Cholestyramine and activated charcoal cause a rapid and significant decrease in blood levels of the active metabolite. Concurrent use of methotrexate and other hepatotoxic drugs increase the risk of hepatotoxicity.

Concurrent administration of rifampicin increase blood levels of the active metabolite.

Headache, dizziness, weakness, bronchitis, urinary tract infection, alopecia, rash, dry skin, ezema, prunitus, hypokalemia, weight loss, arthalgia, back pain, joint disorder, leg cramps, pneumonia,respiratory infection, rhinitis, sinusitis, chest pain, synovitis, tenosynovitis, parathesia, allergic reactions, flu syndrome, increased cough, pharyngitis, abnormal liver emzymes/ hepatotoxicity,anorexia, dyspepsia, gastroenteritis, mouth ulcers, vomiting and infections.

Hypersensitivity: women who are or may become pregnant, significant hepatic impairment including positive serology for hepatitis B or C, compromised immune function including bone marrow dysplasia or severe uncontrolled infection, concurrent vaccination with live vaccines, children < 18 year , lactation.

Special Precautions:

Kidney plays a role in drug elimination, so caution should be used when leflunomide is administered in patients with renal insufficiency. Use with caution in patients with hepatic insufficiency.

Patients with child bearing potential Not recommended in patients with severe immunodeficiency, bone marrow dyspepsia, or severe uncontrolled infection

Stevens- Johnson syndrome has been reported in patients receiving leflunomide. If patients develop this syndrome stop the drug. Risk of malignancy, particularly lymphoproliferative disorders. There are no adequate and well controlled studies evaluting leflunomide in pregnant women.

Leflunomide may increase risk of fetal death or cause tetrogenic effects when administered to pregnant women. Women of child bearing potential must not be started on leflunomide until pregnancy is excluded and it has been confirmed that they are using reliable contraception.

Indication-

Active rheumatoid arthiritis

Dosage-

Adults- 100mg daily for 3 days.

Maintenance dose is 20mg/ day. If intolerance is noticed, the dose may be reduced to 10mg/ day.

EVIDENCE BASED MEDICINE (April 2003)

Pain of Osteoarthiritis

Comparative effectiveness of various interventions

Beneficial

1. Systemic simple analgesics (eg paracetamol for short term pain relief, and improvement in function)

. Systemic NSAIDs (short term pain relief and improvement in function)

3. Topical agents (short term pain relief)

Likely to be beneficial

1. Education, dietary advice,empowerment and support ( improved knowledge of disease and pain relief)

2. Physical support (pain relief and improvement in function)

KEY POINTS

1. There is no good evidence that NSAIDs were superior to simple analgesics such as paracetamol or to suggest that any one of the many available NSAIDs had greater efficacy in relieving pain of osteoarthritis.

2. One systematic review of randomised controlled trials has found that topical agents provide pain relief in patients with osteoarthritis and offer a non-toxic alternative to systemic drug treatment. However there is no evidence to indicate whether the prescribed agents were superior to less expensive, non-prescribtion drugs over the counter (OTC) alternatives, or to other local treatments such as hot or cold packs.

Pharmacology:

Leflunomide exhibits all of its pharmacolgic activity via its active primary metabolite M1. Primary metabolite inhibits dihydroorotate dehydrogenase (DHODH), an enzyme located in cell milochondria that catalyses a key step in de novo pyrimidine synthesis. A secondary mechanism of action is the inhibition of cytokinase and growth factor receptor associated tyrosine kinase activity. The inhibition of DHODH occurs at lower levels of M1 than inhibition of tyrosine kinase and thus DHODH inhibition is considered the primary chemical mechanism of action.

Pharmacokinetics:

Following oral administration, leflunomide is metabloised to an active A77 1726 (M1) which is responsible for all of its activity in vivo. Peak levels of the active metabolite M1 occurs between 6 to 12 hours of dosing. Without a loading dose, it is estimated that attainment of steady-state plasma concentration would require nearly two months of dosing. The active metabolite M1 is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion.

There are no adequate and well controlled studies evaluting leflunomide in pregnant women.

Leflunomide may increase risk of fetal death or cause tetrogenic effects when administered to pregnant women.

Women of child bearing potential must not be started on leflunomide until pregnancy is excluded