NDC 35573-447 Leflunomide

Leflunomide

NDC Product Code 35573-447

NDC CODE: 35573-447

Proprietary Name: Leflunomide What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Leflunomide What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is used to treat rheumatoid arthritis, a condition in which the body's defense system (immune system) fails to recognize the body as itself and attacks the healthy tissues around the joints. Leflunomide helps to reduce the joint damage/pain/swelling and helps you to move better. It works by weakening your immune system and decreasing swelling (inflammation).

Product Characteristics

Color(s):
WHITE (C48325)
Shape: ROUND (C48348)
Size(s):
6 MM
Imprint(s):
LFL;10
Score: 1

NDC Code Structure

  • 35573 - Burel Pharmaceuticals, Llc

NDC 35573-447-30

Package Description: 30 TABLET, FILM COATED in 1 BOTTLE

NDC Product Information

Leflunomide with NDC 35573-447 is a a human prescription drug product labeled by Burel Pharmaceuticals, Llc. The generic name of Leflunomide is leflunomide. The product's dosage form is tablet, film coated and is administered via oral form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 205284 and 205285.

Dosage Form: Tablet, Film Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Leflunomide Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 2165RE0K14)
  • TARTARIC ACID (UNII: W4888I119H)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TALC (UNII: 7SEV7J4R1U)
  • LECITHIN, SOYBEAN (UNII: 1DI56QDM62)
  • XANTHAN GUM (UNII: TTV12P4NEE)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Antirheumatic Agent - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Burel Pharmaceuticals, Llc
Labeler Code: 35573
FDA Application Number: ANDA213497 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 01-03-2022 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Leflunomide Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

Leflunomide Tablets, USP are indicated for the treatment of adults with active rheumatoid arthritis (RA).

  • The recommended dosage of leflunomide is 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient's risk of leflunomide-associated hepatotoxicity and leflunomide-associated myelosuppression. The loading dosage provides steady-state concentrations more rapidly. For patients who are at low risk for leflunomide-associated hepatotoxicity and leflunomide-associated myelosuppression the recommended leflunomide loading dosage is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily. For patients at high risk for leflunomide-associated hepatotoxicity (e.g., those taking concomitant methotrexate) or leflunomide-associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended leflunomide dosage is 20 mg once daily without a loading dose [see Warnings and Precautions (5.2, 5.4)].The maximum recommended daily dosage is 20 mg once per day. Consider dosage reduction to 10 mg once daily for patients who are not able to tolerate 20 mg daily (i.e., for patients who experience any adverse events listed in Table 1). Monitor patients carefully after dosage reduction and after stopping therapy with leflunomide, since the active metabolite of leflunomide, teriflunomide, is slowly eliminated from the plasma [see Clinical Pharmacology (12.3)]. After stopping leflunomide treatment, an accelerated drug elimination procedure is recommended to reduce the plasma concentrations of the active metabolite, teriflunomide [see Warnings and Precautions (5.3)]. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach undetectable plasma teriflunomide concentrations after stopping leflunomide [see Clinical Pharmacology (12.3)].

2.2 Evaluation And Testing Prior To Starting Leflunomide

  • Prior to starting leflunomide treatment the following evaluations and tests are recommended:Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection [see Warnings and Precautions (5.4)]Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts [see Warnings and Precautions (5.2, 5.4)]For females of reproductive potential, pregnancy testing [see Warnings and Precautions (5.1)]Check blood pressure [see Warnings and Precautions (5.10)]

3 Dosage Forms And Strengths

  • Leflunomide tablets, USP are available in two strengths: Tablets: 10 mg, supplied as white to off-white, round, biconvex film-coated tablets debossed with "10" on one side and "LFL" on the other side.Tablets: 20 mg, supplied as white to off-white, round, biconvex film-coated tablets debossed with "20" on one side and "LFL" on the other side.

4 Contraindications

  • Leflunomide is contraindicated in: Pregnant women. Leflunomide may cause fetal harm. If a woman becomes pregnant while taking this drug, stop leflunomide, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure [see Warnings and Precautions (5.1 and 5.3) and Use in Specific Populations (8.1)].Patients with severe hepatic impairment [see Warnings and Precautions (5.2)].Patients with known hypersensitivity to leflunomide or any of the other components of leflunomide. Known reactions include anaphylaxis [see Adverse Reactions (6.1)].Patients being treated with teriflunomide [see Drug Interactions (7)].

5.1 Embryo-Fetal Toxicity

Leflunomide may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryo-lethality occurred in animal reproduction studies with leflunomide at doses lower than the human exposure level [see Use in Specific Populations (8.1)].Leflunomide is contraindicated for use in pregnant women [see Contraindications (4)]. Exclude pregnancy before starting treatment with leflunomide in females of reproductive potential [see Dosage and Administration (2.2)]. Advise females of reproductive potential to use effective contraception during leflunomide treatment and during an accelerated drug elimination procedure after leflunomide treatment [see Use in Specific Populations (8.3)]. If a woman becomes pregnant while taking leflunomide, stop treatment with leflunomide, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve non-detectable plasma concentrations of teriflunomide, the active metabolite of leflunomide [see Warnings and Precautions (5.3)].Upon discontinuing leflunomide, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving leflunomide treatment who wish to become pregnant must discontinue leflunomide and undergo an accelerated drug elimination procedure, which includes verification that plasma concentrations of the active metabolite of leflunomide, teriflunomide, are less than 0.02 mg/L (0.02 mcg/mL). Based on animal data, human plasma concentrations of teriflunomide of less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryo-fetal risk [see Contraindications (4), Warnings and Precautions (5.3), and Use in Specific Populations (8.1)].

5.2 Hepatotoxicity

Severe liver injury, including fatal liver failure, has been reported in some patients treated with leflunomide. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) of greater than twice the upper limits of normal (>2×ULN) before initiating treatment, should not be treated with leflunomide. Use caution when leflunomide is given with other potentially hepatotoxic drugs. Monitoring of ALT levels is recommended at least monthly for six months after starting leflunomide, and thereafter every 6–8 weeks. If ALT elevation > 3 fold ULN occurs, interrupt leflunomide therapy and investigate the cause. If likely leflunomide-induced, perform the accelerated drug elimination procedure and monitor liver tests weekly until normalized [see Warnings and Precautions (5.3)]. If leflunomide-induced liver injury is unlikely because some other cause has been found, resumption of leflunomide therapy may be considered.If leflunomide and methotrexate are given concomitantly, follow the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity with ALT, AST, and serum albumin testing.

5.3 Procedure For Accelerated Elimination Of Leflunomide And Its Active Metabolite

  • The active metabolite of leflunomide, teriflunomide, is eliminated slowly from the plasma [see Clinical Pharmacology (12.3)]. Use of an accelerated drug elimination procedure will rapidly reduce plasma concentrations of leflunomide and its active metabolite, teriflunomide. Therefore, an accelerated elimination procedure should be considered at any time after discontinuation of leflunomide, and in particular, when a patient has experienced a severe adverse reaction (e.g., hepatotoxicity, serious infection, bone marrow suppression, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral neuropathy, interstitial lung disease), suspected hypersensitivity, or has become pregnant. It is recommended that all women of childbearing potential undergo an accelerated elimination procedure after stopping leflunomide treatment. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations of less than 0.02 mg/L, the plasma concentration not associated with embryo-fetal toxicity in animals.Elimination can be accelerated by the following procedures:Administer cholestyramine 8 grams orally 3 times daily for 11 days.Alternatively, administer 50 grams of activated charcoal powder (made into a suspension) orally every 12 hours for 11 days.Verify plasma teriflunomide concentrations of less than 0.02 mg/L (0.02 µg/mL) by two separate tests at least 14 days apart. If plasma teriflunomide concentrations are higher than 0.02 mg/L, repeat cholestyramine and/or activated charcoal treatment. The duration of accelerated drug elimination treatment may be modified based on the clinical status and tolerability of the elimination procedure. The procedure may be repeated as needed, based on teriflunomide concentrations and clinical status.Use of the accelerated drug elimination procedure may potentially result in return of disease activity if the patient had been responding to leflunomide treatment.

5.4 Immunosuppression, Bone Marrow Suppression, And Risk Of Serious Infections

Leflunomide is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. If a serious infection occurs, consider interrupting leflunomide therapy and initiating the accelerated drug elimination procedure [see Warnings and Precautions (5.3)]. 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 arthritis, may predispose patients to infection.Cases of tuberculosis were observed in clinical studies with teriflunomide, the metabolite of leflunomide. Prior to initiating leflunomide, all patients should be screened for active and inactive ("latent") tuberculosis infection as per commonly used diagnostic tests.  Leflunomide has not been studied in patients with a positive tuberculosis screen, and the safety of leflunomide in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with leflunomide and monitored carefully during leflunomide treatment for possible reactivation of the infection.Pancytopenia, agranulocytosis and thrombocytopenia have been reported 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, stop treatment with leflunomide, and perform an accelerated drug elimination procedure to reduce the plasma concentration of the leflunomide active metabolite, teriflunomide [see Warnings and Precautions (5.3)].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.

5.5 Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, And Drug Reactions With Eosinophilia And Systemic Symptoms

Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving leflunomide. If a patient taking leflunomide develops any of these conditions, stop leflunomide treatment and perform an accelerated drug elimination procedure [see Warnings and Precautions (5.3)].

5.6 Malignancy And Lymphoproliferative Disorders

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 dosages and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with leflunomide.

5.7 Peripheral Neuropathy

Cases of peripheral neuropathy have been reported in patients receiving leflunomide and in clinical studies with teriflunomide, the active metabolite of leflunomide. Most patients recovered after discontinuation of treatment, 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 leflunomide develops a peripheral neuropathy, consider discontinuing leflunomide therapy and performing an accelerated drug elimination procedure [see Warnings and Precautions (5.3)].

5.8 Interstitial Lung Disease

Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide and has been associated with fatal outcomes [see Adverse Reactions (6.2)]. The risk of leflunomide-associated interstitial lung disease is increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder that 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 leflunomide therapy and for further investigation as appropriate. If discontinuation of leflunomide is necessary, consider performing an accelerated drug elimination procedure [see Warnings and Precautions (5.3)].

5.9 Vaccinations

No clinical data are available on the efficacy and safety of vaccinations during leflunomide treatment. Vaccination with live vaccines is, however, not recommended. The long half-life of the active metabolite of leflunomide should be considered when contemplating administration of a live vaccine after stopping leflunomide.

5.10 Blood Pressure Monitoring

In placebo-controlled studies with the active metabolite of leflunomide, teriflunomide, elevations in blood pressure were observed in some subjects. Blood pressure should be checked before starting treatment with leflunomide and monitored periodically thereafter [See Adverse Reactions (6.1)].

6 Adverse Reactions

  • The following serious adverse reactions are described elsewhere in the labeling:Hepatotoxicity [see Warnings and Precautions (5.2)]Immunosuppression [see Warnings and Precautions (5.4)]Bone marrow suppression [see Warnings and Precautions (5.4)]Stevens-Johnson syndrome and toxic epidermal necrolysis [see Warnings and Precautions (5.5)]Peripheral neuropathy [see Warnings and Precautions (5.7)]Interstitial lung disease [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with leflunomide administered as either monotherapy or in combination with methotrexate or sulfasalazine. Patients ranged in age from 19 to 85 years, with an overall median age of 58 years. The mean duration of RA was 6 years ranging from 0 to 45 years.

6.2 Post Marketing Experience

The following additional adverse reactions have been identified during post approval use of leflunomide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System: agranulocytosis, leukopenia, neutropenia, pancytopenia; Infection: opportunistic infections, severe infections including sepsis; Gastrointestinal: acute hepatic necrosis, colitis, including microscopic colitis, hepatitis, jaundice/cholestasis, pancreatitis; severe liver injury such as hepatic failureImmune System: angioedema;Nervous system: peripheral neuropathy;Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal, pulmonary hypertension;Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis.

7 Drug Interactions

Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Drug interaction studies have been conducted with both leflunomide and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.

8.3 Females And Males Of Reproductive Potential

Leflunomide may cause fetal harm when administered during pregnancy. Advise females of the potential risk to the fetus. Advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment [see Use in Specific Populations (8.1)]. Women receiving leflunomide treatment who wish to become pregnant should discontinue leflunomide and undergo an accelerated drug elimination procedure to achieve plasma teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)].

8.4 Pediatric Use

The safety and effectiveness of leflunomide in pediatric patients have not been established. The safety and effectiveness of leflunomide in the treatment of polyarticular course juvenile idiopathic arthritis (JIA) was evaluated in a single multicenter, double-blind, active-controlled trial in 94 pediatric patients (1:1 randomization) with polyarticular course juvenile idiopathic arthritis (JIA) as defined by the American College of Rheumatology (ACR). In this population, leflunomide treatment was found not to be effective. The safety of leflunomide was studied in 74 patients with polyarticular course JIA ranging in age from 3–17 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.

8.5 Geriatric Use

Of the total number of subjects in controlled clinical trials (Trials 1, 2, and 3) of leflunomide, 234 subjects were 65 years and over [see Clinical Studies (14)]. 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.

8.6 Hepatic Impairment

Dedicated studies of the effect of hepatic impairment on leflunomide pharmacokinetics have not been conducted. Given the need to metabolize leflunomide into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of leflunomide in patients with hepatic impairment is not recommended.

8.7 Renal Impairment

Dedicated studies of the effect of renal impairment on leflunomide pharmacokinetics have not been conducted. Given that the kidney plays an important role in drug elimination, caution should be used when leflunomide is administered to these patients.

10 Overdosage

There have been reports of chronic overdose in patients taking leflunomide at daily dose up to five times the recommended daily dose and reports of acute overdose in adults and children. Adverse events were consistent with the safety profile for leflunomide [See Adverse Reactions (6)]. The most frequent adverse events observed were diarrhea, abdominal pain, leukopenia, anemia and elevated liver function tests.In the event of a significant overdose or toxicity, perform an accelerated drug elimination procedure to accelerate elimination [see  Warnings and Precautions (5.3)]. Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide, the primary metabolite of leflunomide, is not dialyzable [See Clinical Pharmacology (12.3)].

11 Description

Leflunomide is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4´-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.2 and the following structural formula:Leflunomide is available for oral administration as tablets containing 10 or 20  mg of active drug. Combined with leflunomide are the following inactive ingredients: lactose monohydrate, hydroxypropyl cellulose, tartaric acid, sodium lauryl sulfate, magnesium stearate, opadry white, polyvinyl alcohol, titanium dioxide, talc, lecithin, and xanthan gum.

12.1 Mechanism Of Action

Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial 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.

12.3 Pharmacokinetics

Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Plasma concentrations of the parent drug, leflunomide, have been occasionally seen at very low concentrations. Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of the active metabolite, teriflunomide.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

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 teriflunomide 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 teriflunomide 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 teriflunomide 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 or in the in vivo Chinese hamster bone marrow cell cytogenic test. 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 Chinese hamster cell chromosomal aberration assay. TFMA was not clastogenic in the in vivo mouse micronucleus assay or in the in vivo Chinese hamster bone marrow cell cytogenic test. Leflunomide had no effect on fertility or reproductive performance in either male or female rats at oral doses up to 4.0 mg/kg (approximately 1/30 the human teriflunomide exposure based on AUC) [see Use in Specific Populations (8.1, 8.6)].

14 Clinical Studies

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. In these trials, efficacy was evaluated by:1. Reduction of signs and symptoms Relief of signs and symptoms was assessed using the American College of Rheumatology (ACR) 20 Responder Index, a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An "ACR20 Responder" is a patient who had ≥ 20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure [Modified Health Assessment Questionnaire (MHAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. An "ACR20 Responder at Endpoint" is a patient who completed the study and was an ACR20 Responder at the completion of the study. 2. Inhibition of structural damageInhibition of structural damage compared to control was assessed using the Sharp Score, a composite score of X-ray erosions and joint space narrowing in hands/wrists and forefeet.3. Improvement in physical functionImprovement in physical function was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36).In all leflunomide trials, participants of at least 18 years of age and in ARA functional class of I, II or III received an initial loading dosage of 100 mg leflunomide per day for three days, followed by 20 mg per day thereafter.Exclusion criteria included patients with a history of hypersensitivity to the study medication; women who were pregnant or breast-feeding and men or women of child bearing age and potential who had not received contraceptives for at least 4 weeks before entering the study and to be maintained throughout the study and for at least 6 months after discontinuing treatment; Patients with a history of inflammatory disease, impaired renal function or liver impairment, cardiac failure, congenital or acquired immunodeficiency, impaired coagulation, or a history of recent major traumatic injury; patients taking intra-articular or systemic concomitant medications which could affect the safety and/or efficacy of the study medication.

16 How Supplied/Storage And Handling

How SuppliedLeflunomide Tablets, USPStrengthQuantity NDC Number        Description 10 mg30 count bottle   35573-447-30White to off-white, round, biconvex film-coated tabletsdebossed with "10" on one side and "LFL" on the other side. 20 mg30 count bottle   35573-448-30White to off-white, round, biconvex film-coated tabletsdebossed with "20" on one side and "LFL" on the other side.

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