Gen-Leflunomide affects the immune system and reduces swelling and inflammation in the body.
Gen-Leflunomide is used to treat the symptoms of rheumatoid arthritis. Gen-Leflunomide also helps reduce joint damage and improves physical functioning.
Gen-Leflunomide may also be used for other purposes not listed in this medication guide.
An indication is a term used for the list of condition or symptom or illness for which the medicine is prescribed or used by the patient. For example, acetaminophen or paracetamol is used for fever by the patient, or the doctor prescribes it for a headache or body pains. Now fever, headache and body pains are the indications of paracetamol. A patient should be aware of the indications of medications used for common conditions because they can be taken over the counter in the pharmacy meaning without prescription by the Physician.
Treatment of active rheumatoid arthritis (RA) in adults to reduce signs and symptoms, inhibit structural damage as evidence by X-ray erosions and joint space narrowing, and improve physical function.
Aspirin, nonsteroidal anti-inflammatory agents and/or low dose corticosteroids may be continued during treatment with Gen-Leflunomide. The combined use of Gen-Leflunomide with antimalarials, IM or oral gold, D-penicillamine, azathioprine or methotrexate has not been adequately studied.
How should I use Gen-Leflunomide?
Use Gen-Leflunomide as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Take Gen-Leflunomide by mouth with or without food.
It may take 4 weeks or more to notice any improvement while taking Gen-Leflunomide.
If you miss a dose of Gen-Leflunomide, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.
Ask your health care provider any questions you may have about how to use Gen-Leflunomide.
Uses of Gen-Leflunomide in details
There are specific as well as general uses of a drug or medicine. A medicine can be used to prevent a disease, treat a disease over a period or cure a disease. It can also be used to treat the particular symptom of the disease. The drug use depends on the form the patient takes it. It may be more useful in injection form or sometimes in tablet form. The drug can be used for a single troubling symptom or a life-threatening condition. While some medications can be stopped after few days, some drugs need to be continued for prolonged period to get the benefit from it.
Use: Labeled Indications
Rheumatoid arthritis: Treatment of adults with active rheumatoid arthritis (RA).
Off Label Uses
BK virus (viremia or nephropathy; in kidney transplant recipients)
Data from a small retrospective study suggest Gen-Leflunomide may be of benefit as a replacement for mycophenolate in kidney transplant recipients with BK virus (viremia or nephropathy).
Gen-Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous. Gen-Leflunomide was approved by FDA and in many other countries (e.g., Canada, Europe) in 1999.
Generic name: Gen-Leflunomide 10mg
Dosage form: tablet, film coated
The information at Drugs.com is not a substitute for medical advice. Always consult your doctor or pharmacist.
The recommended dosage of Gen-Leflunomide is 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient's risk of Gen-Leflunomide-associated hepatotoxicity and Gen-Leflunomide-associated myelosuppression. The loading dosage provides steady-state concentrations more rapidly.
For patients who are at low risk for Gen-Leflunomide-associated hepatotoxicity and Gen-Leflunomide-associated myelosuppression the recommended Gen-Leflunomide loading dosage is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily.
For patients at high risk for Gen-Leflunomide-associated hepatotoxicity (e.g., those taking concomitant methotrexate) or Gen-Leflunomide-associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended Gen-Leflunomide dosage is 20 mg once daily without a loading dose.
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 Gen-Leflunomide, since the active metabolite of Gen-Leflunomide, teriflunomide, is slowly eliminated from the plasma. After stopping Gen-Leflunomide treatment, an accelerated drug elimination procedure is recommended to reduce the plasma concentrations of the active metabolite, teriflunomide. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach undetectable plasma teriflunomide concentrations after stopping Gen-Leflunomide.
Evaluation and Testing Prior to Starting Gen-Leflunomide
Prior to starting Gen-Leflunomide treatment the following evaluations and tests are recommended:
Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection
Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts
For females of reproductive potential, pregnancy testing
Following oral administration, Gen-Leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of Gen-Leflunomide's in vivo activity. Drug interaction studies have been conducted with both Gen-Leflunomide (Gen-Leflunomide) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.
Effect of Potent CYP and Transporter Inducers
Gen-Leflunomide is metabolized by CYP450 metabolizing enzymes. Concomitant use of Gen-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 Gen-Leflunomide when coadministered with rifampin. Because of the potential for Gen-Leflunomide concentrations to continue to increase with multiple dosing, caution should be used if patients are to be receiving both Gen-Leflunomide and rifampin.
Effect on CYP2C8 Substrates
Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking Gen-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.
Effect on Warfarin
Coadministration of Gen-Leflunomide with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of Gen-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 Gen-Leflunomide.
Effect on CYP1A2 Substrates
Teriflunomide, the active metabolite of Gen-Leflunomide, may be a weak inducer of CYP1A2 in vivo. In patients taking Gen-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.
Effect on Organic Anion Transporter 3 (OAT3) Substrates
Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking Gen-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.
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 Gen-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 Gen-Leflunomide.
The following serious adverse reactions are described elsewhere in the labeling:
Bone marrow suppression
Stevens-Johnson syndrome and toxic epidermal necrolysis
Interstitial lung disease
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 Gen-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 Gen-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**
Gen-Leflunomide 20 mg/day
MTX 7.5 - 15 mg/wk
SSZ 2.0 g/day
Gen-Leflunomide 20 mg/day
MTX 7.5 - 15 mg/wk
ALT (SGPT) > 3-fold ULN (n %)
Reversed to ≤ 2-fold ULN:
Timing of Elevation
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, Gen-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 Gen-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 Gen-Leflunomide treatment group).
Table 2: Percentage Of Patients With Adverse Events ≥ 5% In Any Gen-Leflunomide Treated Group in all RA Studies in Patients with RA
All RA Studies
Trial 1 and 2
Trial 3 Hypertension as a preexisting condition was overrepresented in all Gen-Leflunomide treatment groups in phase III trials
Adverse events during a second year of treatment with Gen-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 Gen-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;
The following additional adverse reactions have been identified during postapproval use of Gen-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, 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;
Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis.
Known hypersensitivity to Gen-Leflunomide or to any of the components of Gen-Leflunomide.
Use in pregnancy: Gen-Leflunomide can cause fetal harm when administered to pregnant women.
Women of Childbearing Potential: There are no adequate and well-controlled studies evaluating Gen-Leflunomide in pregnant women. However, based on animal studies, Gen-Leflunomide may increase the risk of fetal death or teratogenic effects when administered to a pregnant woman. Women of childbearing potential must not be started on Gen-Leflunomide until pregnancy is excluded and counseled on the potential for serious risk to the fetus. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, notify the physician immediately for pregnancy testing, and if positive, the physician and the patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of the active metabolite by instituting the drug elimination procedure as follows at the first delay of menses may decrease the risk to the fetus from Gen-Leflunomide. Upon discontinuing Gen-Leflunomide, it is recommended that all women of childbearing potential undergo the drug elimination procedure as described as follows. Women receiving Gen-Leflunomide treatment who wish to become pregnant must discontinue Gen-Leflunomide and undergo the drug elimination procedure which includes verification of M1 metabolite plasma levels <0.02 mg/mL (0.02 mcg/mL). Human plasma levels of the active metabolite (M1) <0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk based on available animal data.
Drug Elimination Procedure: The following drug elimination procedure is recommended to achieve nondetectable plasma levels (<0.02 mg/L or 0.02 mcg/mL) after stoping treatment with Gen-Leflunomide: Administer cholestyramine 8 g 3 times daily for 11 days. The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly.
Verify plasma levels <0.02 mg/L (0.02 mcg/mL) by 2 separate tests at least 14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered. Without the drug elimination procedure, it may take up to 2 years to reach plasma M1 metabolite levels <0.02 mg/L due to individual variation in drug clearance.
DailyMed. "LEFLUNOMIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
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