20 . March , 2019 - Wednesday
Check todays hot topics or new products

Find a Drug: Advanced

Please Sign in or Register

All about: Leflunomide

Big Image Dosage Form: Tablets

CONTRAINDICATIONS AND WARNINGS

PREGNANCY MUST BE EXCLUDED BEFORE THE START OF TREATMENT WITH Leflunomide TABLETS. Leflunomide TABLETS ARE CONTRAINDICATED IN PREGNANT WOMEN, OR WOMEN OF CHILDBEARING POTENTIAL WHO ARE NOT USING RELIABLE CONTRACEPTION. (SEE CONTRAINDICATIONS AND WARNINGS.) PREGNANCY MUST BE AVOIDED DURING Leflunomide TABLET TREATMENT OR PRIOR TO THE COMPLETION OF THE DRUG ELIMINATION PROCEDURE AFTER Leflunomide TABLET TREATMENT.

Leflunomide Description

Leflunomide is a pyrimidine synthesis inhibitor. The chemical name for Leflunomide is N-(4’-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has a molecular formula C12H9F3N2O2, a molecular weight of 270.2 and the following structural formula:

Leflunomide is available for oral administration as tablets containing 10 or 20 mg of active drug. Combined with Leflunomide are the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, pregelatinized starch, and talc.

Leflunomide - Clinical Pharmacology

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.

Pharmacokinetics

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

Absorption

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)

1 Concentration at 24 hours after loading dose

2 Concentration at 24 hours after maintenance doses at steady state

*
1
2
Maintenance (Loading) Dose
Parameter 5 mg (50 mg) 10 mg (100 mg) 25 mg (100 mg)
C24 (Day 1) (µg/mL)* 4.0 ± 0.6 8.4 ± 2.1 8.5 ± 2.2
C24 (ss) (µg/mL) 8.8 ± 2.9 18 ± 9.6 63 ± 36
t1/2(DAYS) 15 ± 3 14 ± 5 18 ± 9

Relative to an oral solution, Leflunomide tablets are 80% bioavailable. Co-administration of Leflunomide tablets with a high fat meal did not have a significant impact on M1 plasma levels.

Distribution

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.

Metabolism

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.

Elimination

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.

Special Populations

Gender

Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of M1.

Age

Pharmacokinetic information for pediatric patients is approved for Aventis Pharmaceuticals’ Leflunomide tablets. However, due to Aventis Pharmaceuticals’ marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Smoking

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 Leflunomide tablet is administered to these patients.

Hepatic Insufficiency

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.

Pediatrics

Pharmacokinetic information for pediatric patients is approved for Aventis Pharmaceuticals’ Leflunomide tablets. However, due to Aventis Pharmaceuticals’ marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Drug Interactions

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).

Methotrexate

Coadministration, in 30 patients, of Leflunomide (100 mg/day x 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).

Rifampin

Following concomitant administration of a single dose of Leflunomide to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when Leflunomide was given alone. Because of the potential for Leflunomide levels to continue to increase with multiple dosing, caution should be used if patients are to receive both Leflunomide and rifampin.

Clinical Studies

A. ADULTS

The efficacy of Leflunomide in the treatment of rheumatoid arthritis (RA) was demonstrated in three controlled trials showing reduction in signs and symptoms and inhibition of structural damage.

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.

In all Leflunomide 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 2.

Table 2: Withdrawals in US301

1Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion.

*
1
n(%) patients
Leflunomide Placebo Methotrexate
190 128 190
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)
Other1 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 3.

Table 3: Withdrawals in study MN301/303/305

1 Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion.

*
1
n(%) patients
Leflunomide Placebo Sulfasalazine
133 92 133
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)
Other1 8 (6.0) 6 (6.5) 11 (8.3)
Total 32 (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)
Other1 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 4.

Table 4: Withdrawals in MN302/304

1 Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion.

*
1
n(%) patients
Leflunomide Methotrexate
501 498
Withdrawals in MN302 (Year-1)
Lack of efficacy 37 (7.4) 15 (3.0)
Safety 98 (19.6) 79 (15.9)
Other1 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. Leflunomide 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 Leflunomide 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. Leflunomide treatment effect was evident by 1 month, stabilized by 3 - 6 months, and continued throughout the course of treatment as shown in Figure 2.

Figure 1

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

Figure 2

ACR50 and ACR70 Responders are defined in an analogous manner to the ACR20 Responder, but use improvements of 50% or 70%, respectively (Table 5). Mean change for the individual components of the ACR Responder Index are shown in Table 6.

Table 5. Summary of ACR Response Rates*

* Intent to treat (ITT) analysis using last observation carried forward (LOCF) technique for patients who discontinued early.

N is the number of ITT patients for whom adequate data were available to calculate the indicated rates.

p<0.001 Leflunomide vs placebo

§ p<0.02 Leflunomide vs placebo

*
*
§
#
Þ
ß
à
è
ð
§
ø
ý
£
¥
Study and Treatment Group ACR20 ACR50 ACR70
Placebo-Controlled Studies
US301 (12 months)
Leflunomide (n=178) 52.2 34.3§ 20.2
Placebo (n=118)# 26.3 7.6 4.2
Methotrexate (n=180)Þ 45.6 22.8 9.4
MN301 (6 months)
Leflunomide (n=130)ß 54.6à 33.1è 10.0ð
Placebo (n=91)ø 28.6 14.3 2.2
Sulfasalazine (n=132)ý 56.8 30.3 7.6
Non-Placebo Active-Controlled Studies
MN302 (12 months)
Leflunomide (n=495)£ 51.1 31.1 9.9
Methotrexate (n=489)¥ 65.2 43.8 16.4

Table 6 shows the results of the components of the ACR response criteria for US301, MN301, and MN302. Leflunomide was significantly superior to placebo in all components of the ACR response criteria in study US301 and MN301. In addition, Leflunomide was significantly superior to placebo in improving morning stiffness, a measure of RA disease activity, not included in the ACR Response criteria. No consistent differences were demonstrated between Leflunomide and the active comparators.

Table 6. Mean Change in the Components of the ACR Responder Index*

* Last Observation Carried Forward; Negative Change Indicates Improvement

1 Based on 28 joint count

2 Visual Analog Scale – 0=Best; 10=Worst

*
*
1
1
§
2
2
#
2
Components Placebo-Controlled Studies Non-placebo Controlled Study
US301 (12 months) MN301 Non-US (6 months) MN302 Non-US (12 months)
Leflu-nomide Metho-trexate Placebo Leflu-nomide Sulfa-salazine Placebo Leflu-nomide Metho-trexate
Tender joint count -7.7 -6.6 -3.0 -9.7 -8.1 -4.3 -8.3 -9.7
Swollen joint count -5.7 -5.4 -2.9 -7.2 -6.2 -3.4 -6.8 -9.0
Patient global assessment§ -2.1 -1.5 0.1 -2.8 -2.6 -0.9 -2.3 -3.0
Physician global assessment -2.8 -2.4 -1.0 -2.7 -2.5 -0.8 -2.3 -3.1
Physical function/disability (MHAQ/HAQ) -0.29 -0.15 0.07 -0.50 -0.29 -0.04 -0.37 -0.44
Pain intensity# -2.2 -1.7 -0.5 -2.7 -2.0 -0.9 -2.1 -2.9
Erthrocyte Sedimentation rate -6.26 -6.48 2.56 -7.48 -16.56 3.44 -10.12 -22.18
C-reactive protein -0.62 -0.50 0.47 -2.26 -1.19 0.16 -1.86 -2.45
Not included in the ACR Responder Index
Morning Stiffness (min) -101.4 -88.7 14.7 -93.0 -42.4 -6.8 -63.7 -86.6

Maintenance of effect

After completing 12 months of treatment, patients continuing on study treatment were evaluated for an additional 12 months of double-blind treatment (total treatment period of 2 years) in studies US301, MN305, and MN304. ACR Responder rates at

Recent Drug Updates at DrugIndexOnline:





Abciximab Abciximab
Pronouncation: (ab-SICK-sih-mab) Class: Glycoprotein IIb/IIIa inhibitor Trade Names: ReoPro - Injection 2 mg/mL Mechanism of Action Pharmacology Binds to glycoprotein IIb/IIIa receptors on surface of platelets, thereby preventing platelet aggregation. Pharmacokinetics Distribution Rapidly binds to more...

Advil Caplets Advil Caplets
Some commonly used brand names are: In the U.S.— Actron 9 Advil 7 Advil Caplets 7 Advil, Children's 7 Aleve 14 Anaprox 14 Anaprox DS 14 Ansaid 6 Bayer Select Ibuprofen Pain Relief Formula Caplets 7 Cataflam 1 Clinoril 18 Cotylbutazone 16 Cramp End 7 Daypro 15 Dolgesic 7 Dolobid 2 EC-Napro more...

Altoprev 24-Hour Sustained-Release Tablets Altoprev 24-Hour Sustained-Release Tablets
Generic Name: Lovastatin 24-Hour Sustained-Release Tablets (LOW-vuh-STAT-in) Brand Name: AltoprevAltoprev 24-Hour Sustained-Release Tablets is used for:Lowering cholesterol and triglyceride levels in the blood and for reducing the risk of heart attack, blood vessel blockage, or chest pain in cer more...

clobetasol topical clobetasol topical
Generic Name: clobetasol topical (kloe BAY ta sol) Brand Names: Clobevate, Cormax, Embeline E, Olux, Temovate, Temovate Emollient What is clobetasol topical? Clobetasol is a topical steroid. It reduces or inhibits the actions of chemicals in the body that cause inflammation, redness, and more...

Ecotrin Delayed-Release Tablets Ecotrin Delayed-Release Tablets
Generic Name: Aspirin Delayed-Release Tablets (AS-pir-in) Brand Name: Examples include Bayer Low Strength and EcotrinEcotrin Delayed-Release Tablets is used for:Treating minor aches and pains (eg, caused by headache, muscle aches, backache, arthritis, the common cold, toothache, menstrual cramp more...

Enteral nutrition formulas, modular Enteral nutrition formulas, modular
Some commonly used brand names are: In the U.S.— Accupep HPF 9 Advera 2 Alitraq 9 Amin-Aid 2 Attain 10 Carnation Instant Breakfast 7 Carnation Instant Breakfast No Sugar Added 7 Casec 8 CitriSource 10 Compleat Modified 1 Compleat Regular 1 Comply 10 Criticare HN 9 Crucial 2 Deliver 2.0 10 more...

Fexofenadine/Pseudoephedrine Extended-Release Tablets (24 Hour) Fexofenadine/Pseudoephedrine Extended-Release Tablets (24 Hour)
Generic Name: Fexofenadine/Pseudoephedrine Extended-Release Tablets (24 Hour) (FEX-oh-FEN-a-deen/SOO-doe-e-FED-rin) Brand Name: Allegra-D 24 HourFexofenadine/Pseudoephedrine Extended-Release Tablets (24 Hour) is used for:Relieving seasonal allergy symptoms, including sneezing, runny nose, itchy more...

Protonix tablets Protonix tablets
Generic Name: pantoprazole sodium Dosage Form: Tablets Rx only This product's label may have been revised after this insert was used in production. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free more...