Leflunomide

After completing 12 months of treatment, patients continuing on study treatment were  evaluated for an additional 12 months of double-blind treatment (total treatment period of 2 years) in studies US301, MN305, and MN304. ACR Responder rates at 12 months were maintained over 2 years in most patients continuing a second year of treatment.

3. Inhibition of structural damage

4. Improvement in physical function

LEFLUNOMIDE INDICATIONS AND USAGE

LEFLUNOMIDE CONTRAINDICATIONS

WARNINGS

Hepatotoxicity

Immunosuppression Potential / Bone Marrow Suppression

Skin Reactions

Peripheral Neuropathy

Cases of peripheral neuropathy have been reported in patients receiving leflunomide. Most patients recovered after discontinuation of leflunomide, but some patients had persistent symptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking leflunomide develops a peripheral neuropathy, consider discontinuing leflunomide therapy and performing the drug elimination procedure (see WARNINGS – Drug Elimination Procedure).

Drug Elimination Procedure

The following drug elimination procedure is recommended to achieve non-detectable plasma levels (less than 0.02 mg/L or 0.02 mcg/mL) after stopping treatment with leflunomide:

1)      Administer cholestyramine 8 grams 3 times daily for 11 days. (The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly.)

2)      Verify plasma levels less than 0.02 mg/L (0.02 mcg/mL) by two separate tests at least 14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered.

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.

PRECAUTIONS

General

Information for Patients

• The potential for increased risk of birth defects should be discussed with female patients of childbearing potential. It is recommended that physicians advise women that they may be at increased risk of having a child with birth defects if they are pregnant when taking leflunomide, become pregnant while taking leflunomide, or do not wait to become pregnant until they have stopped taking leflunomide and followed the drug elimination procedure (as described in WARNINGS – Use In Women of Childbearing Potential – Drug Elimination Procedure).
• Patients should be advised of the possibility of rare, serious skin reactions. Patients should be instructed to inform their physicians promptly if they develop a skin rash or mucous membrane lesions.
• Patients should be advised of the potential hepatotoxic effects of leflunomide and of the need for monitoring liver enzymes. Patients should be instructed to notify their physicians if they develop symptoms such as unusual tiredness, abdominal pain or jaundice.
• Patients should be advised that they may develop a lowering of their blood counts and should have frequent hematologic monitoring. This is particularly important for patients who are receiving other immunosuppressive therapy concurrently with leflunomide, who have recently discontinued such therapy before starting treatment with leflunomide, or who have had a history of a significant hematologic abnormality. Patients should be instructed to notify their physicians promptly if they notice symptoms of pancytopenia (such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness).
• Patients should be informed about the early warning signs of interstitial lung disease and asked to contact their physician as soon as possible if these symptoms appear or worsen during therapy.

Laboratory Tests

At minimum, ALT (SGPT) must be performed at baseline and at least monthly for six months after starting leflunomide, and thereafter every 6 to 8 weeks. In addition, if leflunomide and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing every month. (See WARNINGS – Hepatotoxicity.)

Drug Interactions

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of 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 is not known.

Leflunomide was not mutagenic in the Ames Assay, the Unscheduled DNA Synthesis Assay, or in the HGPRT Gene Mutation Assay. In addition, leflunomide was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. However, 4- trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames Assay and in the HGPRT Gene Mutation Assay, and was clastogenic in the in vitro Assay for Chromosome Aberrations in the Chinese Hamster Cells. TFMA was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. Leflunomide had no effect on fertility in either male or female rats at oral doses up to 4 mg/kg (approximately 1/30 the human M1 exposure based on AUC).

Pregnancy

Nursing Mothers

Leflunomide should not be used by nursing mothers. It is not known whether leflunomide is excreted in human milk. Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide. Therefore, a decision should be made whether to proceed with nursing or to initiate treatment with leflunomide, taking into account the importance of the drug to the mother.

Use in Males

Available information does not suggest that leflunomide would be associated with an increased risk of male-mediated fetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. To minimize any possible risk, men wishing to father a child should consider discontinuing use of leflunomide and taking cholestyramine 8 grams 3 times daily for 11 days.

Pediatric Use

The safety and effectiveness of leflunomide in pediatric patients with polyarticular course juvenile rheumatoid arthritis (JRA) have not been fully evaluated (See CLINICAL STUDIES and ADVERSE REACTIONS).

Geriatric Use

Of the total number of subjects in controlled clinical (Phase III) studies of leflunomide, 234 subjects were 65 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is needed in patients over 65.

LEFLUNOMIDE ADVERSE REACTIONS

Cardiovascular: angina pectoris, migraine, palpitation, tachycardia, varicose vein, vasculitis,  vasodilatation;

Gastrointestinal: cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder;

Endocrine: diabetes mellitus, hyperthyroidism;

Hemic and Lymphatic System: anemia (including iron deficiency anemia), ecchymosis;

Metabolic and Nutritional: creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema;

Musculo-Skeletal System: arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture;

Nervous System: anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating increased, vertigo;

Respiratory System: asthma, dyspnea, epistaxis, lung disorder;

Skin and Appendages: acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, maculopapular rash, nail disorder, skin discoloration, skin disorder, skin nodule, subcutaneous nodule, ulcer skin;

Special Senses: blurred vision, cataract, conjunctivitis, eye disorder, taste perversion;

Urogenital System: albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis.

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 <2000 WBC/mm³ (rare).

Adverse events during a second year of treatment with 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:

Body as a whole: opportunistic infections, severe infections including sepsis that may be fatal;

Gastrointestinal: pancreatitis;

Hematologic: agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia;

DRUG ABUSE AND DEPENDENCE

OVERDOSAGE

LEFLUNOMIDE DOSAGE AND ADMINISTRATION

HOW SUPPLIED

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL