⚠️ Warnings
Concomitant or recent use of other disease-modifying antirheumatic drugs with hepatotoxic and haematotoxic properties may increase the risk of severe adverse effects; therefore, a decision to use combination therapy must be preceded by a thorough benefit-risk assessment. Switching from leflunomide to such drugs must be preceded by a washout period. Cases of severe hepatic injury, including fatalities, have been reported. Severe hepatic reactions occur predominantly within the first 6 months. Alanine aminotransferase (ALT) activity should be monitored before initiating treatment, every two weeks for the first 6 months, and subsequently every 8 weeks. Complete blood count, including total and differential white blood cell and platelet counts, should be performed at the same frequency. An ALT increase of 2–3 times above the upper limit of normal indicates the need for dose reduction. If dose reduction does not lead to a decrease in ALT activity, leflunomide should be discontinued and a washout procedure initiated. Treatment should also be discontinued in patients who develop severe haematological disorders. Patients with anaemia, thrombocytopenia and/or leucopenia, and those with a history of bone marrow disorders are at particular risk.
Hepatic impairment and severe hypoproteinaemia lead to increased concentrations of the active metabolite of leflunomide, A771726; therefore, the use of leflunomide is not recommended in such cases.
Due to the long half-life of the active metabolite, adverse effects may occur even after discontinuation of the drug. If accelerated elimination is required, a washout procedure should be performed.
The effects of concomitant use of leflunomide with antimalarial agents used in rheumatic diseases (e.g. chloroquine and hydroxychloroquine), oral or intramuscular gold preparations, D-penicillamine, azathioprine, and other immunosuppressive agents, including tumour necrosis factor (TNF-α) inhibitors, are unknown; therefore, combination with these agents requires particular caution.
Mucosal and skin changes during leflunomide treatment may be associated with the development of ulcerative stomatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug rash with eosinophilia and systemic symptoms. In such cases, leflunomide must be discontinued. Discontinuation of treatment may also be considered in patients who develop severe pustular psoriasis or exacerbation of psoriasis.
Leflunomide increases the risk of developing severe infections. Cases of progressive multifocal leukoencephalopathy have been reported in patients receiving leflunomide in combination with other immunosuppressive agents. Screening for active or latent tuberculosis should be carried out before initiating therapy.
Patients should be monitored for symptoms of interstitial lung disease (cough, dyspnoea), and if necessary, the drug should be discontinued and appropriate diagnostic work-up initiated.
Leflunomide may cause peripheral neuropathy. Risk factors include age over 60 years, concomitant use of neurotoxic drugs, and diabetes.
Blood pressure should be monitored before and during treatment.
Transmission of toxic effects of leflunomide to the foetus via the male reproductive system cannot be excluded; therefore, men must use effective contraception. To minimise the risk of toxic effects on the foetus, men planning to father a child are advised to discontinue treatment and undergo a washout procedure for at least 11 days to reduce the plasma concentration of metabolite A771726 to below 0.02 mg/l. The concentration should be re-measured after at least 14 days. Maintenance of concentrations within the normal range for at least 3 months ensures minimal risk of foetal exposure.
Vaccination with live attenuated vaccines is not recommended during leflunomide therapy due to the lack of confirmed safety and efficacy of vaccination. The long half-life of the drug should be taken into account when planning vaccination after discontinuation of treatment.
