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boxed warning
WARNING: EMBRYO-FETAL TOXICITY and HEPATOTOXICITY Embryo-Fetal Toxicity Leflunomide is contraindicated for use in pregnant women because of the potential for fetal harm. Teratogenicity and embryo-lethality occurred in animals administered leflunomide at doses lower than the human exposure level. Exclude pregnancy before the start of treatment with leflunomide in females of reproductive potential. Advise females of reproductive potential to use effective contraception during leflunomide treatment and during an accelerated drug elimination procedure after leflunomide treatment. Stop leflunomide tablets and use an accelerated drug elimination procedure if the patient becomes pregnant [see Contraindications(4) , Warnings and Precautions( 5.1 , 5.3 ), Use in Speciafic Populations( 8.1 , 8.3 ), and Clinical Pharmacology(12.3) ]. Hepatotoxicity Severe liver injury, including fatal liver failure, has been reported in patients treated with leflunomide. Leflunomide is contraindicated in patients with severe hepatic impairment. Concomitant use of leflunomide with other potentially hepatotoxic drugs may increase the risk of liver injury. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2 x ULN before initiating treatment, are at increased risk and should not be treated with leflunomide. Monitor ALT levels at least monthly for six months after starting leflunomide, and thereafter every 6 to 8 weeks. If leflunomide-induced liver injury is suspected, stop leflunomide treatment, start an accelerated drug elimination procedure, and monitor liver tests weekly until normalized [see Contraindications(4) , Warnings and Precautions( 5.2 , 5.3 ), Use in Specific Populations(8.6 )]. WARNING: EMBRYO-FETAL TOXICITY and HEPATOTOXICITY See full prescribing information for complete boxed warning. Embryo-Fetal Toxicity Teratogenicity and embryo-lethality occurred in animals administered leflunomide. ( 5.1 , 8.1 ) Exclude pregnancy prior to initiating leflunomide tablets therapy. ( 5.1 , 8.3 ) Advise use of effective contraception in females of reproductive potential during treatment and during a drug elimination procedure. ( 5.1 , 5.3 , 8.3 ) Stop leflunomide tablets and use an accelerated drug elimination procedure if the patient becomes pregnant. ( 5.1 , 5.3 , 8.1 ) Hepatotoxicity Severe liver injury and fatal liver failu...
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warnings and cautions
5 WARNINGS AND PRECAUTIONS After stopping leflunomide, it is recommended that an accelerated drug elimination procedure be used to reduce the plasma concentrations of the active metabolite, teriflunomide. (5.3) Severe infections (including sepsis), pancytopenia, agranulocytosis, and thrombocytopenia: Stop leflunomide and use accelerated elimination procedure. Do not start leflunomide in patients with active infection. Monitor CBCs during treatment with leflunomide. (5.4) Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS): Stop leflunomide and use accelerated elimination procedure. (5.5) Skin ulcers: If skin ulcer is suspected, discontinue leflunomide treatment and consider an accelerated drug elimination procedure. (5.6) Peripheral neuropathy: If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing leflunomide. (5.8) Interstitial lung disease: May be fatal. New onset or worsening symptoms may necessitate discontinuation of leflunomide and initiation of accelerated elimination procedure. (5.9) Increased blood pressure: Monitor and treat. (5.11) 5.1 Embryo-Fetal Toxicity Leflunomide may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryo-lethality occurred in animal reproduction studies with leflunomide at doses lower than the human exposure level [see Use in Specific Populations (8.1) ] . Leflunomide is contraindicated for use in pregnant women [see Contraindications (4) ] . Exclude pregnancy before starting treatment with leflunomide in females of reproductive potential [see Dosage and Administration (2.2) ] . Advise females of reproductive potential to use effective contraception during leflunomide treatment and during an accelerated drug elimination procedure after leflunomide treatment [see Use in Specific Populations (8.3) ]. If a woman becomes pregnant while taking leflunomide, stop treatment with leflunomide, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve nondetectable plasma concentrations of teriflunomide, the active metabolite of leflunomide [see Warnings and Precautions (5.3) ] . Upon discontinuing leflunomide, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Wo...
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adverse reactions
6 ADVERSE REACTIONS Hepatotoxicity [see Warnings and Precautions (5.2)] Immunosuppression [see Warnings and Precautions (5.4)] Bone marrow suppression [see Warnings and Precautions (5.4)] Serious infections [see Warnings and Precautions (5.4)] Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reactions with eosinophilia and systemic symptoms [see Warnings and Precautions (5.5)] Skin ulcers [see Warnings and Precautions (5.6)] Peripheral neuropathy [see Warnings and Precautions (5.8)] Interstitial lung disease [see Warnings and Precautions (5.9)] The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, and dyspepsia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-800-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with leflunomide as either monotherapy or in combination with methotrexate or sulfasalazine. Patients ranged in age from 19 to 85 years, with an overall median age of 58 years. The mean duration of RA was 6 years ranging from 0 to 45 years. Elevation of Liver Enzymes Treatment with leflunomide 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 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial 1 and Trial 2. It was notable that the absence of folate use in Trial 3 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate. Table 1: Liver Enzyme Elevations >3-fold Upper Limits of Normal (ULN) in Patients with RA in Trials 1, 2, and 3* Trial 1 Trial 2 Trial 3* LEF PL MTX LEF PL SSZ LEF MTX 20 mg/day (n...