Leflunomide

Question 1

What class does Leflunomide belong to?

Answer 1

Antirheumatoid agents
Immunosuppreive agent
enzyme inhibitor
Adjuvant

Question 2

What is Leflunomide?

Answer 2

Leflunomide is a pyrimidine synthesis inhibitor

Question 3

What is Leflunomide indicated for?

Answer 3

Rheumatoid arthritis if other treatments have failed or are contraindicated
Psoriatic arthritis
Isoxazole immunomodulator

Question 4

What is the role of Leflunomide in Rheumatoid Arthritis therapy?

Answer 4

It has similar efficacy to SLZ and MTX, thus may be used when these drugs cannot be used.

Question 5

What are other drugs in the same class as Leflunomide?

Answer 5

Methotrexate, azathioprine, ciclosporin, cyclophosphamide, cytokine modulators

Question 6

What is the dose of Leflunomide used in Rheumatoid Arthritis?

Answer 6

Adult: initially 100mg OD for 3 days, then 10mg-20mg od (via oral tablet)

Question 7

What is the mechanism of action of Leflunomide?

Answer 7

leflunomide is a prodrug and is rapidly metabolised to its pharmacologically active metabolite.

Leflunomide inhibits dyhydroorotate dehydrogenase (enzyme involved in de novo pyrimidine synthesis) resulting in its antiproliferative ability. This prevents the expansion of activated autoimmune lymphocytes due to interference of the cell cycle process.

Question 8

What are the characteristic pharmacokinetic and pharmacodynamic parameters of Leflunomide?

Answer 8

Pro drug -> rapidly metabolised by first pass metabolism in gut wall and liver.
Absolute bioavailability ranged from 76% (dog) to >90% (mice) human F not available

Half life of ~2 weeks

Metabolised to one primary, and many other minor metabolites/ this is not controlled by a single enzyme

Eliminated renally and bilarily.

Question 9

What are the precautions associated with Leflunomide use?

Answer 9

impaired bone marrow function (anaemia, leucopenia, thrombocytopenia)
Patients with recent treatment with other hepatotoxic or myelototoxic DMARDs,
history of TB,

Pregnancy class X: avoid as the active metabolite is teratogenic in animal studies. effective contraception is ESSENTIAL during , and for at least 2 years post treatment in women, and at least 3 months post treatment in men.
avoid in breastfeeding also

Question 10

What are the contraindications to Leflunomide?

Answer 10

Severe immunodeficiency
serious infection
impaired hepatic function
pregnancy
severe hypoproteinaemia
history of stevens johnson syndrome
toxic epidermal necrolysis
erythema multiforme

Question 11

What are the adverse reactions associated with Leflunomide use?

Answer 11

bone marrow toxicity
Increased risk of infection and malignancy
diarrhoea, nausea, vomiting, anorexia
oral mucosal disorders
abdominal pain
increased BP,
Headache, dizziness, Asthenia, parasthesia, leucopenia, tenosynovitis, alopecia, rash, dry skin, pruritis

Question 12

What are some interactions with Leflunomide?

Answer 12

Plasma concentration increased by rifampicin
Anticoagulant enhanced with warfarin
Hypoglycaemia enhanced with tolbutamide
Increased plasma concentrations of phenytoin when used together
Risk of toxicity when given with methotrexate
Effect of leflunomide decreased by colestyramine
avoid concomitant use with live vaccines

Question 13

What are the alarm bells associated with Leflunomide?

Answer 13

Teratogenic avoid in pregnancy

monitor full blood count and liver function before treatment and every 2 weeks for the first 6 months, then monitor every 8 weeks

Discontinue treatment/initiate wash out procedure/ reduce dose according to liver function abnormality