Leflunomide is indicated for the treatment of active Rheumatoid Arthritis. It is normally used together with non steroidal anti-inflammatory drugs. At present it is likely to be used when other disease modifying anti-rheumatic drugs, such as Sulfasalazine and Methotrexate have been ineffective or not tolerated. Response to treatment cannot be expected before 2 to 3 months and may not occur until 4 to 6 months after treatment starts.

Contraindications

Cautions

Concomitant alcohol consumption can lead to hepatoxicity. As we can not be sure what level is safe, alcohol consumption needs to be kept to a minimum and avoided if possible. Leflunomide has a long half life and a 2 month washout period should be considered if switching to another disease modifying anti-rheumatic drugs, especially Methotrexate. Washout procedure is necessary if considering pregnancy for a woman or a male partner. We advise patients to use reliable contraception during this period.

Washout procedure

Contact Rheumatology Department.

Leflunomide has a long half life of up to 6 weeks. Adverse effects may be seen for a long time after the drug is stopped. A washout procedure can be considered in patients having severe side effects or in men or women considering conception. (If a waiting period of up to approximately 2 years under reliable contraception is considered impractical, prophylactic institution of a washout procedure is advisable).

It is usually recommended to give Cholestryramine 8g tds or activated powdered charcoal 50g qds for 11 days then measure metabolite A771 726 twice at intervals of at least 14 days. This should fall to less than 0.02 mg/I. It is recommended to wait at least 3 months before considering conception.

Drug interactions

Pregnancy and lactation

It is recommended that women considering conception should stop leflunomide for 2 years beforehand. A washout procedure may be contemplated if necessary. Breast feeding is not recommended in women taking Leflunomide. The evidence regarding mens fertility is not clear. To minimise risk of male-mediated foetal toxicity it is recommended that men should consider a washout procedure.

Dosage

Usual recommendation is 100mg daily for 3 days. Maintenance dose of 10 to 20mg daily. Therapeutic effect may be seen after 4 to 6 weeks and patients may improve up to 4 to 6 months. Total duration of treatment - as long as indicated by clinical condition.

Monitoring

Monitoring should continue for 3 months after treatment has stopped.

LABORATORY EVENTS VALUES ACTION
Leucopaenia < 3.5 x 10 9 /l STOP + seek advice
Neutropaenia < 2.5 x 10 9 /l STOP + seek advice
Thrombocytopaenia < 150 x 10 9 /l STOP + seek advice
Macrocytosis > 100fl Check B12 and folate
Sequential falls in  neutrophils > 10% on 3 occasions STOP + recheck WCC
Sequential falls in Platelets > 10% on 3 occasions STOP unless falls are from high level e.g. 600, 500, 400 x 10 3 which are response to treatment
Fall in albumin levels STOP - repeat LFT’s. Early sign of liver toxicity.
Elevation of liver enzymes (AST, ALT) > 3x normal STOP + washout - repeat LFTs in 2 to 4 weeks.
2-3x normal Measure weekly and stop if 2 x normal levels persist

CLINICAL ADVERSE EVENTS MANAGEMENT
Diarrhoea 
  • STOP if severe 
  • Reduce maintenance dose to 10mg daily or 10 mg on alternate days.
  • Consider appropriate medication if necessary
Nausea/vomiting/anorexia
  • STOP if severe 
  • Reduce dose 
  • Take with food, try anti-emetic
Ulcerative stomatitis/StevensJohnson syndrome  STOP if suspicious lesions observed
Blood pressure more than 150/90
  • STOP or treat hypertension appropriately
  • Mild rises in 10% of patients

Source: Dr PR Crook, Consultant Rheumatologist.