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ODAN-LEFLUNOMIDE is a brand name for Leflunomide, supplied as a tablet. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: AND CLINICAL USE ..................................................................... 3 CONTRAINDICATIONS ........................................................................................... 3 WARNINGS AND PRECAUTIONS ......................................................................... 5 ADVERSE REACTIONS…
Verbatim from this product's HC label. Tap a section to expand.
Recommended Dose and Dosage Adjustment Loading Dose Due to the long half-life in patients with rheumatoid arthritis and recommended dosing interval (24 hr), a loading dose is needed to yield steady-state concentrations more rapidly.
Maintenance Therapy Daily dosing of 20 mg is recommended for treatment of patients with rheumatoid arthritis. A small cohort of patients (n=104) treated with 25 mg/day experienced a greater incidence of side effects: alopecia, weight loss, liver enzyme elevations.
Doses higher than 20 mg/day are not recommended. If dosing at 20 mg/day is not well tolerated clinically, the dose may be decreased to 10 mg daily. Due to the prolonged half-life of the active metabolite of leflunomide, patients should be carefully observed after dose reduction since it may take several weeks for metabolite levels to decline (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests section).
A treatment effect may be evident after 4 weeks and may further improve up to 4 to 6 months after start of treatment. Geriatric Use No dosage adjustment is needed in patients over 65 years of age. Pediatrics Use The use in patients less than 18 years of age is contraindicated.
Impaired Renal Function Because the kidney plays a role in the elimination of leflunomide, and without sufficient studies of the use of leflunomide in patients with renal insufficiency, caution should be used when considering the administration of leflunomide to patients with mild renal insufficiency (see CONTRAINDICATIONS section).
Missed Dose If the patient forgot to take a tablet of leflunomide they should be advised to take it as soon as they remember, unless it is nearly time for their next dose. The patient should be advised not to double-up on the next dose to make up for the missed dose.
Administration ODAN-LEFLUNOMIDE tablets should be swallowed whole, with sufficient liquid. ODAN- LEFLUNOMIDE can be taken with or without food, without regard to meals, at the same time everyday. Page 27 of
Adverse Drug Reaction Overview Hypertension, gastrointestinal disturbances, weight loss, headache, dizziness, paresthesia, asthenia, musculoskeletal and skin disorder are considered as some common adverse reactions seen with leflunomide.
Leucopenia and hypersensitivity reactions may occur and cases of Stevens-Johnson syndrome or toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Hepatotoxicity has occurred.
It is usually mild and reversible but cases of severe, sometimes fatal, liver disease, including acute hepatic necrosis, have been observed. There have been reports of pancreatitis, interstitial lung disease, and infections, including fatal sepsis.
(See Clinical Trial Adverse Drug Reactions and Less Common Clinical Trial Adverse Drug Reactions /Post-Market Adverse Drug Reactions sections) Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.
Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. There were a total of 5419 adverse events reported in 1339 subjects treated with ARAVA. 5% discontinued study treatment due to adverse events.
There was a total of 377 serious adverse events which occurred in 294 (22%) leflunomide treated subjects. The percent of leflunomide treated patients experiencing an adverse event was similar to methotrexate, the next largest treatment population.
9% methotrexate). These disorders may as well be associated with concomitant NSAID administration, common in all treatment groups. The occurrences of hypertension and hypokalemia observed in patients treated with leflunomide may have been influenced by concomitant NSAID and/or steroid use.
General The active metabolite of leflunomide, A771726, has a long half-life. g. hepatotoxicity, haematotoxicity or allergic reactions, see below), even if the treatment with leflunomide has been stopped. For the management of the above- mentioned toxicities a washout procedure should be performed.
If a severe adverse reaction to leflunomide occurs, or if for any other reason A771726 needs to be cleared rapidly from the body, cholestyramine or activated charcoal has to be initiated and continued/repeated as clinically necessary (see OVERDOSAGE section).
For suspected severe immunologic/allergic reactions, more prolonged cholestyramine or activated charcoal administration may be necessary to achieve rapid and sufficient clearance (see below the Washout Procedures). g. methotrexate) after treatment with leflunomide a washout procedure should be performed since there exist a possibility of additive risks of adverse events for a long time after the switching (see below the Washout Procedures and see also the CONTRAINDICATIONS and DRUG INTERACTIONS sections).
Recent treatment with hepatotoxic DMARDs may result in increased side effects; therefore, the initiation of leflunomide treatment has to be carefully considered regarding these benefit/risk aspects. Caution and careful monitoring of liver and bone marrow function is necessary if these drugs are used concomitantly (see CONTRAINDICATIONS and DRUG INTERACTIONS sections).
Co-administration of teriflunomide with ODAN-LEFLUNOMIDE is not recommended, since it will lead to an increase in the plasma exposure of A771726 in an additive manner, as leflunomide is the parent compound of teriflunomide. Washout Procedures One of the following is recommended to achieve a fast decrease in plasma levels after stopping treatment with leflunomide: 1) 8 g cholestyramine 3 times daily for 11 days OR 2) 50 g activated charcoal 4 times daily for 11 days The duration may be modified depending on clinical or laboratory variables.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Monitoring blood pressure in patients on leflunomide Page 16 of 70 should be considered as addition to the recommended Monitoring of hematologic and hepatic function. (See WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests section) Adverse reactions associated with the use of leflunomide in rheumatoid arthritis include diarrhea, elevated liver transaminases (ALT [SGPT] and AST [SGOT]), alopecia, rash, and hypertension.
In the controlled studies, the following adverse events were reported regardless of causality: Page 17 of 70 Table 2. Percentage of Patients with Adverse Events ≥3% in any Leflunomide Treated Group All RA Studies Placebo-Controlled Trials Active-Controlled Trials MN 301 and US 301 MN 302† LEF (N=1339) LEF (N=315) PBO (N=210) SSZ (N=133) MTX (N=182) LEF (N=501) MTX (N=498) GENERAL DISORDER Allergic Reaction 2% 5% 2% 0% 6% 1% 2% Worsening RA 8% 5% 11% 20% 4% 17% 19% Asthenia 3% 6% 4% 5% 6% 3% 3% Flu Syndrome 2% 4% 2% 0% 7% 0% 0% Infection 4% 0% 0% 0% 0% 0% 0% Injury Accident 5% 7% 5% 3% 11% 6% 7% Pain 2% 4% 2% 2% 5% 1% <1% Abdominal Pain 6% 5% 4% 4% 8% 6% 4% Back Pain 5% 6% 3% 4% 9% 8% 7% CARDIOVASCULAR DISORDERS Hypertension 10% 9% 4% 4% 3% 10% 4% Chest Pain 2% 4% 2% 2% 4% 1% 2% GASTROINTESTINAL DISORDERS Anorexia 3% 3% 2% 5% 2% 3% 3% Diarrhea 17% 27% 12% 10% 20% 22% 10% Dyspepsia 5% 10% 10% 9% 13% 6% 7% Gastroenteritis 3% 1% 1% 0% 6% 3% 3% Abnormal Liver Function Tests 5% 10% 2% 4% 10% 6% 17% Nausea 9% 13% 11% 19% 18% 13% 18% GI/Abdominal Pain 5% 6% 4% 7% 8% 8% 8% Mouth Ulcer 3% 5% 4% 3% 10% 3% 6% Vomiting 3% 5% 4% 4% 3% 3% 3% BLOOD AND LYMPHATIC DISORDERS Leucopenia ( 2 G/L) 3% - 0% 2% 1% 4% 3% METAB.
& NUTRITION DISORDERS Hypokalemia 1% 3% 1% 1% 1% 1% <1% Weight Decrease 4% 2% 1% 2% 0% 2% 2% MUSCULOSKELETAL SYSTEM and CONNECTIVE TISSUE DISORDERS Leg Cramps 1% 4% 2% 2% 6% 0% 0% Joint Disorder 4% 2% 2% 2% 2% 8% 6% Synovitis 2% <1% 1% 0% 2% 4% 2% Tendosynovitis 3% 2% 0% 1% 2% 5% 1% NERVOUS SYSTEM DISORDERS Dizziness 4% 5% 3% 6% 5% 7% 6% Headache 7% 13% 11% 12% 21% 10% 8% Paresthesia 2% 3% 1% 1% 2% 4% 3% Page 18 of 70 Table 2.
Percentage of Patients with Adverse Events ≥3% in any Leflunomide Treated Group All RA Studies Placebo-Controlled Trials Active-Controlled Trials MN 301 and US 301 MN 302† LEF (N=1339) LEF (N=315) PBO (N=210) SSZ (N=133) MTX (N=182) LEF (N=501) MTX (N=498) RESPIRATORY, THORACIC and MEDIASTINAL DISORDERS Bronchitis 7% 5% 2% 4% 7% 8% 7% Increased Cough 3% 4% 5% 3% 6% 5% 7% Respiratory Infection 15% 21% 21% 20% 32% 27% 25% Pharyngitis 3% 2% 1% 2% 1% 3% 3% Pneumonia 2% 3% 0% 0% 1% 2% 2% Rhinitis 2% 5% 2% 4% 3% 2% 2% Sinusitis 2% 5% 5% 0% 10% 1% 1% SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia 10% 9% 1% 6% 6% 17% 10% Eczema 2% 1% 1% 1% 1% 3% 2% Pruritis 4% 5% 2% 3% 2% 6% 2% Rash 10% 12% 7% 11% 9% 11% 10% Dry Skin 2% 3% 2% 2% 0% 3% 1% RENAL AND URINARY DISORDERS Urinary Tract Infection 5% 5% 7% 4% 2% 5% 6% † Study MN 302, an active-controlled study, treated a total of 999 subjects using 1:1 randomization to (1) leflunomide 20 mg/day after a loading dose of 100 mg/day for 3 days, or (2) methotrexate 10 mg/week or escalation to 15 mg/week.
Treatment duration was 52 weeks. LEF = leflunomide, SSZ= sulfasalazine, PBO= placebo, MTX= methotrexate, RA=Rheumatoid Arthritis Less Common Clinical Trial Adverse Drug Reactions The following adverse […]
Similarly low A771726 plasma levels may be expected 2 years after stopping leflunomide without one of the above washout methods. g. 6 months). . Page 6 of 70 Carcinogenesis and Mutagenesis Malignancy The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications.
There is a potential for immunosuppression with leflunomide. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the clinical trials of leflunomide, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancies or lymphoproliferative disorders with leflunomide.
Carcinogenesis, and Mutagenesis No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human A771726 systemic exposure based on the area under the curve [AUC]).
7 times the human A771726 exposure based on AUC). 5 mg/kg (approximately 1/10 the human A771726 exposure based on AUC). The significance of the findings in mice relative to the clinical use of leflunomide is not known. Leflunomide was not mutagenic in the Ames Assay, the Unscheduled DNA Synthesis Assay, or in the HGPRT Gene Mutation Assay.
In addition, leflunomide was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. However, 4-trifluoromethylanaline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames Assay and in the HGPRT Gene Mutation Assay and was clastogenic in the in vitro Assay for Chromosome Aberrations in the Chinese Hamster Cells.
TFMA was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. Cardiovascular In addition to hypertension noted in Clinical Trials, isolated reports of difficulty with blood pressure control including cases of malignant hypertension and hypertensive crisis have been submitted.
Although a causal relationship to leflunomide has not been established and confounding factors were present in most cases, it is considered essential that monitoring recommendations are closely followed (see WARNINGS and PRECAUTIONS, Monitoring and Laboratory Tests section).
Serious cases of pulmonary hypertension, some with a fatal outcome, have been reported post- marketing in patients treated with leflunomide. The majority of these cases have been reported in patients with underlying heart disease, valvular disorders, lung disorders (ILD), and pulmonary thromboembolism.
Caution should be exercised when leflunomide is used in patients with heart disease, valvular disorders, lung disorders (ILD), or pulmonary thromboembolism. Page 7 of 70 Gastrointestinal Post marketing cases of colitis including ulcerative, microscopic colitis and Crohn’s Disease, have been reported in patients treated with leflunomide.
Some cases were serious and some had a fatal outcome. Patients taking leflunomide and presenting with unexplained chronic diarrhoea or weight loss, should be investigated for colitis. Hematologic Monitoring for hematologic toxicity must be adhered to (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests section).
Leflunomide is contraindicated in patients with impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia due to causes other than rheumatoid […]