Leflunomide
Generic: LEFLUNOMIDE
Basic Information
Manufacturer
KVK-Tech, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
a48e6ef2-48ad-4fcf-9e67-dbba83ab0b79
Indications & Usage
1 INDICATIONS AND USAGE Leflunomide tablets are indicated for the treatment of adults with active rheumatoid arthritis (RA).
Leflunomide tablets are a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis.
(1)
Leflunomide tablets are a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis.
(1)
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) ] Stevens-Johnson syndrome and toxic epidermal necrolysis [ see Warnings and Precautions (5.5) ] Peripheral neuropathy [ see Warnings and Precautions (5.7) ] Interstitial lung disease [ see Warnings and Precautions (5.8) ] The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide tablets treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, dyspepsia.
(6.1) To report SUSPECTED ADVERSE REACTIONS, contact KVK-Tech, Inc.
at 1-215-579-1842 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 were 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.
In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide tablets were 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).
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; table1 table2 6.2 Post Marketing Experience The following additional adverse reactions have been identified during post approval 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, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis, skin ulcer
(6.1) To report SUSPECTED ADVERSE REACTIONS, contact KVK-Tech, Inc.
at 1-215-579-1842 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 were 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.
In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide tablets were 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).
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; table1 table2 6.2 Post Marketing Experience The following additional adverse reactions have been identified during post approval 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, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis, skin ulcer