Leflunomide

Products

Leflunomide is commercially available in the form of film-coated tablets (Arava, generics). It has been approved in many countries since 1998. In 2011, generic versions went on sale in many countries.

Structure and properties

Leflunomide (C12H9F3N2O2, Mr = 270.2 g/mol) is an isoxazole carboxamide. It is a prodrug and is biotransformed in the intestine by ring opening to the active metabolite teriflunomide. Teriflunomide is also marketed as a drug (Aubagio) and used to treat multiple sclerosis.

Effects

Leflunomide (ATC L04AA13) has antiproliferative, immunosuppressive, and anti-inflammatory properties. Responsible for the effects is not the parent compound but the active metabolite teriflunomide (A771726), which reduces pyrimidine synthesis predominantly in lymphocytes. This inhibits DNA and RNA synthesis and T-cell activation and proliferation. Other rapidly dividing cells are also affected (see under side effects). The effects are due to inhibition of the enzyme dihydroorotate dehydrogenase, which plays a central role in the synthesis of pyrimidine. Teriflunomide has a long half-life of up to four weeks.

Indications

For the treatment of active rheumatoid arthritis and active psoriatic arthritis.

Dosage

According to the SmPC. Tablets are usually taken once daily, regardless of meals.

Contraindications

For complete precautions, see the drug label.

Interactions

Drug-drug interactions have been described with liver-toxic, hematotoxic, and immunosuppressive drugs, alcohol, strong protein-binding agents, rifampicin, CYP2C9 substrates, vitamin K antagonists, colestyramine, activated charcoal, and live vaccines.

Adverse effects

The most common potential adverse effects include:

  • Diarrhea, nausea, abdominal pain, vomiting, oral mucosal disorders, loss of appetite, weight loss, weakness
  • Increase in blood pressure
  • Headache, dizziness, paresthesias.
  • Blood count disorders, leukopenia
  • Allergic reactions
  • Hair loss, skin rash, dry skin.
  • Tendinitis
  • Increase in liver enzymes
  • Increased susceptibility to infectious diseases

Leflunomide increases the risk of infectious diseases and neoplasms. It has fertility damaging properties and should not be used during pregnancy or lactation. Leflunomide has liver toxic properties and may rarely cause severe liver injury.