LEFLUNOMIDE tablet

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

LEFLUNOMIDE (UNII: G162GK9U4W) (LEFLUNOMIDE - UNII:G162GK9U4W)

Available from:

Apotex Corp.

INN (International Name):

LEFLUNOMIDE

Composition:

LEFLUNOMIDE 10 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Leflunomide tablets are indicated for the treatment of adults with active rheumatoid arthritis (RA). 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)]. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to leflunomide during pregnancy. Health care providers and patients are encouraged to report pregnancies by calling 1-877-311-8972 or visit http://www.pregnancystudies.org/participate-in­-a-study/. Risk Summary Leflunomide is contraindicated for use in pregnant women because of the potential for fetal harm. In animal reproduction studies, oral administration of leflunomide during organogenesis at a dose of 1/10 of and equivalent to the maximum recommended human dose (MRHD) based on AUC, respectively in rats and rabbits, caused teratogenicity (rats and rabbits) and embryo-lethality (rats) [see Data] . Pregnancy exposure registry data are not available at this time to inform the presence or absence of drug-associated risk with the use of leflunomide during pregnancy. The background risk of major birth defects and miscarriage for the indicated populations is unknown. The background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, stop treatment with leflunomide, apprise the patient of the potential hazard to a fetus, and perform the accelerated drug elimination procedure to achieve teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)]. Clinical Considerations Fetal/Neonatal adverse reactions Lowering the plasma concentration of the active metabolite, teriflunomide, by instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from leflunomide. The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. Data Animal Data In an embryofetal development study, pregnant rats administered leflunomide during organogenesis from gestation days 7 to 19 at a dose approximately 1/10 of the MRHD (on an AUC basis at a maternal oral dose of 15 mg/kg), teratogenic effects, most notably anophthalmia or microophthalmia and internal hydrocephalus, were observed. Under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. In an embryofetal development study, pregnant rabbits administered leflunomide during organogenesis from gestation days 6 to 18 at a dose approximately equivalent to the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg), a teratogenic finding of fused, dysplastic sternebrae was observed. Leflunomide was not teratogenic in rats and rabbits at doses approximately 1/150 and 1/10 of the MRHD, respectively (on an AUC basis at maternal oral dose of 1 mg/kg in both rats and rabbits). In a pre- and post-natal development study, when female rats were treated leflunomide at a dose that was approximately 1/100 of the MRHD (on an AUC basis at a maternal dose of 1.25 mg/kg) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival. Risk Summary Clinical lactation studies have not been conducted to assess the presence of leflunomide in human milk, the effects of leflunomide on the breastfed child, or the effects of leflunomide on milk production. Because of the potential for serious adverse reactions in a breastfed infant from leflunomide, advise a nursing woman to discontinue breastfeeding during treatment with leflunomide. 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)]. Pregnancy Testing Exclude pregnancy in females of reproductive potential before starting treatment with leflunomide. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with leflunomide and while undergoing a drug elimination procedure until verification that the plasma teriflunomide concentration is less than 0.02 mg/L [see Warnings and Precautions (5.3)]. 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 to 17 years (47 patients from the active-controlled study and 27 from an open-label safety and pharmacokinetic study). The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. Less common adverse events included anemia, hypertension, and weight loss. Fourteen pediatric patients experienced ALT and/or AST elevations, nine between 1.2 and 3-fold the upper limit of normal, five between 3 and 8-fold the upper limit of normal. 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. 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. 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.

Product summary:

How Supplied Leflunomide tablets, USP Leflunomide tablets, USP 10 mg are white, round tablets engraved “LE” over “10” on one side and engraved “APO” on the other side. They are supplied as follows: Bottles of 30                 NDC 60505-2502-1 Bottles of 100               NDC 60505-2502-2 Bottles of 1,000             NDC 60505-2502-3 Leflunomide tablets, USP 20 mg are white, triangular-shaped tablets engraved “LE” over “20” on one side and engraved “APO” on the other side. They are supplied as follows: Bottles of 30                 NDC 60505-2503-1 Bottles of 100               NDC 60505-2503-2 Bottles of 1,000             NDC 60505-2503-3 Store at 25°C (77°F); excursions permitted from 15° to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Protect from light.

Authorization status:

Abbreviated New Drug Application

Summary of Product characteristics

LEFLUNOMIDE- LEFLUNOMIDE TABLET
APOTEX CORP.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
LEFLUNOMIDE TABLETS
SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR
LEFLUNOMIDE TABLETS.
LEFLUNOMIDE TABLETS, FOR ORAL USE
INITIAL U.S. APPROVAL: 1998
WARNING: EMBRYO-FETAL TOXICITY AND HEPATOTOXICITY
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
EMBRYO-FETAL TOXICITY
TERATOGENICITY AND EMBRYO-LETHALITY OCCURRED IN ANIMALS ADMINISTERED
LEFLUNOMIDE.
(5.1, 8.1)
EXCLUDE PREGNANCY PRIOR TO INITIATING LEFLUNOMIDE THERAPY. (5.1, 8.3)
ADVISE USE OF EFFECTIVE CONTRACEPTION IN FEMALES OF REPRODUCTIVE
POTENTIAL DURING
TREATMENT AND DURING A DRUG ELIMINATION PROCEDURE. (5.1, 5.3, 8.3)
STOP LEFLUNOMIDE AND USE AN ACCELERATED DRUG ELIMINATION PROCEDURE IF
THE PATIENT
BECOMES PREGNANT. (5.1, 5.3, 8.1)
HEPATOTOXICITY
SEVERE LIVER INJURY AND FATAL LIVER FAILURE HAVE BEEN REPORTED. (5.2)
AVOID LEFLUNOMIDE USE IN PATIENTS WITH PRE-EXISTING LIVER DISEASE, OR
THOSE WITH
SERUM ALANINE AMINOTRANSFERASE (ALT) >2XULN. (5.2, 8.6)
USE CAUTION WHEN LEFLUNOMIDE IS GIVEN WITH OTHER POTENTIALLY
HEPATOTOXIC DRUGS.
(5.2)
MONITOR ALT LEVELS. INTERRUPT LEFLUNOMIDE TREATMENT IF ALT ELEVATION >
3 FOLD ULN. IF
LIKELY LEFLUNOMIDE-INDUCED, START ACCELERATED DRUG ELIMINATION
PROCEDURE AND
MONITOR LIVER TESTS WEEKLY UNTIL NORMALIZED. (5.2, 5.3)
INDICATIONS AND USAGE
Leflunomide is a pyrimidine synthesis inhibitor indicated for the
treatment of adults with active rheumatoid
arthritis. (1)
DOSAGE AND ADMINISTRATION
Loading dosage for patients at low risk for leflunomide-associated
hepatotoxicity and leflunomide-
associated myelosuppression: 100 mg daily for 3 days. (2.1)
Maintenance dosage: 20 mg daily. (2.1)
Maximum recommended daily dosage: 20 mg once daily. (2.1)
If 20 mg once daily is not tolerated, may decrease dosage to 10 mg
once daily. (2.1)
Screen patients for active and latent tuberculosis, pregnancy test
(females), blood pressure, and
laboratory tests before