3 years.
Not applicable.
Tablet core:
Maize starch
Povidone (E1201)
Crospovidone (E1202)
Talc (E553b)
Silica colloidal anhydrous
Magnesium stearate (E470b)
Lactose monohydrate
Film-coating: Talc
(E553b) Hypromellose
(E464) Titanium dioxide
(E171) Macrogol 8000.
Leflunomide, administered orally and intraperitoneally, has been studied in acute toxicity studies in mice and rats. Repeated oral administration of leflunomide to mice for up to 3 months, to rats and dogs for up to 6 months and to monkeys for up to 1 month's duration revealed that the major target organs for toxicity were bone marrow, blood, gastrointestinal tract, skin, spleen, thymus and lymph nodes. The main effects were anaemia, leucopenia, decreased platelet counts and panmyelopathy and reflect the basic mode of action of the compound (inhibition of DNA synthesis). In rats and dogs, Heinz bodies and/or Howell-Jolly bodies were found. Other effects found on heart, liver, cornea and respiratory tract could be explained as infections due to immunosuppression. Toxicity in animals was found at doses equivalent to human therapeutic doses.
Leflunomide was not mutagenic. However, the minor metabolite TFMA (4-trifluoromethylaniline) caused clastogenicity and point mutations in vitro, whilst insufficient information was available on its potential to exert this effect in vivo.
In a carcinogenicity study in rats, leflunomide did not show carcinogenic potential. In a carcinogenicity study in mice an increased incidence of malignant lymphoma occurred in males of the highest dose group, considered to be due to the immunosuppressive activity of leflunomide. In female mice an increased incidence, dose-dependent, of bronchiolo-alveolar adenomas and carcinomas of the lung was noted. The relevance of the findings in mice relative to the clinical use of leflunomide is uncertain.
Leflunomide was not antigenic in animal models.
Leflunomide was embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic range and exerted adverse effects on male reproductive organs in repeated dose toxicity studies. Fertility was not reduced.
Leflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ring opening) in gut wall and liver. In a study with radiolabelled 14C-leflunomide in three healthy volunteers, no unchanged leflunomide was detected in plasma, urine or faeces. In other studies, unchanged leflunomide levels in plasma have rarely been detected, however, at ng/ml plasma levels. The only plasma-radiolabelled metabolite detected was A771726. This metabolite is responsible for essentially all the in vivo activity of Arava.
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 medicinal products 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 litres). There is no preferential uptake in erythrocytes.
Biotransformation
Leflunomide is metabolised 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 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.
Renal impairment
Leflunomide was administered as a single oral 100 mg dose to 3 haemodialysis 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 haemodialysis subjects which was not due to extraction of medicinal product in the dialysate.
Hepatic impairment
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.
Paediatric population
The pharmacokinetics of A771726 following oral administration of leflunomide have been investigated in 73 paediatric 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 paediatric patients with body weights ≤40 kg have a reduced systemic exposure (measured by Css) of A771726 relative to adult rheumatoid arthritis patients.
Elderly
Pharmacokinetic data in elderly (>65 years) are limited but consistent with pharmacokinetics in younger adults.
14 July 2017
Washout procedure
After stopping treatment with leflunomide:
- colestyramine 8 g is administered 3 times daily for a period of 11 days,
- alternatively, 50 g of activated powdered charcoal is administered 4 times daily for a period of 11 days.
However, also following either of the washout procedures, verification by 2 separate tests at an interval of at least 14 days and a waiting period of one-and-a-half months between the first occurrence of a plasma concentration below 0.02 mg/L and fertilisation is required.
Women of childbearing potential should be told that a waiting period of 2 years after treatment discontinuation is required before they may become pregnant. 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.
Both colestyramine and activated powdered charcoal may influence the absorption of oestrogens and progestogens such that reliable contraception with oral contraceptives may not be guaranteed during the washout procedure with colestyramine or activated powdered charcoal. Use of alternative contraceptive methods is recommended.
Breast-feeding
Animal studies indicate that leflunomide or its metabolites pass into breast milk. Breast-feeding women must, therefore, not receive leflunomide.
Fertility
Results of animal fertility studies have shown no effect on male and female fertility, but adverse effects on male reproductive organs were observed in repeated dose toxicity studies.
4.7 Effects on ability to drive and use machinesIn 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.
4.8 Undesirable effectsSummary 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 phosphatise, 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. |
| 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. |
| Not known: | pulmonary hypertension |
| Gastrointestinal disorders | |
| Common: | colitis including microscopic colitis such as lymphocytic colitis, collagenous colitis, 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 |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
Ireland
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: [email protected]
4.9 OverdoseSymptoms
There have been reports of chronic overdose in patients taking Arava 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.
5. Pharmacological properties 5.1 Pharmacodynamic propertiesPharmacotherapeutic group: selective immunosuppressants, ATC code: L04AA13.
Human pharmacology
Leflunomide is a disease-modifying anti-rheumatic agent with antiproliferative properties.
Animal pharmacology
Leflunomide is effective in animal models of arthritis and of other autoimmune diseases and transplantation, mainly if administered during the sensitisation phase. It has immunomodulating/ immunosuppressive characteristics, acts as an antiproliferative agent, and displays anti-inflammatory properties. Leflunomide exhibits the best protective effects on animal models of autoimmune diseases when administered in the early phase of the disease progression.
In vivo, it is rapidly and almost completely metabolised to A771726 which is active in vitro, and is presumed to be responsible for the therapeutic effect.
Mechanism of action
A771726, the active metabolite of leflunomide, inhibits the human enzyme dihydroorotate dehydrogenase (DHODH) and exhibits antiproliferative activity.
Clinical efficacy and safety
Rheumatoid arthritis
The efficacy of Arava in the treatment of rheumatoid arthritis was demonstrated in 4 controlled trials (1 in phase II and 3 in phase III). The phase II trial, study YU203, randomised 402 subjects with active rheumatoid arthritis to placebo (n=102), leflunomide 5 mg (n=95), 10 mg (n=101) or 25 mg/day (n=104). The treatment duration was 6 months.
All leflunomide patients in the phase III trials used an initial dose of 100 mg for 3 days.
Study MN301 randomised 358 subjects with active rheumatoid arthritis to leflunomide 20 mg/day (n=133), sulphasalazine 2 g/day (n=133), or placebo (n=92). Treatment duration was 6 months. Study MN303 was an optional 6-month blinded continuation of MN301 without the placebo arm, resulting in a 12-month comparison of leflunomide and sulphasalazine.
Study MN302 randomised 999 subjects with active rheumatoid arthritis to leflunomide 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was optional and only used in 10% of patients. Treatment duration was 12-months.
Study US301 randomised 482 subjects with active rheumatoid arthritis to leflunomide 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg bid. Treatment duration was 12 months.
Leflunomide at a daily dose of at least 10 mg (10 to 25 mg in study YU203, 20 mg in studies MN301 and US301) was statistically significantly superior to placebo in reducing the signs and symptoms of rheumatoid arthritis in all 3 placebo-controlled trials. The ACR (American College of Rheumatology) response rates in study YU203 were 27.7% for placebo, 31.9% for 5 mg, 50.5% for 10 mg and 54.5% for 25 mg/day. In the phase III trials, the ACR response rates for leflunomide 20 mg/day versus placebo were 54.6% versus 28.6% (study MN301), and 49.4% versus 26.3% (study US301).After 12 months with active treatment, the ACR response rates in leflunomide patients were 52.3% (studies MN301/303), 50.5% (study MN302) and 49.4% (study US301), compared to 53.8% (studies MN301/303) in sulphasalazine patients, 64.8% (study MN302), and 43.9% (study US301) in methotrexate patients. In study MN302 leflunomide was significantly less effective than methotrexate. However, in study US301 no significant differences were observed between leflunomide and methotrexate in the primary efficacy parameters. No difference was observed between leflunomide and sulphasalazine (study MN301). The leflunomide treatment effect was evident by 1 month, stabilised by 3 to 6 months and continued throughout the course of treatment.
A randomised, double-blind, parallel-group non-inferiority study compared the relative efficacy of two different daily maintenance doses of leflunomide, 10 mg and 20 mg. From the results it can be concluded that efficacy results of the 20 mg maintenance dose were more favourable, on the other hand, the safety results favoured the 10 mg daily maintenance dose.
Paediatric population
Leflunomide was studied in a single multicenter, randomized, double-blind, active-controlled trial in 94 patients (47 per arm) with polyarticular course juvenile rheumatoid arthritis. Patients were 3-17 years of age with active polyarticular course JRA regardless of onset type and naive to methotrexate or leflunomide. In this trial, the loading dose and maintenance dose of leflunomide was based on three weight categories: <20 kg, 20-40 kg, and >40 kg. After 16 weeks treatment, the difference in response rates was statistically significant in favour of methotrexate for the JRA Definition of Improvement (DOI) >30% (p=0.02). In responders, this response was maintained during 48 weeks.
The pattern of adverse events of leflunomide and methotrexate seems to be similar, but the dose used in lighter subjects resulted in a relatively low exposure. These data do not allow an effective and safe dose recommendation.
Psoriatic arthritis
The efficacy of Arava was demonstrated in one controlled, randomised, double blind study 3L01 in 188 patients with psoriatic arthritis, treated at 20 mg/day. Treatment duration was 6 months.
Leflunomide 20 mg/day was significantly superior to placebo in reducing the symptoms of arthritis in patients with psoriatic arthritis: the PsARC (Psoriatic Arthritis treatment Response Criteria) responders were 59% in the leflunomide group and 29.7% in the placebo group by 6 months (p<0.0001). The effect of leflunomide on improvement of function and on reduction of skin lesions was modest.
Postmarketing studies
A randomised study assessed the clinical efficacy response rate in DMARD-naïve patients (n=121) with early RA, who received either 20 mg or 100 mg of leflunomide in two parallel groups during the initial three day double blind period. The initial period was followed by an open label maintenance period of three months, during which both groups received leflunomide 20 mg daily. No incremental overall benefit was observed in the studied population with the use of a loading dose regimen. The safety data obtained from both treatment groups were consistent with the known safety profile of leflunomide, however, the incidence of gastrointestinal adverse events and of elevated liver enzymes tended to be higher in the patients receiving the loading dose of 100 mg leflunomide.
5.2 Pharmacokinetic propertiesLeflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ring opening) in gut wall and liver. In a study with radiolabelled 14C-leflunomide in three healthy volunteers, no unchanged leflunomide was detected in plasma, urine or faeces. In other studies, unchanged leflunomide levels in plasma have rarely been detected, however, at ng/ml plasma levels. The only plasma-radiolabelled metabolite detected was A771726. This metabolite is responsible for essentially all the in vivo activity of Arava.
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 medicinal products 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 litres). There is no preferential uptake in erythrocytes.
Biotransformation
Leflunomide is metabolised 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 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.
Renal impairment
Leflunomide was administered as a single oral 100 mg dose to 3 haemodialysis 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 haemodialysis subjects which was not due to extraction of medicinal product in the dialysate.
Hepatic impairment
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.
Paediatric population
The pharmacokinetics of A771726 following oral administration of leflunomide have been investigated in 73 paediatric 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 paediatric patients with body weights ≤40 kg have a reduced systemic exposure (measured by Css) of A771726 relative to adult rheumatoid arthritis patients.
Elderly
Pharmacokinetic data in elderly (>65 years) are limited but consistent with pharmacokinetics in younger adults.
5.3 Preclinical safety dataLeflunomide, administered orally and intraperitoneally, has been studied in acute toxicity studies in mice and rats. Repeated oral administration of leflunomide to mice for up to 3 months, to rats and dogs for up to 6 months and to monkeys for up to 1 month's duration revealed that the major target organs for toxicity were bone marrow, blood, gastrointestinal tract, skin, spleen, thymus and lymph nodes. The main effects were anaemia, leucopenia, decreased platelet counts and panmyelopathy and reflect the basic mode of action of the compound (inhibition of DNA synthesis). In rats and dogs, Heinz bodies and/or Howell-Jolly bodies were found. Other effects found on heart, liver, cornea and respiratory tract could be explained as infections due to immunosuppression. Toxicity in animals was found at doses equivalent to human therapeutic doses.
Leflunomide was not mutagenic. However, the minor metabolite TFMA (4-trifluoromethylaniline) caused clastogenicity and point mutations in vitro, whilst insufficient information was available on its potential to exert this effect in vivo.
In a carcinogenicity study in rats, leflunomide did not show carcinogenic potential. In a carcinogenicity study in mice an increased incidence of malignant lymphoma occurred in males of the highest dose group, considered to be due to the immunosuppressive activity of leflunomide. In female mice an increased incidence, dose-dependent, of bronchiolo-alveolar adenomas and carcinomas of the lung was noted. The relevance of the findings in mice relative to the clinical use of leflunomide is uncertain.
Leflunomide was not antigenic in animal models.
Leflunomide was embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic range and exerted adverse effects on male reproductive organs in repeated dose toxicity studies. Fertility was not reduced.
6. Pharmaceutical particulars 6.1 List of excipientsTablet core:
Maize starch
Povidone (E1201)
Crospovidone (E1202)
Talc (E553b)
Silica colloidal anhydrous
Magnesium stearate (E470b)
Lactose monohydrate
Film-coating: Talc
(E553b) Hypromellose
(E464) Titanium dioxide
(E171) Macrogol 8000.
6.2 IncompatibilitiesNot applicable.
6.3 Shelf life3 years.
6.4 Special precautions for storageStore in the original package.
6.5 Nature and contents of containerAluminium / Aluminium blister. Pack size: 3 film-coated tablets.
6.6 Special precautions for disposal and other handlingNo special requirements for disposal.
7. Marketing authorisation holderSanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
Store in the original package.
Aluminium / Aluminium blister. Pack size: 3 film-coated tablets.
EU/1/99/118/009
No special requirements for disposal.
Date of first authorisation: 02 September 1999
Date of latest renewal: 02 September 2009
