Leflunomide

10MG, 20MG tabletVerenigde StatenIn de handelToegelaten op 13 sep 2005

Inhoud in het Engels

Openen in het registerVraag Osler ernaar

Indicaties

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

Contra-indicaties

Leflunomide tablet is contraindicated in: Pregnant women. Leflunomide tablets may cause fetal harm. If a woman becomes pregnant while taking this drug, stop leflunomide tablets, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure [see Warnings and Precautions ( 5.1 , 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 tablets. 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 tablets or any of its inactive components. ( 4 ) Current teriflunomide treatment.

( 4 )

Waarschuwingen en voorzorgen

After stopping leflunomide tablets, 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 tablets and use accelerated elimination procedure. Do not start leflunomide tablets in patients with active infection. Monitor CBCs during treatment with leflunomide tablets ( 5.4 ) Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS): Stop leflunomide tablets and use accelerated elimination procedure.

( 5.5 ) Skin ulcers: If skin ulcer is suspected, discontinue leflunomide treatment and consider an accelerated drug elimination procedure. ( 5.6 ) Peripheral neuropathy: If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing leflunomide tablets. ( 5.8 ) Interstitial lung disease: May be fatal. New onset or worsening symptoms may necessitate discontinuation of leflunomide tablets and initiation of accelerated elimination procedure.

Contra-indicaties

( 4 )

Waarschuwingen en voorzorgen

Interacties

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 tablets 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 tablets when coadministered with rifampin. Because of the potential for leflunomide tablets concentrations to continue to increase with multiple dosing, caution should be used if patients are to be receiving both leflunomide tablets and rifampin [see Clinical Pharmacology ( 12.3 )].

Effect on CYP2C8 Substrates Teriflunomide is an inhibitor of CYP2C8 in vivo . In patients taking leflunomide tablets, 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 tablets with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of leflunomide tablets, 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 tablets [ see Clinical Pharmacology ( 12.3 )]. Effect on CYP1A2 Substrates Teriflunomide, the active metabolite of leflunomide tablets, may be a weak inducer of CYP1A2 in vivo . In patients taking leflunomide tablets, 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 tablets, 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 tablets, 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 tablets [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 tablets. ( 7 )

Zwangerschap en borstvoeding

8.1Pregnancy Risk Summary

Leflunomide tablet 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 tablets 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 tablets, 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 tablets. 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 with 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.

Bijwerkingen

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 )] Serious infections [see Warnings and Precautions ( 5.4 )] Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reactions with eosinophilia and systemic symptoms [see Warnings and Precautions ( 5.5 )] Skin ulcers [see Warnings and Precautions ( 5.6 )] Peripheral neuropathy [see Warnings and Precautions ( 5.8 )] Interstitial lung disease [see Warnings and Precautions ( 5.9 )] The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide tablets treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes and dyspepsia.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceutical, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 tablets 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 tablets 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 tablets 20mg/day (n=182) PL (n=118) MTX 7.5 to 15 mg/wk (n=182) Leflunomide tablets 20mg/day (n=133) PL (n=92) SSZ 2 mg/day (n=133) Leflunomide tablets 20mg/day (n=501) MTX 7.5 to 15 mg/wk (n=498) ALT (SGPT) >3-fold ULN (n %) 8(4.4) 3(2.5) 5(2.7) 2(1.5) 1(1.1) 2(1.5) 13(2.6) 83(16.7) Reversed to ≤ 2-fold ULN: 8 3 5 2 1 2 12 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 limit of normal *Only 10% of patients in Trial 3 received folate.

All patients in Trial 1 received folate. In a 6-month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide tablets 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 tablets -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 tablets treatment group). Table 2. Percentage Of Patients With Adverse Events ≥5% In Any Leflunomide tablets 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 * Leflunomide tablets 20mg/day (n=315) PL (n=210) SSZ 2 g/day (n=133) MTX 7.5-15 mg/wk (n=182) Leflunomide tablets 20mg/day (n=501) MTX 7.5-15 mg/wk (n=498) Leflunomide tablets (n=1339) † 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% Abnormal Liver Enzymes 10% 2% 4% 10% 6% 17% 5% Alopecia 9% 1% 6% 6% 17% 10% 10% Hypertension † 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/Abdominal Pain 6% 4% 7% 8% 8% 8% 5% Abdominal Pain 5% 4% 4% 8% 6% 4% 6% Allergic Reaction 5% 2% 0% 6% 1% 2% 2% Bronchitis 5% 2% 4% 7% 8% 7% 7% Dizziness 5% 3% 6% 5% 7% 6% 4% Mouth Ulcer 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 * Only 10% of patients in Trial 3 received folate.

All patients in Trial 1 received folate; none in Trial 2 received folate. † Includes all controlled and uncontrolled trials with leflunomide tablets (duration up to 12 months). ‡ Hypertension as a preexisting condition was overrepresented in all leflunomide tablets treatment groups in phase III trials Adverse events during a second year of treatment with leflunomide tablets 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 tablets 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

6.2Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use of leflunomide tablets. 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, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis.

Verpakking	Code	Status
LEFLUNOMIDE 20MG	ANDA077086-002	Prescription
LEFLUNOMIDE 10MG	ANDA077086-001	Prescription
LEFLUNOMIDE 20MG	ANDA211863-002	Prescription
LEFLUNOMIDE 10MG	ANDA211863-001	Prescription
LEFLUNOMIDE 20MG	ANDA213652-002	Prescription
LEFLUNOMIDE 10MG	ANDA213652-001	Prescription
LEFLUNOMIDE 10MG	ANDA077084-001	Discontinued
LEFLUNOMIDE 20MG	ANDA077084-002	Discontinued
LEFLUNOMIDE 20MG	ANDA077090-002	Prescription
LEFLUNOMIDE 10MG	ANDA077090-001	Prescription
LEFLUNOMIDE 20MG	ANDA212308-002	Prescription
LEFLUNOMIDE 10MG	ANDA212308-001	Prescription
LEFLUNOMIDE 10MG	ANDA077085-001	Discontinued
LEFLUNOMIDE 20MG	ANDA077085-002	Discontinued
LEFLUNOMIDE 20MG	ANDA091369-002	Prescription
LEFLUNOMIDE 10MG	ANDA091369-001	Prescription
LEFLUNOMIDE 20MG	ANDA077083-002	Discontinued
LEFLUNOMIDE 10MG	ANDA077083-001	Discontinued
LEFLUNOMIDE 20MG	ANDA077087-002	Prescription
LEFLUNOMIDE 10MG	ANDA077087-001	Prescription
LEFLUNOMIDE 10MG	ANDA212453-001	Prescription
LEFLUNOMIDE 20MG	ANDA212453-002	Prescription
LEFLUNOMIDE 10MG	ANDA213497-001	Prescription
LEFLUNOMIDE 20MG	ANDA213497-002	Prescription

Leflunomide

Indicaties

Contra-indicaties

Waarschuwingen en voorzorgen

Twee geneesmiddelen in één vraag?

Leflunomide

Indicaties

Contra-indicaties

Waarschuwingen en voorzorgen

Twee geneesmiddelen in één vraag?

5.1Embryo-Fetal Toxicity

5.2Hepatotoxicity

5.3Procedure for Accelerated Elimination

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

Interacties

Zwangerschap en borstvoeding

8.1Pregnancy Risk Summary

Bijwerkingen

6.1Clinical Trials Experience

6.2Postmarketing Experience

In andere landen

Verpakkingen

Documenten

Bronnen en licenties

In het kort