Azathioprine: English spelling of azathioprin
Azathioprine is the international English spelling of the active substance azathioprin. It appears in international literature, in English summaries of product characteristics and in many drug indexes. Pharmacologically the substance is identical, with identical indications and risks. The German spelling azathioprin is used in EU SmPCs and German-language literature.
Azathioprine belongs to the classic immunosuppressants and has been on the market since the 1960s (Imurek, Imuran, many generics). The substance acts as a prodrug, first converted non-enzymatically to 6-mercaptopurine (6-MP) and then activated by hypoxanthine phosphoribosyltransferase (HGPRT) and other enzymes to cytotoxic 6-thioguanine nucleotides.
Mechanism of action
The cytotoxic 6-thioguanine nucleotides are incorporated into DNA and RNA and disrupt purine synthesis, particularly in proliferating cells. Lymphocytes are especially sensitive because they depend on the de novo purine synthesis pathway. Antibody production, T-cell mediated immune reactions and pro-inflammatory cytokine release are reduced.
Three key enzymes determine individual toxicity and efficacy:
- Thiopurine S-methyltransferase (TPMT): degrades 6-MP to inactive 6-methylmercaptopurine; in genetic TPMT deficiency active metabolites rise sharply, with the risk of severe myelosuppression
- Nudix hydrolase 15 (NUDT15): particularly relevant in Asian populations, with similar consequences in deficiency
- Xanthine oxidase: degrades 6-MP to thiouric acid; inhibition by allopurinol dramatically raises active metabolites
Determining TPMT activity before therapy is standard. In homozygous TPMT deficiency (about 0.3 % of the population), azathioprine is contraindicated.
Indications
- Organ transplantation: maintenance therapy to prevent rejection after kidney, liver, heart or bone marrow transplantation, usually combined with calcineurin inhibitors
- Autoimmune hepatitis: maintenance after initial steroid induction
- Inflammatory bowel disease (IBD): Crohn's disease and ulcerative colitis for steroid sparing and maintenance of remission
- Rheumatology: systemic lupus erythematosus, vasculitides, rheumatoid arthritis (second line)
- Neurology: myasthenia gravis, multiple sclerosis (off-label)
- Dermatology: pemphigus vulgaris, severe atopic dermatitis, pyoderma gangrenosum
Dosing and administration
Standard: 1 to 3 mg per kg body weight daily, orally as a single dose or split into two. The dose is titrated individually based on clinical response and blood count.
Transplantation: initially 3 to 5 mg per kg, later reduced to maintenance dose. IBD and autoimmune diseases: 2 to 2.5 mg per kg.
Tablets are taken with plenty of fluid, ideally with a meal to reduce gastrointestinal complaints. Because of their cytotoxic properties, film-coated tablets should not be split or crushed.
Onset of action: clinical effects appear at the earliest after 6 to 12 weeks, the full effect often only after 3 to 6 months. During this phase, steroids are often used to bridge the gap.
Side effects
Common: bone marrow suppression (leukopenia, anaemia, thrombocytopenia), gastrointestinal complaints (nausea, vomiting, diarrhoea), elevated liver transaminases, susceptibility to infection (bacterial, viral such as herpes zoster, pneumocystosis).
Uncommon: pancreatitis (idiosyncratic, dose independent), cholestasis, alopecia, rash.
Rare and very rare: hepatosplenic T-cell lymphoma (especially in young men, combination with anti-TNF increases the risk), non-melanoma skin cancer (basal cell, squamous cell carcinoma), cervical dysplasia, hepatic veno-occlusive disease (VOD), interstitial pneumonitis, Stevens Johnson syndrome.
Important safety aspects:
- Close blood count monitoring, weekly in the first 8 weeks
- UV protection because skin cancer risk is increased
- Annual skin cancer screening
- Sudden abdominal pain should rule out pancreatitis
- Live vaccinations are contraindicated during therapy
Interactions
- Allopurinol and febuxostat: dramatic level increase via xanthine oxidase inhibition; reduce azathioprine dose to one quarter or avoid combination
- ACE inhibitors: increased risk of anaemia and leukopenia
- Cotrimoxazole: additive myelosuppression
- Mesalazine and sulfasalazine: moderate TPMT inhibition, slightly increased levels
- Anti-TNF biologics: increased risk of lymphoma in combination, often clinically acceptable on strict indication
- Live vaccinations: contraindicated during therapy and several months afterwards
- Warfarin: reduced efficacy, monitor INR
Special considerations
Pregnancy: contrary to earlier teaching, azathioprine is acceptable in many indications. Experience from transplant medicine and IBD shows no clear increase in malformation risk. Planned conception should be discussed with the treating specialist.
Breastfeeding: small amounts pass into milk and are usually clinically acceptable; current recommendations allow breastfeeding under therapy after individual evaluation.
Before starting therapy:
- TPMT genotyping or activity testing
- NUDT15 testing in Asian patients
- Hepatitis B and C status, HIV, EBV, CMV
- Updated vaccination status, live vaccines beforehand
- Skin examination
Sun protection: patients should consistently use SPF 50 and avoid direct UV exposure.
Life stage: in young men on anti-TNF combination, the risk of hepatosplenic T-cell lymphoma is to be considered; alternatives may be methotrexate or monotherapy.
Related substances
- Azathioprin, German spelling of the same substance
- Methotrexat, alternative immunosuppressant
- Golimumab, biologic for rheumatology and gastroenterology
- Infliximab, anti-TNF with extensive combination experience
- Mesalazin, frequently the basic medication in ulcerative colitis
Frequently asked questions
Why is a TPMT test done before starting therapy?
TPMT degrades azathioprine metabolites. In people with low or absent TPMT activity, active metabolites accumulate massively, with the risk of severe and potentially fatal myelosuppression. The test prevents such events and allows dosing tailored to genotype.
Can I take azathioprine with allopurinol?
Only with adjusted dose and strict monitoring. Allopurinol inhibits xanthine oxidase and leads to a massive rise in active metabolites. In practice the azathioprine dose is reduced to about a quarter of the standard dose or an alternative is chosen.
Can I become pregnant on azathioprine?
Pregnancy on azathioprine is possible. In transplant medicine and IBD there is extensive experience without a clear increase in malformation risk. A planned pregnancy should be coordinated with the treating specialist.
How long can I take azathioprine?
In transplantation and chronic inflammatory disease, multi-year to lifelong therapy is possible. Regular checks of blood count, liver values and skin cancer screening are important. Some studies discuss reduction or discontinuation after several years of stable remission.
Sources
- EMA European Medicines Agency
- BfArM Federal Institute for Drugs and Medical Devices
- AWMF guidelines IBD, autoimmune diseases
- Gelbe Liste azathioprin monograph
Legal notice and disclaimer
The information on this page is provided for general information purposes only and does not constitute medical advice, diagnosis or treatment recommendation. It does not replace the advice of a licensed physician or pharmacist. Medicines should only be used after a doctor's prescription or pharmacy supply. All information is based on summaries of product characteristics and accepted scientific sources at the time of writing; the current SmPC of the manufacturer is always decisive. Sanoliste accepts no liability for completeness, timeliness or accuracy. In a medical emergency, dial the emergency number 112.