Arava

Other Specific Antirheumatics
Pyrimidine Synthesis Inhibitors

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.

Oral Administration

Administer tablets with or without food. Give the daily dose at approximately the same time each day.

Severe

tendon rupture / Delayed / 1.0-2.9
anaphylactoid reactions / Rapid / 0-1.0
pancreatitis / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
coagulopathy / Delayed / Incidence not known
cirrhosis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
fetal death / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known
pulmonary fibrosis / Delayed / Incidence not known

Moderate

elevated hepatic enzymes / Delayed / 5.0-33.0
hypertension / Early / 9.0-10.0
oral ulceration / Delayed / 3.0-5.0
chest pain (unspecified) / Early / 1.0-4.0
synovitis / Delayed / 0-4.0
melena / Delayed / 1.0-3.0
constipation / Delayed / 1.0-3.0
colitis / Delayed / 1.0-3.0
stomatitis / Delayed / 1.0-3.0
gastritis / Delayed / 1.0-3.0
esophagitis / Delayed / 1.0-3.0
hypokalemia / Delayed / 1.0-3.0
cholelithiasis / Delayed / 1.0-2.9
skin ulcer / Delayed / 1.0-2.9
hematoma / Early / 1.0-2.9
contact dermatitis / Delayed / 1.0-2.9
sinus tachycardia / Rapid / 1.0-2.9
palpitations / Early / 1.0-2.9
angina / Early / 1.0-2.9
migraine / Early / 1.0-2.9
depression / Delayed / 1.0-2.9
neuropathic pain / Delayed / 1.0-2.9
neuritis / Delayed / 1.0-2.9
anemia / Delayed / 1.0-2.9
dyspnea / Early / 1.0-2.9
cystitis / Delayed / 1.0-2.9
hematuria / Delayed / 1.0-2.9
dysuria / Early / 1.0-2.9
proteinuria / Delayed / 1.0-2.9
hyperthyroidism / Delayed / 1.0-2.9
hyperlipidemia / Delayed / 1.0-2.9
diabetes mellitus / Delayed / 1.0-2.9
hyperglycemia / Delayed / 1.0-2.9
peripheral edema / Delayed / 1.0-2.9
bone pain / Delayed / 1.0-2.9
cataracts / Delayed / 0-2.9
blurred vision / Early / 0-2.9
conjunctivitis / Delayed / 0-2.9
peripheral neuropathy / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
encephalopathy / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
psoriasis / Delayed / Incidence not known
immunosuppression / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
pneumonitis / Delayed / Incidence not known

Mild

diarrhea / Early / 17.0-27.0
infection / Delayed / 1.0-27.0
alopecia / Delayed / 9.0-17.0
nausea / Early / 9.0-13.0
headache / Early / 7.0-13.0
rash / Early / 10.0-12.0
dyspepsia / Early / 5.0-10.0
abdominal pain / Early / 5.0-8.0
back pain / Delayed / 6.0-8.0
dizziness / Early / 4.0-7.0
pruritus / Rapid / 4.0-6.0
asthenia / Delayed / 3.0-6.0
vomiting / Early / 3.0-5.0
sinusitis / Delayed / 1.0-5.0
rhinitis / Early / 2.0-5.0
cough / Delayed / 3.0-5.0
paresthesias / Delayed / 2.0-4.0
weight loss / Delayed / 2.0-4.0
arthralgia / Delayed / 0-4.0
muscle cramps / Delayed / 0-4.0
xerostomia / Early / 1.0-3.0
gingivitis / Delayed / 1.0-3.0
anorexia / Delayed / 3.0-3.0
flatulence / Early / 1.0-3.0
pharyngitis / Delayed / 2.0-3.0
acne vulgaris / Delayed / 1.0-2.9
hair discoloration / Delayed / 1.0-2.9
skin discoloration / Delayed / 1.0-2.9
ecchymosis / Delayed / 1.0-2.9
maculopapular rash / Early / 1.0-2.9
anxiety / Delayed / 1.0-2.9
vertigo / Early / 1.0-2.9
insomnia / Early / 1.0-2.9
hyperhidrosis / Delayed / 1.0-2.9
epistaxis / Delayed / 1.0-2.9
increased urinary frequency / Early / 1.0-2.9
menstrual irregularity / Delayed / 1.0-2.9
myalgia / Early / 1.0-2.9
dysgeusia / Early / 0-2.9
pelvic pain / Delayed / 0-2.9
fever / Early / 0-2.9
malaise / Early / 0-2.9
urticaria / Rapid / 0-1.0

Alcoholism, hepatic disease, hepatitis, hepatotoxicity, jaundice

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).

Pregnancy

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.

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

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.

Arava

Rx

Disease-modifying antirheumatic drug (DMARD); isoxazol derivative; has a fast onset of action (4 weeks) relative to other DMARDs; decreases symptoms and retards structural joint damage in RA; under investigation as an immunosuppressive agent for organ transplants and for SLE.

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.

†Indicates off-label use

Hepatic Impairment

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.

Renal Impairment

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.

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.
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.
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.
Atorvastatin; Ezetimibe: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of 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.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking leflunomide. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a BCRP substrate and leflunomide is a BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Lesinurad: (Moderate) Use lesinurad and leflunomide together with caution; leflunomide may increase the systemic exposure of lesinurad. Leflunomide is an inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
Lesinurad; Allopurinol: (Moderate) Use lesinurad and leflunomide together with caution; leflunomide may increase the systemic exposure of lesinurad. Leflunomide is an inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
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.
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.
Metformin; 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.
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.
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.
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.
Niacin; Simvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of 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.
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.
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.
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.
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.
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.
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.
Tolbutamide: (Minor) The hypoglycemic effect of tolbutamide may be enhanced if leflunomide is administered concurrently. Patients receiving tolbutamide who begin treatment with leflunomide may need to be monitored for increases in hypoglycemia or other side effects.
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.

Arava/Leflunomide Oral Tab: 10mg, 20mg

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.

Mechanism of Action: 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.

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.

Pregnancy

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.