Azathioprine and mercaptopurine

Azathioprine is a thiopurine analogue drug that suppresses the immune system by altering white blood cell function. It is changed in the liver to a related drug, mercaptopurine and then into metabolites called thioguanine (tioguanine) nucleotides, which inhibit cell growth.

Azathioprine and mercaptopurine are used in a number of severe skin disorders including:

• Atopic dermatitis (eczema)
• Bullous pemphigoid
• Pemphigus vulgaris
• Cutaneous polyarteritis nodosa
• Pyoderma gangrenosum
• Cutaneous lupus erythematosus
• Cutaneous vasculitis

In New Zealand azathioprine is available as 50mg tablets or as an injection, trade name Imuran®, Azamun®, Imuprine or Thioprine®. Mercaptopurine is available as 10mg or 50mg tablets, trade name Puri-nethol®. The dose is generally one or two tablets once or twice daily (1 to 3 mg/kg/day). Occasionally doses as high as 5mg per kg body weight per day prove necessary.

Side effects and risks

Side effects are generally mild but occasionally are severe enough to stop treatment with azathioprine or mercaptopurine.

• Loss of appetite, nausea, vomiting or diarrhoea (more common if the medications is taken on an empty stomach). Mouth ulceration may also occur.
• Liver upset (cholestatic hepatitis). Hypersensitivity reaction to azathioprine usually affects the liver, most often several weeks after starting treatment.
• Pancreatitis
• Bone marrow suppression, particularly leucopaenia (reduced number of white blood cells); azathioprine should be stopped if the neutrophil count drops below 1.0x10^9/L, the lymphocyte count drops below 0.5x10^9/L or the platelet count below 50x10^9/L.
• Megabloblastic erythropoeisis or macrocytosis (production of large red blood cells).
• Rarely, severe prolonged drug hypersensitivity syndrome resulting in widespread rash, fever, enlarged lymph glands and organ failure (heart, lungs, kidneys, liver).
• Hair loss
• Immunosuppression leads to an increased risk of serious infections.
• Skin cancer. This is more likely after several years´ treatment with azathioprine, especially on skin that has been exposed to the sun. Protect your skin from the sun at all times, using a broad spectrum sunscreen on exposed areas every day.

Azathioprine and mercaptopurine are FDA Pregnancy Category D. Where possible, these drugs should not be taken during pregnancy, except where the benefits outweigh the risks. Those taking these medications should not breast feed. In some circumstances it may also be advisable for males to ensure their partners do not become pregnant, but overall it is thought that azathioprine does not affect fertility in males. Discuss your own situation with your physician.

Prevention of infection

Tests to exclude latent tuberculosis and hepatitis B/C are wise before starting azathioprine, and to determine measles and varicella immunity. It is also important to consider need to update immunisation in immunosuppressed dermatology patients.

Monitoring

Patients taking azathioprine or mercaptopurine should receive regular blood tests to monitor the safety of treatment, at first fortnightly then monthly long term.

• Complete blood count (CBC or FBC)
• Liver function tests.

Azathioprine and mercaptopurine are not metabolised properly by some people, who have a faulty enzyme called thiopurine methyltransferase. They may have one gene for the bad enzyme (found in 11% of the population) or two bad genes (in 0.3%). Those with both genes are at severe risk of dangerous marrow suppression i.e. reduction of white cells (leucopaenia) or of all blood cells (pancytopaenia). Some other individuals have high levels of enzyme activity and may require a higher dose than normal for therapeutic effect.

Thiopurine methyltransferase (TPMT) levels can be measured to determine a patient's level of risk before starting treatment. Low levels are < 5 U/mL, intermediate levels are 5-13.7 U/mL, and high levels are > 13.8 U/mL. A typical therapeutic dose of azathioprine is 1mg/kg/day when the TPMT level is 10 U/mL and 3.5 mg/kg/day when it is 20 U/mL.

6-Thioguanine nucleotide levels are sometimes used to check whether the dose is correct.

Drug interactions

If you take azathioprine, you must advise any medical practitioner or pharmacist. It is particularly important if you take allopurinol for gout, as the dose of azathioprine will need to be reduced to one-quarter to one-third of normal to avoid severe toxicity.

The following drugs are best avoided, but if unavoidable it is important to monitor blood count very carefully:

• Neuromuscular blocking agents (such as rocuronium, mivacurium, vercuronium, atracurium, tubocurarine)
• Warfarin (the warfarin dose requirement may go up by 3-4 times during treatment with azathioprine)
• D-penicillamine
• Cotrimoxazole
• Captopril, enalapril, lisinopril and other angiotensin-converting enzyme (ACE) inhibitors
• Cimetidine
• Indomethacin
• Sulfasalazine and other benzoic acid derivatives
• Live vaccines e.g. yellow fever