Leflunomide Tablets 10 mg and 20 mg

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 to 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.

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.

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.

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 to 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).

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.

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.

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.

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.

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 WARNINGS: Hepatotoxicity).

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).

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.

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.

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:

1. 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.)
2. 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.

• 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.

No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human M1 systemic exposure based on AUC). However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied (1.7 times the human M1 exposure based on AUC). Female mice, in the same study, exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg (approximately 1/10 the human M1 exposure based on AUC). The significance of the findings in mice relative to the clinical use of leflunomide is not known.

Leflunomide was not mutagenic in the Ames Assay, the Unscheduled DNA Synthesis Assay, or in the HGPRT Gene Mutation Assay. In addition, leflunomide was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames Assay and in the HGPRT Gene Mutation Assay, and was clastogenic in the in vitro Assay for Chromosome Aberrations in the Chinese Hamster Cells. TFMA was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. Leflunomide had no effect on fertility in either male or female rats at oral doses up to 4.0 mg/kg (approximately 1/30 the human M1 exposure based on AUC).

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.

Available information does not suggest that leflunomide would be associated with an increased risk of male-mediated fetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. To minimize any possible risk, men wishing to father a child should consider discontinuing use of leflunomide and taking cholestyramine 8 grams 3 times daily for 11 days.

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).

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.

abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain;

angina pectoris, migraine, palpitation, tachycardia, varicose vein, vasculitis, vasodilatation;

cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder;

diabetes mellitus, hyperthyroidism;

anemia (including iron deficiency anemia), ecchymosis;

creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema;

arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture;

anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating increased, vertigo;

asthma, dyspnea, epistaxis, lung disorder;

acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, maculopapular rash, nail disorder, skin discoloration, skin disorder, skin nodule, subcutaneous nodule, ulcer skin;

blurred vision, cataract, conjunctivitis, eye disorder, taste perversion;

albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis.

Other less common adverse events seen in clinical trials include: 1 case of anaphylactic reaction occurred in Phase 2 following rechallenge of drug after withdrawal due to rash (rare); urticaria; eosinophilia; transient thrombocytopenia (rare); and leukopenia <2000 WBC/mm³ (rare).

Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.

In post-marketing experience, the following have been reported rarely:

opportunistic infections, severe infections including sepsis that may be fatal;

pancreatitis;

agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia;

angioedema;

hepatitis, jaundice/cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal;

interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal;

peripheral neuropathy;

erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis.

The safety of leflunomide was studied in 74 patients with polyarticular course juvenile rheumatoid arthritis ranging in age from 3 to 17 years (47 patients from the active-controlled study and 27 from an open-label safety and pharmacokinetic study). The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. Less common adverse events included anemia, hypertension, and weight loss. Fourteen pediatric patients experienced ALT and/or AST elevations, nine between 1.2- and 3-fold the upper limit of normal, five between 3- and 8-fold the upper limit of normal.

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).

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.

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.