LEFLUNOMIDA MEDAC 20mg tablets medication leaflet

Leflunomide medac 10 mg film-coated tablets

Leflunomide medac 15 mg film-coated tablets

Leflunomide medac 20 mg film-coated tablets

Leflunomide medac 10 mg film-coated tablets

Each film-coated tablet contains 10 mg of leflunomide.

Leflunomide medac 15 mg film-coated tablets

Each film-coated tablet contains 15 mg of leflunomide.

Leflunomide medac 20 mg film-coated tablets

Each film-coated tablet contains 20 mg of leflunomide.

Leflunomide medac 10 mg film-coated tablets

Each film-coated tablet contains 76 mg of lactose (as monohydrate) and 0.06 mg of soya lecithin.

Leflunomide medac 15 mg film-coated tablets

Each film-coated tablet contains 114 mg of lactose (as monohydrate) and 0.09 mg of soya lecithin.

Leflunomide medac 20 mg film-coated tablets

Each film-coated tablet contains 152 mg of lactose (as monohydrate) and 0.12 mg of soya lecithin.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Leflunomide medac 10 mg film-coated tablets

White to almost white, round film-coated tablet with a diameter of about 6 mm.

Leflunomide medac 15 mg film-coated tablets

White to almost white, round film-coated tablet, debossed with “15” on one side with a diameter ofabout 7 mm.

Leflunomide medac 20 mg film-coated tablets

White to almost white, round film-coated tablet with a diameter of 8 mm and a break-mark on one sideof the tablet. The tablet can be divided into equal halves.

Leflunomide is indicated for the treatment of adult patients with:

* active rheumatoid arthritis as a 'disease-modifying antirheumatic drug' (DMARD).

* active psoriatic arthritis.

Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) mayresult in an increased risk of serious adverse reactions; therefore, the initiation of leflunomidetreatment has to be carefully considered regarding these benefit/risk aspects.

Moreover, switching from leflunomide to another DMARD without following the washout procedure(see section 4.4) may also increase the risk of serious adverse reactions even for a long time after theswitching.

The treatment should be initiated and supervised by specialists experienced in the treatment ofrheumatoid arthritis and psoriatic arthritis.

Alanine aminotransferase (ALT) (or serum glutamopyruvate transferase SGPT) and a complete bloodcell count, including a differential white blood cell count and a platelet count, must be checkedsimultaneously and with the same frequency:

* before initiation of leflunomide,

* every two weeks during the first six months of treatment, and

* every 8 weeks thereafter (see section 4.4).

* In rheumatoid arthritis: leflunomide therapy is usually started with a loading dose of 100 mgonce daily for 3 days. Omission of the loading dose may decrease the risk of adverse events (seesection 5.1).

The recommended maintenance dose is leflunomide 10 mg to 20 mg once daily depending onthe severity (activity) of the disease.

* In psoriatic arthritis: leflunomide therapy is started with a loading dose of 100 mg once daily for3 days.

The recommended maintenance dose is leflunomide 20 mg once daily (see section 5.1)

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.

Leflunomide medac is not recommended for use in patients below 18 years since efficacy and safety injuvenile rheumatoid arthritis (JRA) have not been established (see sections 5.1 and 5.2).

Leflunomide medac tablets should be swallowed whole with sufficient amounts of liquid. The extentof leflunomide absorption is not affected if it is taken with food.

* Hypersensitivity (especially previous Stevens-Johnson syndrome, toxic epidermal necrolysis,erythema multiforme) to the active substance, to the principal active metabolite teriflunomide,peanut or soya or to any of the excipients listed in section 6.1.

* 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 section 4.4).

* Patients with moderate to severe renal insufficiency, because insufficient clinical experience isavailable 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 contraceptionduring treatment with leflunomide and thereafter as long as the plasma levels of the activemetabolite are above 0.02 mg/l (see section 4.6). Pregnancy must be excluded before start oftreatment with leflunomide.

* Breast-feeding women (see section 4.6).

Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) is notadvisable.

The active metabolite of leflunomide, A771726, has a long half-life, usually 1 to 4 weeks. Seriousundesirable effects might occur (e.g. hepatotoxicity, haematotoxicity or allergic reactions, see below),even if the treatment with leflunomide has been stopped. Therefore, when such toxicities occur or iffor any other reason A771726 needs to be cleared rapidly from the body, the washout procedure has tobe followed. The procedure may be repeated as clinically necessary.

For washout procedures and other recommended actions in case of desired or unintended pregnancy,see section 4.6.

Rare cases of severe liver injury, including cases with fatal outcome, have been reported duringtreatment with leflunomide. Most of the cases occurred within the first 6 months of treatment.

Co-treatment with other hepatotoxic medicinal products was frequently present. It is consideredessential that monitoring recommendations are strictly adhered to.

ALT (SGPT) must be checked before initiation of leflunomide and at the same frequency as thecomplete blood cell count (every two weeks) during the first six months of treatment and every8 weeks thereafter.

For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, dose reduction to 10 mgmay be considered and monitoring must be performed weekly. If ALT (SGPT) elevations of more than2-fold the upper limit of normal persist or if ALT elevations of more than 3-fold the upper limit ofnormal are present, leflunomide must be discontinued and wash-out procedures initiated. It isrecommended that monitoring of liver enzymes be maintained after discontinuation of leflunomidetreatment, until liver enzyme levels have normalised.

Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption beavoided during treatment with leflunomide.

Since the active metabolite of leflunomide, A771726, is highly protein bound and cleared via hepaticmetabolism and biliary secretion, plasma levels of A771726 are expected to be increased in patientswith hypoproteinaemia. Leflunomide medac is contraindicated in patients with severehypoproteinaemia or impairment of liver function (see section 4.3).

Together with ALT, a complete blood cell count, including differential white blood cell count andplatelets, must be performed before start of leflunomide treatment as well as every 2 weeks for the first6 months of treatment and every 8 weeks thereafter.

In patients with pre-existing anaemia, leucopenia, and/or thrombocytopenia as well as in patients withimpaired bone marrow function or those at risk of bone marrow suppression, the risk ofhaematological disorders is increased. If such effects occur, a washout (see below) to reduce plasmalevels of A771726 should be considered.

In case of severe haematological reactions, including pancytopenia, Leflunomide medac and anyconcomitant myelosuppressive treatment must be discontinued and a leflunomide washout procedureinitiated.

The use of leflunomide with antimalarials used in rheumatic diseases (e.g. chloroquine andhydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and otherimmunosuppressive agents including Tumour Necrosis Factor alpha-Inhibitors has not beenadequately studied up to now in randomised trials (with the exception of methotrexate, seesection 4.5). The risk associated with combination therapy, in particular in long-term treatment, isunknown. Since such therapy can lead to additive or even synergistic toxicity (e.g. hepato- orhaematotoxicity), combination with another DMARD (e.g. methotrexate) is not advisable.

Co-administration of teriflunomide with leflunomide is not recommended, as leflunomide is the parentcompound of teriflunomide.

As leflunomide has a long persistence in the body, a switching to another DMARD (e.g. methotrexate)without performing the washout procedure (see below) may raise the possibility of additive risks evenfor 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 carefullybe considered regarding these benefit/risk aspects and closer monitoring is recommended in the initialphase after switching.

In case of ulcerative stomatitis, leflunomide administration should be discontinued.

Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis and Drug Reaction with

Eosinophilia and Systemic Symptoms (DRESS) have been reported in patients treated withleflunomide. As soon as skin and/or mucosal reactions are observed which raise the suspicion of suchsevere reactions, Leflunomide medac and any other possibly associated treatment must bediscontinued, and a leflunomide washout procedure initiated immediately. A complete washout isessential in such cases. In such cases re-exposure to leflunomide is contraindicated (see section 4.3).

Pustular psoriasis and worsening of psoriasis have been reported after the use of leflunomide.

Treatment withdrawal may be considered taking into account patient’s disease and past history.

Skin ulcers can occur in patients during therapy with leflunomide. If leflunomide-associated skin ulceris suspected or if skin ulcers persist despite appropriate therapy, leflunomide discontinuation and acomplete washout procedure should be considered. The decision to resume leflunomide following skinulcers should be based on clinical judgment of adequate wound healing.

It is known that medicinal products with immunosuppressive properties - like leflunomide - may causepatients to be more susceptible to infections, including opportunistic infections. Infections may bemore severe in nature and may, therefore, require early and vigorous treatment. In the event thatsevere, uncontrolled infections occur, it may be necessary to interrupt leflunomide treatment andadminister a washout procedure as described below.

Rare cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in patientsreceiving leflunomide among other immunosuppressants.

Before starting treatment, all patients should be evaluated for active and inactive (“latent”)tuberculosis, as per local recommendations. This can include medical history, possible previouscontact with tuberculosis, and/or appropriate screening such as lung x-ray, tuberculin test and/orinterferon-gamma release assay, as applicable. Prescribers are reminded of the risk of false negativetuberculin skin test results, especially in patients who are severely ill or immunocompromised.

Patients with a history of tuberculosis should be carefully monitored because of the possibility ofreactivation of the infection.

Interstitial lung disease, as well as rare cases of pulmonary hypertension have been reported duringtreatment with leflunomide (see section 4.8). The risk of their occurrence can be increased in patientswith a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder, whichmay occur acutely during therapy. Pulmonary symptoms, such as cough and dyspnoea, may be areason for discontinuation of the therapy and for further investigation, as appropriate.

Cases of peripheral neuropathy have been reported in patients receiving Leflunomide medac. Mostpatients improved after discontinuation of Leflunomide medac. However there was a wide variabilityin final outcome, i.e. in some patients the neuropathy resolved and some patients had persistentsymptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increasethe risk for peripheral neuropathy. If a patient taking Leflunomide medac develops a peripheralneuropathy, consider discontinuing Leflunomide medac therapy and performing the drug eliminationprocedure (see section 4.4).

Colitis, including microscopic colitis has been reported in patients treated with leflunomide. Inpatients on leflunomide treatment presenting unexplained chronic diarrhoea appropriate diagnosticprocedures should be performed.

Blood pressure must be checked before the start of leflunomide treatment and periodically thereafter.

Male patients should be aware of the possible male-mediated foetal toxicity. Reliable contraceptionduring treatment with leflunomide should also be guaranteed.

There are no specific data on the risk of male-mediated foetal toxicity. However, animal studies toevaluate this specific risk have not been conducted. To minimise any possible risk, men wishing tofather a child should consider discontinuing use of leflunomide and taking colestyramine 8 g 3 timesdaily for 11 days or 50 g of activated powdered charcoal 4 times daily for 11 days.

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 bothplasma concentrations are below 0.02 mg/l, and after a waiting period of at least 3 months, the risk offoetal toxicity is very low.

Colestyramine 8 g is administered 3 times daily. Alternatively, 50 g of activated powdered charcoal isadministered 4 times daily. Duration of a complete washout is usually 11 days. The duration may bemodified depending on clinical or laboratory variables.

The measurement of ionised calcium levels might show falsely decreased values under treatment withleflunomide and/or teriflunomide (the active metabolite of leflunomide) depending on the type ofionised calcium analyser used (e.g. blood gas analyser). Therefore, the plausibility of observeddecreased ionised calcium levels needs to be questioned in patients under treatment with leflunomideor teriflunomide. In case of doubtful measurements, it is recommended to determine the total albuminadjusted serum calcium concentration.

Leflunomide medac contains lactose. Patients with rare hereditary problems of galactose intolerance,the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Soya lecithin

Leflunomide medac contains soya lecithin. If a patient is hypersensitive to peanut or soya,

Leflunomide medac must not be used.

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to sayessentially ‘sodium-free’.

Interactions studies have only been performed in adults.

Increased side effects may occur in case of recent or concomitant use of hepatotoxic or haematotoxicmedicinal products or when leflunomide treatment is followed by such medicinal products without awashout period (see also guidance concerning combination with other treatments, section 4.4).

Therefore, closer monitoring of liver enzymes and haematological parameters is recommended in theinitial phase after switching.

In a small (n = 30) study with co-administration of leflunomide (10 to 20 mg per day) withmethotrexate (10 to 25 mg per week) a 2- to 3-fold elevation in liver enzymes was seen on 5 of30 patients. All elevations resolved, 2 with continuation of both medicinal products and 3 afterdiscontinuation of leflunomide. A more than 3-fold increase was seen in another 5 patients. All ofthese also resolved, 2 with continuation of both medicinal products and 3 after discontinuation ofleflunomide.

In patients with rheumatoid arthritis, no pharmacokinetic interaction between the leflunomide (10 to20 mg per day) and methotrexate (10 to 25 mg per week) was demonstrated.

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 ofleflunomide should be considered when contemplating administration of a live attenuated vaccine afterstopping Leflunomide medac.

Warfarin and other coumarin anticoagulants

There have been case reports of increased prothrombin time, when leflunomide and warfarin wereco-administered. A pharmacodynamics interaction with warfarin was observed with A771726 in aclinical pharmacology study (see below). Therefore, when warfarin or another coumarin anticoagulantis co-administered, close international normalised ratio (INR) follow-up and monitoring isrecommended.

If the patient is already receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and/orcorticosteroids, these may be continued after starting leflunomide.

It is recommended that patients receiving leflunomide are not treated with colestyramine or activatedpowdered charcoal because this leads to a rapid and significant decrease in plasma A771726 (theactive metabolite of leflunomide; see also section 5) concentration. The mechanism is thought to be byinterruption of enterohepatic recycling and/or gastrointestinal dialysis of A771726.

In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19and 3A4 are involved in leflunomide metabolism. An in vivo interaction study with leflunomide andcimetidine (non-specific weak cytochrome P450 (CYP) inhibitor) has demonstrated a lack of asignificant impact on A771726 exposure. Following concomitant administration of a single dose ofleflunomide to subjects receiving multiple doses of rifampicin (non-specific cytochrome P450inducer) A771726 peak levels were increased by approximately 40 %, whereas the AUC was notsignificantly changed. The mechanism of this effect is unclear.

In a study in which leflunomide was given concomitantly with a triphasic oral contraceptive pillcontaining 30 μg ethinyloestradiol to healthy female volunteers, there was no reduction incontraceptive activity of the pill, and A771726 pharmacokinetics were within predicted ranges. Apharmacokinetic interaction with oral contraceptives was observed with A771726 (see below).

The following pharmacokinetic and pharmacodynamic interaction studies were conducted with

A771726 (principal active metabolite of leflunomide). As similar drug-drug interactions cannot beexcluded for leflunomide at recommended doses, the following study results and recommendationsshould be considered in patients treated with leflunomide:

There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), followingrepeated 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 asrepaglinide, paclitaxel, pioglitazone or rosiglitazone, is recommended as they may have higherexposure.

Repeated doses of A771726 decreased mean Cmax 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, theophyllineand tizanidine) should be used with caution during treatment, as it could lead to the reduction of theefficacy of these products.

There was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), followingrepeated doses of A771726, suggesting that A771726 is an inhibitor of OAT3 in vivo. Therefore, whenco-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 B1and B3 (OATP1B1/B3) substrates

There was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, respectively),following repeated doses of A771726. However, there was no apparent impact of this increase inplasma rosuvastatin exposure on the HMG-CoA reductase activity. If used together, the dose ofrosuvastatin 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-CoAreductase inhibitors (e.g. simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide,rifampicin) concomitant administration should also be undertaken with caution. Patients should beclosely monitored for signs and symptoms of excessive exposure to the medicinal products andreduction of the dose of these medicinal products should be considered.

There was an increase in mean ethinylestradiol Cmax and AUC0-24 (1.58- and 1.54-fold, respectively)and levonorgestrel Cmax and AUC0-24 (1.33- and 1.41-fold, respectively) following repeated doses of

A771726. While this interaction is not expected to adversely impact the efficacy of oralcontraceptives, consideration should be given to the type of oral contraceptive treatment.

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 internationalnormalised ratio (INR) was observed when A771726 was co-administered with warfarin as comparedwith warfarin alone. Therefore, when warfarin is co-administered, close INR follow-up andmonitoring is recommended.

The active metabolite of leflunomide, A771726 is suspected to cause serious birth defects whenadministered during pregnancy. Leflunomide medac is contraindicated during pregnancy (seesection 4.3).

Women of childbearing potential have to use effective contraception during and up to 2 years aftertreatment (see “waiting period” below) or up to 11 days after treatment (see abbreviated “washoutperiod” below).

The patient must be advised that if there is any delay in onset of menses or any other reason to suspectpregnancy, they must notify the physician immediately for pregnancy testing, and if positive, thephysician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering theblood level of the active metabolite, by instituting the drug elimination procedure described below, atthe first delay of menses may decrease the risk to the foetus from leflunomide.

In a small prospective study in women (n = 64) who became inadvertently pregnant while takingleflunomide for no more than three weeks after conception and followed by a drug eliminationprocedure, no significant differences (p = 0.13) were observed in the overall rate of major structuraldefects (5.4 %) compared to either of the comparison groups (4.2 % in the disease matched group[n = 108] and 4.2 % in healthy pregnant women [n = 78]).

For women receiving leflunomide treatment and who wish to become pregnant, one of the followingprocedures is recommended in order to ascertain that the foetus is not exposed to toxic concentrationsof A771726 (target concentration below 0.02 mg/l):

A771726 plasma levels can be expected to be above 0.02 mg/l for a prolonged period. Theconcentration may be expected to decrease below 0.02 mg/l about 2 years after stopping the treatmentwith 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 least14 days. If both plasma concentrations are below 0.02 mg/l no teratogenic risk is to be expected.

For further information on the sample testing please contact the Marketing Authorisation Holder or itslocal representative (see section 7).

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 of11 days.

However, also following either of the washout procedures, verification by 2 separate tests at aninterval of at least 14 days and a waiting period of one-and-a-half months between the first occurrenceof 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 treatmentdiscontinuation is required before they may become pregnant. If a waiting period of up toapproximately 2 years under reliable contraception is considered unpractical, prophylactic institutionof a washout procedure may be advisable.

Both colestyramine and activated powdered charcoal may influence the absorption of oestrogens andprogestogens such that reliable contraception with oral contraceptives may not be guaranteed duringthe washout procedure with colestyramine or activated powdered charcoal. Use of alternativecontraceptive methods is recommended.

Animal studies indicate that leflunomide or its metabolites pass into breast milk. Breast-feedingwomen must, therefore, not receive leflunomide.

Results of animal fertility studies have shown no effect on male and female fertility, but adverseeffects on male reproductive organs were observed in repeated dose toxicity studies (see section 5.3).

In the case of side effects such as dizziness the patient's ability to concentrate and to react properlymay be impaired. In such cases patients should refrain from driving cars and using machines.

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, weightloss (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 availabledata).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Rare: severe infections, including sepsis which may be fatal

Like other agents with immunosuppressive potential, leflunomide may increase susceptibility toinfections, including opportunistic infections (see also section 4.4). Thus, the overall incidence ofinfections 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 someimmunosuppressive agents.

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 ahigher risk of haematological effects.

Common: mild allergic reactions

Very rare: severe anaphylactic/anaphylactoid reactions, vasculitis, including cutaneousnecrotizing vasculitis

Common: CPK increased

Uncommon: hypokalaemia, hyperlipidemia, hypophosphataemia

Rare: LDH increased

Not known: hypouricemia

Uncommon: anxiety

Common: paraesthesia, headache, dizziness, peripheral neuropathy

Common: mild increase in blood pressure

Rare: severe increase in blood pressure

Rare: interstitial lung disease (including interstitial pneumonitis), which may be fatal

Not known: pulmonary hypertension

Common: colitis including microscopic colitis such as lymphocytic colitis, collagenous colitis,diarrhoea, nausea, vomiting, oral mucosal disorders (e.g., aphthous stomatitis, mouthulceration), abdominal pain

Uncommon: taste disturbances

Very rare: pancreatitis

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

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), skin ulcer

Common: tenosynovitis

Uncommon: tendon rupture

Not known: renal failure

Not known: marginal (reversible) decreases in sperm concentration, total sperm count and rapidprogressive motility

Common: anorexia, weight loss (usually insignificant), asthenia

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There have been reports of chronic overdose in patients taking Leflunomide medac at daily doses up tofive times the recommended daily dose, and reports of acute overdose in adults and children. Therewere no adverse events reported in the majority of case reports of overdose. Adverse events consistentwith the safety profile for leflunomide were: abdominal pain, nausea, diarrhoea, elevated liverenzymes, anaemia, leucopenia, pruritus and rash.

In the event of an overdose or toxicity, colestyramine or charcoal is recommended to accelerateelimination. Colestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthyvolunteers decreased plasma levels of A771726 by approximately 40 % in 24 hours and by 49 % to65 % 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 activemetabolite A771726 by 37 % in 24 hours and by 48 % in 48 hours. These washout procedures may berepeated if clinically necessary.

Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that

A771726, the primary metabolite of leflunomide, is not dialysable.

Pharmacotherapeutic group: selective immunosuppressants, ATC code: L04AA13.

Leflunomide is a disease-modifying anti-rheumatic agent with antiproliferative properties.

Leflunomide is effective in animal models of arthritis and of other autoimmune diseases andtransplantation, mainly if administered during the sensitisation phase. It hasimmunomodulating/immunosuppressive characteristics, acts as an antiproliferative agent, and displaysanti-inflammatory properties. Leflunomide exhibits the best protective effects on animal models ofautoimmune 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 ispresumed to be responsible for the therapeutic effect.

A771726, the active metabolite of leflunomide, inhibits the human enzyme dihydroorotatedehydrogenase (DHODH) and exhibits antiproliferative activity.

The efficacy of leflunomide in the treatment of rheumatoid arthritis was demonstrated in 4 controlledtrials (1 in phase II and 3 in phase III). The phase II trial, study YU203, randomised 402 subjects withactive rheumatoid arthritis to placebo (n = 102), leflunomide 5 mg (n = 95), 10 mg (n = 101) or25 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 supplementationwas 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). Allpatients 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 MN301and US301) was statistically significantly superior to placebo in reducing the signs and symptoms ofrheumatoid 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 and54.5 % for 25 mg/day. In the phase III trials, the ACR response rates for leflunomide 20 mg/day vs.placebo were 54.6 % vs. 28.6 % (study MN301), and 49.4 % vs. 26.3 % (study US301). After12 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) inmethotrexate patients. In study MN302 leflunomide was significantly less effective than methotrexate.

However, in study US301 no significant differences were observed between leflunomide andmethotrexate in the primary efficacy parameters. No difference was observed between leflunomideand 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 twodifferent daily maintenance doses of leflunomide, 10 mg and 20 mg. From the results it can beconcluded that efficacy results of the 20 mg maintenance dose were more favourable, on the otherhand, the safety results favoured the 10 mg daily maintenance dose.

Leflunomide was studied in a single multicenter, randomized, double-blind, active-controlled trial in94 patients (47 per arm) with polyarticular course juvenile rheumatoid arthritis. Patients were3-17 years of age with active polyarticular course JRA regardless of onset type and naive tomethotrexate or leflunomide. In this trial, the loading dose and maintenance dose of leflunomide wasbased on three weight categories: < 20 kg, 20 - 40 kg, and > 40 kg. After 16 weeks treatment, thedifference 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 maintainedduring 48 weeks (see section 4.2).

The pattern of adverse events of leflunomide and methotrexate seems to be similar, but the dose usedin lighter subjects resulted in a relatively low exposure (see section 5.2). These data do not allow aneffective and safe dose recommendation.

The efficacy of leflunomide was demonstrated in one controlled, randomised, double blind study 3L01in 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 inpatients 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 lesionswas modest.

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 with matching placebo in twoparallel groups during the initial three day double blind period. The initial period was followed by anopen label maintenance period of three months, during which both groups received leflunomide 20 mgdaily. The efficacy of leflunomide was confirmed in this study, but no incremental overall benefit wasobserved in the studied population with the use of a loading dose regimen. The safety data obtainedfrom 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 inthe patients receiving the loading dose of 100 mg leflunomide.

Leflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ringopening) in gut wall and liver. In a study with radiolabelled 14C-leflunomide in three healthyvolunteers, 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 foressentially all the in-vivo activity of Leflunomide medac.

Excretion data from the 14C study indicated that at least about 82 to 95 % of the dose is absorbed. Thetime to peak plasma concentrations of A771726 is very variable; peak plasma levels can occurbetween 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-lifeof A771726 (approximately 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studiesto facilitate the rapid attainment of steady-state levels of A771726. Without a loading dose, it isestimated that attainment of steady-state plasma concentrations would require nearly two months ofdosing. In multiple dose studies in patients with rheumatoid arthritis, the pharmacokinetic parametersof A771726 were linear over the dose range of 5 to 25 mg. In these studies, the clinical effect wasclosely related to the plasma concentration of A771726 and to the daily dose of leflunomide. At a doselevel of 20 mg/day, average plasma concentration of A771726 at steady state is approximately35 μg/ml. At steady state plasma levels accumulate about 33- to 35-fold compared with single dose.

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 withrheumatoid arthritis or chronic renal insufficiency. The extensive protein binding of A771726 couldlead to displacement of other highly-bound drugs. In vitro plasma protein binding interaction studieswith warfarin at clinically relevant concentrations, however, showed no interaction. Similar studiesshowed 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 proteinbinding A771726 has a low apparent volume of distribution (approximately 11 litres). There is nopreferential uptake in erythrocytes.

Leflunomide is metabolised to one primary (A771726) and many minor metabolites including TFMA(4-trifluoromethylaniline). The metabolic biotransformation of leflunomide to A771726 andsubsequent metabolism of A771726 is not controlled by a single enzyme and has been shown to occurin microsomal and cytosolic cellular fractions. Interaction studies with cimetidine (non-specificcytochrome P450 inhibitor) and rifampicin (non-specific cytochrome P450 inducer), indicate thatin vivo CYP enzymes are involved in the metabolism of leflunomide only to a small extent.

Elimination of A771726 is slow and characterised by an apparent clearance of about 31 ml/hr. Theelimination half-life in patients is approximately 2 weeks. After administration of a radiolabelled doseof leflunomide, radioactivity was equally excreted in faeces, probably by biliary elimination, and inurine. A771726 was still detectable in urine and faeces 36 days after a single administration. Theprincipal urinary metabolites were glucuronide products derived from leflunomide (mainly in 0 to24 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 orcolestyramine leads to a rapid and significant increase in A771726 elimination rate and decline inplasma concentrations (see section 4.9). This is thought to be achieved by a gastrointestinal dialysismechanism and/or by interrupting enterohepatic recycling.

Leflunomide was administered as a single oral 100 mg dose to 3 haemodialysis patients and 3 patientson continuous peritoneal dialysis (CAPD). The pharmacokinetics of A771726 in CAPD subjectsappeared to be similar to healthy volunteers. A more rapid elimination of A771726 was observed inhaemodialysis subjects which was not due to extraction of medicinal product in the dialysate.

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. Theseprocesses may be affected by hepatic dysfunction.

The pharmacokinetics of A771726 following oral administration of leflunomide have beeninvestigated 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 thesetrials have demonstrated that paediatric patients with body weights ≤ 40 kg have a reduced systemicexposure (measured by Css) of A771726 relative to adult rheumatoid arthritis patients (see section 4.2).

Pharmacokinetic data in elderly (> 65 years) are limited but consistent with pharmacokinetics inyounger adults.

Leflunomide, administered orally and intraperitoneally, has been studied in acute toxicity studies inmice and rats. Repeated oral administration of leflunomide to mice for up to 3 months, to rats and dogsfor up to 6 months and to monkeys for up to 1 month's duration revealed that the major target organsfor 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 reflectthe basic mode of action of the compound (inhibition of DNA synthesis). In rats and dogs, Heinzbodies and/or Howell-Jolly bodies were found. Other effects found on heart, liver, cornea andrespiratory tract could be explained as infections due to immunosuppression. Toxicity in animals wasfound 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 itspotential to exert this effect in vivo.

In a carcinogenicity study in rats, leflunomide did not show carcinogenic potential. In acarcinogenicity study in mice an increased incidence of malignant lymphoma occurred in males of thehighest dose group, considered to be due to the immunosuppressive activity of leflunomide. In femalemice an increased incidence, dose-dependent, of bronchiolo-alveolar adenomas and carcinomas of thelung was noted. The relevance of the findings in mice relative to the clinical use of leflunomide isuncertain.

Leflunomide was not antigenic in animal models.

Leflunomide was embryotoxic and teratogenic in rats and rabbits at doses in the human therapeuticrange and exerted adverse effects on male reproductive organs in repeated dose toxicity studies.

Fertility was not reduced.

Tablet corelactose monohydratelow-substituted hydroxypropyl cellulosetartaric acidsodium laurylsulfatemagnesium stearate

Film-coatinglecithin (soybeans)poly(vinyl alcohol)talctitanium dioxide (E 171)xanthan gum

Not applicable.

3 years

Keep the bottle tightly closed in order to protect from moisture.

Leflunomide medac 10 mg film-coated tablets40 ml HDPE-wide-necked bottle, with screw cap with integrated desiccant container (white silica gel),containing either 30, 60 or 100 film-coated tablets per container.

Leflunomide medac 15 mg film-coated tablets40 ml HDPE-wide-necked bottle, with screw cap with integrated desiccant container (white silica gel),containing either 30, 60, 90 or 100 film-coated tablets per container.

Leflunomide medac 20 mg film-coated tablets40 ml HDPE-wide-necked bottle, with screw cap with integrated desiccant container (white silica gel),containing either 15, 30, 60 or 100 film-coated tablets per container.

Not all pack sizes may be marketed.

No special requirements for disposal.

medac

Gesellschaft für klinische Spezialpräparate mbH

Theaterstr. 622880 Wedel

Germany

Leflunomide medac 10 mg film-coated tablets

EU/1/10/637/001 (30 tablets)

EU/1/10/637/002 (60 tablets)

EU/1/10/637/004 (100 tablets)

Leflunomide medac 15 mg film-coated tablets

EU/1/10/637/010 (30 tablets)

EU/1/10/637/011 (60 tablets)

EU/1/10/637/012 (90 tablets)

EU/1/10/637/013 (100 tablets)

Leflunomide medac 20 mg film-coated tablets

EU/1/10/637/005 (15 tablets)

EU/1/10/637/006 (30 tablets)

EU/1/10/637/007 (60 tablets)

EU/1/10/637/009 (100 tablets)

Date of first authorisation: 27 July 2010

Date of latest renewal: 23 March 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.