Leflunomide Information
Leflunomide (Leflunomide) Contraindications And Warnings
PREGNANCY MUST BE EXCLUDED BEFORE THE START OF TREATMENT WITH Leflunomide (Leflunomide) . Leflunomide (Leflunomide) IS CONTRAINDICATED IN PREGNANT WOMEN, OR WOMEN OF CHILDBEARING POTENTIAL WHO ARE NOT USING RELIABLE CONTRACEPTION. (SEE AND .) PREGNANCY MUST BE AVOIDED DURING Leflunomide (Leflunomide) TREATMENT OR PRIOR TO THE COMPLETION OF THE DRUG ELIMINATION PROCEDURE AFTER Leflunomide (Leflunomide) TREATMENT.
Leflunomide (Leflunomide) Description
Leflunomide (Leflunomide) is a pyrimidine synthesis inhibitor. The chemical name for Leflunomide (Leflunomide) is N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula CHFNO, a molecular weight of 270.2 and the following structural formula:
Leflunomide (Leflunomide) is available for oral administration as tablets containing 10 or 20 mg of active drug. Combined with Leflunomide (Leflunomide) are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc, titanium dioxide, and yellow ferric oxide (20 mg tablet only).
Leflunomide (Leflunomide) Indications And Usage
Leflunomide (Leflunomide) is indicated in adults for the treatment of active rheumatoid arthritis (RA):
(see )
Aspirin, nonsteroidal anti-inflammatory agents and/or low dose corticosteroids may be continued during treatment with Leflunomide (Leflunomide) (see ). The combined use of Leflunomide (Leflunomide) with antimalarials, intramuscular or oral gold, D penicillamine, azathioprine, or methotrexate has not been adequately studied. (See ).
Leflunomide (Leflunomide) Contraindications
Leflunomide (Leflunomide) is contraindicated in patients with known hypersensitivity to Leflunomide (Leflunomide) or any of the other components of Leflunomide (Leflunomide) tablets.
Leflunomide (Leflunomide) can cause fetal harm when administered to a pregnant woman. Leflunomide (Leflunomide) , when administered orally to rats during organogenesis at a dose of 15 mg/kg, was teratogenic (most notably anophthalmia or microophthalmia and internal hydrocephalus). The systemic exposure of rats at this dose was approximately 1/10 the human exposure level based on AUC. Under these exposure conditions, Leflunomide (Leflunomide) also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. In rabbits, oral treatment with 10 mg/kg of Leflunomide (Leflunomide) during organogenesis resulted in fused, dysplastic sternebrae. The exposure level at this dose was essentially equivalent to the maximum human exposure level based on AUC. At a 1 mg/kg dose, Leflunomide (Leflunomide) was not teratogenic in rats and rabbits.
When female rats were treated with 1.25 mg/kg of Leflunomide (Leflunomide) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival. The systemic exposure level at 1.25 mg/kg was approximately 1/100 the human exposure level based on AUC.
Leflunomide (Leflunomide) is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Leflunomide (Leflunomide) Warnings
Leflunomide (Leflunomide) is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. In the event that a serious infection occurs, it may be necessary to interrupt therapy with Leflunomide (Leflunomide) and administer cholestyramine or charcoal (see ). Medications like Leflunomide (Leflunomide) that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections, especially pneumonia, tuberculosis (including extra-pulmonary tuberculosis) and aspergillosis. Severe infections including sepsis, which may be fatal, have been reported in patients receiving Leflunomide (Leflunomide) , especially pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection.
There have been rare reports of pancytopenia, agranulocytosis and thrombocytopenia in patients receiving Leflunomide (Leflunomide) alone. These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality.
Patients taking Leflunomide (Leflunomide) tablets should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6 to 8 weeks thereafter. If used with concomitant methotrexate and/or other potential immunosuppressive agents, chronic monitoring should be monthly. If evidence of bone marrow suppression occurs in a patient taking Leflunomide (Leflunomide) tablets, treatment with Leflunomide (Leflunomide) should be stopped, and cholestyramine or charcoal should be used to reduce the plasma concentration of Leflunomide (Leflunomide) active metabolite (see ). In any situation in which the decision is made to switch from Leflunomide (Leflunomide) to another anti-rheumatic agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Leflunomide (Leflunomide) washout with cholestyramine or charcoal may decrease this risk, but also may induce disease worsening if the patient had been responding to Leflunomide (Leflunomide) treatment.
RARE CASES OF SEVERE LIVER INJURY, INCLUDING CASES WITH FATAL OUTCOME, HAVE BEEN REPORTED DURING TREATMENT WITH Leflunomide (Leflunomide) . MOST CASES OF SEVERE LIVER INJURY OCCUR WITHIN 6 MONTHS OF THERAPY AND IN A SETTING OF MULTIPLE RISK FACTORS FOR HEPATOTOXICITY (liver disease, other hepatotoxins). (See ).
At minimum, ALT (SGPT) must be performed at baseline and monitored initially at monthly intervals during the first six months then, if stable, every 6 to 8 weeks thereafter. In addition, if Leflunomide (Leflunomide) tablets and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly.
Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT elevation are recommended as follows: For confirmed ALT elevations between 2- and 3-fold ULN, dose reduction to 10 mg/day may allow continued administration of Leflunomide (Leflunomide) tablets under close monitoring. If elevations between 2- and 3-fold ULN persist despite dose reduction or if ALT elevations of >3-fold ULN are present, Leflunomide (Leflunomide) should be discontinued and cholestyramine or charcoal should be administered (see ) with close monitoring, including retreatment with cholestyramine or charcoal as indicated.
In clinical trials, Leflunomide (Leflunomide) treatment as monotherapy or in combination with methotrexate was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤ 2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 8 shows liver enzyme elevations seen with monthly monitoring in clinical trials US301 and MN301. It was notable that the absence of folate use in MN302 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.
In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, Leflunomide (Leflunomide) was added to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo added.
There are no adequate and well-controlled studies evaluating Leflunomide (Leflunomide) in pregnant women. However, based on animal studies, Leflunomide (Leflunomide) may increase the risk of fetal death or teratogenic effects when administered to a pregnant woman (see ). Women of childbearing potential must not be started on Leflunomide (Leflunomide) until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with Leflunomide (Leflunomide) , patients must be fully counseled on the potential for serious risk to the fetus.
The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of the active metabolite by instituting the drug elimination procedure described below at the first delay of menses may decrease the risk to the fetus from Leflunomide (Leflunomide) .
Upon discontinuing Leflunomide (Leflunomide) , it is recommended that all women of childbearing potential undergo the drug elimination procedure described below. Women receiving Leflunomide (Leflunomide) treatment who wish to become pregnant must discontinue Leflunomide (Leflunomide) and undergo the drug elimination procedure described below which includes verification of M1 metabolite plasma levels less than 0.02 mg/L (0.02 µg/mL). Human plasma levels of the active metabolite (M1) less than 0.02 mg/L (0.02 µg/mL) are expected to have minimal risk based on available animal data.
The following drug elimination procedure is recommended to achieve non-detectable plasma levels (less than 0.02 mg/L or 0.02 µg/mL) after stopping treatment with Leflunomide (Leflunomide) :
Without the drug elimination procedure, it may take up to 2 years to reach plasma M1 metabolite levels less than 0.02 mg/L due to individual variation in drug clearance.
Leflunomide (Leflunomide) Precautions
No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of Leflunomide (Leflunomide) up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human M1 systemic exposure based on AUC). However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied (1.7 times the human M1 exposure based on AUC). Female mice, in the same study, exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg (approximately 1/10 the human M1 exposure based on AUC). The significance of the findings in mice relative to the clinical use of Leflunomide (Leflunomide) is not known.
Leflunomide (Leflunomide) was not mutagenic in the Ames Assay, the Unscheduled DNA Synthesis Assay, or in the HGPRT Gene Mutation Assay. In addition, Leflunomide (Leflunomide) was not clastogenic in the Mouse Micronucleus Assay nor in the Cytogenetic Test in Chinese Hamster Bone Marrow Cells. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of Leflunomide (Leflunomide) , was mutagenic in the Ames Assay and in the HGPRT Gene Mutation Assay, and was clastogenic in the Assay for Chromosome Aberrations in the Chinese Hamster Cells. TFMA was not clastogenic in the Mouse Micronucleus Assay nor in the Cytogenetic Test in Chinese Hamster Bone Marrow Cells. Leflunomide (Leflunomide) had no effect on fertility in either male or female rats at oral doses up to 4.0 mg/kg (approximately 1/30 the human M1 exposure based on AUC).
Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Leflunomide (Leflunomide) , health care providers are encouraged to register such patients by calling 1-877-311-8972.
Leflunomide (Leflunomide) Adverse Reactions
Adverse reactions associated with the use of Leflunomide (Leflunomide) in RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. In the controlled studies at one year, the following adverse events were reported, regardless of causality. (See .)
Adverse events during a second year of treatment with Leflunomide (Leflunomide) in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.
In addition, the following adverse events have been reported in 1% to
Other less common adverse events seen in clinical trials include: 1 case of anaphylactic reaction occurred in Phase 2 following rechallenge of drug after withdrawal due to rash (rare); urticaria; eosinophilia; transient thrombocytopenia (rare); and leukopenia
Adverse events during a second year of treatment with Leflunomide (Leflunomide) in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.
In post-marketing experience, the following have been reported rarely:
Leflunomide (Leflunomide) Drug Abuse And Dependence
Leflunomide (Leflunomide) has no known potential for abuse or dependence.
Leflunomide (Leflunomide) Overdosage
In mouse and rat acute toxicology studies, the minimally toxic dose for oral Leflunomide (Leflunomide) was 200 – 500 mg/kg and 100 mg/kg, respectively (approximately >350 times the maximum recommended human dose, respectively).
There have been reports of chronic overdose in patients taking Leflunomide (Leflunomide) at daily dose up to five times the recommended daily dose and reports of acute overdose in adults or children. There were no adverse events reported in the majority of case reports of overdose. Adverse events were consistent with the safety profile for Leflunomide (Leflunomide) (see ). The most frequent adverse events observed were diarrhea, abdominal pain, leukopenia, anemia and elevated liver function tests.
In the event of a significant overdose or toxicity, cholestyramine or charcoal administration is recommended to accelerate elimination (see ).
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1, the primary metabolite of Leflunomide (Leflunomide) , is not dialyzable. (See ).
Leflunomide (Leflunomide) Dosage And Administration
Due to the long half-life in patients with RA and recommended dosing interval (24 hours), a loading dose is needed to provide steady-state concentrations more rapidly. It is recommended that Leflunomide (Leflunomide) therapy be initiated with a loading dose of one 100 mg (ARAVA) tablet* per day for 3 days.
Elimination of the loading dose regimen may decrease the risk of adverse events. This could be especially important for patients at increased risk of hematologic or hepatic toxicity, such as those receiving concomitant treatment with methotrexate or other immunosuppressive agents or on such medications in the recent past. (See ).
Leflunomide (Leflunomide) How Supplied
Leflunomide (Leflunomide) tablets in 10 and 20 mg strengths are packaged in bottles.
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light.
*100 mg Leflunomide (Leflunomide) (ARAVA) tablets are available through sanofi-aventis U.S. LLC.
Revised February 2007
Manufactured by: sanofi-aventis U.S. LLCBridgewater, NJ 08807
10 and 20 mg tablets manufactured for: Prasco Laboratories Cincinnati, OH 45249
ARAVA is a registered trademark of sanofi-aventis U.S. LLC
