Disease modifying antirheumatic drugs (DMARDs).

Leflunomide

Arava 10 mg film-coated tablets Arava 20 mg film-coated tablets Arava 100 mg film-coated tablets

Film-coated tablet. Arava 10 mg film-coated tablets are white to almost white, round film-coated tablets with a diameter of about 7 mm, imprinted with ZBN on one side. Arava 20 mg film-coated tablets are yellowish to ochre and triangular film-coated tablets, imprinted with ZBO on one side. Arava 100 mg film-coated tablets are white to almost white, round film-coated tablets with a diameter of about 1 cm, imprinted with ZBP on one side.

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) 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 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.

The therapeutic effect usually starts after 4 to 6 weeks and may further improve up to 4 to 6 months.

Arava is not recommended for use in patients below 18 years since efficacy and safety in juvenile rheumatoid arthritis (JRA) have not been established.

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

• before initiation of leflunomide,

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

• every 8 weeks thereafter.

Posology

Leflunomide therapy is started with a loading dose of 100 mg once daily for 3 days.

• The recommended maintenance dose for rheumatoid arthritis 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.

• The recommended maintenance dose is 20 mg once daily for patients with psoriatic arthritis.

There is no dose adjustment recommended in patients with mild renal insufficiency.

No dosage adjustment is required in patients above 65 years of age.

Administration

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

Under 18 years, not recommended.

• hypersensitivity to the active substance (especially previous Stevens- Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) or to any of the excipients,

• patients with impairment of liver function,

• patients with severe immunodeficiency states, e.g. AIDS,

• patients with significantly impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia due to causes other than rheumatoid or psoriatic arthritis,

• patients with serious infections

• patients with moderate to severe renal insufficiency, because insufficient clinical experience is available in this patient group,

• patients with severe hypoproteinaemia, e.g. in nephrotic syndrome,

• pregnant women, 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 are above 0.02 mg/l. Pregnancy must be excluded before start of treatment with leflunomide,

• breast-feeding women

Arava should be administered to patients only under careful medical supervision.

Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) is not advisable.

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

Liver reactions

Rare cases of severe liver injury, including cases with fatal outcome, have been reported during treatment with leflunomide. Most of the cases occurred within the first 6 months of treatment. Co-medication with other hepatotoxic medicinal products was frequently present. It is considered essential that monitoring recommendations are strictly adhered to.

ALT (SGPT) must be checked before initiation of leflunomide and at the same frequency as the complete blood cell count (every two weeks) during the first six months of treatment and every 8 weeks thereafter.

For ALT (SGPT) elevations between 2 and 3fold the upper limit of normal, dose reduction from 20 mg to 10 mg may be considered and monitoring must be performed weekly. If ALT (SGPT) elevations of more than 2fold the upper limit of normal persist or if ALT elevations of more than 3fold the upper limit of normal are present, leflunomide must be discontinued and wash-out procedures initiated. It is recommended that monitoring of liver enzymes be maintained after discontinuation of leflunomide treatment, until liver enzyme levels have normalised.

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

Since the active metabolite of leflunomide, A771726, is highly protein bound and cleared via hepatic metabolism and biliary secretion, plasma levels of A771726 are expected to be increased in patients with hypoproteinaemia. Arava is contraindicated in patients with severe hypoproteinaemia or impairment of liver function.

Haematological reactions

Together with ALT, a complete blood cell count, including differential white blood cell count and platelets, must be performed before start of leflunomide treatment as well as every 2 weeks for the first 6 months of treatment and every 8 weeks thereafter.

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 (see below) to reduce plasma levels of A771726 should be considered.

In case of severe haematological reactions, including pancytopenia, Arava and any concomitant myelosuppressive medication 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, Dpenicillamine, azathioprine and other immunosuppressive agents has not been studied up to now. 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, metabolised 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 (see below) may raise the possibility of additive risks even for a long time after the switching (i.e. kinetic interaction, organ toxicity).

Similarly, recent treatment with hepatotoxic or haematotoxic medicinal products (e.g. methotrexate) may result in increased side effects; therefore, the initiation of leflunomide treatment has to carefully be considered regarding these benefit/risk aspects and closer monitoring is recommended in the initial phase after switching.

Skin reactions

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

Very rare cases of Stevens Johnson syndrome or toxic epidermal necrolysis have been reported in patients treated with leflunomide. As soon as skin and/or mucosal reactions are observed which raise the suspicion of such severe reactions, Arava and any other possibly associated medication must be discontinued, and a leflunomide washout procedure initiated immediately. A complete washout is essential in such cases. In such cases re-exposure to leflunomide is contra-indicated.

Infections

It is known that medications with immunosuppressive properties like leflunomide may cause patients to be more susceptible to infections, including opportunistic infections. Infections may be more severe in nature and may, therefore, require early and vigorous treatment. In the event that severe, uncontrolled infections occur, it may be necessary to interrupt leflunomide treatment and administer a washout procedure as described below.

Patients with tuberculin reactivity must be carefully monitored because of the risk of tuberculosis reactivation.

Respiratory reactions

Interstitial Lung disease has been reported during treatment with leflunomide. 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.

Blood pressure

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

Procreation (recommendations for men)

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

There are no specific data on the risk of male-mediated foetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. To minimise any possible risk, men wishing to father a child should consider discontinuing use of leflunomide and taking colestyramine 8 g 3 times daily 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 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.

Lactose

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

Interactions studies have only been performed in adults.

Increased side effects may occur in case of recent or concomitant use of hepatotoxic or haematotoxic drugs or when leflunomide treatment is followed by such drugs without a washout period.Therefore, closer monitoring of liver enzymes and haematological parameters is recommended in the initial phase after switching.

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 3fold elevation in liver enzymes was seen on 5 of 30 patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. A more than 3fold increase was seen in another 5 patients. All of these also resolved,2 with continuation of both drugs and 3 after discontinuation of leflunomide.

In patients with rheumatoid arthritis, no pharmacokinetic interaction between the leflunomide (10 to 20 mg per day) and methotrexate (10 to 25 mg per week) was demonstrated.

It is recommended that patients receiving leflunomide are not treated with colestyramine or activated powdered charcoal because this leads to a rapid and significant decrease in plasma A771726 concentration. The mechanism is thought to be by interruption of enterohepatic recycling and/or gastrointestinal dialysis of A771726.

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

The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known. An in vivo interaction study with cimetidine (non-specific cytochrome P450 inhibitor) has demonstrated a lack of a significant interaction. 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.

In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. In clinical trials no safety problems were observed when leflunomide and NSAIDs metabolised by CYP2C9 were co-administered. Caution is advised when leflunomide is given together with drugs, other than NSAIDs, metabolised by CYP2C9 such as phenytoin, warfarin, phenprocoumon and tolbutamide.

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.

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 Arava.

The most frequently adverse effects reported commonly (1/100 to <1/10) 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.

sanofi-aventis

(POM)

29 June 2009