Full Prescribing Info
Each film coated tablet contains: Leflunomide USP 20 mg.
Excipients/Inactive Ingredients: Starlac, povidone (K-30), croscarmellose sodium, sodium lauryl sulphate, colloidal silicon dioxide, purified talc, kollicoat IR white & purified water.
Pharmacotherapeutic Group: Selective Immunosuppressants. ATC code: L04AA13.
Pharmacology: Pharmacodynamics: Leflunomide is a prodrug that is rapidly and almost completely metabolized following oral administration to its pharmacologically active metabolite, A771726. This metabolite is responsible for essentially all of the drug's activity in-vivo.
The active metabolite of leflunomide A771726 inhibits dehydroorotate-dehydrogenase enzyme and exerts an antiproliferative effect on activated lymphocytes, which play important roles in the pathogenesis of rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, as well as cutaneous manifestations of psoriasis, which is an autoimmune T-cell-mediated disease.
Pharmacokinetics: Leflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ring opening) in gut wall and liver. The only plasma-radiolabelled metabolite detected was A771726. This metabolite is responsible for essentially all the in vivo activity of Lefno.
Absorption: Excretion data from the 14C study indicated that at least about 82 to 95% of the dose is absorbed. The time to peak plasma concentrations of A771726 is very variable; peak plasma levels can occur between 1 hour and 24 hours after single administration. Leflunomide can be administered with food, since the extent of absorption is comparable in the fed and fasting state. Due to the very long half-life of A771726 (approximately 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of A771726. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing. In multiple dose studies in patients with rheumatoid arthritis, the pharmacokinetic parameters of A771726 were linear over the dose range of 5 to 25 mg. In these studies, the clinical effect was closely related to the plasma concentration of A771726 and to the daily dose of leflunomide. At a dose level of 20 mg/day, average plasma concentration of A771726 at steady state is approximately 35 μg/ml. At steady state plasma levels accumulate about 33- to 35-fold compared with single dose.
Distribution: In human plasma, A771726 is extensively bound to protein (albumin). The unbound fraction of A771726 is about 0.62%. Binding of A771726 is linear in the therapeutic concentration range. Binding of A771726 appeared slightly reduced and more variable in plasma from patients with rheumatoid arthritis or chronic renal insufficiency. The extensive protein binding of A771726 could lead to displacement of other highly-bound drugs. Consistent with extensive protein binding A771726 has a low apparent volume of distribution (approximately 11 litres). There is no preferential uptake in erythrocytes.
Elimination: Elimination of A771726 is slow and characterised by an apparent clearance of about 31 ml/hr. The elimination half-life in patients is approximately 2 weeks. After administration of a radiolabelled dose of leflunomide, radioactivity was equally excreted in faeces, probably by biliary elimination, and in urine. A771726 was still detectable in urine and faeces 36 days after a single administration. The principal urinary metabolites were glucuronide products derived from leflunomide (mainly in 0 to 24 hour samples) and an oxanilic acid derivative of A771726. The principal faecal component was A771726.
It has been shown in man that administration of an oral suspension of activated powdered charcoal or colestyramine leads to a rapid and significant increase in A771726 elimination rate and decline in plasma concentrations. This is thought to be achieved by a gastrointestinal dialysis mechanism and/or by interrupting enterohepatic recycling.
Lefno is indicated for the treatment of adult patients with: active rheumatoid arthritis as a "disease-modifying antirheumatic drug" (DMARD); active psoriatic arthritis.
Dosage/Direction for Use
In rheumatoid arthritis: leflunomide therapy is usually started with a loading dose of 100 mg once daily for 3 days. Omission of the loading dose may decrease the risk of adverse events. The recommended maintenance dose is leflunomide 10 mg to 20 mg once daily depending on the severity (activity) of the disease.
In psoriatic arthritis: leflunomide therapy is started with a loading dose of 100 mg once daily for 3 days. The recommended maintenance dose is leflunomide 20 mg once daily. The therapeutic effect usually starts after 4 to 6 weeks and may further improve up to 4 to 6 months. There is no dose adjustment recommended in patients with mild renal insufficiency. No dosage adjustment is required in patients above 65 years of age.
Paediatric population: Lefno is not recommended for use in patients below 18 years since efficacy and safety in juvenile rheumatoid arthritis (JRA) have not been established.
Method of Administration: Lefno tablets are for oral use and should be swallowed whole with sufficient amounts of liquid. The extent of leflunomide absorption is not affected if it is taken with food.
Symptoms: There have been reports of chronic overdose in patients taking leflunomide at daily doses up to five times the recommended daily dose, and reports of acute overdose in adults and children. There were no adverse events reported in the majority of case reports of overdose. Adverse events consistent with the safety profile for leflunomide were: abdominal pain, nausea, diarrhoea, elevated liver enzymes, anaemia, leucopenia, pruritus and rash.
Management: In the event of an overdose or toxicity, colestyramine or charcoal is recommended to accelerate elimination. Colestyramine given orally at dose of 8 g three times a day for 24 hours to three healthy volunteers decreased plasma levels of A771726 by approximately 40% in 24 hours and by 49% to 65% in 48 hours.
Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active metabolite A771726 by 37% in 24 hours and by 48% in 48 hours.
These washout procedures may be repeated if clinically necessary.
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that A771726, the primary metabolite of leflunomide, is not dialysable.
Hypersensitivity (especially previous Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) to the active substance, to the principal active metabolite teriflunomide or to any of the excipients used in preparation of Lefno tablet.
Patients with impairment of liver function.
Patients with severe immunodeficiency states, e.g. AIDS.
Patients with significantly impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia due to causes other than rheumatoid or psoriatic arthritis.
Patients with serious infections.
Patients with moderate to severe renal insufficiency, because insufficient clinical experience is available in this patient group.
Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome.
Pregnant women, women of childbearing potential who are not using reliable contraception during treatment with leflunomide and thereafter as long as the plasma levels of the active metabolite are above 0.02 mg/l. Pregnancy must be excluded before start of treatment with leflunomide.
Breast-feeding women.
Special Precautions
Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) is not advisable.
The active metabolite of leflunomide, A771726, has a long half-life, usually 1 to 4 weeks. Serious undesirable effects might occur (e.g. hepatotoxicity, haematotoxicity or allergic reactions, see as follows), even if the treatment with leflunomide has been stopped. Therefore, when such toxicities occur or if for any other reason A771726 needs to be cleared rapidly from the body, the washout procedure has to be followed. The procedure may be repeated as clinically necessary.
Combinations with other treatments: The use of leflunomide with antimalarials used in rheumatic diseases (e.g. chloroquine and hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and other immunosuppressive agents including Tumour Necrosis Factor alpha-inhibitors has not been adequately studied up to now in randomised trials (with the exception of methotrexate. The risk associated with combination therapy, in particular in long-term treatment, is unknown. Since such therapy can lead to additive or even synergistic toxicity (e.g. hepato- or haematotoxicity), combination with another DMARD (e.g. methotrexate) is not advisable.
Co-administration of teriflunomide with leflunomide is not recommended, as leflunomide is the parent compound of teriflunomide.
Switching to other treatments: As leflunomide has a long persistence in the body, a switching to another DMARD (e.g. methotrexate) without performing the washout procedure (see as follows) may raise the possibility of additive risks even for a long time after the switching (i.e. kinetic interaction, organ toxicity).
Similarly, recent treatment with hepatotoxic or haematotoxic medicinal products (e.g. methotrexate) may result in increased side effects; therefore, the initiation of leflunomide treatment has to carefully be considered regarding these benefit/risk aspects and closer monitoring is recommended in the initial phase after switching.
Skin reactions: In case of ulcerative stomatitis, leflunomide administration should be discontinued.
Very rare cases of Stevens Johnson syndrome or toxic epidermal necrolysis have been reported in patients treated with leflunomide. As soon as skin and/or mucosal reactions are observed which raise the suspicion of such severe reactions, Lefno and any other possibly associated treatment must be discontinued, and a leflunomide washout procedure initiated immediately. A complete washout is essential in such cases. In such cases re-exposure to leflunomide is contra-indicated.
Infections: It is known that medicinal products with immunosuppressive properties - like leflunomide - may cause patients to be more susceptible to infections, including opportunistic infections.
Rare cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in patients receiving leflunomide among other immunosuppressants.
Before starting treatment, all patients should be evaluated for active and inactive ("latent") tuberculosis, as per local recommendations. Patients with a history of tuberculosis should be carefully monitored because of the possibility of reactivation of the infection.
Respiratory reactions: Interstitial lung disease has been reported during treatment with leflunomide. The risk of its occurrence is increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder, which may occur acutely during therapy. Pulmonary symptoms, such as cough and dyspnoea, may be a reason for discontinuation of the therapy and for further investigation, as appropriate.
Peripheral Neuropathy: Cases of peripheral neuropathy have been reported in patients receiving Lefno. Most patients improved after discontinuation of Lefno. However there was a wide variability in final outcome, i.e. in some patients the neuropathy resolved and some patients had persistent symptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking Lefno develops a peripheral neuropathy, consider discontinuing Lefno therapy and performing the drug elimination procedure.
Blood pressure: Blood pressure must be checked before the start of leflunomide treatment and periodically thereafter.
Effects on Ability to Drive and Use Machines: During treatment with Lefno there may be slowing of psychomotor reactions, and the patient's ability to concentrate due to side effects such as dizziness. In such cases, patients should refrain from driving motor transport and work with potentially dangerous machinery.
Use In Pregnancy & Lactation
Pregnancy: The active metabolite of leflunomide, A771726 is suspected to cause serious birth defects when administered during pregnancy. Lefno is contraindicated in pregnancy.
Women of childbearing potential have to use effective contraception during and up to 2 years after treatment or up to 11 days after treatment.
For women receiving leflunomide treatment and who wish to become pregnant, one of the following procedures is recommended in order to ascertain that the foetus is not exposed to toxic concentrations of A771726 (target concentration below 0.02 mg/l): Waiting period: A771726 plasma levels can be expected to be above 0.02 mg/l for a prolonged period. The concentration may be expected to decrease below 0.02 mg/l about 2 years after stopping the treatment with leflunomide.
After a 2-year waiting period, the A771726 plasma concentration is measured for the first time. Thereafter, the A771726 plasma concentration must be determined again after an interval of at least 14 days. If both plasma concentrations are below 0.02 mg/l no teratogenic risk is to be expected.
Breast-feeding: Animal studies indicate that leflunomide or its metabolites pass into breast milk. Breast-feeding women must, therefore, not receive leflunomide.
Adverse Reactions
Summary of the safety profile: The most frequently reported adverse effects with leflunomide are: mild increase in blood pressure, leucopenia, paraesthesia, headache, dizziness, diarrhoea, nausea, vomiting, oral mucosal disorders (e.g. aphthous stomatitis, mouth ulceration), abdominal pain, increased hair loss, eczema, rash (including maculo-papular rash), pruritus, dry skin, tenosynovitis, CPK increased, anorexia, weight loss (usually insignificant), asthenia, mild allergic reactions and elevation of liver parameters (transaminases (especially ALT), less often gamma-GT, alkaline phosphatase, bilirubin)).
Classification of expected frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Infections and infestations: Rare: Severe infections, including sepsis which may be fatal.
Like other agents with immunosuppressive potential, leflunomide may increase susceptibility to infections, including opportunistic infections. Thus, the overall incidence of infections can increase (in particular of rhinitis, bronchitis and pneumonia).
Neoplasms benign, malignant and unspecified (incl. cysts and polyps): The risk of malignancy, particularly lymphoproliferative disorders, is increased with use of some immunosuppressive agents.
Blood and lymphatic system disorders: Common: Leucopenia (leucocytes >2 G/l).
Uncommon: Anaemia, mild thrombocytopenia (platelets <100 G/l).
Rare: Pancytopenia (probably by antiproliferative mechanism), leucopenia (leucocytes <2 G/l), eosinophilia.
Very rare: Agranulocytosis.
Recent, concomitant or consecutive use of potentially myelotoxic agents may be associated with a higher risk of haematological effects.
Immune system disorders: Common: Mild allergic reactions.
Very rare: Severe anaphylactic/anaphylactoid reactions, vasculitis, including cutaneous necrotizing vasculitis.
Metabolism and nutrition disorders: Common: CPK increased.
Uncommon: Hypokalaemia, hyperlipidemia, hypophosphataemia.
Rare: LDH increased.
Not known: Hypouricemia.
Psychiatric disorders: Uncommon: Anxiety.
Nervous system disorders: Common: Paraesthesia, headache, dizziness, peripheral neuropathy.
Cardiac disorders: Common: Mild increase in blood pressure.
Rare: Severe increase in blood pressure.
Respiratory, thoracic and mediastinal disorders: Rare: Interstitial lung disease (including interstitial pneumonitis), which may be fatal.
Gastrointestinal disorders: Common: diarrhoea, nausea, vomiting, oral mucosal disorders (e.g., aphthous stomatitis, mouth ulceration), abdominal pain.
Uncommon: Taste disturbances.
Very rare: Pancreatitis.
Hepatobiliary disorders: Common: Elevation of liver parameters (transaminases [especially ALT], less often gamma-GT, alkaline phosphatase, bilirubin).
Rare: Hepatitis, jaundice/cholestasis.
Very rare: Severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal.
Skin and subcutaneous tissue disorders: Common: Increased hair loss, eczema, rash (including maculopapular rash), pruritus, dry skin.
Uncommon: Urticaria.
Very rare: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.
Not known: Cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
Musculoskeletal and connective tissue disorders: Common: Tenosynovitis.
Uncommon: Tendon rupture.
Renal and urinary disorders: Not known: Renal failure.
Reproductive system and breast disorders: Not known: Marginal (reversible) decreases in sperm concentration, total sperm count and rapid progressive motility.
General disorders and administration site conditions: Common: Anorexia, weight loss (usually insignificant), asthenia.
Adverse Drug Reactions: Inform doctors about unexpected reactions after using drugs.
Drug Interactions
Interactions studies have only been performed in adults.
Increased side effects may occur in case of recent or concomitant use of hepatotoxic or haematotoxic drugs or when leflunomide treatment is followed by such drugs without a washout period. Therefore, closer monitoring of liver enzymes and haematological parameters is recommended in the initial phase after switching.
Methotrexate: In patients with rheumatoid arthritis, no pharmacokinetic interaction between the leflunomide (10 to 20 mg per day) and methotrexate (10 to 25 mg per week) was demonstrated.
Vaccinations: No clinical data are available on the efficacy and safety of vaccinations under leflunomide treatment. Vaccination with live attenuated vaccines is, however, not recommended.
Warfarin and other coumarine anticoagulants: There have been case reports of increased prothrombin time, when leflunomide and warfarin were co-administered. Therefore, when warfarin or another coumarin anticoagulant is co-administered, close international normalised ratio (INR) follow-up and monitoring is recommended.
NSAIDS/Corticosteroids: If the patient is already receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids, these may be continued after starting leflunomide.
Store below 30°C.
Shelf-Life: 36 months.
ATC Classification
L04AA13 - leflunomide ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.
FC tab 20 mg (white to off white, biconvex, oval shaped, plain on both sides) x 3 x 10's.
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