ARAVA® (leflunomide) is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.2 and the following structural formula:
ARAVA is available for oral administration as tablets containing 10, 20, or 100 mg of active drug. Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc, titanium dioxide, and yellow ferric oxide (20 mg tablet only).
Mechanism of Action
Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.
Following oral administration, leflunomide is metabolized to an active metabolite A77 1726 (hereafter referred to as M1) which is responsible for essentially all of its activity in vivo. Plasma levels of leflunomide are occasionally seen, at very low levels. Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of this active metabolite.
Following oral administration, peak levels of the active metabolite, M1, occurred between 6 – 12 hours after dosing. Due to the very long half-life of M1 (~2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of M1. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that M1 plasma levels are dose proportional.
Table 1. Pharmacokinetic Parameters for M1 after Administration of Leflunomide at Doses of 5, 10, and 25 mg/day for 24 Weeks to Patients (n=54) with Rheumatoid Arthritis (Mean ± SD) (Study YU204)
|Maintenance (Loading) Dose|
|Parameter||5 mg (50 mg)||10 mg (100 mg)||25 mg (100 mg)|
|C24 (Day 1) (µg/mL)Concentration at 24 hours after loading dose||4.0 ± 0.6||8.4 ± 2.1||8.5 ± 2.2|
|C24 (ss) (µg/mL)Concentration at 24 hours after maintenance doses at steady state||8.8 ± 2.9||18 ± 9.6||63 ± 36|
|t1/2(DAYS)||15 ± 3||14 ± 5||18 ± 9|
Relative to an oral solution, ARAVA tablets are 80% bioavailable. Co-administration of leflunomide tablets with a high fat meal did not have a significant impact on M1 plasma levels.
M1 has a low volume of distribution (Vss = 0.13 L/kg) and is extensively bound (>99.3%) to albumin in healthy subjects. Protein binding has been shown to be linear at therapeutic concentrations. The free fraction of M1 is slightly higher in patients with rheumatoid arthritis and approximately doubled in patients with chronic renal failure; the mechanism and significance of these increases are unknown.
Leflunomide is metabolized to one primary (M1) and many minor metabolites. Of these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, occurring at low levels in the plasma of some patients. The parent compound is rarely detectable in plasma. At the present time the specific site of leflunomide metabolism is unknown. In vivo and in vitro studies suggest a role for both the GI wall and the liver in drug metabolism. No specific enzyme has been identified as the primary route of metabolism for leflunomide; however, hepatic cytosolic and microsomal cellular fractions have been identified as sites of drug metabolism.
The active metabolite M1 is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. Subsequent analysis of the samples revealed the primary urinary metabolites to be leflunomide glucuronides and an oxanilic acid derivative of M1. The primary fecal metabolite was M1. Of these two routes of elimination, renal elimination is more significant over the first 96 hours after which fecal elimination begins to predominate. In a study involving the intravenous administration of M1, the clearance was estimated to be 31 mL/hr.
In small studies using activated charcoal (n=1) or cholestyramine (n=3) to facilitate drug elimination, the in vivo plasma half-life of M1 was reduced from >1 week to approximately 1 day. (See PRECAUTIONS - General - Need for Drug Elimination). Similar reductions in plasma half-life were observed for a series of volunteers (n=96) enrolled in pharmacokinetic trials who were given cholestyramine. This suggests that biliary recycling is a major contributor to the long elimination half-life of M1. Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1 is not dialyzable.
Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of M1.
Age has been shown to cause a change in the in vivo pharmacokinetics of M1 (see CLINICAL PHARMACOLOGY – Special Populations - Pediatrics).
A population based pharmacokinetic analysis of the phase III data indicates that smokers have a 38% increase in clearance over non-smokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.
Chronic Renal Insufficiency
In single dose studies in patients (n=6) with chronic renal insufficiency requiring either chronic ambulatory peritoneal dialysis (CAPD) or hemodialysis, neither had a significant impact on circulating levels of M1. The free fraction of M1 was almost doubled, but the mechanism of this increase is not known. In light of the fact that the kidney plays a role in drug elimination and without adequate studies of leflunomide use in subjects with renal insufficiency, caution should be used when ARAVA is administered to these patients.
Studies of the effect of hepatic insufficiency on M1 pharmacokinetics have not been done. Given the need to metabolize leflunomide into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of leflunomide in patients with hepatic insufficiency is not recommended.
The pharmacokinetics of M1 following oral administration of leflunomide have been investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA) who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these trials have demonstrated that pediatric patients with body weights ≤40 kg have a reduced clearance of M1 (see Table 2) relative to adult rheumatoid arthritis patients.
Table 2: Population Pharmacokinetic Estimate of M1 Clearance Following Oral Administration of Leflunomide in Pediatric Patients with Polyarticular Course JRA Mean ±SD [Range]
|N||Body Weight (kg)||CL (mL/h)|
|10||<20||18 ± 9.8 [6.8–37]|
|30||20–40||18 ± 9.5 [4.2–43]|
|33||>40||26 ± 16 [9.7–93.6]|
In vivo drug interaction studies have demonstrated a lack of a significant drug interaction between leflunomide and tri-phasic oral contraceptives, and cimetidine.
In vitro studies of protein binding indicated that warfarin did not affect M1 protein binding. At the same time M1 was shown to cause increases ranging from 13 – 50% in the free fraction of diclofenac, ibuprofen and tolbutamide at concentrations in the clinical range. In vitro studies of drug metabolism indicate that M1 inhibits CYP 450 2C9, which is responsible for the metabolism of phenytoin, tolbutamide, warfarin and many NSAIDs. M1 has been shown to inhibit the formation of 4'-hydroxydiclofenac from diclofenac in vitro. The clinical significance of these findings with regard to phenytoin and tolbutamide is unknown; however, there was extensive concomitant use of NSAIDs in the clinical studies and no differential effect was observed. (See PRECAUTIONS – Drug Interactions).
Coadministration, in 30 patients, of ARAVA (100 mg/day × 2 days followed by 10 – 20 mg/day) with methotrexate (10 – 25 mg/week, with folate) demonstrated no pharmacokinetic interaction between the two drugs. However, co-administration increased risk of hepatotoxicity (see PRECAUTIONS – Drug Interactions – Hepatotoxic Drugs).
Following concomitant administration of a single dose of ARAVA to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when ARAVA was given alone. Because of the potential for ARAVA levels to continue to increase with multiple dosing, caution should be used if patients are to receive both ARAVA and rifampin.
The efficacy of ARAVA in the treatment of rheumatoid arthritis (RA) was demonstrated in three controlled trials showing reduction in signs and symptoms, and inhibition of structural damage. In two placebo controlled trials, efficacy was demonstrated for improvement in physical function.
1. Reduction of signs and symptoms
Relief of signs and symptoms was assessed using the American College of Rheumatology (ACR)20 Responder Index, a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An "ACR20 Responder" is a patient who had ≥ 20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure [Modified Health Assessment Questionnaire (MHAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. An "ACR20 Responder at Endpoint" is a patient who completed the study and was an ACR20 Responder at the completion of the study.
2. Inhibition of structural damage
Inhibition of structural damage compared to control was assessed using the Sharp Score (Sharp, JT. Scoring Radiographic Abnormalities in Rheumatoid Arthritis, Radiologic Clinics of North America, 1996; vol. 34, pp. 233–241), a composite score of X-ray erosions and joint space narrowing in hands/wrists and forefeet.
3. Improvement in physical function
Improvement in physical function was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36).
In all Arava monotherapy studies, an initial loading dose of 100 mg per day for three days only was used followed by 20 mg per day thereafter.
US301 Clinical Trial in Adults
Study US301, a 2 year study, randomized 482 patients with active RA of at least 6 months duration to leflunomide 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg BID. Primary analysis was at 52 weeks with blinded treatment to 104 weeks.
Overall, 235 of the 508 randomized treated patients (482 in primary data analysis and an additional 26 patients), continued into a second 12 months of double-blind treatment (98 leflunomide, 101 methotrexate, 36 placebo). Leflunomide dose continued at 20 mg/day and the methotrexate dose could be increased to a maximum of 20 mg/week. In total, 190 patients (83 leflunomide, 80 methotrexate, 27 placebo) completed 2 years of double-blind treatment.
The rate and reason for withdrawal is summarized in Table 3.
Table 3: Withdrawals in US301
|Withdrawals in Year-1|
| Lack of efficacy||33 (17.4)||70 (54.7)||50 (26.3)|
| Safety||44 (23.2)||12 (9.4)||22 (11.6)|
|| 15 (7.9) || 10 (7.8) || 17 (9.0) |
| Total||92 (48.4)||92 (71.9)||89 (46.8)|
| Patients entering Year 2||98||36||101|
|Withdrawals in Year-2|
| Lack of efficacy||4 (4.1)||1 (2.8)||4 (4.0)|
| Safety||8 (8.2)||0 (0.0)||10 (9.9)|
| Other|| 3 (3.1) || 8 (22.2) || 7 (6.9) |
| Total||15 (15.3)||9 (25.0)||21 (20.8)|
MN301/303/305 Clinical Trial in Adults
Study MN301 randomized 358 patients with active RA to leflunomide 20 mg/day (n=133), sulfasalazine 2.0 g/day (n=133), or placebo (n=92). Treatment duration was 24 weeks. An extension of the study was an optional 6-month blinded continuation of MN301 without the placebo arm, resulting in a 12-month comparison of leflunomide and sulfasalazine (study MN303).
Of the 168 patients who completed 12 months of treatment in MN301 and MN303, 146 patients (87%) entered a 1-year extension study of double blind active treatment (MN305; 60 leflunomide, 60 sulfasalazine, 26 placebo/sulfasalazine). Patients continued on the same daily dosage of leflunomide or sulfasalazine that they had been taking at the completion of MN301/303. A total of 121 patients (53 leflunomide, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment.
Patient withdrawal data in MN301/303/305 is summarized in Table 4.
Table 4: Withdrawals in study MN301/303/305
|Withdrawals in MN301 (Mo 0–6)|
| Lack of efficacy||10 (7.5)||29 (31.5)||14 (10.5)|
| Safety||19 (14.3)||6 (6.5)||25 (18.8)|
|| 8 (6.0) || 6 (6.5) || 11 (8.3) |
| Total||37 (27.8)||41 (44.6)||50 (37.6)|
| Patients entering MN303||80||76|
|Withdrawals in MN303 (Mo 7–12)|
| Lack of efficacy||4 (5.0)||2 (2.6)|
| Safety||2 (2.5)||5 (6.6)|
| Other|| 3 (3.8) || 1 (1.3) |
| Total||9 (11.3)||8 (10.5)|
| Patients entering MN305||60||60|
|Withdrawals in MN305 (Mo 13–24)|
| Lack of efficacy||0 (0.0)||3 (5.0)|
| Safety||6 (10.0)||8 (13.3)|
| Other|| 1 (1.7) || 2 (3.3) |
| Total||7 (11.7)||13 (21.7)|
MN302/304 Clinical Trial in Adults
Study MN302 randomized 999 patients with active RA to leflunomide 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was used in 10% of patients. Treatment duration was 52 weeks.
Of the 736 patients who completed 52 weeks of treatment in study MN302, 612 (83%) entered the double-blind, 1-year extension study MN304 (292 leflunomide, 320 methotrexate). Patients continued on the same daily dosage of leflunomide or methotrexate that they had been taking at the completion of MN302. There were 533 patients (256 leflunomide, 277 methotrexate) who completed 2 years of double-blind treatment.
Patient withdrawal data in MN302/304 is summarized in Table 5.
Table 5: Withdrawals in MN302/304
|Withdrawals in MN302 (Year-1)|
| Lack of efficacy||37 (7.4)||15 (3.0)|
| Safety||98 (19.6)||79 (15.9)|
|| 17 (3.4) || 17 (3.4) |
| Total||152 (30.3)||111 (22.3)|
| Patients entering MN304||292||320|
|Withdrawals in MN304 (Year-2)|
| Lack of efficacy||13 (4.5)||9 (2.8)|
| Safety||11 (3.8)||22 (6.9)|
| Other|| 12 (4.1) || 12 (3.8) |
| Total||36 (12.3)||43 (13.4)|
Clinical Trial Data
1. Signs and symptoms Rheumatoid Arthritis
The ACR20 Responder at Endpoint rates are shown in Figure 1. ARAVA was statistically significantly superior to placebo in reducing the signs and symptoms of RA by the primary efficacy analysis, ACR20 Responder at Endpoint, in study US301 (at the primary 12 months endpoint) and MN301 (at 6 month endpoint). ACR20 Responder at Endpoint rates with ARAVA treatment were consistent across the 6 and 12 month studies (41 – 49%). No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine. ARAVA treatment effect was evident by 1 month, stabilized by 3 – 6 months, and continued throughout the course of treatment as shown in Figure 2.
|Comparisons||95%Confidence Interval||p Value|
|US301||Leflunomide vs. Placebo||(12, 32)||<0.0001|
|Methotrexate vs. Placebo||(8, 30)||<0.0001|
|Leflunomide vs. Methotrexate||(-4, 16)||NS|
|MN301||Leflunomide vs. Placebo||(7, 33)||0.0026|
|Sulfasalazine vs. Placebo||(4, 29)||0.0121|
|Leflunomide vs. Sulfasalazine||(-8, 16)||NS|
|MN302||Leflunomide vs. Methotrexate||(-19, -7)||<0.0001|
|Comparisons||95%Confidence Interval||p Value|
|US301||Leflunomide vs. Placebo||(-0.58, -0.29)||0.0001|
|Leflunomide vs. Methotrexate||(-0.34, -0.07)||0.0026|
|MN301||Leflunomide vs. Placebo||(-0.67, -0.36)||<0.0001|
|Leflunomide vs. Sulfasalazine||(-0.33, -0.03)||0.0163|
|MN302||Leflunomide vs. Methotrexate||(0.01, 0.16)||0.0221|
Maintenance of effect
The improvement in physical function demonstrated at 6 and 12 months was maintained over two years. In those patients continuing therapy for a second year, this improvement in physical function as measured by HAQ and SF-36 (PCS) was maintained.
Clinical Trials in Pediatrics
ARAVA was studied in a single multicenter, double-blind, active-controlled trial in 94 patients (1:1 randomization) with polyarticular course juvenile rheumatoid arthritis (JRA) as defined by the American College of Rheumatology (ACR). Approximately 68% of pediatric patients receiving ARAVA, versus 89% of pediatric patients receiving the active comparator, improved by Week 16 (end-of-study) employing the JRA Definition of Improvement (DOI) ≥ 30 % responder endpoint. In this trial, the loading dose and maintenance dose of ARAVA was based on three weight categories: <20 kg, 20–40kg, and >40 kg. The response rate to ARAVA in pediatric patients ≤40 kg was less robust than in pediatric patients >40 kg suggesting suboptimal dosing in smaller weight pediatric patients, as studied, resulting in less than efficacious plasma concentrations, despite reduced clearance of M1. (See Pharmacokinetics - Pediatrics).