LEFLUNOMIDE 20MG 30 TAB
Generic: Leflunomide
LEFLUNOMIDE 20MG 30 TAB
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Identification
Leflunomide
Leflunomide
Lupin Pharmaceuticals, Inc.
HUMAN PRESCRIPTION DRUG
Administration
TABLET, FILM COATED
ORAL
ANDA211863
Active Ingredients
| Ingredient | Strength |
|---|---|
| LEFLUNOMIDE | 20 mg/1 |
Pharmacological Class
Data sourced from openFDA / DailyMed. For full prescribing information, consult the drug label.
Wholesale compliance resources
Drug Resources
Clinical Drug Information
Indications & Usage
1 INDICATIONS AND USAGE Leflunomide is a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis. ( 1 ) Leflunomide tablets USP are indicated for the treatment of adults with active rheumatoid arthritis (RA).
Dosage & Administration
2 DOSAGE AND ADMINISTRATION Loading dosage for patients at low risk for leflunomide tablets -associated hepatotoxicity and leflunomide tablets-associated myelosuppression: 100 mg daily for 3 days. ( 2.1 ) Maintenance dosage: 20 mg daily. ( 2.1 ) Maximum recommended daily dosage: 20 mg once daily. ( 2.1 ) If 20 mg once daily is not tolerated, may decrease dosage to 10 mg once daily. ( 2.1 ) Screen patients for active and latent tuberculosis, pregnancy test (females), blood pressure, and laboratory tests before starting leflunomide tablets. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of leflunomide tablets is 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient's risk of leflunomide tablets -associated hepatotoxicity and leflunomide tablets -associated myelosuppression. The loading dose provides steady-state concentrations more rapidly. For patients who are at low risk for leflunomide tablets -associated hepatotoxicity and leflunomide tablets - associated myelosuppression, the recommended leflunomide tablets loading dose is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily. For patients at high risk for leflunomide tablets - associated hepatotoxicity (e.g., those taking concomitant methotrexate) or leflunomide tablets -associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended leflunomide tablets dosage is 20 mg once daily without a loading dose [see Warnings and Precautions ( 5.2 , 5.4 )]. The maximum recommended daily dose is 20 mg once per day. Consider dosage reduction to 10 mg once daily for patients who are not able to tolerate 20 mg daily (i.e., for patients who experience any adverse events listed in Table 1). Monitor patients carefully after dosage reduction and after stopping therapy with leflunomide tablets, since the active metabolite of leflunomide, teriflunomide, is slowly eliminated from the plasma [ see Clinical Pharmacology ( 12.3 ) ]. After stopping leflunomide tablets treatment, an accelerated drug elimination procedure is recommended to reduce the plasma concentrations of the active metabolite, teriflunomide [see Warnings and Precautions ( 5.3 )]. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach undetectable plasma teriflunomide concentrations after stopping leflunomide tablets [see Clinical Pharmacology ( 12.3 )]. 2.2 Evaluation and Testing Prior to Starting leflunomide tablets Prior to starting leflunomide tablets treatment, the following evaluations and tests are recommended: Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection [see Warnings and Precautions ( 5.4 )] Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts [see Warnings and Precautions ( 5.2 , 5.4 )] For females of reproductive potential, pregnancy testing [see Warnings and Precautions ( 5.1 )] Check blood pressure [see Warnings and Precautions ( 5.11 )]
Adverse Reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: 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 tablets treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, and dyspepsia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceutical, Inc. at 1-800-399-2561 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 tablets administered 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 tablets 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 * Leflunomide tablets 20mg/day (n=182) PL (n=118) MTX 7.5 to 15 mg/wk (n=182) Leflunomide tablets 20mg/day (n=133) PL (n=92) SSZ 2 mg/day (n=133) Leflunomide tablets 20mg/day (n=501) MTX 7.5 to 15 mg/wk (n=498) ALT (SGPT) >3-fold ULN (n %) 8 (4.4) 3 (2.5) 5 (2.7) 2 (1.5) 1 (1.1) 2 (1.5) 13 (2.6) 83 (16.7) Reversed to ≤ 2-fold ULN: 8 3 5 2 1 2 12 82 Timing of Elevation 0 to 3 Months 6 1 1 2 1 2 7 27 4 to 6 Months 1 1 3 - - - 1 34 7 to 9 Months 1 1 1 - - - - 16 10 to 12 Months - - - - - - 5 6 MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal *Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate. In a 6-month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide tablets was administered 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. Most Common Adverse Reactions The most common adverse reactions in leflunomide tablets -treated patients with RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. Table 2 displays the most common adverse reactions in the controlled studies in patients with RA at one year ( ≥ 5% in any leflunomide tablets treatment group). Table 2. Percentage Of Patients With Adverse Events ≥5% In Any Leflunomide tablets Treated Group in all RA Studies in Patients with RA Placebo-Controlled Trials Active-Controlled Trials All RA Studies Trial 1 and 2 Trial 3 * Leflunomide tablets 20mg/day (n=315) PL (n=210) SSZ 2 g/day (n=133) MTX 7.5-15 mg/wk (n=182) Leflunomide tablets 20mg/day (n=501) MTX 7.5-15 mg/wk (n=498) Leflunomide tablets (n=1339) † Diarrhea 27% 12% 10% 20% 22% 10% 17% Headache 13% 11% 12% 21% 10% 8% 7% Nausea 13% 11% 19% 18% 13% 18% 9% Rash 12% 7% 11% 9% 11% 10% 10% Abnormal Liver Enzymes 10% 2% 4% 10% 6% 17% 5% Alopecia 9% 1% 6% 6% 17% 10% 10% Hypertension † 9% 4% 4% 3% 10% 4% 10% Asthenia 6% 4% 5% 6% 3% 3% 3% Back Pain 6% 3% 4% 9% 8% 7% 5% GI/Abdominal Pain 6% 4% 7% 8% 8% 8% 5% Abdominal Pain 5% 4% 4% 8% 6% 4% 6% Allergic Reaction 5% 2% 0% 6% 1% 2% 2% Bronchitis 5% 2% 4% 7% 8% 7% 7% Dizziness 5% 3% 6% 5% 7% 6% 4% Mouth Ulcer 5% 4% 3% 10% 3% 6% 3% Pruritus 5% 2% 3% 2% 6% 2% 4% Rhinitis 5% 2% 4% 3% 2% 2% 2% Vomiting 5% 4% 4% 3% 3% 3% 3% Tenosynovitis 2% 0% 1% 2% 5% 1% 3% MTX = methotrexate, PL = placebo, SSZ = sulfasalazine * Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate; none in Trial 2 received folate. † Includes all controlled and uncontrolled trials with leflunomide tablets (duration up to 12 months). ‡ Hypertension as a preexisting condition was overrepresented in all leflunomide tablets treatment groups in phase III trials Adverse events during a second year of treatment with leflunomide tablets in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence. Less Common Adverse Reactions In addition, in controlled clinical trials, the following adverse events in the leflunomide tablets treatment group occurred at a higher incidence than in the placebo group. These adverse events were deemed possibly related to the study drug. Blood and Lymphatic System : leukocytosis, thrombocytopenia Cardiovascular: chest pain, palpitation, thrombophlebitis of the leg, varicose vein Eye: blurred vision, eye disorder, papilledema, retinal disorder, retinal hemorrhage Gastrointestinal: alkaline phosphatase increased, anorexia, bilirubinemia, flatulence, gamma-GT increased, salivary gland enlarged, sore throat, vomiting, dry mouth General Disorders: malaise Immune System : anaphylactic reaction Infection : abscess, flu syndrome, vaginal moniliasis Nervous System: dizziness, headache, somnolence Respiratory System : dyspnea 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of leflunomide tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System: agranulocytosis, leukopenia, neutropenia, pancytopenia Infection: opportunistic infections, severe infections including sepsis Gastrointestinal: acute hepatic necrosis, colitis, including microscopic colitis, hepatitis, jaundice/cholestasis, pancreatitis; severe liver injury such as hepatic failure Immune System: angioedema Nervous system: peripheral neuropathy Respiratory : interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal, pulmonary hypertension Skin and Appendages: erythema multiforme, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis.
Information for Patients
17 PATIENT COUNSELING INFORMATION Embryo-Fetal Toxicity Advise females of reproductive potential: Of the potential for fetal harm if leflunomide tablets are taken during pregnancy. To notify their healthcare provider immediately if a pregnancy occurs or is suspected. To use effective contraception during treatment with leflunomide tablets and until the active metabolite (teriflunomide) plasma concentration is verified to be less than 0.02 mg/L [see Warnings and Precautions ( 5.1 , 5.3 ), Use in Specific Populations ( 8.1 , 8.3 ), and Clinical Pharmacology ( 12.3 )]. Serious Skin Reactions Advise patients of the possibility of rare, serious skin reactions. Instruct patients to promptly seek medical attention if they develop a skin rash, mucous membrane lesions, or skin ulcers. Lactation Advise nursing women to discontinue breastfeeding during treatment with leflunomide tablets [see Use in Specific Populations ( 8.2 )]. Investigations Advise patients of the potential hepatotoxic effects of leflunomide tablets and of the need for monitoring liver enzymes. Instruct patients to report if they develop symptoms such as unusual tiredness, abdominal pain or jaundice. Advise patients 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 tablets, who have recently discontinued such therapy before starting treatment with leflunomide tablets, or who have had a history of a significant hematologic abnormality. Instruct patients to promptly report if they notice symptoms consistent with pancytopenia, such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness. Inform patients about the early warning signs of interstitial lung disease and ask them to contact their physician promptly if these symptoms appear or worsen during therapy.
Clinical data sourced from openFDA drug labeling. For complete prescribing information, consult the full drug label.