Leflunomide And Diclofenac Sodium Gel
FDA Drug Information • Also known as: Lefluniclo
- Brand Names
- Lefluniclo
- Dosage Form
- KIT
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
WARNING: EMBRYO-FETAL TOXICITY and HEPATOTOXICITY Embryo-Fetal Toxicity Leflunomide tablet is contraindicated for use in pregnant women because of the potential for fetal harm. Teratogenicity and embryo-lethality occurred in animals administered leflunomide at doses lower than the human exposure level. Exclude pregnancy before the start of treatment with leflunomide tablets in females of reproductive potential. Advise females of reproductive potential to use effective contraception during leflunomide tablets treatment and during an accelerated drug elimination procedure after leflunomide tablets treatment. Stop leflunomide tablets and use an accelerated drug elimination procedure if the patient becomes pregnant. [see Contraindications (4), Warnings and Precautions (5.1, 5.3), Use in Special Populations (8.1, 8.3)], and Clinical Pharmacology (12.3)] Hepatotoxicity Severe liver injury, including fatal liver failure, has been reported in patients treated with leflunomide tablets. Leflunomide tablet is contraindicated in patients with severe hepatic impairment. Concomitant use of leflunomide tablets with other potentially hepatotoxic drugs may increase the risk of liver injury. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2xULN before initiating treatment, are at increased risk and should not be treated with leflunomide tablets. Monitor ALT levels at least monthly for six months after starting leflunomide tablets, and thereafter every 6 to 8 weeks. If leflunomide-induced liver injury is suspected, stop leflunomide tablets treatment, start an accelerated drug elimination procedure, and monitor liver tests weekly until normalized. [see Contraindications (4), Warnings and Precautions (5.2, 5.3), Use in Special Populations (8.6)]
Description
LEFLUNICLO DESCRIPTION LEFFLUNICLO is supplied as 2 components in a kit: 1 BOTTLE OF LEFLUNOMIDE TABLETS USP; 20MG (30 TABLETS) White to off-white, round film coated tablet, debossed with "L" on one side and "A5" on the other side. 1 TUBE OF DICLOFENAC SODIUM (NSAID*) 1% (equivalent to 0.93% diclofenac), 100 g TUBE. 11 DESCRIPTION Leflunomide USP is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4´-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C 12 H 9 F 3 N 2 O 2 , a molecular weight of 270.2 and the following structural formula: Leflunomide USP is available for oral administration as film coated tablets containing 10, 20 mg of active drug. Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, corn starch, HPMC 2910/Hypromellose USP (6 mPas), Titanium Dioxide USP, Macrogol/PEG 6000 NF, Talc USP and Iron Oxide Yellow NF (20 mg tablet only). Image
What Is Leflunomide And Diclofenac Sodium Gel Used For?
INDICATION AND USAGE For the treatment of adults with active rheumatoid arthritis (RA). For the temporary relief of arthritis pain. 1 INDICATIONS AND USAGE Leflunomide tablets USP are indicated for the treatment of adults with active rheumatoid arthritis (RA). Uses
Dosage and Administration
DOSAGE AND ADMINISTRATION SEE PRESCRIBING DIRECTIONS FOR EACH COMPONENT CONTAINED IN THIS KIT Take one leflunimide 20 mg once daily. The maximum recommended daily dosage is 20 mg once per day. Apply 2-4 grams of diclofenac 1% gel to treated area as needed up to 4 times per day. Do not usea on more than 2 body areas at the same time. "These highlights do not include all the information needed to use" "see full prescribing information for" and "Initial U.S. Approval" Loading dosage for patients at low risk for leflunomide tablets -associated hepatotoxicity and leflunomide tablets-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 starting leflunomide tablets. (2.2) 2.1 Recommended Dosage The recommended dosage of leflunomide tablets USP is 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient's risk of leflunomide tablets USP -associated hepatotoxicity and leflunomide tablets -associated myelosuppression. The loading dosage provides steady-state concentrations more rapidly. For patients who are at low risk for leflunomide tablets -associated hepatotoxicity and leflunomide tablets USP - associated myelosuppression the recommended leflunomide tablets USP loading dosage is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily. For patients at high risk for leflunomide tablets USP -associated hepatotoxicity (e.g., those taking concomitant methotrexate) or leflunomide tablets -associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended leflunomide tablets USP 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 tablets, since the active metabolite of leflunomide, teriflunomide, is slowly eliminated from the plasma [see Clinical Pharmacology (12.3)]. After stopping leflunomide tablets 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 tablets [see Clinical Pharmacology (12.3)]. 2.2 Evaluation and Testing Prior to Starting leflunomide tablets USP Prior to starting leflunomide tablets...
Side Effects (Adverse Reactions)
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)] The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide tablets treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, 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 6.1 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 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. 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). 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...
Warnings and Precautions
Warnings For external use only Allergy alert: Diclofenac may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include:
Drug Interactions
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. 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...
Contraindications
CONTRADICTIONS Do not use if known hypersensitivity to any of the listed ingredients of any of the components included on the kit. 4 CONTRAINDICATIONS 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 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 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)
Pregnancy and Breastfeeding
8.1 Pregnancy 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...
Overdosage
10 OVERDOSAGE There have been reports of chronic overdose in patients taking leflunomide tablets 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 tablets [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 )].
How Supplied
Store at 20°-25°C (68° to 77°F); Keep away from heat and flame. Protect from freezing. [See USP Controlled Room Temperature.] Protect from light. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Leflunomide tablets USP; 10 mg and 20 mg Strength Quantity NDC Number Description 10 mg 30 count bottle packed in a monocarton 70748-129-06 White to off-white, round film coated tablet, debossed with "L" on one side and "A4" on the other side. 20 mg 30 count bottle packed in a monocarton 70748-130-06 Yellow colour, film coated, round shaped tablet, debossed with "L" on one side and "A5" on the other side. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.