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Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g., methotrexate) is not advisable.
Due to the prolonged half-life of the active metabolite, A771726, adverse reaction may occur (e.g., hepatotoxicity, haemototoxicity or allergic reactions) or persist even after leflunomide administration has been discontinued (see Adverse Reactions). Therefore, when such toxicities occur or when switching to another DMARD (e.g., methotrexate) after treatment with leflunomide a washout procedure should be performed.
If a severe adverse reaction to leflunomide occurs, or if for other reason A771726 needs to be cleared rapidly from the body, cholestyramine or activated charcoal has to be initiated as described in Overdosage and continued/repeated as clinically necessary. For suspected severe immunologic/allergic reactions, more prolonged cholestyramine or activated charcoal administration may be necessary to achieve rapid and sufficient clearance (see Use in Pregnancy & Lactation).
For washout procedures and other recommended actions in case of desired or unintended pregnancy (see Use in Pregnancy & Lactation).
Co-administration of teriflunomide with leflunomide is not recommended, as leflunomide is the parent compound of teriflunomide.
Liver: Since the active metabolite of leflunomide, A771726, is highly protein bound and cleared via hepatic metabolism and biliary secretion, and given the possible risk of hepatotoxicity, leflunomide should be used with caution in patients with impairment of liver function. Leflunomide is not recommended in patients with significant hepatic impairment or preexisting hepatic disease.
ALT (SGPT) must be checked before start of treatment and at least at monthly intervals during the first 6 months of treatment, then every 6-8 weeks thereafter.
Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be avoided during treatment with leflunomide.
Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT elevation are recommended as follows: For confirmed ALT elevations between 2 and 3 fold the upper limit of normal dose reduction from 20 to 10 mg/day may allow continued administration of leflunomide under close monitoring.
If ALT (SGPT) elevations between 2 and 3 fold the upper limit of normal persist or if confirmed ALT elevations of more than 3 fold the upper limit of normal are present, leflunomide should be discontinued. Cholestyramine or activated charcoal should be administered to more rapidly lower A771726 levels.
Rare cases of serious liver injury, in isolated cases with fatal outcome, have been reported during treatment with leflunomide. Most of the cases occurred within the first 6 months of treatment. Although a causal relationship to leflunomide has not been established and multiple confounding factors were present in most cases, it is considered essential that monitoring recommendations are closely followed.
Haematological reactions: In patients with pre-existing anaemia, leucopenia, and/or thrombocytopenia as well as in patients with impaired bone marrow function or those at risk of bone marrow suppression, the risk of haematological disorders is increased. If such effects occur, a washout to reduce plasma levels of A771726 should be considered.
A complete blood cell count, including differential white blood cell count and platelets, must be performed before start of leflunomide treatment as well as monthly for the first 6 months of treatment and every 6-8 weeks thereafter.
Frequent haematological monitoring (complete blood cell count, including differential white blood cell count and platelets count) should be performed in: Patients with recent or concomitant treatment with immunosuppressive or haematotoxic drugs, and when leflunomide treatment is followed by such substances without a washout period; Patients with history of relevant haematological abnormalities; Patients with relevant haematological abnormalities at baseline due to causes other than arthritic disease.
Due to the potential for immunosuppression, although there is no clinical experience, leflunomide is not recommended in patients with: Severe immunodeficiency (e.g. AIDS); Significant impairment of bone marrow function; Serious infection.
In case of severe haematological reactions, including pancytopenia, leflunomide and any concomitant myelosuppressive treatment must be discontinued and a leflunomide washout procedure initiated.
Combinations with other treatments: The use of leflunomide with antimalarials used in rheumatic diseases (e.g. chloroquine and hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and other immunosuppressive agents (with the exception of methotrexate, see Interactions). The risk associated with combination therapy, in particular in long-term treatment, is unknown. Since such therapy can lead to additive or even synergistic toxicity (e.g. hepato- or haematotoxicity), combination with another DMARD (e.g. methotrexate) is not advisable.
Caution is advised when leflunomide is given together with drugs, other than NSAIDs, metabolized by CYP2C9 such as phenytoin, warfarin, phenprocoumon and tolbutamide.
Switching to other treatments: As leflunomide has a long persistence in the body, a switching to another DMARD (e.g. methotrexate) without performing the washout procedure may raise the possibility of additive risks even for a long time after the switching (e.g. kinetic interaction, organ toxicity).
Similarly, recent treatment with hepatotoxic or haematotoxic medicinal products (e.g. methotrexate) may result in increased side effects; therefore, the initiation of leflunomide treatment has to carefully be considered regarding these benefit/risk aspects and closer monitoring is recommended in the initial phase after switching.
Skin reactions: In case of ulcerative stomatitis, leflunomide administration should be discontinued.
Cases of Stevens Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients treated with leflunomide (see Adverse Reactions). As soon as skin and/or mucosal reactions are observed which raise the suspicion of such severe reactions, leflunomide and any other possibly associated treatment must be discontinued, and a leflunomide washout procedure initiated immediately (see Overdosage). A complete washout is essential in such cases. In such cases re-exposure to leflunomide is contraindicated (see Contraindications).
Infections: Medications like leflunomide that have immunosuppression may cause patients to be more susceptible to infections, including opportunistic infections (see Adverse Reactions). Infections may be more severe in nature and may, therefore, require early and vigorous treatment. In the event that a serious infections occur, it may be necessary to interrupt leflunomide treatment and administer a washout procedure as described in Overdosage.
Before starting treatment, all patients should be evaluated for active and inactive ("latent") tuberculosis, as per local recommendations. Patients with a history of tuberculosis should be carefully monitored because of the possibility of reactivation of the infection.
Respiratory reactions: Interstitial lung disease has been reported rarely during treatment with leflunomide (see Adverse Reactions). The risk of its occurrence is increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder, which may occur acutely during therapy. Pulmonary symptoms, such as cough and dyspnoea, may be a reason for discontinuation of the therapy and for further investigation, as appropriate.
Peripheral Neuropathy: Cases of peripheral neuropathy have been reported in patients receiving leflunomide. Most patients improved after discontinuation of leflunomide. However, there was a wide variability in final outcome, i.e., in some patients the neuropathy resolved and some patients had persistent symptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking Leflunomide develops a peripheral neuropathy, consider discontinuing Leflunomide therapy and performing the drug elimination procedure (see Precautions).
Blood pressure: Blood pressure must be checked before the start of leflunomide treatment and periodically thereafter.
Use in Males: Available information does not suggest that leflunomide would be associated with an increased risk of male-mediated fetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. To minimize any possible risk, men wishing to father a child should consider discontinuing leflunomide and go through the drug elimination procedure described in Use in Pregnancy & Lactation.
In either case the A771726 plasma concentration is then measured for the first time. Thereafter, the A771726 plasma concentration must be determined again after an interval of at least 14 days. If both plasma concentrations are below 0.02 mg/l, and after a waiting period of at least 3 months, the risk of foetal toxicity is very low.
Washout procedure: Colestyramine 8 g is administered 3 times daily. Alternatively, 50 g of activated powdered charcoal is administered 4 times daily. Duration of a complete washout is usually 11 days. The duration may be modified depending on clinical or laboratory variables.
Effects on ability to drive and use machines: In the case of side effects such as dizziness the patient's ability to concentrate and to react properly may be impaired. In such cases patients should refrain from driving cars and using machines.
