leflunomide 10 MG Oral Tablet

WARNINGS

Immunosuppression Potential/Bone Marrow Suppression Leflunomide is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections.

In the event that a serious infection occurs, it may be necessary to interrupt therapy with leflunomide and administer cholestyramine or charcoal (see PRECAUTIONS: General: Need for Drug Elimination ).

Medications like leflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis.

Severe infections including sepsis, which may be fatal, have been reported in patients receiving leflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis.

Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection.

There have been rare reports of pancytopenia, agranulocytosis and thrombocytopenia in patients receiving leflunomide alone.

These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality.

Patients taking leflunomide should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6 to 8 weeks thereafter.

If used with concomitant methotrexate and/or other potential immunosuppressive agents, chronic monitoring should be monthly.

If evidence of bone marrow suppression occurs in a patient taking leflunomide, treatment with leflunomide should be stopped, and cholestyramine or charcoal should be used to reduce the plasma concentration of leflunomide active metabolite (see PRECAUTIONS: General: Need for Drug Elimination ).

In any situation in which the decision is made to switch from leflunomide to another anti-rheumatic agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds.

Leflunomide washout with cholestyramine or charcoal may decrease this risk, but also may induce disease worsening if the patient had been responding to leflunomide treatment.

Hepatotoxicity RARE CASES OF SEVERE LIVER INJURY, INCLUDING CASES WITH FATAL OUTCOME, HAVE BEEN REPORTED DURING TREATMENT WITH LEFLUNOMIDE.

MOST CASES OF SEVERE LIVER INJURY OCCUR WITHIN 6 MONTHS OF THERAPY AND IN A SETTING OF MULTIPLE RISK FACTORS FOR HEPATOTOXICITY (liver disease, other hepatotoxins).

(See PRECAUTIONS .) At minimum, ALT (SGPT) must be performed at baseline and monitored initially at monthly intervals during the first six months then, if stable, every 6 to 8 weeks thereafter.

In addition, if leflunomide and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly.

Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT elevation are recommended as follows: For confirmed ALT elevations between 2- and 3-fold ULN, dose reduction to 10 mg/day may allow continued administration of leflunomide under close monitoring.

If elevations between 2- and 3-fold ULN persist despite dose reduction or if ALT elevations of >3-fold ULN are present, leflunomide should be discontinued and cholestyramine or charcoal should be administered (see PRECAUTIONS: General: Need for Drug Elimination ) with close monitoring, including retreatment with cholestyramine or charcoal as indicated.

In clinical trials, leflunomide treatment as monotherapy or in combination with methotrexate 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 8 shows liver enzyme elevations seen with monthly monitoring in clinical trials US301 and MN301.

It was notable that the absence of folate use in MN302 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.

Table 8.

Liver Enzyme Elevations >3-fold Upper Limits of Normal (ULN) US301 MN301 MN302 LEF PL MTX LEF PL SSZ LEF MTX ALT (SGPT) >3-fold ULN 8 3 5 2 1 2 13 83 (n %) (4.4) (2.5) (2.7) (1.5) (1.1) (1.5) (2.6) (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, leflunomide was added 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 added.

Pre-existing Hepatic Disease Given the possible risk of increased hepatotoxicity, and the role of the liver in drug activation, elimination and recycling, the use of leflunomide is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses.

(See : Hepatotoxicity ).

Skin Reactions Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients receiving leflunomide.

If a patient taking leflunomide develops any of these conditions, leflunomide therapy should be stopped, and a drug elimination procedure is recommended (see PRECAUTIONS: General: Need for Drug Elimination ).

Malignancy The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppression medications.

There is a potential for immunosuppression with leflunomide.

No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the clinical trials of leflunomide, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with leflunomide.

Use in Women of Childbearing Potential There are no adequate and well-controlled studies evaluating leflunomide in pregnant women.

However, based on animal studies, leflunomide may increase the risk of fetal death or teratogenic effects when administered to a pregnant woman (see CONTRAINDICATIONS ).

Women of childbearing potential must not be started on leflunomide until pregnancy is excluded and it has been confirmed that they are using reliable contraception.

Before starting treatment with leflunomide, patients must be fully counseled on the potential for serious risk to the fetus.

The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the pregnancy.

It is possible that rapidly lowering the blood level of the active metabolite by instituting the drug elimination procedure described below at the first delay of menses may decrease the risk to the fetus from leflunomide.

Upon discontinuing leflunomide, it is recommended that all women of childbearing potential undergo the drug elimination procedure described below.

Women receiving leflunomide treatment who wish to become pregnant must discontinue leflunomide and undergo the drug elimination procedure described below which includes verification of M1 metabolite plasma levels less than 0.02 mg/L (0.02 mcg/mL).

Human plasma levels of the active metabolite (M1) less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk based on available animal data.

Drug Elimination Procedure The following drug elimination procedure is recommended to achieve non-detectable plasma levels (less than 0.02 mg/L or 0.02 mcg/mL) after stopping treatment with leflunomide: Administer cholestyramine 8 grams 3 times daily for 11 days.

(The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly.) Verify plasma levels less than 0.02 mg/L (0.02 mcg/mL) by two separate tests at least 14 days apart.

If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered.

Without the drug elimination procedure, it may take up to 2 years to reach plasma M1 metabolite levels less than 0.02 mg/L due to individual variation in drug clearance.

DRUG INTERACTIONS

Drug Interactions Cholestyramine and Charcoal Administration of cholestyramine or activated charcoal in patients (n=13) and volunteers (n=96) resulted in a rapid and significant decrease in plasma M1 (the active metabolite of leflunomide) concentration (see PRECAUTIONS: General: Need for Drug Elimination ).

Hepatotoxic Drugs Increased side effects may occur when leflunomide is given concomitantly with hepatotoxic substances.

This is also to be considered when leflunomide treatment is followed by such drugs without a drug elimination procedure.

In a small (n=30) combination study of leflunomide with methotrexate, a 2- to 3-fold elevation in liver enzymes was seen in 5 of 30 patients.

All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide.

A >3-fold increase was seen in another 5 patients.

All of these also resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide.

Three patients met “ACR criteria” for liver biopsy (1: Roegnik Grade I, 2: Roegnik Grade IIIa).

No pharmacokinetic interaction was identified (see CLINICAL PHARMACOLOGY ).

NSAIDs In in vitro studies, M1 was shown to cause increases ranging from 13 to 50% in the free fraction of diclofenac and ibuprofen at concentrations in the clinical range.

The clinical significance of this finding is unknown; however, there was extensive concomitant use of NSAIDs in clinical studies and no differential effect was observed.

Tolbutamide In in vitro studies, M1 was shown to cause increases ranging from 13 to 50% in the free fraction of tolbutamide at concentrations in the clinical range.

The clinical significance of this finding is unknown.

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 be receiving both leflunomide and rifampin.

Warfarin Increased INR (International Normalized Ratio) when leflunomide and warfarin were co-administered has been rarely reported.

OVERDOSAGE

In mouse and rat acute toxicology studies, the minimally toxic dose for oral leflunomide was 200 to 500 mg/kg and 100 mg/kg, respectively (approximately >350 times the maximum recommended human dose, respectively).

There have been reports of chronic overdose in patients taking leflunomide at daily dose up to five times the recommended daily dose and reports of acute overdose in adults or children.

There were no adverse events reported in the majority of case reports of overdose.

Adverse events were consistent with the safety profile for leflunomide (see ADVERSE REACTIONS ).

The most frequent adverse events observed were diarrhea, abdominal pain, leukopenia, anemia and elevated liver function tests.

In the event of a significant overdose or toxicity, cholestyramine or charcoal administration is recommended to accelerate elimination (see PRECAUTIONS: General: Need for Drug Elimination ).

Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1, the primary metabolite of leflunomide, is not dialyzable (see CLINICAL PHARMACOLOGY: Elimination ).

DESCRIPTION

Leflunomide is a pyrimidine synthesis inhibitor.

The chemical name for leflunomide is N-(4’-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide.

It has an empirical formula C 12 H 9 F 3 N 2 O 2 , a molecular weight of 270.2 and the following structural formula: Each leflunomide tablet, for oral administration, contains 10 mg or 20 mg of leflunomide.

In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, pregelatinized starch, and titanium dioxide.

leflunomide chemical structure

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.

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 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 b.i.d.

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 n (%) patients Leflunomide 190 Placebo 128 Methotrexate 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) Other Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion.

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 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 n (%) patients Leflunomide 133 Placebo 92 Sulfasalazine 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) Other Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion.

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 n (%) patients Leflunomide 501 Methotrexate 498 Withdrawals in MN302 (Year-1) Lack of efficacy 37 (7.4) 15 (3.0) Safety 98 (19.6) 79 (15.9) Other Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion.

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 to 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 to 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 *Last Observation Carried Forward.

ACR50 and ACR70 Responders are defined in an analogous manner to the ACR20 Responder, but use improvements of 50% or 70%, respectively ( Table 6 ).

Mean change for the individual components of the ACR Responder Index are shown in Table 7 .

Table 6.

Summary of ACR Response Rates Study and Treatment Group ACR20 ACR50 ACR70 Placebo-Controlled Studies US301 (12 months) Leflunomide (n=178) N is the number of ITT patients for whom adequate data were available to calculate the indicated rates.

52.2 p<0.001 leflunomide vs placebo 34.3 20.2 Placebo (n=118) 26.3 7.6 4.2 Methotrexate (n=180) 45.6 22.8 9.4 MN301 (6 months) Leflunomide (n=130) 54.6 33.1 10.0 Placebo (n=91) 28.6 14.3 2.2 Sulfasalazine (n=132) 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 7 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 7.

Mean Change in the Components of the ACR Responder Index Placebo-Controlled Studies Non-placebo Controlled Study US301 (12 Months) MN301 Non-US (6 Months) MN302 Non-US (12 Months) Components Leflunomide Methotrexate Placebo Leflunomide Sulfasalazine Placebo Leflunomide Methotrexate Tender joint count Based on 28 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 Visual Analog Scale – 0=Best; 10=Worst -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 Erythrocyte 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 2.

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 12 months were maintained over 2 years in most patients continuing a second year of treatment.

Improvement from baseline in the individual components of the ACR responder criteria was also sustained in most patients during the second year of leflunomide treatment in all three trials.

3.

Inhibition of structural damage The change from baseline to endpoint in progression of structural disease, as measured by the Sharp X-ray score, is displayed in Figure 3 .

Leflunomide was statistically significantly superior to placebo in inhibiting the progression of disease by the Sharp Score.

No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine.

Figure 3 Comparisons 95% Confidence Interval p Value US301 Leflunomide vs.

Placebo (-4.0, -1.1) 0.0007 Methotrexate vs.

Placebo (-2.6, -0.2) 0.0196 Leflunomide vs.

Methotrexate (-2.3, 0.0) 0.0499 MN301 Leflunomide vs.

Placebo (-6.2, -1.8) 0.0004 Sulfasalazine vs.

Placebo (-6.9, 0.0) 0.0484 Leflunomide vs.

Sulfasalazine (-3.3, 1.2) NS MN302 Leflunomide vs.

Methotrexate (-2.2, 7.4) NS 4.

Improvement in physical function The Health Assessment Questionnaire (HAQ) assesses a patient’s physical function and degree of disability.

The mean change from baseline in functional ability as measured by the HAQ Disability Index (HAQ DI) in the 6 and 12 month placebo and active controlled trials is shown in Figure 4 .

Leflunomide was statistically significantly superior to placebo in improving physical function.

Superiority to placebo was demonstrated consistently across all eight HAQ DI subscales (dressing, arising, eating, walking, hygiene, reach, grip and activities) in both placebo controlled studies.

The Medical Outcomes Survey Short Form 36 (SF-36), a generic health-related quality of life questionnaire, further addresses physical function.

In US301, at 12 months, leflunomide provided statistically significant improvements compared to placebo in the Physical Component Summary (PCS) Score.

Figure 4 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.

B.

Pediatrics Clinical Trials in Pediatrics Leflunomide 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 leflunomide, 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 leflunomide was based on three weight categories: 40 kg.

The response rate to leflunomide 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 CLINICAL PHARMACOLOGY: Special Populations: Pediatrics ).

graph % ACR 20 responder at endpoint graph US301 ACR responders over time graph change in sharp score graph change in functional measure

HOW SUPPLIED

Leflunomide tablets, 10 mg are white, round, film-coated tablets, debossed GG on one side and 993 on the reverse side and are supplied as follows: Bottles of 30 NDC 54868-6170-0 Leflunomide tablets, 20 mg are white, round, film-coated tablets, debossed GG on one side and 994 on the reverse side and are supplied as follows: Bottles of 30 NDC 54868-2319-0 Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature).

Dispense in a well-closed container as described in the USP.

Protect from light.

GERIATRIC USE

Geriatric Use Of the total number of subjects in controlled clinical (Phase III) studies of leflunomide, 234 subjects were 65 years and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

No dosage adjustment is needed in patients over 65.

INDICATIONS AND USAGE

Leflunomide is indicated in adults for the treatment of active rheumatoid arthritis (RA): to reduce signs and symptoms to inhibit structural damage as evidenced by X-ray erosions and joint space narrowing to improve physical function (see CLINICAL STUDIES ).

Aspirin, nonsteroidal anti-inflammatory agents and/or low dose corticosteroids may be continued during treatment with leflunomide (see PRECAUTIONS: Drug Interactions: NSAIDs ).

The combined use of leflunomide with antimalarials, intramuscular or oral gold, D penicillamine, azathioprine, or methotrexate has not been adequately studied (see WARNINGS: Immunosuppression Potential/Bone Marrow Suppression ).

PEDIATRIC USE

Pediatric Use The safety and effectiveness of leflunomide in pediatric patients with polyarticular course juvenile rheumatoid arthritis (JRA) have not been fully evaluated.

(See CLINICAL STUDIES and ADVERSE REACTIONS ).

PREGNANCY

Pregnancy Pregnancy Category X (See CONTRAINDICATIONS section.) Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to leflunomide, health care providers are encouraged to register such patients by calling 1-877-311-8972.

NUSRING MOTHERS

Nursing Mothers Leflunomide should not be used by nursing mothers.

It is not known whether leflunomide is excreted in human milk.

Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide.

Therefore, a decision should be made whether to proceed with nursing or to initiate treatment with leflunomide, taking into account the importance of the drug to the mother.

BOXED WARNING

CONTRAINDICATIONS AND WARNINGS PREGNANCY MUST BE EXCLUDED BEFORE THE START OF TREATMENT WITH LEFLUNOMIDE.

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 TREATMENT OR PRIOR TO THE COMPLETION OF THE DRUG ELIMINATION PROCEDURE AFTER LEFLUNOMIDE TREATMENT.

INFORMATION FOR PATIENTS

Information for Patients The potential for increased risk of birth defects should be discussed with female patients of childbearing potential.

It is recommended that physicians advise women that they may be at increased risk of having a child with birth defects if they are pregnant when taking leflunomide, become pregnant while taking leflunomide, or do not wait to become pregnant until they have stopped taking leflunomide and followed the drug elimination procedure (as described in WARNINGS: Use in Women of Childbearing Potential and WARNINGS: Drug Elimination Procedure ).

Patients should be advised of the possibility of rare, serious skin reactions.

Patients should be instructed to inform their physicians promptly if they develop a skin rash or mucous membrane lesions.

Patients should be advised of the potential hepatotoxic effects of leflunomide and of the need for monitoring liver enzymes.

Patients should be instructed to notify their physicians if they develop symptoms such as unusual tiredness, abdominal pain or jaundice.

Patients should be advised 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, who have recently discontinued such therapy before starting treatment with leflunomide, or who have had a history of a significant hematologic abnormality.

Patients should be instructed to notify their physicians promptly if they notice symptoms of pancytopenia (such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness).

Patients should be informed about the early warning signs of interstitial lung disease and asked to contact their physician as soon as possible if these symptoms appear or worsen during therapy.

DOSAGE AND ADMINISTRATION

Loading Dose Due to the long half-life in patients with RA and recommended dosing interval (24 hours), a loading dose is needed to provide steady-state concentrations more rapidly.

It is recommended that leflunomide therapy be initiated with a loading dose of one 100 mg tablet per day for 3 days.

Elimination of the loading dose regimen may decrease the risk of adverse events.

This could be especially important for patients at increased risk of hematologic or hepatic toxicity, such as those receiving concomitant treatment with methotrexate or other immunosuppressive agents or on such medications in the recent past.

(See WARNINGS: Hepatotoxicity ).

Maintenance Therapy Daily dosing of 20 mg is recommended for treatment of patients with RA.

A small cohort of patients (n=104), treated with 25 mg/day, experienced a greater incidence of side effects; alopecia, weight loss, liver enzyme elevations.

Doses higher than 20 mg/day are not recommended.

If dosing at 20 mg/day is not well tolerated clinically, the dose may be decreased to 10 mg daily.

Liver enzymes must be monitored and dose adjustments may be necessary (see WARNINGS: Hepatotoxicity ).

Due to the prolonged half-life of the active metabolite of leflunomide, patients should be carefully observed after dose reduction, since it may take several weeks for metabolite levels to decline.