Azathioprine

Azathioprine: Blood Count Checks and the TPMT Test — Why Safety Is Decided in the Lab

Azathioprine is an immunosuppressant that has been used for decades after organ transplants, in chronic inflammatory bowel disease and in autoimmune diseases. It works slowly and dampens the immune system by slowing down the multiplication of immune cells — the same property also affects the bone marrow and makes regular blood count checks indispensable. A test for the enzyme TPMT shows before treatment starts who can tolerate the drug only at a greatly reduced dose.

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Contents

  1. At a Glance: Technical Data Sheet
  2. How it works: why azathioprine also affects the bone marrow
  3. Dosing: based on body weight and step by step
  4. Taking it in everyday life
  5. Side effects: common, rare, dangerous
  6. The TPMT test and NUDT15: what genetics reveals
  7. Interactions: allopurinol, febuxostat and others
  8. Blood count and liver values: the monitoring plan
  9. Special situations: pregnancy, vaccinations, surgery, stopping
  10. Azathioprine experiences: what patients really ask
  11. FAQ: Common questions about azathioprine

1. At a Glance: Technical Data Sheet

PropertyDetails
Active ingredientAzathioprine (a precursor of 6-mercaptopurine)
ATC codeL04AX01
Drug classImmunosuppressant, an antimetabolite from the thiopurine group
Dosage formsFilm-coated tablets in various strengths
Half-lifeVery short in the blood; the active breakdown products (thioguanine nucleotides), however, build up in the cells over weeks
Maximum daily doseBased on body weight: in autoimmune diseases usually 1 to 3 mg per kg according to the SmPC, after a transplant initially up to 5 mg/kg; with allopurinol only a quarter of the usual dose
Onset of effectSlow: weeks to months; if there is no improvement after about 3 to 4 months, the treatment is usually reconsidered
Prescription statusPrescription-only medicine
Notable featureRegular blood count checks are mandatory; TPMT testing before treatment starts; life-threatening interaction with allopurinol and febuxostat
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2. How it works: why azathioprine also affects the bone marrow

Azathioprine is not yet active in itself. In the body it is converted into 6-mercaptopurine, and this intermediate product stands at a fork in the road with three directions:¹

  • The active route: part of it becomes thioguanine nucleotides (6-TGN). They resemble the building blocks of genetic material and slow down the multiplication of dividing cells — above all activated immune cells.
  • Breakdown via TPMT: the enzyme thiopurine methyltransferase converts part of it into inactive products. How active this enzyme is, is something you are born with (section 6).
  • Breakdown via xanthine oxidase: this is precisely the enzyme blocked by the gout medicines allopurinol and febuxostat — the reason for the most dangerous interaction (section 7).

Lymphocytes, the conductors of the immune defence, depend particularly heavily on newly made building blocks of this kind when they multiply. If that supply is sabotaged, an excessive immune reaction dies down — whether it is directed against a transplanted organ, your own intestinal lining or the inner lining of the joints.

The central drawback follows from the same principle: the bone marrow is constantly dividing too. Azathioprine can throttle the production of white and red blood cells as well as platelets — usually only slightly, in some people dangerously strongly. That is why the blood count is the most important safety parameter of this treatment. And because the active substances only build up over weeks, azathioprine is never a remedy for an acute flare, but one for the long haul.

Important for context: the cortisone saver. One of azathioprine's main jobs is to reduce cortisone or make it unnecessary. In Crohn's disease and ulcerative colitis, for example, it is used when the inflammation keeps flaring up again as soon as prednisolone is reduced.² At the start the two often run in parallel: cortisone bridges the gap until azathioprine takes effect.

Azathioprine is used after organ transplants (usually combined with other immunosuppressants), in chronic inflammatory bowel disease, autoimmune hepatitis, systemic lupus erythematosus, inflammation of the blood vessels and some blood and skin diseases. In rheumatoid arthritis it now plays only a minor role, since better-studied disease-modifying drugs such as methotrexate have become available.¹

3. Dosing: based on body weight and step by step

The figures below describe what the SmPC gives as the usual approach. They are not a dosing instruction — the dose, the increases and the monitoring intervals are set by the treating practice.¹

  • Based on body weight: in autoimmune diseases the daily dose according to the SmPC is usually between 1 and 3 mg per kilogram, and initially higher after a transplant.
  • Starting low: treatment often begins at a low dose that is increased weekly. This is easier on the stomach and allows time to keep an eye on the blood count.
  • The TPMT result: with intermediate enzyme activity, treatment often starts at a reduced dose; with absent activity, the dose is drastically reduced or a different drug is chosen.
  • With allopurinol: according to the SmPC, the azathioprine dose must be cut to a quarter — not a matter of fine-tuning, but a question of safety.
  • In older age and with impaired kidney or liver function the dose is lower and checks are more frequent; see medications for kidney and liver disease.

Once the disease is stable, the aim is usually to find the lowest dose that still works. In rheumatology, therapy information sheets give a clear summary of dosing, checks and reasons for a pause — ask your practice for one.³

Patience is part of the treatment. The early period often feels like "side effects without any effect" — and that is exactly when many people give up. Ask specifically at the start: from when should I notice an improvement, and how will I recognise it? Tips in the guide preparing for a doctor's appointment.

4. Taking it in everyday life

Azathioprine is a long-term treatment, often for years. Small routines count for more than big resolutions.¹,⁴

  1. With a meal and a large glass of water. That is what the SmPC says; it eases the nausea at the beginning. More important than the exact time is that it is the same every day.
  2. Keep a gap from milk. Milk itself contains xanthine oxidase, which can break the drug down. The SmPC therefore recommends taking it at least one hour before or two hours after milk or dairy products.
  3. Report nausea. According to the SmPC, splitting the daily dose often helps. Whether that suits you is something to clarify with your practice.
  4. Do not crush the tablets. Azathioprine is a cytotoxic drug. Anyone setting out tablets for someone else should wash their hands afterwards; pregnant women should avoid contact with broken tablets.
  5. Missed dose: usually take it later the same day, carry on as normal the next day, never take a double dose — see missed a medication.
Report these signs straight away. According to the SmPC, fever, a sore throat or mouth ulcers, frequent infections, unusual bruising and bleeding should be reported without delay. They can point to damage to the bone marrow — even if your last check was normal. Do not wait for the next routine appointment.

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5. Side effects: common, rare, dangerous

According to the SmPC, the type and frequency of side effects depend heavily on the dose, the duration and the underlying disease — after a transplant the profile looks different from that in bowel disease.¹ It therefore makes sense to group them by how much they matter.

Common and usually manageable

  • Nausea and loss of appetite, mainly in the first few weeks; taking it with food and a slow start often help. See also nausea.
  • A drop in white blood cells: possible in more than half of those treated according to the SmPC, often only slight. That is what the checks are for.
  • Enlarged red blood cells: a raised MCV value is typical, dose-dependent and harmless in itself.
  • Susceptibility to infection: infections last longer, and shingles occurs more often. Repeated fever needs to be investigated.

Rare, but serious

Hypersensitivity reaction: usually in the first few weeks, with a general feeling of being unwell, fever, chills, rash, muscle and joint pain or a drop in blood pressure. Azathioprine is then stopped immediately and must never be taken again. Inflammation of the pancreas: typically early in treatment, especially in bowel disease; the key symptom is severe upper abdominal pain that can radiate into the back. Liver damage, up to and including a build-up of bile (cholestasis), is possible — which is why liver values are part of the monitoring programme.¹

Skin cancer and lymphomas: on immunosuppressants, skin tumours occur more often, especially on areas exposed to the sun. The risk of lymphoma is also slightly increased — in rheumatoid arthritis, according to the SmPC, at least partly because of the disease itself.¹

When you need to act immediately. High fever with a sore throat or sore patches in the mouth, bleeding gums or nosebleeds for no reason, pinpoint bleeding under the skin, severe upper abdominal pain, or a flu-like feeling of illness with a rash in the first few weeks: take the next tablet only after speaking to a doctor, and get yourself examined on the same day. If you have shortness of breath, circulatory collapse or impaired consciousness, call 112 (emergency number in Germany).

6. The TPMT test and NUDT15: what genetics reveals

How much active 6-TGN is produced from one tablet depends heavily on how well your body breaks azathioprine down via TPMT. The SmPC describes three groups:¹

TPMT statusFrequency according to the SmPCWhat it means
Normal activityAround 90 %Usual dosing, usual checks
Intermediate activity (one working copy of the gene)About 10 %Usually tolerated, sometimes a dose reduction is needed; treatment often starts lower
No or hardly any activityAbout 0.3 % (1 in 300)High risk of life-threatening bone marrow damage at usual doses — a considerable reduction or a different drug
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The SmPC recommends determining TPMT status before treatment starts — either by genotyping (looking for the known gene variants) or by phenotyping (measuring the enzyme activity in the red blood cells). The activity measurement can be distorted after a recent blood transfusion, because donor cells are then measured as well. A second gene has since been added: NUDT15. Certain variants of it also lead to marked sensitivity, typically with early-onset leucopenia and hair loss; they are considerably more common in people of East Asian origin than in people of European origin. The pharmacogenetics consortium CPIC has published genotype-based dosing recommendations for both genes.¹,⁵

A normal TPMT result does not replace a single blood check. This is the most common misunderstanding. According to the SmPC, TPMT tests do not identify everyone at risk of serious side effects. A large proportion of bone marrow damage occurs with normal enzyme activity — triggered, for example, by interactions, infections or weak kidney function. The test shows who needs to start particularly cautiously. Whether you tolerate azathioprine is shown only by the blood count.

In specialist centres for chronic inflammatory bowel disease, the breakdown products can also be measured in the blood if the drug is not working or is poorly tolerated. Some centres then even deliberately combine greatly reduced azathioprine with allopurinol — a specialist strategy with close monitoring, not a licence for the combination in everyday life.

7. Interactions: allopurinol, febuxostat and others

With azathioprine, your medication list decides how safe the treatment is — and several of the most important partners are prescribed by a different practice.¹

CombinationConsequenceWhat to do
AllopurinolBreakdown blocked, active substances accumulate; severe bone marrow damage, deaths also describedCombine only deliberately: azathioprine cut to a quarter according to the SmPC, frequent blood counts
FebuxostatSame mechanism; data for a safe dose adjustment are lackingNot recommended according to the SmPC
Mesalazine, sulfasalazineInhibit breakdown via TPMT; stronger effect on the bone marrowA common combination in bowel disease — frequent blood counts
ACE inhibitors such as ramipril, co-trimoxazoleChanges in the blood count describedNot forbidden, but keep an eye on the blood count
Coumarins such as phenprocoumonThe anticoagulant effect may be weakenedCheck the INR closely when starting, changing the dose and stopping
Methotrexate, cytotoxic drugs, other immunosuppressantsEffects on the immune defence and bone marrow add upOnly as a planned combination under specialist supervision
RibavirinSevere bone marrow damage reportedNot recommended according to the SmPC
Live vaccinesThe vaccine virus can cause the diseaseContraindicated until at least 3 months after the end of treatment
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Alcohol has no direct interaction with azathioprine, but it puts additional strain on the liver, whose values are being monitored anyway. Restraint makes sense; more under medications and alcohol.

The allopurinol scenario: a classic failure between practices

You have been taking azathioprine stably for years, prescribed by the gastroenterology or rheumatology practice. Then you have a gout attack, the GP practice prescribes allopurinol — and nobody has the combination on their radar. Within a few weeks the bone marrow can become exhausted. According to the SmPC, deaths have been reported with this combination when the dose was not adjusted.¹ So: whenever something new is prescribed, actively mention "I take azathioprine", never start a drug to lower uric acid without consulting the prescribing practice, and keep your medication plan up to date.

Combinations like this from two different practices are exactly what the brite interaction check picks up as soon as both drugs are on your list. It does not replace a medical review, but it makes sure the question gets asked. The basics are in the guide drug interactions.

8. Blood count and liver values: the monitoring plan

The SmPC sets out clear requirements; professional societies sometimes work with slightly different schedules. What counts is the plan your practice agrees with you.¹,³

  1. Before starting: blood count, liver and kidney values, TPMT status (and NUDT15 where appropriate), often tests for hepatitis viruses and a look at your vaccination record.
  2. First 8 weeks: blood count including platelets at least once a week; more often at higher doses, in older age and with impaired kidney function.
  3. After that: monthly, but at least every three months; liver values (transaminases, alkaline phosphatase, bilirubin) are checked regularly as well.
  4. After every change: a dose increase, new concomitant medicines, feverish infections — then outside the regular schedule.
  5. Even after years: changes in the blood count usually occur at the start, but according to the SmPC they can also occur later. Stable long-term treatment does not mean no more checks.
Lab valueWhat it showsWhat to watch for
LeucocytesImmune cells overallA marked drop is the most important warning sign; the practice has fixed thresholds for a pause or a reduction
PlateletsBlood platelets, clottingA drop can cause a tendency to bleed
Haemoglobin and MCVRed blood cells and their sizeA rising MCV is typical and usually harmless; anaemia is investigated
Liver valuesStrain on the liver, build-up of bileIncreases may require a dose reduction or a pause
Creatinine / eGFRKidney functionWith weak kidney function a lower dose and more frequent checks
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Important: according to the SmPC, leucocytes and platelets can continue to fall even after stopping. If azathioprine is stopped because of abnormal values, the monitoring programme therefore carries on for the time being.¹

Make the values your values. Ask for copies of your results and enter leucocytes, platelets and liver values in your health history. A creeping downward trend over three checks stands out earlier in the history than in a single result — and you can show it to any practice. What the values mean is explained in the guide understanding blood values.

9. Special situations: pregnancy, vaccinations, surgery, stopping

Wanting children, pregnancy and breastfeeding

Here the SmPC and specialist advice differ markedly. The SmPC is strict: effective contraception for women and men during treatment and for six months afterwards, pregnancy only after a strict weighing of benefits and risks, no breastfeeding. It also cites case reports according to which a copper coil (IUD) can fail on azathioprine.¹ Embryotox, by contrast, rates the experience from several thousand pregnancies as reassuring: no increased risk of malformations or miscarriage compared with women who have the same underlying disease. Women who are stable on their treatment should not be switched, treatment of the father does not require any change, and breastfeeding is considered possible.⁶ A flare of the disease during pregnancy is often riskier than the medicine. So plan early with your practice and also read medications during pregnancy.

Vaccinations

Live vaccines — for example against measles, mumps and rubella, chickenpox or yellow fever — are off-limits. Inactivated vaccines are possible and expressly recommended for people on immunosuppression, for example against flu, pneumococci and — depending on age and the current recommendation of STIKO (Germany's Standing Committee on Vaccination) — against shingles. Because the vaccine response can be weaker during treatment, any missing vaccinations are ideally caught up on before starting.⁷ More under vaccines and medications.

Surgery, sun and screening

  • Before surgery: azathioprine affects the action of muscle relaxants. Tell the anaesthesia team; whether it is continued is decided by everyone involved together — see medications before surgery.
  • Sun protection is a must: the SmPC calls for protection from unnecessary UV radiation, protective clothing, a high sun protection factor and regular skin checks. No sunbeds. More under medications and sun and on non-melanoma skin cancer.
  • Gynaecological screening: on immunosuppressants, precancerous stages of cervical cancer are more common — do not skip your screening.

Stopping: never on impulse

According to the SmPC, azathioprine should always be stopped gradually and under close medical supervision. There is no withdrawal syndrome — the risk is the underlying disease, which can flare up again.¹ Because the effect lingers for weeks, a relapse often shows up with a delay, and the connection with stopping is overlooked. Background in the guide stopping medications.

After a transplant: never stop on your own. Here azathioprine protects the new organ together with other immunosuppressants. Taking a break on your own initiative can put the transplant at risk. Report problems to your transplant centre immediately; with fever, pain in the area of the transplant or markedly less urine after a kidney transplant, every hour counts — in an emergency call 112 (emergency number in Germany).

10. Azathioprine experiences: what patients really ask

"My TPMT test was normal. Why do I still have to have blood taken every week?"

Because the test covers only one of several causes of dangerous changes in the blood count. A normal result says: your body breaks azathioprine down normally along this route. It says nothing about rare gene variants, interactions, a viral infection or declining kidney function. The SmPC is clear: the test does not replace the checks. The good news: after the first eight weeks the intervals become considerably longer.

"I have been taking it for eight weeks and don't notice anything at all."

That is normal and not a sign of failure. Whether azathioprine is helping is often only assessed after three to four months. What matters is that the bridging is right until then — often with cortisone, which is reduced according to a plan. Anyone who leaves out the cortisone on their own because azathioprine "is there now" risks exactly the flare that both are meant to prevent; see stopping cortisone.

"Does azathioprine cause cancer?"

The honest answer: on long-term immunosuppression the risk of non-melanoma skin cancer is increased, and to a lesser extent the risk of lymphomas. How great it is for you depends on age, skin type, sun exposure, duration and other immunosuppressants. Set against this is the benefit: less cortisone, fewer flares and, for transplant recipients, a functioning organ. You can lower the risk with consistent sun protection, an annual skin check and the recommended screening examinations. Weighing this up for your own case belongs in a conversation with the treating practice.

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FAQ: Common questions about azathioprine

Azathioprine works slowly because the active breakdown products only build up in the cells over weeks. An improvement usually shows after several weeks to months; the effect is generally assessed after about three to four months. Until then, cortisone is often used to bridge the gap.
The enzyme TPMT breaks down azathioprine, and its activity is something you are born with. About one in 300 people has practically no activity and can develop life-threatening bone marrow damage even at usual doses. The test shows in advance who needs a greatly reduced dose or a different drug. It does not replace the regular blood count checks.
According to the SmPC, at least once a week in the first eight weeks, then monthly, but at least every three months. Extra checks are done after dose changes, when new concomitant medicines are added or if you have a fever, and liver values are part of it too. The exact plan is set by the treating practice.
Only as a deliberately planned combination. Allopurinol blocks the breakdown of azathioprine, so the active substances build up to dangerous levels. According to the SmPC, the azathioprine dose must then be cut to a quarter and the blood count checked closely. Febuxostat is not recommended together with azathioprine.
Yes, but with a gap from the tablet. Milk contains an enzyme that can partly break the drug down. The SmPC recommends taking azathioprine at least one hour before or two hours after milk or dairy products, ideally with a large glass of water.
The SmPC is cautious; the Embryotox advisory centre, by contrast, rates the extensive experience as reassuring and advises against switching women who are stable on their treatment; breastfeeding is also considered possible there. Plan a pregnancy early with your practice and do not stop azathioprine on your own.
No. According to the SmPC, azathioprine is always stopped gradually and under medical supervision. There is no withdrawal syndrome, but the underlying disease can flare up again, and after a transplant there is a risk of rejection. If you have side effects, contact your practice instead of quietly leaving the tablets out.

Sources

  1. Summary of Product Characteristics (SmPC) for azathioprine film-coated tablets (e.g. Azathioprin dura N, as of May 2026; other products accordingly), sections 4.2 to 4.8 and 5.2 — German source. fachinfo.de
  2. Updated S3 guideline on the diagnosis and treatment of Crohn's disease (German Society for Gastroenterology, Digestive and Metabolic Diseases, DGVS; AWMF reg. no. 021-004, version 4.1, 2024) — German source. awmf.org
  3. German Society for Rheumatology (DGRh), Pharmacotherapy Committee: therapy information sheet on azathioprine. Accessed 2026 — German source. dgrh.de
  4. Kompetenznetz Darmerkrankungen (German competence network for inflammatory bowel disease): patient information — treatment with azathioprine or 6-mercaptopurine (2022) — German source. kompetenznetz-darmerkrankungen.de
  5. Relling MV et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther 2019. cpicpgx.org
  6. Embryotox, Charité Berlin — German pharmacovigilance and advisory centre for embryonic toxicology: azathioprine in pregnancy and breastfeeding. Accessed 2026. embryotox.de
  7. Robert Koch Institute / STIKO (German Standing Committee on Vaccination): guidance on vaccination in immunodeficiency, part on autoimmune diseases, chronic inflammatory diseases and immunomodulatory therapy (Bundesgesundheitsblatt 2019) — German source. rki.de

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Medical disclaimer: This article is for general information and does not replace medical advice, diagnosis or treatment. Do not stop azathioprine on your own and do not change the dose yourself — after a transplant this can put the organ at risk. Do not start any new medicine, especially a gout medicine such as allopurinol or febuxostat, without consulting the practice that prescribes your azathioprine. If you have a fever, a sore throat with sore patches in the mouth, unusual bleeding or severe upper abdominal pain, contact a doctor straight away or, in an emergency, call 112 (emergency number in Germany). The choice of medicine, the dose and the monitoring schedule are always set individually by the treating practice. Last updated: September 2026.