Lefno

White to off white, biconvex, oval shaped, film coated tablets plain on both sides.
Each film-coated tablet contains Leflunomide 20 mg.
Excipients/Inactive Ingredients: Starlac, povidone, croscarmellose sodium, sodium lauryl sulphate, colloidal anhydrous silica, purified talc, Opadry KB white and purified water.

Pharmacotherapeutic group: Selective immunosuppressants. ATC code: L04AA13.
Pharmacology: Pharmacodynamics: Human pharmacology: Leflunomide is a disease-modifying anti-rheumatic agent with antiproliferative properties. Leflunomide has shown to improve signs and symptoms and to slow down the progression of joint destruction in active rheumatoid arthritis. In the respective studies the large majority of patients used concomitant NSAIDs or low doses of corticosteroids.
Animal pharmacology: Leflunomide is effective in animal models of arthritis and of other autoimmune diseases and transplantation. It has immunomodulating/immunosuppressive characteristics, acts as an antiproliferative agent, and displays anti-inflammatory properties.
In vivo, it is rapidly and almost completely metabolized to A771726 which is active in vitro, and is presumed to be the active medicinal product.
Leflunomide exhibits the best protective effects on animal models of autoimmune diseases when administered in the early phase of the disease progression. In animal models of chronic graft versus host disease and solid organ graft rejection, leflunomide has prolonged rejection time or reversed ongoing rejection reactions. In addition, leflunomide has exhibited anti-inflammatory activity, yet only weak to no analgesics or antipyretic activity. In a model of experimental septicaemia, leflunomide did not alter the resistance of mice to bacterial pathogens.
Mechanism of action: A771726, the active metabolite of leflunomide, slows down the progress of target cells through different phases of cell cycle. In vitro, alter mitogen stimulation, A771726, the active metabolite, inhibits T-cell proliferation and DNA synthesis. It inhibits mitogen-stimulated proliferation of human peripheral blood mononuclear cells (PBMCs), and proliferation in transformed murine and human cell lines, in a dose-dependent fashion. This antiproliferative activity is reversed by the addition of uridine to the cell culture, indicating that A771726 acts at the level of the pyrimidine biosynthesis pathway. Binding studies using radiolabeled ligand demonstrate that the active metabolite binds to and inhibits the human enzyme dihydroorotate dehydrogenase (DHODH). Together, these data suggest that, in vivo, at concentrations achievable in patients receiving leflunomide, pyrimidine synthesis in lymphocytes and other rapidly dividing cell populations may be inhibited. Further, the inhibition of tyrosine kinase activity has been reported, for both in vitro and in vivo situations. The in vitro activity does not seem to be mediated directly through enzyme inhibition and takes place only at much higher concentrations of A771726 than is necessary for the inhibition of DHODH.
Pharmacokinetics: Leflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ring opening) in gut wall and liver. In a study with radiolabeled ¹⁴C-leflunomide in three healthy volunteers, no unchanged leflunomide was detected in plasma, urine or feces. In other studies, unchanged leflunomide levels in plasma have rarely been detected, however, at ng/ml plasma levels. The only plasma radiolabeled metabolite detected was A771726. This metabolite is responsible for essentially all the in vivo activity of Leflunomide.
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. In vitro plasma protein binding interaction studies with warfarin at clinically relevant concentrations, however, showed no interaction. Similar studies showed that ibuprofen and diclofenac did not displace A771726, whereas the unbound fraction of A771726 is increased 2- to 3-fold in the presence of tolbutamide. A771726 displaced ibuprofen, diclofenac and tolbutamide but the unbound fraction of these drugs is only increased by 10% to 50%. There is no indication that these effects are of clinical relevance. Consistent with extensive protein binding A771726 has a low apparent volume of distribution (approximately 11 liters). There is no preferential uptake in erythrocytes.
Metabolism: Leflunomide is metabolized to one primary (A771726) and many minor metabolites including TFMA (4-trifluoromethylaniline). The metabolic biotransformation of leflunomide to A771726 and subsequent metabolism of A771726 is not controlled by a single enzyme and has been shown to occur in microsomal and cytosolic cellular fractions. Interaction studies with cimetidine (non-specific cytochrome P450 inhibitor) and rifampicin (non-specific cytochrome P450 inducer), indicate that in vivo CYP enzymes are involved in the metabolism of leflunomide only to a small extent.
Elimination: Elimination of A771726 is slow and characterized 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 hours 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 (see Overdosage). This is thought to be achieved by a gastrointestinal dialysis mechanism and/or by interrupting enterohepatic recycling.
Pharmacokinetics in renal failure: Leflunomide was administered as a single oral 100 mg dose to 3 hemodialysis patients and 3 patients on continuous peritoneal dialysis (CAPD). The pharmacokinetics of A771726 in CAPD subjects appeared to be similar to healthy volunteers. A more rapid elimination of A771726 was observed in hemodialysis subjects which was not due to extraction of drug in the dialysate but instead to displacement of protein binding. Population kinetic analysis of all 6 of these patients demonstrated that although clearance of A771726 is increased approximately 2-fold, terminal half-life of elimination is similar to that for healthy subjects since the volume of distribution is also increased.
Pharmacokinetics in liver failure: No data are available regarding treatment of patients with hepatic impairment. The active metabolite A771726 is extensively protein bound and cleared via hepatic metabolism and biliary secretion. These processes may be affected by hepatic dysfunction.
Pharmacokinetics in Pediatrics: The pharmacokinetics of A771726 following oral administration of leflunomide have been investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA) who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these trials have demonstrated that pediatric patients with body weights ≤40 kg have a reduced systemic exposure (measured by C_ss) of A771726 relative to adult rheumatoid arthritis patients (see Dosage & Administration).
Influence of age: Pharmacokinetics in children and adolescents have not been studied. Pharmacokinetic data in elderly (>65 years) are limited but consistent with pharmacokinetics in younger adults.
Smoking: A population-based pharmacokinetic analysis of the Phase III data indicated that smokers had a 38% increase in clearance over nonsmokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.

Leflunomide is indicated for the treatment of adult patients with: active rheumatoid arthritis (to reduce signs and symptoms, to slow radiographic progression of joint destruction and to improve physical function) as a "disease-modifying antirheumatic drug" (DMARD); active psoriatic arthritis.
Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g., methotrexate) may result in an increased risk of serious adverse reactions; therefore, the initiation of leflunomide treatment has to be carefully considered regarding these benefit/risk aspects.
Moreover, switching from leflunomide to another DMARD without following the washout procedure (see Precautions) may also increase the risk of serious adverse reactions even for a long time after the switching.

The treatment should be initiated and supervised by specialists experienced in the treatment of rheumatoid arthritis and psoriatic arthritis.
Alanine aminotransferase (ALT) or serum glutamopyruvate transferase (SGPT) and a complete blood cell count, including differential white blood cell count and platelet must be checked before start of treatment and at least at monthly intervals during the first 6 months of treatment, then every 6-8 weeks thereafter (see Precautions).
Dosage: 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. For additional information regarding the use of the loading dose in rheumatoid arthritis patients, see Pharmacology: Pharmacodynamics under Actions.
The recommended maintenance dose is leflunomide 10 mg to 20 mg once daily. Patients may be started on leflunomide 10 mg or 20 mg 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 for patients with psoriatic arthritis (see Pharmacology: Pharmacodynamics under Actions).
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 dose adjustment is required in patients above 65 years of age.
Leflunomide is not recommended for use in patients below 18 years of age as it has not been studied in this age group.
Method of administration: Leflunomide 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 a 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 Leflunomide 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 (see Precautions).
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, or 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, A771726, are above 0.02 mg/l. Pregnancy must be excluded before start of treatment with leflunomide.
Breast-feeding women (see Use in Pregnancy & Lactation).

Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g., methotrexate) is not advisable.
Due to the prolonged half-life of the active metabolite, A771726, adverse reaction may occur (e.g., hepatotoxicity, haemototoxicity or allergic reactions) or persist even after leflunomide administration has been discontinued (see Adverse Reactions). Therefore, when such toxicities occur or when switching to another DMARD (e.g., methotrexate) after treatment with leflunomide a washout procedure should be performed.
If a severe adverse reaction to leflunomide occurs, or if for other reason A771726 needs to be cleared rapidly from the body, cholestyramine or activated charcoal has to be initiated as described in Overdosage and continued/repeated as clinically necessary. For suspected severe immunologic/allergic reactions, more prolonged cholestyramine or activated charcoal administration may be necessary to achieve rapid and sufficient clearance (see Use in Pregnancy & Lactation).
For washout procedures and other recommended actions in case of desired or unintended pregnancy (see Use in Pregnancy & Lactation).
Co-administration of teriflunomide with leflunomide is not recommended, as leflunomide is the parent compound of teriflunomide.
Liver: Since the active metabolite of leflunomide, A771726, is highly protein bound and cleared via hepatic metabolism and biliary secretion, and given the possible risk of hepatotoxicity, leflunomide should be used with caution in patients with impairment of liver function. Leflunomide is not recommended in patients with significant hepatic impairment or preexisting hepatic disease.
ALT (SGPT) must be checked before start of treatment and at least at monthly intervals during the first 6 months of treatment, then every 6-8 weeks thereafter.
Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be avoided during treatment with leflunomide.
Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT elevation are recommended as follows: For confirmed ALT elevations between 2 and 3 fold the upper limit of normal dose reduction from 20 to 10 mg/day may allow continued administration of leflunomide under close monitoring.
If ALT (SGPT) elevations between 2 and 3 fold the upper limit of normal persist or if confirmed ALT elevations of more than 3 fold the upper limit of normal are present, leflunomide should be discontinued. Cholestyramine or activated charcoal should be administered to more rapidly lower A771726 levels.
Rare cases of serious liver injury, in isolated cases with fatal outcome, have been reported during treatment with leflunomide. Most of the cases occurred within the first 6 months of treatment. Although a causal relationship to leflunomide has not been established and multiple confounding factors were present in most cases, it is considered essential that monitoring recommendations are closely followed.
Haematological reactions: In patients with pre-existing anaemia, leucopenia, and/or thrombocytopenia as well as in patients with impaired bone marrow function or those at risk of bone marrow suppression, the risk of haematological disorders is increased. If such effects occur, a washout to reduce plasma levels of A771726 should be considered.
A complete blood cell count, including differential white blood cell count and platelets, must be performed before start of leflunomide treatment as well as monthly for the first 6 months of treatment and every 6-8 weeks thereafter.
Frequent haematological monitoring (complete blood cell count, including differential white blood cell count and platelets count) should be performed in: Patients with recent or concomitant treatment with immunosuppressive or haematotoxic drugs, and when leflunomide treatment is followed by such substances without a washout period; Patients with history of relevant haematological abnormalities; Patients with relevant haematological abnormalities at baseline due to causes other than arthritic disease.
Due to the potential for immunosuppression, although there is no clinical experience, leflunomide is not recommended in patients with: Severe immunodeficiency (e.g. AIDS); Significant impairment of bone marrow function; Serious infection.
In case of severe haematological reactions, including pancytopenia, leflunomide and any concomitant myelosuppressive treatment must be discontinued and a leflunomide washout procedure initiated.
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 (with the exception of methotrexate, see Interactions). 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.
Caution is advised when leflunomide is given together with drugs, other than NSAIDs, metabolized by CYP2C9 such as phenytoin, warfarin, phenprocoumon and tolbutamide.
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 may raise the possibility of additive risks even for a long time after the switching (e.g. 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.
Cases of Stevens Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients treated with leflunomide (see Adverse Reactions). As soon as skin and/or mucosal reactions are observed which raise the suspicion of such severe reactions, leflunomide and any other possibly associated treatment must be discontinued, and a leflunomide washout procedure initiated immediately (see Overdosage). A complete washout is essential in such cases. In such cases re-exposure to leflunomide is contraindicated (see Contraindications).
Infections: Medications like leflunomide that have immunosuppression may cause patients to be more susceptible to infections, including opportunistic infections (see Adverse Reactions). Infections may be more severe in nature and may, therefore, require early and vigorous treatment. In the event that a serious infections occur, it may be necessary to interrupt leflunomide treatment and administer a washout procedure as described in Overdosage.
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 rarely during treatment with leflunomide (see Adverse Reactions). 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 leflunomide. Most patients improved after discontinuation of leflunomide. 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 Leflunomide develops a peripheral neuropathy, consider discontinuing Leflunomide therapy and performing the drug elimination procedure (see Precautions).
Blood pressure: Blood pressure must be checked before the start of leflunomide treatment and periodically thereafter.
Use in Males: Available information does not suggest that leflunomide would be associated with an increased risk of male-mediated fetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. To minimize any possible risk, men wishing to father a child should consider discontinuing leflunomide and go through the drug elimination procedure described in Use in Pregnancy & Lactation.
In either case the A771726 plasma concentration is then 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, and after a waiting period of at least 3 months, the risk of foetal toxicity is very low.
Washout procedure: Colestyramine 8 g is administered 3 times daily. Alternatively, 50 g of activated powdered charcoal is administered 4 times daily. Duration of a complete washout is usually 11 days. The duration may be modified depending on clinical or laboratory variables.
Effects on ability to drive and use machines: In the case of side effects such as dizziness the patient's ability to concentrate and to react properly may be impaired. In such cases patients should refrain from driving cars and using machines.

Pregnancy: There are no clinical studies evaluating leflunomide in pregnant women, however, A771726 is teratogenic in rats and rabbits, and it may cause fetal harm in humans.
Leflunomide is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception (see Interactions) during treatment with leflunomide and thereafter as long as the plasma levels of active metabolite, A771726, are above 0.02 mg/l. Pregnancy must be excluded before start of treatment with leflunomide.
Patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing, and if positive, the physician and 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 described as follows, at the first delay of menses may decrease the risk to the fetus from leflunomide.
For women receiving leflunomide treatment and who wish to become pregnant, one of the following procedures is recommended: After stopping treatment with leflunomide, cholestyramine 8 g is administered 3 times daily for a period of 11 days; After stopping treatment with leflunomide, 50 g of activated charcoal is administered 4 times daily for a period of 11 days.
The 11 days do not need to be consecutive unless there is a need to lower the A771726 plasma level rapidly.
In either case, the A771726 plasma levels <0.02 mg/l must be verified by 2 separate tests at least 14 days apart. Human plasma levels of the active metabolite less than 0.02 mg/l (0.02 μg/ml) are expected to have minimal risk based on available data.
Without the drug elimination procedure, it may take up to 2 years to reach A771726 level <0.02 mg/l, due to individual variation in drug clearance. However, also altera such a waiting period, verification of A771726 levels <0.02 mg/l by 2 separate tests at an interval of at least 14 days is required.
If a waiting period of up to approximately 2 years under reliable contraception is considered unpractical, prophylactic institution of a washout procedure may be advisable.
Reliable contraception with oral contraceptives may not be guaranteed during the washout procedure with cholestyramine or activated charcoal. Use of alternative contraceptive methods is recommended.
Risk of birth defects and other adverse pregnancy outcomes occurring in women who inadvertently became pregnant while taking leflunomide for any length of time in the 1^st trimester of pregnancy are described in Pharmacology: Pharmacodynamics under Actions.
Breast-feeding: Animal studies indicate that leflunomide or its metabolites pass into breast milk. Breast-feeding women must, therefore, not receive leflunomide.

Summary of the safety profile: 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.
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.
Very rare: 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.
Not known: pulmonary hypertension.
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.

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 (see also guidance concerning combination with other treatments, Precautions). Therefore, closer monitoring of liver enzymes and haematological parameters is recommended in the initial phase after switching.
Methotrexate: In a small (n=30) study with co-administration of leflunomide (10 to 20 mg per day) with methotrexate (10 to 25 mg per week) a 2- to 3-fold elevation in liver enzymes was seen in 5 of 30 patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. A more than 3-fold increase was seen in another 5 patients. All of these also resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. Therefore, although, in general, no waiting period is necessary when changing from leflunomide to methotrexate, closer monitoring of liver enzymes is recommended in the initial phase after switching.
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. The long half-life of leflunomide should be considered when contemplating administration of a live attenuated vaccine after stopping Leflunomide.
Warfarin and other coumarin anticoagulants: There have been case reports of increased prothrombin time, when leflunomide and warfarin were co-administered. A pharmacodynamics interaction with warfarin was observed with A771726 in a clinical pharmacology study. 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.
Effect of other medicinal products on leflunomide: Cholestyramine or activated charcoal: It is recommended that patients receiving leflunomide are not treated with cholestyramine or activated powdered charcoal because this leads to a rapid and significant decrease in plasma A771726 (the active metabolite of leflunomide) concentration. The mechanism is thought to be by interruption of enterohepatic recycling and/or gastrointestinal dialysis of A771726.
CYP450 inhibitors and inducers: In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19 and 3A4 are involved in leflunomide metabolism. An in vivo interaction study with leflunomide and cimetidine (non-specific weak cytochrome P450 (CYP) inhibitor) has demonstrated a lack of a significant impact on A771726 exposure. Following concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampicin (non-specific cytochrome P450 inducer) A771726 peak levels were increased by approximately 40%, whereas the AUC was not significantly changed. The mechanism of this effect is unclear.
Effect of leflunomide on other medicinal products: Oral contraceptives: In a study in which leflunomide was given concomitantly with a triphasic oral contraceptive pill containing 30 μg ethinyloestradiol to healthy female volunteers, there was no reduction in contraceptive activity of the pill, and A771726 pharmacokinetics were within predicted ranges. A pharmacokinetic interaction with oral contraceptives was observed with A771726 (see as follows).
The following pharmacokinetic and pharmacodynamic interaction studies were conducted with A771726 (principal active metabolite of leflunomide). As similar drug-drug interactions cannot be excluded for leflunomide at recommended doses, the following study results and recommendations should be considered in patients treated with leflunomide: Effect on repaglinide (CYP2C8 substrate): There was an increase in mean repaglinide C_max and AUC (1.7 and 2.4 fold, respectively), following repeated doses of A771726, suggesting that A771726 is an inhibitor of CYP2C8 in vivo. Therefore, monitoring patients with concomitant use of medicinal products metabolised by CYP2C8, such as repaglinide, paclitaxel, pioglitazone or rosiglitazone, is recommended as they may have higher exposure.
Effect on caffeine (CYP1A2 substrate): Repeated doses of A771726 decreased mean C_max and AUC of caffeine (CYP1A2 substrate) by 18% and 55%, respectively, suggesting that A771726 may be a weak inducer of CYP1A2 in vivo. Therefore, medicinal products metabolised by CYP1A2 (such as duloxetine, alosetron, theophylline and tizanidine) should be used with caution during treatment, as it could lead to the reduction of the efficacy of these products.
Effect on organic anion transporter 3 (OAT3) substrates: There was an increase in mean cefaclor C_max and AUC (1.43 and 1.54 fold, respectively), following repeated doses of A771726, suggesting that A771726 is an inhibitor of OAT3 in vivo. Therefore, when co-administered with substrates of OAT3, such as cefaclor, benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, cimetidine, methotrexate, zidovudine, caution is recommended.
Effect on BCRP (Breast Cancer Resistance Protein) and/or organic anion transporting polypeptide B1 and B3 (OATP1B1/B3) substrates: There was an increase in mean rosuvastatin C_max and AUC (2.65 and 2.51 fold, respectively), following repeated doses of A771726. However, there was no apparent impact of this increase in plasma rosuvastatin exposure on the HMG-CoA reductase activity. If used together, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) and the OATP family especially HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampicin) concomitant administration should also be undertaken with caution. Patients should be closely monitored for signs and symptoms of excessive exposure to the medicinal products and reduction of the dose of these medicinal products should be considered.
Effect on oral contraceptive (0.03 mg ethinylestradiol and 0.15 mg levonorgestrel): There was an increase in mean ethinylestradiol C_max and AUC_0-24 (1.58 and 1.54 fold, respectively) and levonorgestrel C_max and AUC_0-24 (1.33 and 1.41 fold, respectively) following repeated doses of A771726. While this interaction is not expected to adversely impact the efficacy of oral contraceptives, consideration should be given to the type of oral contraceptive treatment.
Effect on warfarin (CYP2C9 substrate): Repeated doses of A771726 had no effect on the pharmacokinetics of S-warfarin, indicating that A771726 is not an inhibitor or an inducer of CYP2C9. However, a 25% decrease in peak international normalised ratio (INR) was observed when A771726 was co-administered with warfarin as compared with warfarin alone. Therefore, when warfarin is co-administered, close INR follow-up and monitoring is recommended.

Store below 30°C.
Shelf life: 36 months.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

L04AK01 - leflunomide ; Belongs to the class of dihydroorotate dehydrogenase (DHODH) inhibitors. Used as immunosuppressants.

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