Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use

Concomitant administration of hepatotoxic or haematotoxic DMARDs “disease-modifying antirheumatic drug" (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.

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

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- treatment 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 3-fold 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 2-fold the upper limit of normal persist or if ALT elevations of more than 3-fold 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 (see section 4.3).


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 treatment must be discontinued and a leflunomide washout procedure initiated.

Combinations with other treatments

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

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

Switching to other treatments

As leflunomide has a long persistence in the body, a switching to another DMARD (e.g. methotrexate) without performing the washout procedure (see 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 and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 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 treatment must be discontinued, and a leflunomide washout procedure initiated immediately. A complete washout is essential in such cases.
In such cases re-exposure to leflunomide is contra-indicated (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 ulcer is suspected or if skin ulcers persist despite appropriate therapy, leflunomide discontinuation and a complete washout procedure should be considered. The decision to resume leflunomide following skin ulcers should be based on clinical judgement of adequate wound healing.

Impaired wound-healing after surgery can occur in patients during therapy with leflunomide. Based on an individual assessment, it may be considered to interrupt leflunomide treatment in the peri-surgical period and administer a washout procedure as described below. In case of interruption, the decision to resume leflunomide should be based on clinical judgment of adequate wound healing.


Infections
It is known that medicinal products 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.

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

Before starting treatment, all patients should be evaluated for active and inactive (“latent”) tuberculosis, as per local recommendations. This can include medical history, possible previous contact with tuberculosis, and/or appropriate screening such as lung x-ray, tuberculin test and/or interferon-gamma release assay, as applicable. Prescribers are reminded of the risk of false negative tuberculin 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 of reactivation of the infection.

Respiratory reactions

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

Peripheral neuropathy

Cases of peripheral neuropathy have been reported in patients receiving Arava. Most patients improved after discontinuation of Arava. However there was a wide variability in final outcome, i.e. in some patients the neuropathy resolved and some patients had persistent symptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking Arava develops a peripheral neuropathy, consider discontinuing Arava therapy and performing the drug elimination procedure (see section 4.4).

Colitis

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

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.

Interference with determination of ionised calcium levels

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

Effects on Driving

4.7 Effects on ability to drive and use machines

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