NTP-Leflunomide Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

NTP-LEFLUNOMIDE (leflunomide) should only be prescribed by physicians who have fully familiarized themselves with the efficacy and safety profile of NTP-LEFLUNOMIDE and who are experienced in the therapy of rheumatoid diseases.

NTP-LEFLUNOMIDE is indicated in adults for the treatment of active rheumatoid arthritis.

Geriatrics (> 65 years of age):

No dosage adjustment is needed in patients over 65 years of age.

Pediatrics (< 18 years of age):

The use in patients less than 18 years of age is contraindicated.

CONTRAINDICATIONS

NTP-LEFLUNOMIDE is contraindicated in:

1. 1) Patients with known hypersensitivity to leflunomide (especially previous Stevens-Johnson syndrome, toxic epidermal necrolysis or erythema multiforme) or to any of NTP-LEFLUNOMIDE excipients.
2. 2)

   Due to the lack of clinical experience in the following three patient populations, NTP-

   LEFLUNOMIDE is not to be administered to these patients due to its potential for immunosuppression:

   1. i) Patients with immunodeficiency states (e.g. AIDS), due to causes other than rheumatoid arthritis (see WARNINGS AND PRECAUTIONS, Immune).

ii) Patients with impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia due to causes other than rheumatoid arthritis. iii) Patients with serious infections.

1. 3) Patients with moderate to severe renal insufficiency because the kidney plays a role in the elimination of leflunomide.
2. 4)

   Patients with impairment of liver function (NTP-LEFLUNOMIDE in monotherapy or in combination with other hepatotoxic drugs e.g. Disease Modifying Antirheumatic Drugs [DMARDs] such as methotrexate) given the possible risk of increased hepatotoxicity and the role of the liver in activation, elimination and recycling of leflunomide (see DRUG INTERACTIONS).

   While the mechanism of action of leflunomide and methotrexate are different, their pharmacodynamic action of interfering with cell division is similar. Concomitant treatment with methotrexate and/or other liver and bone marrow toxic medications is associated with an increased risk of serious hepatic or marrow reactions and requires strict vigilance in monitoring (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

   If a switch in treatment from leflunomide to another hepatotoxic DMARD is required the washout and monitoring must be adhered to as mentioned in the WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests and General, Washout procedures).

3. 5) Patients with severe hypoproteinemia (e.g. in nephrotic syndrome). Since the active metabolite of NTP-LEFLUNOMIDE, A771726, is highly protein-bound and cleared via hepatic metabolism and biliary secretion.
4. 6) Pregnant women, or women of childbearing potential who are not using reliable contraception before, during, and for a period of two years after treatment with NTP-LEFLUNOMIDE (or as long as the plasma levels of the active metabolite are above 0.02 mg/L). Pregnancy must be excluded before start of treatment with NTP-LEFLUNOMIDE (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).
5. 7)

   Women who are breast feeding (see WARNINGS AND PRECAUTIONS, Special

   Population, Nursing Women).

6. 8) Patients less than 18 years of age.

Male patients should be aware of the possible male-mediated foetal toxicity. Reliable contraception during treatment with NTP-LEFLUNOMIDE should also be guaranteed (see WARNINGS AND PRECAUTIONS, Sexual Function/Reproduction and Special Population, Pregnant Women).

WARNINGS AND PRECAUTIONS

General

The active metabolite of leflunomide, A771726, has a long half-life. Serious undesirable effects might occur (e.g. hepatotoxicity, haematotoxicity or allergic reactions, see below), even if the treatment with NTP-LEFLUNOMIDE has been stopped. For the management of the above-mentioned toxicities a washout procedure should be performed.

If a severe adverse reaction to NTP-LEFLUNOMIDE occurs, or if for any other reason A771726 needs to be cleared rapidly from the body, cholestyramine or activated charcoal has to be initiated and continued/repeated as clinically necessary (see OVERDOSAGE). For suspected severe immunologic/allergic reactions, more prolonged cholestyramine or activated charcoal administration may be necessary to achieve rapid and sufficient clearance (see below the Washout Procedures).

Similarly, when switching to another DMARD (e.g. methotrexate) after treatment with NTP-LEFLUNOMIDE a washout procedure should be performed since there exist a possibility of additive risks of adverse events for a long time after the switching (see below the Washout Procedures and see also the CONTRAINDICATIONS and DRUG INTERACTIONS sections).

Recent treatment with hepatotoxic DMARDs may result in increased side effects; therefore, the initiation of NTP-LEFLUNOMIDE treatment has to be carefully considered regarding these benefit/risk aspects. Caution and careful monitoring of liver and bone marrow function is necessary if these drugs are used concomitantly (see CONTRAINDICATIONS and DRUG INTERACTIONS).

Washout Procedures

One of the following is recommended to achieve a fast decrease in plasma levels after stopping treatment with NTP-LEFLUNOMIDE:

1. 1) 8 g cholestyramine 3 times daily for 11 days OR
2. 2) 50 g activated charcoal 4 times daily for 11 days

The duration may be modified depending on clinical or laboratory variables.

Similarly low A771726 plasma levels may be expected 2 years after stopping NTP-LEFLUNOMIDE without one of the above washout methods. Due to individual variation in drug clearance, some patients may decrease to below this plasma level in less time (e.g. 6 months).

Carcinogenesis and Mutagenesis

Malignancy

The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with NTP-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 malignancies or lymphoproliferative disorders with leflunomide.

Carcinogenesis, and Mutagenesis

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 A771726 systemic exposure based on the area under the curve [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 A771726 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 A771726 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 c1astogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. However, 4-trifluoromethylanaline (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 c1astogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells.

Dependence/Tolerance

NTP-LEFLUNOMIDE should have no potential for abuse or dependence.

Hematologic

Monitoring for hematologic toxicity must be adhered to (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

NTP-LEFLUNOMIDE is contraindicated in patients with impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia due to causes other than rheumatoid arthritis. (see CONTRAINDICATIONS) In patients with a lesser degree of pre-existing anemia, leucopenia, and/or thrombocytopenia as well as in patients with impaired bone marrow function or those at risk of bone marrow suppression, the risk of hematological disorders is increased. The same effects also occur in patients on concomitant myelosuppresive medications, for example methotrexate, therefore strict vigilance in monitoring is recommended for all patients on NTP-LEFLUNOMIDE on concomitant myelosuppressive medication. If such effects occur, a washout procedure to reduce plasma levels of A771 726 should be considered.

In case of severe hematological reactions, including pancytopenia, NTP-LEFLUNOMIDE and any concomitant myelosuppressive medication must be discontinued and a washout procedure initiated (see WARNINGS AND PRECAUTIONS, General, Washout Procedures).

Hepatic/Biliary/Pancreatic

Monitoring for hepatotoxicity must be adhered to (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

NTP-LEFLUNOMIDE is contraindicated in patients with impairment of liver function (see CONTRAINDICATIONS). Given the possible risk of increased hepatotoxicity and the role of the liver in drug activation, elimination and recycling, the use of NTP-LEFLUNOMIDE is not recommended in patients with positive Hepatitis B or C serologies or pre-existing hepatic disease.

Rare cases (defined by Regulatory definition as events occurring at a frequency ranging from 0.01 to 0.1%) of serious liver injury, including liver failure some with a fatal outcome, have been reported during treatment with leflunomide. Most of the cases occurred within the first 6 months of treatment. While confounding factors were seen in many cases such as other hepatotoxic drugs such as methotrexate and/or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), a causal relationship to leflunomide cannot be excluded. It is essential that the monitoring recommendations be adhered to and washout procedure performed in appropriate cases (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be avoided during treatment with leflunomide.

In clinical trials, leflunomide treatment was associated with elevations of liver function tests, primarily ALT (SGPT) and AST (SGOT) in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤ 2xULN) (upper limit of normal) and usually resolved while continuing treatment. Clinically significant elevations (>2 and ≤ 3xULN) were less common and were generally asymptomatic and reversible with dose reduction or, if persistent, by discontinuing leflunomide. More marked elevations (>3xULN) occurred infrequently and usually reversed with dose reduction; persistent elevations resolved after discontinuation of leflunomide. Some patients received cholestyramine to enhance clearance. Overall, persistent elevations after dose reduction were uncommon and were usually associated with concomitant NSAIDs use. Limited biopsy data did not suggest that leflunomide was associated with the development of cirrhosis or hepatic fibrosis.

The following table shows liver enzyme elevations seen with monthly monitoring in clinical trials US301, MN301 and MN302. 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 1. Liver Enzyme Elevations > 3-fold Upper Limit of Normal (ULN)

LEF=Ieflunomide, SSZ= sulfasalazine, PBO=placebo, MTX=methotrexate

Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT (SGPT) elevation are recommended as follows: If ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal persist or if ALT (SGPT) elevations of more than 3-fold the upper limit of normal are present, leflunomide should be discontinued. Cholestyramine or activated charcoal should be administered to more rapidly lower A771726 level (see WARNINGS AND PRECAUTIONS, General, Washout Procedures and Monitoring and Laboratory Tests).

Rare elevations of alkaline phosphatase and bilirubin have been observed. Trial US301 used ACR Methotrexate Liver Biopsy Guidelines for monitoring therapy. One of 182 patients receiving leflunomide and 1 of 182 patients receiving methotrexate underwent liver biopsy at 106 and 50 weeks, respectively. The biopsy for the leflunomide subject was Roegnik Grade IIIA and for the methotrexate subject Roegnik Grade I.

Immune

NTP-LEFLUNOMIDE is not recommended for patients with bone marrow dysplasia, or severe, uncontrolled infections or immuno-deficiency due to causes other than rheumatoid arthritis (see CONTRAINDICATIONS).

Medications like leflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections (see ADVERSE REACTIONS). Infections may be more severe in nature.

It is known that patients with rheumatoid arthritis have an increased risk of severe infections, which may lead to sepsis and death. Rare cases of severe infection (including Pneumocystis jiroveci and cytomegalovirus infections) and sepsis (with fatal outcome in isolated cases) were reported in patients treated with leflunomide. Although in most cases a causal relationship to leflunomide has not been established and multiple confounding factors were present, infections developing in patients receiving NTP-LEFLUNOMIDE may require early and vigorous treatment.

In the event that a severe or uncontrolled infection occurs, it may be necessary to interrupt NTP-LEFLUNOMIDE treatment and administer a washout procedure (see WARNINGS AND PRECAUTIONS, General, Washout Procedures).

Patients should be questioned about history of tuberculosis or tuberculin reactivity and, if positive, they should be carefully monitored for tuberculosis reactivation.

Peripheral Neuropathy

Cases of peripheral neuropathy have been reported in patients receiving leflunomide. Most patients recovered after discontinuation of leflunomide, but some patients had persistent symptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking NTP-LEFLUNOMIDE develops a peripheral neuropathy, consider discontinuing NTP-LEFLUNOMIDE, and performing a washout procedure (see WARNINGS AND PRECAUTIONS, General, Washout Procedures).

Renal

NTP-LEFLUNOMIDE is contraindicated in patients with moderate to severe renal impairment. Because the kidney plays a role in the elimination of leflunomide, and without sufficient studies of the use of leflunomide in patients with renal insufficiency, caution should be used when considering the administration of NTP-LEFLUNOMIDE to patients with mild renal insufficiency.

Respiratory

Rare (<0.1%) spontaneous reports of interstitial lung disease occurring during treatment with leflunomide have been received worldwide (see ADVERSE REACTIONS, Respiratory, Thoracic and Mediastinal Disorders). Several of these cases had a fatal outcome. A large-scale cohort study to assess the risk of Interstitial lung disease (ILD) associated with leflunomide use was performed. The study used linked databases, prescribing and administrative information, for more than 235,000 patients with rheumatoid arthritis (RA). It was found that the risk of ILD was increased in patients with a history of methotrexate (MTX) use or interstitial lung disease (RR=2.6 [95% CI: 1.2-5.6]).

In a Japanese postmarketing surveillance program of 3658 patients with rheumatoid arthritis, the rate of interstitial lung disease was estimated at 0.8%, regardless of causality. Twenty-nine (29) cases of interstitial pneumonitis were reported, 11 with a fatal outcome. Assessment of the causality between leflunomide use and the reported interstitial lung disease is frequently confounded by pre-existing pulmonary disease (e.g. interstitial pneumonitis), and/or previous or concomitant use of other DMARDs known to induce interstitial lung disease (including methotrexate).

In patients with a current or previous history of pulmonary disease or who have been recently treated with drugs known to induce interstitial lung disease, it is recommended that pulmonary status be evaluated prior to initiation of NTP-LEFLUNOMIDE therapy and that patients be closely monitored during treatment.

Interstitial lung disease is a potentially fatal disorder, which may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy and for further investigation, as appropriate. If discontinuation of the drug is needed, the long half-life of the active metabolite of leflunomide may necessitate the initiation of wash-out procedures (see WARNINGS AND PRECAUTIONS, General, Washout Procedures).

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.

Sexual Function/Reproduction

Procreation:

Pregnancy must be avoided if either partner is receiving NTP-LEFLUNOMIDE.

Females

There are no adequate and well-controlled studies evaluating leflunomide in pregnant women. However, based on animal studies, leflunomide may cause fetal death or teratogenic effects when administered to a pregnant woman. Women of childbearing potential must not be started on NTP-LEFLUNOMIDE until pregnancy is excluded and it has been confirmed that they are using reliable contraception.

Before starting treatment with NTP-LEFLUNOMIDE, patients must be fully counselled on the potential for serious risk to the fetus. 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. Should pregnancy occur, the physician and patient should discuss the risk of continuing the pregnancy (see CONSUMER INFORMATION). 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.

For women who have received NTP-LEFLUNOMIDE treatment and wish to become pregnant, one of the following procedures is recommended:

• After stopping treatment with NTP-LEFLUNOMIDE, cholestyramine 8 g is administered 3 times daily for a period of 11 days OR
• After stopping treatment with NTP-LEFLUNOMIDE, 50 g of activated charcoal is administered 4 times daily for a period of 11 days.

The plasma levels of the active metabolite (A771726) must be less than 0.02 mg/L (0.02 µg/ml.).

Below this plasma level (to be verified by 2 separate tests at an interval of at least 14 days), the teratogenic risk is considered very low (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, General, Washout Procedures).

Without the drug elimination procedure, it may take up to 2 years to reach A771726 levels <0.02 mg/L. However, also after such waiting period, verification of A771726 levels less than 0.02 mg/L (0.02 µg/mL) by 2 separate tests at an interval of at least 14 days is required.

If a waiting period of up to approximately 2 years under reliable contraception is considered unpractical, prophylactic institution of a washout procedure may be advisable. (see WARNINGS AND PRECAUTIONS, General, Washout Procedures)

Reliable contraception with oral contraceptive may not be guaranteed during the washout procedure with cholestyramine or activated charcoal. Use of alternative contraceptive methods is recommended.

Males

NTP-LEFLUNOMIDE must not be used by men who could potentially father a child and are not using reliable contraception during and for a total of 2 years after treatment with NTP-LEFLUNOMIDE, if no elimination procedure is used.

There are no specific data on the risk of male-mediated foetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. To minimise any possible risk, men wishing to father a child should consider discontinuing use of NTP-LEFLUNOMIDE and use elimination procedure or wait 2 years after treatment cessation.

For men having received NTP-LEFLUNOMIDE treatment and wishing to father a child, plasma levels of the active metabolite (A771726) must be less than 0.02 mg/L (0.02 µg/mL) to be verified by two separate tests at an interval of at least 14 days. After the second test confirming that the plasma concentration is below 0.02 mg/L an additional waiting period of 3 months is required. After that period, the risk of male-mediated foetal toxicity is considered very low (see CONTRAINDlCATIONS and WARNINGS AND PRECAUTIONS, General, Washout Procedures).

Impairment of Fertility

Leflunomide had no effect on fertility in either male or female rats at oral doses up to 0.4 mg/kg (approximately 1/30 the human A771726 exposure based on AUC).

Skin

In case of ulcerative stomatitis, NTP-LEFLUNOMIDE administration should be discontinued.

Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in patients treated with leflunomide. As soon as skin and/or mucosal reactions are observed which raise the suspicion of such severe reactions, leflunomide and any other possibly associated medication must be discontinued, and a washout procedure initiated immediately. A complete washout is essential in such cases. In such cases re-exposure to leflunomide is contraindicated (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, General, Washout Procedures).

Special Populations

Pregnant Women:

NTP-LEFLUNOMIDE must not be administered to pregnant women or women of child bearing potential.

NTP-LEFLUNOMIDE must not be administered to male subjects who wish to father a child (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Sexual Function/Reproduction).

Nursing Women:

Animal studies indicate that leflunomide or its metabolites pass into breast milk. Therefore, NTP-LEFLUNOMIDE must not be administered to nursing mothers (see CONTRAINDICATIONS).

Pediatrics (< 18 years of age):

The safety and efficacy of leflunomide in the pediatric population have not been fully evaluated, and its use in patients less than 18 years of age is contraindicated.

Geriatrics (> 65 years of age):

No dosage adjustment is needed in patients over 65 years of age.

Monitoring and Laboratory Tests

NTP-LEFLUNOMIDE should be administered to patients only under careful medical supervision.

AST (SGOT) and ALT (SGPT) must be checked before initiation of the treatment and at monthly or more frequent intervals during the first 6 months, and every 8 weeks thereafter (See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

ALT (SGPT) values are elevated more frequently than AST (SGOT).

For confirmed ALT (SGPT) elevations between 2- and 3-times the upper limit of normal, dose may be reduced from 20 to 10 mg/day and monitoring should be performed weekly. If ALT (SGPT) elevations of more than 2- times the upper limit of normal persist, or, if confirmed ALT (SGPT) increases to more than 3- times the upper limit of normal, NTP-LEFLUNOMIDE must be discontinued and washout procedures initiated.

If a severe undesirable effect of NTP-LEFLUNOMIDE occurs, or if for any other reason the active metabolite needs to be cleared rapidly from the body (e.g.: desired or unintended pregnancy, switching to another DMARD such as methotrexate), the washout procedures should be initiated.

Cholestyramine or activated charcoal should be administered to more rapidly lower A771726 levels. (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, General, Washout Procedures).

A complete blood cell count, including differential white blood cell count and platelets, must be performed before start of NTP-LEFLUNOMIDE treatment as well as every 2 weeks for the first 6 months of treatment and every 8 weeks thereafter (see WARNINGS AND PRECAUTIONS, Hematologic).

In addition to hypertension noted in Clinical Trials, isolated reports of difficulty with blood pressure control including cases of malignant hypertension and hypertensive crisis have been submitted. Although a causal relationship to leflunomide has not been established and confounding factors were present in most cases, it is considered essential that monitoring recommendations are closely followed. Therefore, blood pressure must be checked before the start of NTP-LEFLUNOMIDE treatment and periodically thereafter (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions).

In patients with a current or previous history of pulmonary disease or who have been recently treated with drugs known to induce interstitial lung disease, it is recommended that pulmonary status be evaluated prior to initiation of NTP-LEFLUNOMIDE therapy and that patients be closely monitored during treatment.

Other Laboratory Tests Changes:

Due to an uricosuric effect presumably at the brush border of the proximal renal tubule, uric acid levels usually decrease. Phosphaturia and hypokalemia may also occur.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Hypertension, gastrointestinal disturbances, weight loss, headache, dizziness, paresthesia, asthenia, musculoskeletal and skin disorder are considered as some common adverse reactions seen with leflunomide.

Leucopenia and hypersensitivity reactions may occur and very rarely, cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported.

Hepatotoxicity has occurred. It is usually mild and reversible but cases of severe, sometimes fatal, liver disease, including acute hepatic necrosis, have been observed. There have been reports of pancreatitis, interstitial lung disease, and infections, including fatal sepsis. (See Clinical Trial Adverse Drug Reactions and Less Common Clinical Trial Adverse Drug Reactions / Post-Market Adverse Drug Reactions)

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

There were a total of 5419 adverse events reported in 1339 subjects treated with leflunomide. Four percent (4%) of the subjects in controlled studies of leflunomide had a dose reduction as a result of an adverse event and 15.5% discontinued study treatment due to adverse events. There was a total of 377 serious adverse events which occurred in 294 (22%) leflunomide-treated subjects. The percent of leflunomide-treated patients experiencing an adverse event was similar to methotrexate, the next largest treatment population.

The most common adverse events, in the controlled clinical trials, considered related to leflunomide administration were of gastrointestinal origin and consisted predominantly of diarrhea (26.7% leflunomide, 11.9% placebo, 9.8% sulfasalazine, 12.5% methotrexate), LFT (liver function test) abnormalities (10.2% leflunomide, 2.4% placebo, 3.8% sulfasalazine, 15.1% methotrexate), abdominal pain (5.7% leflunomide, 4.3% placebo, 6.8% sulfasalazine, 7.5% methotrexate), and nausea and/or vomiting (17.8% leflunomide, 14.3% placebo, 22.6% sulfasalazine, 19.9% methotrexate). These disorders may as well be associated with concomitant NSAID administration, common in all treatment groups. The occurrences of hypertension and hypokalemia observed in patients treated with leflunomide may have been influenced by concomitant NSAID and/or steroid use. Monitoring blood pressure in patients on leflunomide should be considered as addition to the recommended Monitoring of hematologic and hepatic function. (See WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests)

Adverse reactions associated with the use of leflunomide in rheumatoid arthritis include diarrhea, elevated liver transaminases (ALT [SGPT] and AST [SGOT]), alopecia, rash, and hypertension. In the controlled studies, the following adverse events were reported regardless of causality:

Table 2. Percentage of Patients with Adverse Events ≥3% in any Leflunomide Treated Group

^† Study MN 302, an active-controlled study, treated a total of 999 subjects using 1:1 randomization to (1)

leflunomide 20 mg/day after a loading dose of 100 mg/day for 3 days, or (2) methotrexate 10 mg/week or escalation to 15 mg/week. Treatment duration was 52 weeks.

LEF = leflunomide, SSZ = sulfasalazine, PBO = placebo, MTX = methotrexate, RA=Rheumatoid Arthritis

Less Common Clinical Trial Adverse Drug Reactions

The following adverse events have been reported in 1% to <3%, less than 1%, less than 0.1% or less than 0.01% of the rheumatoid arthritis patients in the leflunomide treatment group in controlled clinical trials or during post-marketing surveillance:

Blood and Lymphatic System Disorders:

1% to <3%: anemia (including iron deficiency anemia), ecchymosis, leucopenia (leucocytes > 2X10⁹/1 [2 G/L])

Less than 1%: eosinophilia, leucopenia (leucocytes <2G/L), lymphadenopathy

Cardiovascular Disorders:

1% to <3%: angina pectoris, palpitation, tachycardia, vasodilatation, varicose vein

Endocrine Disorders

1% to <3%: diabetes mellitus, hyperthyroidism

Eye Disorders:

1% to <3%: amblyopia, cataract, conjunctivitis, eye disorders

Gastrointestinal Disorders:

1% to <3%: colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder, taste perversion

General Disorders:

1% to <3%: abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain, migraine

The risk of malignancy, particularly lymphoproliferative disorders, is also known to be increased with use of some immunosuppressive drugs. (See WARNINGS and PRECAUTIONS, Carcinogenesis and Mutagenesis)

Hepatobiliary Disorders:

1% to <3%: cholelithiasis

severe disturbances in liver function; increase in alkaline phosphatase and lactate dehydrogenase (LDH)

Infection and Infestations:

Less than 0.1%: Severe infections including opportunistic infections and sepsis, which may be fatal.

Metabolism and nutrition disorders:

1% to <3%: creatine phosphokinase increased, peripheral edema, hyperglycemia, hyperlipidemia Less than 1%: hypokalemia, hypophosphatemia

Uric acid level usually decrease, due to an uricosuric effect.

Musculoskeletal System and Connective Tissue Disorders:

1% to <3%: arthrosis, bursitis, muscle cramps, myalgia, bone necrosis, bone pain, tendon rupture

Nervous System Disorders:

1% to <3%: anxiety, asthenia, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating, vertigo

Respiratory, Thoracic and Mediastinal Disorders:

1% to <3%: asthma, dyspnea, epistaxis, lung disorder

Skin and Subcutaneous Tissue Disorders and Allergic Reactions

1% to <3%: acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, nail disorder, skin nodule, subcutaneous nodule, maculopapular rash, skin disorder, skin discolouration, skin ulcer

Less than 1%: urticaria, anaphylactoid reactions, severe anaphylactic reaction

Renal and Urinary Disorders:

1% to <3%: albuminuria, cystitis, dysuria, hematuria, prostate disorder, urinary frequency

Reproductive System and Breast Disorders:

1% to <3%: menstrual disorder, vaginal moniliasis

Causal relationship of these events to leflunomide has not been established.

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.

Post-Market Adverse Drug Reactions

Blood and Lymphatic System Disorders:

Leucopenia, pancytopenia, thrombocytopenia, agranulocytosis.

Hepatobiliary Disorders:

Hepatitis, jaundice/ cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal, pancreatitis.

Hypersensitivity:

Angioedema.

Infection and Infestations:

Severe infections including opportunistic infections and sepsis, which may be fatal.

Nervous System Disorders:

Peripheral neuropathy.

Respiratory, Thoracic and Mediastinal Disorders:

Interstitial lung disease (including interstitial pneumonitis and pulmonary fibrosis), sometimes fatal.

Skin and Subcutaneous Tissue Disorders and Allergic Reactions:

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

DRUG INTERACTIONS

Overview

Increased side effects may occur when leflunomide is given concomitantly with hepatotoxic, hematotoxic or immunosuppressive substances. This is also to be considered when NTP-LEFLUNOMIDE treatment is followed by such drugs without a washout period (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, General, Washout Procedures). Strict vigilance in monitoring of hepatic and hematologic functions is recommended for all patients prescribed leflunomide with other medications associated with increased risk of hepatotoxicity or hematotoxicity.

Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be avoided during treatment with NTP-LEFLUNOMIDE.

In vitro studies indicate that A77l726 inhibits cytochrome P4502C9 (CYP2C9) activity. In clinical trials no safety problems were observed when leflunomide and NSAIDs metabolised by CYP2C9 were co-administered. Caution is advised when leflunomide is given together with drugs, other than NSAIDs, that are metabolised by CYP2C9 such as phenytoin, warfarin, and tolbutamide. (See Drug-Drug Interactions)

Drug-Drug Interactions

Aspirin, NSAIDs, Corticosteroids

In clinical trials of over 1339 rheumatoid arthritis patients there were no apparent interactions between leflunomide and concomitantly administered aspirin (acetylsalicylic acid), NSAIDs, and/or low dose corticosteroids. It has been shown that corticosteroid doses may be reduced gradually in patients who respond to leflunomide.

In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. In clinical trials no safety problems were observed when leflunomide and NSAIDs metabolised by CYP2C9 were co-administered. Based on protein binding measured in vitro using therapeutic concentrations, there was no effect of ibuprofen, or diclofenac on the protein binding of A771726. A771726 lead to a 13% to 50% increase in the unbound fractions of diclofenac and ibuprofen, which would not be expected to be clinically significant.

Aspirin (acetylsalicylic acid), NSAIDs, and/or low dose corticosteroids may be continued during treatment with NTP-LEFLUNOMIDE. These combined uses of NTP-LEFLUNOMIDE with NSAIDS and/or corticosteroids may be associated with hypertension.

Cholestryramine or activated charcoal

Concomitant administration of NTP-LEFLUNOMIDE with cholestyramine or activated charcoal will lead to a rapid and significant decrease in plasma A771726 (the active metabolite of leflunomide) concentration.

Cimetidine

When co-administered with cimetidine (nonspecific Cytochrome P450 inhibitor), there were no changes in the pharmacokinetics of A771726 or TFMA, and slight increases in leflunomide concentrations were observed in some subjects.

Methotrexate

Concomitant administration of leflunomide with methotrexate has not been approved in Canada.

In an open label study, 30 patients with active rheumatoid arthritis despite methotrexate therapy (17 ± 4 mg/week (mean ± S.D.) for at least six months were administered leflunomide 10-20 mg/day. Twenty-three patients completed one year of treatment. No pharmacokinetic interaction between the methotrexate and leflunomide was noted. 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 more than 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. Sixteen patients met ACR 20% criteria for clinical response. In the two patients that underwent liver biopsies there was no evidence of significant fibrosis.

Changing from NTP-LEFLUNOMIDE to methotrexate without a washout period may raise the possibility of additive risks even for a long time after the switching (i.e, kinetic interaction, organ toxicity) (see WARNINGS AND PRECAUTIONS, General). In addition, if NTP-LEFLUNOMIDE and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT (SGPT), AST (SGOT), and serum albumin testing monthly (See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Other DMARDs

The combined use of leflunomide with antimalarials, intramuscular or oral gold, D penicillamine or azathioprine has not been adequately studied. The risk associated with combination therapy, in particular in long-term treatment, is unknown. Since such therapy can lead to additive or even synergistic toxicity (e.g. hepato- or hematotoxicity), combination with another DMARD is not advisable.

Phenytoin

In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. Caution is advised when leflunomide is given together with drugs, other than NSAIDs that are metabolised by CYP2C9 such as phenytoin.

Warfarin

In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. Caution is advised when NTP-LEFLUNOMIDE is given together with drugs, other than NSAIDs that are metabolised by CYP2C9 such as warfarin.

Based on protein binding measured in vitro using therapeutic concentrations, there was no effect of warfarin on the protein binding of A771726. A771726 had no effect on the binding of warfarin.

There have been case reports of increased prothrombin time when leflunomide and warfarin were co-administered.

Tolbutamide

In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. Caution is advised when leflunomide is given together with drugs, other than NSAIDs that are metabolised by CYP2C9 such as tolbutamide.

In vitro, A771726 lead to a 13% to 50% increase in the unbound fractions of tolbutamide, which would not be expected to be clinically significant. Tolbutamide led to an increase in the percent of unbound A771726, which was dependent upon the concentration of tolbutamide but independent of the concentration ofA771726.

Oral contraceptives

In a study in which leflunomide was given concomitantly with a triphasic oral contraceptive pill containing 30 µg ethinyloestradiol to healthy female volunteers, there was no reduction in contraceptive activity and A771726 pharmacokinetic parameters were within predicted ranges.

Rifampin

Following concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampin, A771726 levels were increased approximately 40% over those seen when leflunomide was administered alone. Because of the potential for NTP-LEFLUNOMIDE levels to continue to increase with multiple dosing, caution should be used if patients are to be receiving both NTP-LEFLUNOMIDE and rifampin.

Vaccination

No clinical data are available on the efficacy and safety of vaccination during leflunomide treatment. Vaccination with live vaccines is, however, not recommended. A live vaccine should only be given after a period of at least 6 months has elapsed after stopping NTP-LEFLUNOMIDE.

Drug-Food Interactions

NTP-LEFLUNOMIDE can be taken during meals or at any time between meals.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Loading Dose

Due to the long half-life in patients with rheumatoid arthritis and recommended dosing interval (24 hr), a loading dose is needed to yield steady-state concentrations more rapidly. It is recommended that NTP-LEFLUNOMIDE therapy be initiated with a loading dose of 100 mg per day for 3 days.

Maintenance Therapy

Daily dosing of 20 mg is recommended for treatment of patients with rheumatoid arthritis. 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. 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 (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

NTP-LEFLUNOMIDE can be taken with or without food, without regard to meals, at the same time everyday.

A treatment effect may be evident after 4 weeks and may further improve up to 4 to 6 months after start of treatment.

Geriatric Use

No dosage adjustment is needed in patients over 65 years of age.

Impaired Renal Function

Because the kidney plays a role in the elimination of leflunomide, and without sufficient studies of the use of leflunomide in patients with renal insufficiency, caution should be used when considering the administration of NTP-LEFLUNOMIDE to patients with mild renal insufficiency (see CONTRAINDICATIONS).

Missed Dose

If the patient forgot to take a tablet of NTP-LEFLUNOMIDE they should be advised to take it as soon as they remember, unless it is nearly time for their next dose. The patient should be advised not to double-up on the next dose to make up for the missed dose.

Administration

NTP-LEFLUNOMIDE tablets should be swallowed whole, with sufficient liquid.

OVERDOSAGE

There have been reports of chronic overdose in patients taking leflunomide at daily doses up to five times the recommended daily dose and reports of acute overdose in adults or children. The majority of the reported overdoses were without adverse events. In cases where adverse events were reported, they were consistent with the safety profile for leflunomide (see ADVERSE REACTIONS). The most frequent adverse events observed were diarrhea, abdominal pain, leucopenia, anemia and elevated liver function tests.

In the event of relevant overdose or toxicity, cholestyramine or activated charcoal administration is recommended.

Cholestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy volunteers decreased plasma levels of A771726 by approximately 40% in 24 hours and by 4965% in 48 hours (see WARNINGS AND PRECAUTIONS, General, Washout Procedures).

Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active metabolite, A771726, by 37% in 24 hours and by 48% in 48 hours.

These washout procedures may be repeated if clinically necessary.

Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that A771726, the primary metabolite of leflunomide, is not dialyzable.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Leflunomide is an isoxazole immunomodulatory agent which inhibits de novo pyrimidine synthesis and has antiproliferative activity. Following oral administration, it is rapidly metabolized to A771726, which is active in vitro and is presumed to be the active drug in vivo. Leflunomide has demonstrated prophylactic and therapeutic effects in animal models of autoimmune disease. In addition, leflunomide has exhibited antiinflammatory and weak analgesic and antipyretic activity. In a model of experimental septicemia, leflunomide did not alter the resistance of mice to bacterial pathogens.

In vitro, after mitogen stimulation, A771726 inhibits T-cell proliferation, DNA synthesis, and expression of certain cell surface and nuclear antigens directly involved in T-cell activation and proliferation. It inhibits antigen-stimulated proliferation of human peripheral blood mononuclear cells (PBMCs) and proliferation in transformed murine and human cell lines, in a dose-dependent fashion. The antiproliferative activity is reversed by the addition of uridine to the cell culture, indicating that A771726 acts at the level of the de novo pyrimidine biosynthesis. Leflunomide inhibition of GvHD in vivo is also reversed by feeding uridine, further indicating that A771726 acts at the level of the de novo pyrimidine biosynthesis pathway.

It has been demonstrated that A771726 binds to and is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway important for DNA synthesis. In the heterotopic cardiac transplant model, DHODH activity is decreased in lymphocytes infiltrating heart allograft tissue in leflunomide-treated animals. In vitro, incubation of PHA/IL 2 stimulated human peripheral T cells with A771726 triggered cell cycle arrest at the G1 phase or, in those cells undergoing DNA synthesis, at S phase. Exogenous uridine reversed this effect, and no increase in apoptotic cell numbers was observed. Increased levels of the tumor suppressor protein p53 with subsequent expression of the cyclin-dependent kinase (CDK) inhibitor p21 appear to mediate this reversible cell cycle arrest.

In vitro incubation of A771726 with rat, mouse, and human DHODH demonstrated inhibition of enzyme activity at concentrations lower than those, which exert antiproliferative effects upon rapidly dividing cells (10-367 mM). Rat and mouse enzymes are more sensitive to the inhibitory effect of A771726 (IC₅₀ 0.14 ± 0.08 and 16 ± 11 µM, respectively) than the human enzyme (IC₅₀ 46± 6 µM).

Together, these data suggest that, in vivo at concentrations achievable in patients, leflunomide inhibits de novo pyrimidine synthesis in activated lymphocytes and other rapidly dividing cell populations resulting in reversible cell cycle arrest.

The inhibition of tyrosine kinase activities has also been reported for both in vitro and in vivo situations. These effects are observed at A771726 concentrations much higher than those needed for DHODH inhibition and could be secondary to the effect on DHODH. In addition, leflunomide orally and A771726 in vitro have been demonstrated to modulate the cell adhesion process in rheumatoid arthritis patients.

Pharmacokinetics

The pharmacokinetics of leflunomide, based upon plasma concentrations of the active metabolite, A771726, have been studied in healthy subjects and in patients with rheumatoid arthritis.

Absorption

After oral administration of a 100 mg dose of ¹⁴C-Ieflunomide to healthy volunteers, leflunomide was not detectable (< 25 ng/mL) in plasma over the plasma sampling period (0.5 hrs to 37 days). Plasma concentrations of total radioactivity and A771726 were superimposable, demonstrating extensive conversion to the active metabolite A771726 during the absorption process. The minor metabolite 4-trifluoromethylaniline (TFMA) has been detected in the plasma of animals and man, but at concentrations (ng/mL) much less than those of A771726 (µg/ml.). The slow but nearly complete recovery of radioactivity as metabolites indicated near complete absorption of leflunomide in man.

In a 24-week study in patients with rheumatoid arthritis, steady-state was reached between 7 and 8 weeks. Mean plasma A771726 concentrations 24 hours after a 100 mg loading dose (8.5 µg/mL) were twice those after a 50 mg loading dose (4.0 µg/mL). Pre-dose plasma concentrations after 24 weeks of dosing were linearly related to the maintenance dose (9, 18, and 63 µg/mL after 5, 10 or 25 mg/day, respectively). The pharmacokinetics of A771726 are, therefore, linear over the range of loading and maintenance doses to be used clinically.

After single doses of leflunomide to healthy subjects, peak plasma concentrations of A771726 were approached between 6 and 12 hours. Based on determination of A771726, the bioavailability of leflunomide from a tablet formulation relative to an oral solution was 80%. leflunomide administered with a high fat/high carbohydrate meal was bioequivalent to administration under fasted conditions.

Distribution:

In studies with plasma samples obtained from healthy subjects, A771726 was extensively bound to protein (> 99%) (albumin). The unbound fraction of A771726 was 0.62%. Binding of A771726 was linear up to 573 µg/mL. Compared to healthy subjects, the unbound fraction was slightly increased (0.80%) in plasma from patients with rheumatoid arthritis and was approximately doubled in patients with chronic renal insufficiency. The extensive protein binding of A771726 is consistent with its low volume of distribution. After independent intravenous administration of A771726, steady-state volume of distribution averaged 11 L.

Metabolism:

Following oral administration, leflunomide is rapidly converted to the active metabolite, A771726. Animal studies suggest that conversion takes place during passage through both the gut wall and the liver. The metabolic biotransformation of A771726 is not controlled by a single enzyme and has been shown to occur in microsomal and cytosolic cellular fractions.

The urinary metabolites were primarily glucuronide conjugates of leflunomide and an oxanilic acid derivative of A771726, while A771726 was the primary metabolite in the feces.

Excretion:

After oral administration of a 100 mg dose of ¹⁴C-leflunomide to healthy volunteers, urinary and fecal recovery of ¹⁴C-Ieflunomide over 28 days accounted for 43% and 48% of total radioactivity, respectively. Unchanged leflunomide was not detected in urine or feces. A771726 is cleared by slow excretion in feces, probably by biliary elimination and slow metabolism to the oxanilic acid metabolite excreted in urine.

After independent intravenous administration of A771726, clearance averaged 31 mL/hr and elimination half-life 10 days. A similar clearance estimate (29 ± 17 mL/hr) was obtained from population pharmacokinetics analysis of rheumatoid arthritis patients enrolled in pivotal safety and efficacy studies.

After single doses of leflunomide to healthy subjects, plasma concentrations of A771726 declined monoexponentially, with a half-life of approximately 8 days. After 24 weeks, the elimination half-life averaged 14 - 18 days.

The elimination half-life in patients is approximately 2 weeks. Oral administration of activated charcoal or cholestyramine is effective in enhancing the elimination of A771726. During oral administration of activated charcoal (50 g four times a day) or cholestyramine (8 g three times a day), the half-life of A771726 decreased to approximately 24 hours. Although the mechanism for the enhanced elimination is unknown, it may be related to interruption of enterohepatic recycling and/or dialysis across the gastrointestinal mucosa.

Special Populations and Conditions

Renal Insufficiency: When subjects with end-stage renal disease were administered a single 100 mg dose of leflunomide orally, plasma concentrations of A771726 both prior to and after dialysis (chronic ambulatory peritoneal dialysis [CAPD] or hemodialysis) were comparable to those of healthy volunteers administered the same dose. With hemodialysis, A771726 was cleared somewhat more rapidly and with a shorter half-life. The pharmacokinetic parameters for the CAPD patients were consistent with the values for healthy volunteers.

STORAGE AND STABILITY

Store between 15°C and 30°C. Protect from light and moisture. Keep in a safe place out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

NTP-LEFLUNOMIDE is available for oral administration as film-coated tablets containing 10 mg and 20 mg of leflunomide.

NTP-LEFLUNOMIDE 10 mg tablets are white to off-white, round film-coated tablets, engraved N on one side and 10 on the other side. Available in white polyethylene bottles of 30 and 100.

NTP-LEFLUNOMIDE 20 mg tablets are cream, triangular shaped film-coated tablets, engraved N on one side and 20 on the other side. Available in white polyethylene bottles of 30 and 100.

Non-medicinal ingredients are: lactose monohydrate impalpable, lactose anhydrous, povidone, crospovidone, prege1atinized starch, colloidal silicon dioxide, talc, magnesium stearate, titanium dioxide, hydroxypropyl methylcellulose and polyethylene glycol. Additional non-medicinal ingredients in the 10 mg tablet are po1ydextrose and triethyl citrate. Additional non-medicinal ingredients in the 20 mg tablet are polysorbate 80, and iron oxide yellow. .

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Leflunomide

Chemical name: N-(4'trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide

Molecular formula: C₁₂H₉F₃N₂O₂

Molecular mass: 270.2 g/mol

Structural formula:

N O

NH

CH₃

O CF3

Physicochemical properties: Leflunornide is a white to almost white powder.

Leflunomide is practically insoluble in water and aqueous buffer systems. Leflunomide is freely soluble in methanol, ethanol, isopropanol, ethyl acetate, propylene carbonate, acetone and acetonitrile. pKa values: 10.8 at 23°C. Melting point between 165 and 167°C.

CLINICAL TRIALS

Comparative Bioavailability Studies

A comparative, one-way, single-dose, parallel study was performed on two Leflunomide tablet products, NTP-LEFLUNOMIDE 20 mg tablets and ARAVA 20 mg tablets, in healthy female volunteers under fasting conditions.

The pharmacokinetic data calculated for the NTP-LEFLUNOMIDE and ARAVA tablet formulation, under fasting conditions, based on the measurement of metabolite data is tabulated as below:

* Expressed as arithmetic mean (CV%) only.

** Arava 20 mg tablets (Aventis Pharma Inc., Canada) purchased in Canada.

*** Due to design of the study, meaningful AUC_I, and t_'/2 parameters could not be calculated.

A comparative, one-way, single-dose, parallel study was performed on two Leflunomide tablet products, NTP-LEFLUNOMIDE 20 mg tablets and ARAVA 20 mg tablets, in healthy female volunteers under fed conditions.

The pharmacokinetic data calculated for the NTP-LEFLUNOMIDE and ARAVA tablet formulation, under fed conditions, based on the measurement of metabolite data is tabulated as below:

* Expressed as arithmetic mean (CV%) only.

** Arava 20 mg tablets (Aventis Pharma Inc., Canada) purchased in Canada.

*** Due to design of the study, meaningful AUC_I, and t_'/2 parameters could not be calculated.

The efficacy and safety of leflunomide in the treatment of rheumatoid arthritis was demonstrated in two placebo-controlled pivotal clinical studies. For these studies, summaries of the results are presented for the “ACR Success Rates” per treatment group, “ACR Responder Rates” over time, X-ray evaluation of disease progression, and health-related quality of life measures. An “ACR Success”, based upon the American College of Rheumatology (ACR) criteria, is a patient who completes the trial and is an ACR Responder at the trial endpoint. An “ACR Responder” is a patient with ≥ 20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: [i] physician global assessment, [ii] patient global assessment, [iii] function/disability measure Health Assessment Questionnaire (HAQ) or Modified HAQ (MHAQ), [iv] visual analog pain scale, and [v] erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Improvements in function/disability and health-related quality of life were measured by the HAQ, the MHAQ, the Problem Elicitation Technique (PET), and the Medical Outcomes Survey Short Form 36 (SF-36).

Study US301 enrolled 511 subjects with active rheumatoid arthritis of at least 6 months duration, using a 3:2:3 randomization to one of the following 3 groups: (1) leflunomide 20 mg/day after a loading dose of 100 mg/day for 3 days, (2) placebo, or (3) methotrexate 7.5 mg/week or escalation to 15 mg/week. Treatment duration was 52 weeks. Of the patients who completed the first 12 months of study US301, 235 continued into a second 12 months of double-blind treatment. leflunomide dose continued at 20 mg/day and the methotrexate dose could be increased to a maximum of 20 mg/week. 190 patients completed 2 years of double-blind treatment.

Study MN301/303/305 enrolled 358 subjects with active rheumatoid arthritis with at least 6 tender joints and 6 swollen joints. Patients were randomized on a 3:2:3 basis to 1 of 3 treatment arms: (1) leflunomide 20 mg/day after a loading dose of 100 mg/day for 3 days, (2) placebo, (3) sulfasalazine 2.0 g/day. Treatment duration was 24 weeks. Study MN303 was a 6-month blinded continuation of MN301 resulting in a 12-month comparison of the MN301 leflunomide and sulfasalazine treatment groups. 146 of 168 patients who completed the 12 months of treatment in study MN303 entered the double-blind, 1-year extension study MN305. Patients continued on the same daily dosage of leflunomide or sulfasalazine that they had been taking at the completion of MN303. 116 patients completed 2 years of double-blind treatment.

Study MN302/304, a clinical trial complementary to study US301, randomized 999 subjects with active RA to leflunomide 20 mg/day or methotrexate at 7.5 mg/week increasing to 15 mg/week. Treatment duration was 52 weeks. 612 of the 736 patients who completed 12 months of treatment in study MN302 entered the double-blind, l-year extension study MN304. Patients continued on the same daily dosage of leflunomide or methotrexate that they had been taking at the completion of MN302. 497 patients completed 2 years of double-blind treatment.

ACR Responder Rates

ACR Success Rates for the placebo-controlled pivotal studies (including MN303 extension of MN301) are shown in Figure 1. Leflunomide was statistically significantly superior to placebo in reducing the signs and symptoms of rheumatoid arthritis by the primary efficacy analysis, ACR Success Rate. ACR Success Rates with leflunomide treatment were consistent across the 6 and 12 month studies (41-49%).

Figure 1.

* p ≤0.01 leflunomide vs. placebo

+ Active comparator statistically equivalent to leflunomide LEF= leflunomide

MTX= methotrexate

PL = placebo

SSZ= sulfasalazine

ACR Responder Rates over time in the placebo-controlled pivotal studies are shown in Figures 2 and 3. Leflunomide was statistically significantly superior to placebo in all efficacy measures including ACR Responder Rate and all individual components of the ACR Responder criteria (tender joint count, swollen joint count, patient and physician global assessments, pain intensity assessment, HAQ or MHAQ, and ESR or CRP) as well as morning stiffness and rheumatoid factor levels. Leflunomide treatment effect was evident by 1 month, stabilizing by 3-6 months, and continuing throughout the course of treatment. ACR Responder Rates at end of study with leflunomide treatment were consistent across the 6 and 12 month studies (52-55%).

Figure 2

Figure 3

After completing 12 months of treatment in the original pivotal studies, patients were evaluated for an additional 12 months of double-blind treatment (total treatment period of 2 years) in studies US301, MN305, and MN304. Improvement in the ACR response demonstrated at 6 and 12 months was maintained over two years,

In addition, in a placebo-controlled dose ranging study enrolling 402 subjects with active rheumatoid arthritis, leflunomide 5 mg/day was not effective; whereas leflunomide 10 mg/day and 25 mg/day were statistically significantly superior to placebo. ACR Responder Rates at endpoint for 10 mg and 25 mg doses were consistent with those in the placebo-controlled pivotal clinical studies.

X-ray Findings

Results of the analyzed Sharp X-ray scores for the two placebo-controlled pivotal studies (including MN303 extension of MN301) are shown in Table 3. Leflunomide was statistically significantly superior to placebo in retarding disease progression as measured by x-ray analysis of both erosions and joint space narrowing. The retarding of progression of erosive disease by leflunomide treatment was further evidenced by statistically significant decreases in the percentage of patients with progression of erosions compared to placebo (US301 3% vs. 12%, and MN301 3% vs. 16%). Thirty percent of patients did not have paired X-rays and sensitivity analyses were required to support the validity of the results. There was a lack of correlation between changes in X-rays and changes in clinical assessments.

Table 3. Analysis of X-rays by Sharp Scores

* P ≤ 0.05 leflunomide vs. placebo

^† p ≤ 0.05 leflunomide vs. active control

LEF=leflunomide, SSZ= sulfasalazine, PBO=placebo, MTX=methotrexate

As demonstrated in placebo-controlled pivotal studies, leflunomide reduces pain, articular swelling and tenderness, and ameliorates the signs and symptoms of rheumatoid arthritis. Joint damage as assessed by X-ray analysis of joint space narrowing and erosions may be retarded by leflunomide compared to placebo at the end of one year of therapy, but no consistent differences were noted between leflunomide and methotrexate or leflunomide and sulfasalazine on assessments of joint damage.

Physical function

The Health Assessment Questionnaire (HAQ) assesses disease-specific physical function and degree of disability in patients - (dressing, rising, eating, walking, hygiene, reach, grip and activities). The HAQ Disability Index (HAQ DI) uses the scores of the worst items within each of the eight categories, modified by the use of devices and aids.

The mean change from baseline in the HAQ Disability Index in the 6 and 12 month placebo and active controlled trials is shown in Figure 4 below.

Figure 4

Change in HAQ Disability Index

MX: Methotrexate, SSZ: Sulfasalazine, LEF= leflunomide, PBO= placebo

Leflunomide was statistically significantly superior to placebo in improving physical function from baseline to endpoint as assessed by the HAQ Disability Index. The magnitude of improvement in all subscales in the leflunomide treated group was clinically significant, i.e. exceeded the 0.22 unit change threshold. Superiority to placebo was demonstrated consistently across all eight HAQ sub-domains in both placebo controlled studies.

The improvement in physical function and disability demonstrated at 6 and 12 months was maintained over two years, as shown below in Figure 5. In patients continuing leflunomide for a second year of double-blind treatment in US301, MN301-305 and MN302-304, marked, clinically meaningful improvement from baseline in HAQ Disability Index continued to be documented at 24 months in all three trials with no clinically meaningful differences between month 12 and month 24.

Figure 5

Change in HAQ Disability Index - Year-2 cohort

The Health Outcomes Survey Short Form 36 (SF-36) is a generic instrument that assesses physical function as well as social and emotional function. In US301, at 12 months, leflunomide provided statistically significant improvements compared to placebo in 5 of 8 SF-36 scales (physical functioning, pain, general health perception, vitality, and social functioning), the physical component score, and the work productivity score based on work limitations questionnaire. The improvement in physical and emotional functions, as measured by the SF-36, was maintained from 12 to 24 months for subjects treated with leflunomide as shown in Figure 6.

Figure 6

Change in SF-36, Year-2 Cohort

DETAILED PHARMACOLOGY

Animal Pharmacology

Autoimmunity Models

In rats, leflunomide dose dependently prevented the symptoms of induced arthritis with a median effective dose (ED₅₀) of 1 to 4.5 mg/kg/day. Leflunomide suppressed radiographically detectable changes in bone structure and periarticular tissues when treatment was started within 12 days of disease induction, and the benefits persisted for as long as 79 days. Mice with such induced disease, however, required about 3 times as much drug as rats to obtain the same efficacy. In antigen-induced monoarticular arthritis in rats, leflunomide (10 mg/kg/day, po) administered during the effector phase produced significant inhibition of the DTH (delayed-type hypersensitivity) inflammation.

Leflunomide reduced the occurrence of chronic secondary lesions in adjuvant-induced arthritis caused by immunopathological mechanisms and was thus comparable to immunosuppressant drugs. In rats with T cell-mediated, allergic encephalomyelitis, a condition with characteristics similar to those of multiple sclerosis, leflunomide and A771726 were effective at dosages of 10 mg/kg/day, po, administered for 17 days. In rats with tubulointerstitial nephritis, a condition with characteristics of autoimmune kidney disorder, leflunomide was effective at dosages of 5 to 10 mg/kg/day, po, administered for 13 days.

In several studies, leflunomide was effective in preventing as well as treating the autoimmune condition, reducing antibody formation and improving survival rates, and the effects continued long after therapy had ceased. In rats administered leflunomide (10 mg/kg/day, po) as collagen-induced arthritis was developing, leflunomide produced significant inhibition of arthritic paw edema, paw lesions, acute phase response, anti-collagen antibodies and collagen dermal Arthus and DTH-like inflammation.

Beginning 17 days after the injection of parental lymphoid cells decreased proteinuria, administration of leflunomide (10-30 mg/kg/day, po) lowered immune complex deposition, and lowered the index of GvH (graft versus host) disease evaluated 10 weeks after disease induction. In addition, the response of splenic lymphocytes to mitogen stimulation, which is decreased in diseased animals, was normalized by leflunomide treatment.

Immunomodulatory Models

Studies of immunomodulation included studies of cell-mediated cytotoxicity (a T cell response to antigen), skin transplantation, and Type 1 allergy. Cell-mediated cytotoxicity was inhibited by leflunomide. In mice, leflunomide (50 mg/kg, po or ip) prevented the generation and proliferation of antigen-induced cytotoxic T lymphocytes, although A771726 did not interfere directly in the natural killer cytotoxicity of human peripheral blood mononuclear cells (PBMC) against K-562 target cells. In mice, leflunomide (12.5 mg/kg/day, po; 25 to 100 mg/kg/day, ip) and A771726 (10-20 mg/kg/day, po; 10 mg/kg/day, ip) inhibited the T cell-dependent and T cell-independent B cell responses. A771726 inhibited proliferation of B cells and the secretion of IgM, possibly by suppressing the expansion of antibody secreting cells or by inhibiting B cell differentiation or secretion. Leflunomide modified the immune system by depressing lymphocyte activity, especially in B cells. Therefore, these agents have immunosuppressive activity in both humoral and cell-mediated responses.

Mechanisms Underlying Anti-Autoimmune and Immunomodulatory Effects

Leflunomide was antiproliferative in in vitro experiments using mouse, rat, monkey and human lymphocytes either unstimulated or stimulated with a variety of B and T cell mitogens. Antiproliferation was also seen in transformed but unstimulated murine and human cell lines and in the murine mixed lymphocyte reaction of allogeneic spleen cells. The 50% inhibitory concentration (IC₅₀) values were < 1.0 mM in rat cells, although cells from mice and humans were less sensitive, with IC₅₀ values up to 10.0 mM.

In several species, A771726 dose dependently inhibited proliferation of splenocytes, thymocytes, lymphocytes, and peripheral blood mononuclear cells (PBMC) stimulated by various mitogens and interleukins. A771726 inhibited the expression of the interleukin-2 (IL-2) receptor and the nuclear protein antigens Ki-67 and PCNA in human PBMC. Both of these nuclear proteins are associated with progression into the cell cycle.

In rodent spleen cells, human PBMC, and several cell lines, A771726 blocked lymphocyte activation at a point downstream of initial signalling events. A771726 had similar kinetics on inhibition of proliferation of cells as the immunosuppressant drugs brequinar and rapamycin. However, the mechanism of inhibiting cell cycle progression did not include general protein synthesis.

An important finding related to the effects on the cell cycle was that A771726 is an inhibitor of de novo pyrimidine biosynthesis. A771726 inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyses the conversion of dihydroorotate (DHO) to orotate, the fourth step in de novo biosynthesis of the pyrimidine nucleotides uridine and cytidine. Pyrimidine nucleotides are essential for normal immune cell functions. That inhibition of pyrimidine synthesis underlies the antiproliferative effects of A771726 is evidenced by the following findings in murine systems:

• A771726 failed to block mitogen-induced cell proliferation in the presence but not the absence of uridine.
• Inhibition of the DTH response showed a qualitative relationship with binding affinities of several A771726 analogues and with inhibition of DHODH activity.
• Uridine counteracts inhibition of the graft-versus host reaction.

A771726 IC₅₀ values for the recombinant human and rat DHODH enzymes were 1 nM and 19 nM, respectively. Leflunomide was a relatively weak inhibitor of the recombinant human and rat eymes: IC₅₀ =98 nM and 6.3 nM, respectively.

Induction of cell-cycle arrest at the Gl/S boundary in T cells treated in vitro with A771726 is mediated through DHODH inhibition and subsequent pyrimidine depletion, activating the p53 and p21WAF-1 pathways.

The rank order of IC₅₀ values for inhibition of DHODH for the rat, mouse, and human enzymes (16 + 2 nM, 81 + 12 nM, and 657 + 46 nM) parallels the rank order of IC₅₀ values for inhibition of cell proliferation (0.14 + 0.08 µM, 16 + 11 µM, and 46 + 6 µM).

Studies of Inflammation

Leflunomide (1-25 mg/kg) had an anti-inflammatory activity similar to NSAIDs in several animal models of inflammation, including ultraviolet (UV) -induced erythema in guinea pigs, carrageenan-induced paw edema, and granuloma formation in response to implantation of cotton pellets in rats. The effectiveness depended on the dose and time of application. Leflunomide was also effective in rats adrenalectomized 3 days previously, indicating that it did not act by stimulating release of endogenous corticosteroids. Various studies indicated that A771726 reduced arachidonic acid-induced ear edema in mice. Topical application of leflunomide was not effective.

The effects of leflunomide and A771726 on platelet aggregation were weak and variable. The enzymes of arachidonic acid metabolism, phosphorylase A2, 5-lipoxygenase and LTB4-hydrolase, thus are not targets for A771726.

Adherence of leucocytes to endothelium, basement membranes and other surfaces is seen in inflammatory responses. A771726 inhibited adhesion in studies including f-Met-Leu-Phe (FMLP) -induced leucocyte adhesion to rat mesenteric venule endothelium in vivo, aggregation of PBMC and spleen-derived mononuclear cells in experimental autoimmune diabetes in mice, and spontaneous and phorbol-ester homotypic adhesion of PBMC and mononuclear cells from synovial fluid of rheumatoid arthritis patients.

Safety Pharmacology

Leflunomide administered intraduodenally (1-100 mg/kg) to dogs did not affect cardiovascular parameters. Although leflunomide bears some resemblance to anilines and anilides, which cause methemoglobinemia, at concentrations of 37 - 370 mM leflunomide did not alter methemoglobin production by human whole blood (in vitro).

The effect of leflunomide on the gastrointestinal tract was studied in rats. Acute administration of leflunomide to fasted rats produced an ulcerative median dose (UD₅₀) of approximately 33 mg/kg. Under the same conditions the UD₅₀ for naproxen was 19 mg/kg and for phenylbutazone was 53 mg/kg. In fed rats that were dosed subacutely with leflunomide for 4 days a UD₅₀ of approximately 70 mg/kg was observed.

Oral administration of 20 mg/kg of leflunomide to male Cebus monkeys caused a marked increase in uric acid excretion but did not change the excretion of urine and electrolytes compared to vehicle-treated monkeys.

In a series of experiments in mice and rats, leflunomide (10-100 mg/kg, po) had either no or only slight effects on general behaviour, the central nervous system, and the autonomic nervous system.

The effect of leflunomide on respiratory parameters in pentobarbital anaesthetized dogs administered intraduodenal doses of 1, 10, and 100 mg/kg was evaluated. The bronchospasmolytic effects of leflunomide (4-15 mg/kg) were specific against bradykinin but not against acetylcholine, histamine or serotonin in anaesthetized guinea pigs.

Leflunomide administered orally at 10, 20 and 40 mg/kg produced no antagonistic effect on reserpine or tetrabenazine-induced ptosis.

The inhibition of ex vivo platelet aggregation induced by collagen was evaluated in rabbits following oral doses of 5, 10, 15, 20, and 25 mg/kg of leflunomide. These doses produced a slight to moderate inhibition of platelet aggregation.

Drug Interactions

Rats administered leflunomide (0.1 - 3.0 mg/kg/day, po) with indomethacin (4.25 mg/kg/day, po) administered twice a day for 4 days did not show significantly increased gastrointestinal ulcers or erosions relative to rats receiving indomethacin alone.

In a study of saluresis and diuresis of conventional diuretic drugs in rats, leflunomide was administered at doses of 5, 10, and 20 mg/kg, po, alone and with hydrochlorothiazide (HCT) at 50 mg/kg and furosemide at 25 and 50 mg/kg. Phenylbutazone was used as a reference drug employing doses of 20, 50, and 100 mg/kg.

In rats saline-loaded orally, leflunomide had a slight diuretic effect but no substantial effects on the diuresis induced by HCT or furosemide. Phenylbutazone significantly reduced the diuretic effects of HCT and furosemide. Leflunomide produced a slight reduction in the excretion of Na⁺ and Cl^-, but not K⁺, but had no additional affect on the activity of HCT and furosemide. In rats saline-loaded intraperitoneally, leflunomide did not significantly induce diuretic effects or affect the diuretic activity produced by HCT or furosemide. In rats with no saline loading, leflunomide produced no diuretic effect alone, and tended to decrease the effect of HCT and slightly decreased the effect of furosemide. Leflunomide did not affect ion excretion alone or in combination with HCT but did increase ion excretion induced by furosemide. Phenylbutazone increased the diuretic activity of both HCT and furosemide.

TOXICOLOGY

Acute Toxicity

Table 4 - List of Acute Toxicity Studies for Leflunomide and its Metabolites

Long-Term Toxicity

Table 5 - List of Long-Term Toxicity Studies for Leflunomide and Metabolites

Reproduction & Teratology

Leflunomide was teratogenic and caused embryo/fetal death while not causing systemic toxicity or affecting fertility in the parental generation. This was demonstrated in reproductive and developmental toxicity studies with leflunomide in the rat and rabbit.

Conclusions from fertility study

• in the rat, there were no effects on fertility ≤ 4 mg/kg/day
• there were no pre-and postnatal effects at 0.4 mg/kg/day
• leflunomide was teratogenic at ≥ 1.25 mg/kg/day

Conclusions from embryo-fetal/teratogenicity studies

• in the rat, there were no maternal or developmental effects at 1 mg/kg/day
• in the rabbit, there were no maternal effects at ≤ 10 mg/kg/day and no developmental effects at 1 mg/kg/day
• leflunomide was teratogenic at 15 mg/kg/day in the rat and 10 mg/kg/day in the rabbit

Conclusions from peri/postnatal studies

• in the rat, there were no maternal effects ≤ 1.25 mg/kg/day
• there were developmental effects at 0.4 mg/kg/day
• leflunomide was teratogenic at 4 mg/kg/day

Conclusions from in vitro study

• leflunomide and its major metabolite were teratogenic
• A771726 (metabolite) was twice as active as HWA 486 (parent compound)

Conclusions from Toxicokinetic Studies

• in the rabbit, there was no clear relation of T_max at the dose level or number of administrations
• only at the 10 mg/kg (as opposed to 1 mg/kg) dose level was any effect of repeat dosing observed.

Table 6 - Reproduction and Teratology Studies

* Toxicokinetic study in Himalayan Rabbit identical to the Segment II rabbit study performed to generate toxicokinetic data in pregnant rabbits.

Carcinogenicity

Table 7 - Carcinogenicity Studies in Mouse and Rat

* 16 male and 16 female animals from groups 2-5 served as satellite animals for toxicokinetic examinations.

Mutagenicity

Testing of leflunomide, with and without metabolic activation, has yielded consistently negative results in various mutagenicity assays, including point mutation assays with Salmonella typhimurium and E. coli (Ames test), in vitro HGPRT test with V79 Chinese hamster cells, the unscheduled DNA synthesis assay using rat primary hepatocyte cultures, the in vivo micronucleus test in NMRI mice, and the in vivo chromosomal aberration assay in bone marrow of Chinese hamsters.

In contrast, TFMA (the minor metabolite of leflunomide) was found in the literature to be mutagenic in the Ames test but inactive in the unscheduled DNA synthesis assay in rat hepatocytes. Additional mutagenicity testing revealed mutagenic potential in vitro in the Ames test, HGPRT test, and in vitro chromosomal aberration test in V79 Chinese hamster cells. No mutagenic/genotoxic effects were observed in 2 in vivo studies (micronucleus test after ip dosing and chromosomal aberration test in Chinese hamster bone marrow).

Toxicokinetics

Leflunomide was well absorbed and quickly metabolised to the active metabolite A771726 in mouse, rat, dog and man. The conversion to A771726 was virtually completed on first-pass (gut-wall and liver) and parent leflunomide concentrations were only occasionally above the detection limit in plasma. It was not possible to calculate AUC and hence compare exposure to leflunomide across the species.

The metabolite A771726 had a low volume of distribution (l0.9litres in man, 3.5 litres in dog), due to extensive plasma protein binding (> 98% in animals and >99% in man). The elimination half-lives of A771726 (or total radioactivity which reflected almost exclusively the metabolite A771726), in plasma were 10.6 hours in mouse, 9 hours in rat, approximately 15-20 hours in dog and 185 hours in man. There was no evidence for accumulation in rat or dog and in man steady-state plasma concentrations were close to those predicted from single dose data. The following table shows a comparison of the AUC and C_max data for A771726 in animals and man upon repeated daily dosing. In rat and dog these data were obtained during toxicity studies whilst the human data was obtained during Phase II studies in rheumatoid patients at dose levels of 5, 10 and 25 mg. There were no significant differences in these parameters between healthy volunteers and rheumatoid patients.

Table 8 - AUC and C_max Data Comparison for A771726

The following table presents the IC₅₀s for the effects of A771726 on DHO-DH activity and cell proliferation in rat, mouse and human.

Table 9

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