Arava
Generic: LEFLUNOMIDE
Basic Information
Manufacturer
sanofi-aventis U.S. LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
320f63f2-fac3-4aee-aff8-85724e00ef52
Indications & Usage
1 INDICATIONS AND USAGE ARAVA is indicated for the treatment of adults with active rheumatoid arthritis (RA).
ARAVA is a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis.
( 1 )
ARAVA is 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) ] 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 ARAVA treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, and dyspepsia.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S.
LLC at 1-800-633-1610 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 ARAVA 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 ARAVA 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 Only 10% of patients in Trial 3 received folate.
All patients in Trial 1 received folate.
Trial 1 Trial 2 Trial 3 ARAVA PL MTX ARAVA PL SSZ ARAVA MTX 20 mg/day (n=182) (n=118) 7.5–15 mg/wk (n=182) 20 mg/day (n=133) (n=92) 2 g/day (n=133) 20 mg/day (n=501) 7.5–15 mg/wk (n=498) MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal 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 0–3 Months 6 1 1 2 1 2 7 27 4–6 Months 1 1 3 - - - 1 34 7–9 Months 1 1 1 - - - - 16 10–12 Months - - - - - - 5 6 In a 6-month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, ARAVA 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 ARAVA-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 ARAVA treatment group).
Table 2: Percentage Of Patients With Adverse Events ≥5% In Any ARAVA 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 Only 10% of patients in Trial 3 received folate.
All patients in Trial 1 received folate; none in Trial 2 received folate.
ARAVA 20 mg/day (n=315) PL (n=210) SSZ 2 g/day (n=133) MTX 7.5–15 mg/wk (n=182) ARAVA 20 mg/day (n=501) MTX 7.5–15 mg/wk (n=498) ARAVA (n=1339) Includes all controlled and uncontrolled trials with ARAVA (duration up to 12 months).
MTX = methotrexate, PL = placebo, SSZ = sulfasalazine 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 Hypertension as a preexisting condition was overrepresented in all ARAVA treatment groups in phase III trials.
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% Adverse events during a second year of treatment with ARAVA 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 ARAVA 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 ARAVA.
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
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S.
LLC at 1-800-633-1610 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 ARAVA 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 ARAVA 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 Only 10% of patients in Trial 3 received folate.
All patients in Trial 1 received folate.
Trial 1 Trial 2 Trial 3 ARAVA PL MTX ARAVA PL SSZ ARAVA MTX 20 mg/day (n=182) (n=118) 7.5–15 mg/wk (n=182) 20 mg/day (n=133) (n=92) 2 g/day (n=133) 20 mg/day (n=501) 7.5–15 mg/wk (n=498) MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal 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 0–3 Months 6 1 1 2 1 2 7 27 4–6 Months 1 1 3 - - - 1 34 7–9 Months 1 1 1 - - - - 16 10–12 Months - - - - - - 5 6 In a 6-month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, ARAVA 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 ARAVA-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 ARAVA treatment group).
Table 2: Percentage Of Patients With Adverse Events ≥5% In Any ARAVA 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 Only 10% of patients in Trial 3 received folate.
All patients in Trial 1 received folate; none in Trial 2 received folate.
ARAVA 20 mg/day (n=315) PL (n=210) SSZ 2 g/day (n=133) MTX 7.5–15 mg/wk (n=182) ARAVA 20 mg/day (n=501) MTX 7.5–15 mg/wk (n=498) ARAVA (n=1339) Includes all controlled and uncontrolled trials with ARAVA (duration up to 12 months).
MTX = methotrexate, PL = placebo, SSZ = sulfasalazine 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 Hypertension as a preexisting condition was overrepresented in all ARAVA treatment groups in phase III trials.
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% Adverse events during a second year of treatment with ARAVA 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 ARAVA 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 ARAVA.
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