at lower levels of M1 than inhibition of tyrosine kinases and thus DHODH inhibition is considered the primary clinical mechanism of action. Suppressed pyrimidine synthesis in T and B lymphocytes interferes with RNA and protein synthesis within the cells, and activation of sensor molecules prevents further cell cycle progression at the G1 phase. The effect appears to be cytostatic, rather than cytotoxic, at normal clinical doses. T and B cell collaborative actions are interrupted and immunoglobulin production is suppressed. In addition, A77 1726 appears to have anti-inflammatory properties related to an ability to reduce histamine release, and to inhibit the induction of cyclooxygenase-2 (COX-2). In vitro studies have shown that the activation, proliferation, aggregation, and adhesion of both peripheral and synovial fluid mononuclear cells is decreased after leflunomide therapy. All actions appear to be dose dependent. Reduction in the activity of lymphocytes leads to reduced cytokine and antibody mediated destruction of the synovial joints and attenuation of the inflammatory process.
In addition to T and B cell inhibition, the therapeutic effect of leflunomide may also be partially due to osteoclast inhibition. In mice that lacked T and B cells, leflunomide inhibited bone destruction and osteoclast formation after a large dose of lipopolysaccharide endotoxin, which normally would cause bone destruction. In wild-type mice that received leflunomide, the anti-inflammatory reaction was accompanied by a more powerful suppression of osteoclast formation. The data suggest a contributory role of T cell repression on the bone-protective effect of leflunomide. In vitro data suggest that leflunomide suppresses the transcription factor, nuclear factor of activated T cells c1 (NF-ATc1). Normally, receptor activator of NF-kappa-B ligand (RANKL) induces NF-ATc1 to cause osteoclast differentiation. Data are needed to determine if NF-ATc1 expression is up-regulated in tissues from humans afflicted with rheumatoid arthritis.
Leflunomide, via A77 1726, exhibits a uricosuric effect. It competitively inhibits the active reabsorption of uric acid via a specific effect on the brush border of the renal proximal convoluted tubule. A separate effect of hypophosphaturia is seen in some individuals. Leflunomide has not been associated with changes in the glomerular filtration rate.
Leflunomide is administered orally. It is rapidly metabolized to a primary active metabolite, teriflunomide (M1), which is almost entirely responsible for its activity in vivo. Most of the in vivo pharmacokinetic data pertains to teriflunomide. Teriflunomide is extensively bound to plasma protein (more than 99%) and is mainly distributed in plasma. The volume of distribution is 11 L. In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19 and 3A4 are involved in leflunomide metabolism. In vivo, leflunomide is metabolized to 1 primary (teriflunomide) and many minor metabolites. In vitro, teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase enzymes. Leflunomide itself is rarely detectable in plasma. Elimination is complex. Teriflunomide, the active metabolite of leflunomide, has a median half-life of 18 to 19 days in healthy volunteers. The elimination of teriflunomide can be accelerated by administration of cholestyramine or activated charcoal. A few studies have shown that it would take up to 2 years in some individuals to reach plasma teriflunomide levels less than 0.02 mg/L after halting leflunomide administration. For this reason, the need to rapidly lower leflunomide and teriflunomide plasma concentrations requires the use of a specialized procedure to speed drug elimination. Teriflunomide, the active metabolite of leflunomide, is eliminated by direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces).
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2C8, CYP1A2, and OAT3; also BRCP and OATP1B1/1B3
Leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for almost all of leflunomide's in vivo activity. Teriflunomide affects several CYP450 enzymes and drug transporters. 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 leflunomide.
-Route-Specific Pharmacokinetics
Oral Route
Leflunomide rarely achieves detectable plasma concentrations. Following oral administration, peak teriflunomide concentrations occurred between 6 to 12 hours after dosing. Due to the very long half-life of teriflunomide (18 to 19 days), an oral loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state teriflunomide concentrations. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require about 2 months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that plasma teriflunomide concentrations are dose proportional. Administration of leflunomide tablets with a high fat meal did not have a significant impact on teriflunomide plasma concentrations.
-Special Populations
Hepatic Impairment
Dedicated studies of the effect of hepatic impairment on leflunomide pharmacokinetics have not been conducted. Given the need to metabolize leflunomide into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of the drug in patients with hepatic impairment is not recommended.
Renal Impairment
Pharmacokinetic data for leflunomide from patients with renal impairment are lacking. Due to the absence of adequate data, caution is recommended for leflunomide use in patients with renal impairment. Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide is not dialyzable.
Pediatrics
Limited pharmacokinetic data for leflunomide are available for children. During receipt of 20 mg PO once daily in children (aged 3 to 17 years) and of a weight more than 40 kg, the steady state concentration of 36.7 mcg/mL was similar to the concentration achieved in adults (34 mcg/mL); the mean clearance of M1 (teriflunomide) was 26 +/-16 mL/hour. In contrast, the concentration in children less than 20 kg body weight was 12.6 mcg/mL after receipt of 5 mg PO once daily and the concentration in children that weighed between 20 and 40 kg after receipt of 10 mg PO once daily was 26.2 mcg/mL; the mean clearance for children weighing less than 20 kg or between 20 and 40 kg was 18 +/- 9.5 mL/hour and 18 +/- 9.5 mL/hour, respectively. Despite reduced teriflunomide clearance in pediatric patients 40 kg or less as compared with heavier weight patients, the response rate was less robust. The reason for the apparent paradoxical reaction is unclear.
Gender Differences
Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of teriflunomide, the active metabolite of leflunomide.
Other
Smoking
Smokers in analysis of clinical trial data had a 38% increase in leflunomide clearance verus non-smokers, but this did not appear to affect clinical efficacy.