Antirheumatic Agent

Leflunomide

Approved 21 Nov 2011OralTablet

The FDA lists this product in 24 strengths and forms.

Indications

Leflunomide tablets USP are indicated for the treatment of adults with active rheumatoid arthritis (RA). Leflunomide is a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis. (1)

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)]. · Pregnancy. (4, 5.1, 8.1) · Severe hepatic impairment. (4, 5.2) · Hypersensitivity to leflunomide or any of its inactive components. (4) · Current teriflunomide treatment. (4)

Warnings and precautions

· After stopping leflunomide, it is recommended that an accelerated drug elimination procedure be used to reduce the plasma concentrations of the active metabolite, teriflunomide. (5.3) · Severe infections (including sepsis), pancytopenia, agranulocytosis and thrombocytopenia: Stop leflunomide and use accelerated elimination procedure. Do not start leflunomide in patients with active infection. Monitor CBCs during treatment with leflunomide.

(5.4) · Stevens-Johnson syndrome and toxic epidermal necrolysis: Stop leflunomide and use accelerated elimination procedure. (5.5) · Peripheral neuropathy: If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing leflunomide. (5.7) · Interstitial lung disease: May be fatal. New onset or worsening symptoms may necessitate discontinuation of leflunomide and initiation of accelerated elimination procedure.

(5.8) · Increased blood pressure: Monitor and treat. (5.10)

5.1Embryo-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)] .

At a glance

Brand name: Leflunomide
Pharmacologic class: Antirheumatic Agent
Route: Oral
Dosage form: Tablet
Applicant: Alembic Pharms LTD
Status: Prescription
FDA approval: 21 Nov 2011
Application: ANDA091369-002

Contraindications

Warnings and precautions

(5.8) · Increased blood pressure: Monitor and treat. (5.10)

5.1Embryo-Fetal Toxicity

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. Effect of potent CYP and transporter inducers Leflunomide is metabolized by CYP450 metabolizing enzymes.

Concomitant use of leflunomide and rifampin, a potent inducer of CYP and transporters, increased the plasma concentration of teriflunomide by 40%. However, when co-administered with the metabolite, teriflunomide, rifampin did not affect its pharmacokinetics. No dosage adjustment is recommended for leflunomide when coadministered with rifampin. Because of the potential for leflunomide concentrations to continue to increase with multiple dosing, caution should be used if patients are to be receiving both leflunomide and rifampin [see Clinical Pharmacology (12.3)] .

Effect on CYP2C8 substrates Teriflunomide is an inhibitor of CYP2C8 in vivo . In patients taking leflunomide, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required [see Clinical Pharmacology (12.3)] . Effect on warfarin Coadministration of leflunomide with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of leflunomide, may decrease peak INR by approximately 25%.

Effect on oral contraceptives Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with leflunomide [see Clinical Pharmacology (12.3)] . Effect on CYP1A2 substrates Teriflunomide, the active metabolite of leflunomide, may be a weak inducer of CYP1A2 in vivo . In patients taking leflunomide, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced.

Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required [see Clinical Pharmacology (12.3)] . Effect on organic anion transporter 3 (OAT3) substrates Teriflunomide inhibits the activity of OAT3 in vivo . In patients taking leflunomide, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased.

Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required [see Clinical Pharmacology (12.3)] . Effect on BCRP and organic anion transporting polypeptide B1 and B3 (OATP1B1/1B3) substrates Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo . For a patient taking leflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking leflunomide [see Clinical Pharmacology (12.3)] . · Drugs metabolized by CYP2C8 and OAT3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs.

(7) · Teriflunomide may increase exposure of ethinylestradiol and levonorgestrel. Choose an appropriate oral contraceptive. (7) · Drugs metabolized by CYP1A2: Monitor patients because teriflunomide may decrease exposure of these drugs. (7) · Warfarin: Monitor INR as teriflunomide may decrease INR. (7) · Drugs metabolized by BCRP and OATP1B1/B3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs.

(7) · Rosuvastatin: The dose of rosuvastatin should not exceed 10 mg once daily in patients taking leflunomide. (7)

Pregnancy and breastfeeding

8.1Pregnancy 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-ina-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.

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)] · The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, dyspepsia.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatc

6.1Clinical 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. Elevation of Liver Enzymes Treatment with leflunomide was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤ 2-fold ULN) and usually resolved while continuing treatment.

Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial 1 and Trial 2. It was notable that the absence of folate use in Trial 3 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate. Table 1. Liver Enzyme Elevations >3-fold Upper Limits of Normal (ULN) in Patients with RA in Trials 1, 2, and 3* Trial 1 Trial 2 Trial 3* Leflunomide 20 mg/day (n=182) PL (n=118) MTX 7.5 to 15 mg/wk(n=182) Leflunomide 20mg/day (n=133) PL (n=92) SSZ 2 g/day (n=133) Leflunomide 20 mg/day(n=501) MTX 7.5 to 15 mg/wk (n=498) ALT (SGPT) >3-fold ULN (n %) Reversed to≤ 2foldULN: 8(4.4) 8 3(2.5) 3 5(2.7) 5 2(1.5) 2 1(1.1) 1 2(1.5) 2 13(2.6) 12 83 (16.7) 82 Timing of Elevation 0 to 3 Months 6 1 1 2 1 2 7 27 4 to 6 Months 1 1 3 - - - 1 34 7 to 9 Months 1 1 1 - - - - 16 10 to 12 Months - - - - - - 5 6 MTX = methotrexate,PL = placebo,SSZ = sulfasalazine, ULN = Upper limitofnormal *Only10% ofpatients in Trial 3 receivedfolate.All patients in Trial 1 receivedfolate.

In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide was administered to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo. Most Common Adverse Reactions The most common adverse reactions in leflunomide-treated patients with RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash.

Table 2 displays the most common adverse reactions in the controlled studies in patients with RA at one year (≥ 5% in any leflunomide treatment group). Table 2. Percentage Of Patients With Adverse Events ³ 5% In Any Leflunomide Treated Group in all RA Studies in Patients with RA Placebo-Controlled Trials Active-Controlled Trials All RA Studies Trial 1 and 2 Trial 3 1 Leflunomide 20 mg/day(N=315) PL (N=210) SSZ 2 g/day (N=133) MTX 7.5 to 15 mg/wk (N=182) Leflunomide 20 mg/day(N=501) MTX 7 .5 to 15 mg/wk (N=498) Leflunomide (N=1339) 2 Diarrhea 27% 12% 10% 20% 22% 10% 17% Headache 13% 11% 12% 21% 10% 8% 7% Nausea 13% 11% 19% 18% 13% 18% 9% Rash 12% 7% 11% 9% 11% 10% 10% AbnormalLiverEnzymes 10% 2% 4% 10% 6% 17% 5% Alopecia 9% 1% 6% 6% 17% 10% 10% Hypertension 3 9% 4% 4% 3% 10% 4% 10% Asthenia 6% 4% 5% 6% 3% 3% 3% Back Pain 6% 3% 4% 9% 8% 7% 5% GI/AbdominalPain 6% 4% 7% 8% 8% 8% 5% AbdominalPain 5% 4% 4% 8% 6% 4% 6% AllergicReaction 5% 2% 0% 6% 1% 2% 2% Bronchitis 5% 2% 4% 7% 8% 7% 7% Dizziness 5% 3% 6% 5% 7% 6% 4% MouthUlcer 5% 4% 3% 10% 3% 6% 3% Pruritus 5% 2% 3% 2% 6% 2% 4% Rhinitis 5% 2% 4% 3% 2% 2% 2% Vomiting 5% 4% 4% 3% 3% 3% 3% Tenosynovitis 2% 0% 1% 2% 5% 1% 3% MTX = methotrexate, PL = placebo, SSZ = sulfasalazine 1 Only 10% of patients in Trial3 received folate.

All patients in Trial 1 received folate; none in Trial 2 received folate. 2 Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 months). 3 Hypertension as a preexisting condition was overrepresented in all leflunomide treatment groups in phase III trials. 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.

Less Common Adverse Reactions In addition, in controlled clinical trials, the following adverse events in the leflunomide treatment group occurred at a higher incidence than in the placebo group. These adverse events were deemed possibly related to the study drug. Blood and Lymphatic System: leukocytosis, thrombocytopenia; Cardiovascular: chest pain, palpitation, thrombophlebitis of the leg, varicose vein; Eye: blurred vision, eye disorder, papilledema, retinal disorder, retinal hemorrhage; Gastrointestinal: alkaline phosphatase increased, anorexia, bilirubinemia, flatulence, gamma-GT increased, salivary gland enlarged, sore throat, vomiting, dry mouth; General Disorders : malaise; Immune System: anaphylactic reaction; Infection: abscess, flu syndrome, vaginal moniliasis; Nervous System: dizziness, headache, somnolence; Respiratory System: dyspnea;

6.2Post Marketing Experience

The following additional adverse reactions have been identified during postapproval 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 failure Immune 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.

Leflunomide

Indications

Contraindications

Warnings and precautions

5.1Embryo-Fetal Toxicity

At a glance

Two medicines in one question?

Leflunomide

Indications

Contraindications

Warnings and precautions

5.1Embryo-Fetal Toxicity

At a glance

Two medicines in one question?

5.2Hepatotoxicity

5.3Procedure for Accelerated Elimination of Leflunomide

5.4Immunosuppression, Bone Marrow Suppression, and Risk of Serious Infections

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Exposure Registry

Adverse reactions

6.1Clinical Trials Experience

6.2Post Marketing Experience

Composition

Strengths and forms

Official product information