Thiopurines

for Inflammatory Bowel Disease (IBD)

KEY POINTS:

Thiopurines are used to treat both Crohn’s disease and ulcerative colitis.The two medicines in this family are azathioprine (AZA) (Imuran) and 6-mercaptopurine (6-MP) (Purinthol).
These medicines have been used to treat inflammatory diseases, to prevent rejection of transplants, and even to treat some cancers, for over 50 years.
In IBD they are used with the goal of maintaining remission after active disease has been brought under control with corticosteroids.In ulcerative colitis they are used if 5-ASA medications are not effective in maintaining remission.
Combination treatment: They are used in combination with anti-TNF medicines to improve the likelihood of getting into and staying in remission
Thiopurines have been shown to reduce the likelihood of needing corticosteroids in the future - called a “steroid-sparing” effect.
Cost: These medicines are not as costly as many of the other medicines used with IBD. Usually they are covered under provincial and private drug plans. (See the fact sheet Managing Costs of Medicine for Inflammatory Bowel Disease for more information.)

How do these medicines work?

Thiopurines interfere with the ability of lymphocytes, (a type of white blood cell involved in the normal function of the immune system) to cause inflammation
It takes about 3 weeks to reach steady blood levels once you start the medicine.If the medicine is helpful, it is usually continued for at least a few years, if not indefinitely.

How well do they work?

Thiopurines are generally not used to settle active disease. Once IBD has been treated and settled, these medicines are generally used with the goal of keeping a patient in remission.
In Crohn’s disease and ulcerative colitis 1 to 2 out of every 3 patients (33 – 50%) who start a thiopurine with a goal of staying in remission it will find it to be effective.When thiopurines are used together with an anti-TNF drug, it is thought to increase the ability to reach a remission in either Crohn’s disease or ulcerative colitis in an additional 1 out of 5 patients (20%) .
Combination treatment: When thiopurines are used with anti-TNF medicines over years, there is evidence that this will increase the likelihood that the anti-TNF will keep working
Azathioprine and 6-mercaptopurine are considered to be equally effective.

How are they taken?

Thiopurines are only given in pill form.
Before taking the medicine: About 1-2 of 100 people (1-2%) of people cannot use thiopurines because their bodies do not make enough of a substance, TMPT, that breaks down the drug. Before you start a thiopurine, your doctor should check your blood for the level of TMPT. If your TMPT level is very low, you should not use thiopurine drugs. If your TPMT level is considered intermediate then you can receive thiopurines at reduced doses. If you live in an area where TPMT levels are not checked then you need to have very frequent blood testing (for example every week for 4 weeks and then every 2 weeks for 4 weeks).
Duration of treatment: If the medicine is helpful, it is usually continued for at least a few years, if not indefinitely..
Stopping thiopurines: When these medicines are used as the lone treatment then it could be stopped after a prolonged use, however before stopping the drug it should be determined that there is no active inflammation either by colonoscopy, imaging and/or blood tests. When thiopurines are used together with anti-TNF drugs at some point the dosing of thiopurines may be reduced or the drug may be stopped altogether to simplify the drug regimen.

Azathioprine

The daily dose of azathioprine is determined by your weight. Generally the dose is between 1.5and 2.5 mg per kilogram, rounded to the nearest 25mg dose
Azathioprine pills come in 50mg tablets, so the daily dose may range from 1½ pills per day for a 50 kg person, to 5 pills a day for a 100 kg person.
Azathioprine pills can be broken in half if needed
Generally, the total dose is taken once per day, though it can be split up to be taken 2 or 3 times per day if that is preferred

6-Mercaptopurine

The daily dose of 6-mercaptopuine is determined by your weight. Generally the dose will be between 0.5and 1.5 mg per kilogram, rounded to the nearest 25mg dose
6-mercaptopuine pills come in 50 mg tablets, so the daily dose may range from 1/2 pill per day for a 50 kg person, to 3 pills a day for a 100 kg person.
Generally, the total dose will be taken once per day, though it can be split up to be taken 2 or 3 times per day if that is preferred.

Side effects

About 10-15% of people will experience side effects when starting thiopurines. The most common side effects are nausea, skin rash, and hair loss. These may get better when the dose is lowered.If patients do not tolerate azathioprine they may be able to tolerate 6-mercaptopurine.
White blood cells: About 1 in 4 people (25%) may have a decrease in their white blood cell count (cells which protect the body from infections). This may increase the risk of infections. If your white blood cell count drops, it is typically not serious and a reduction in the dose can allow for the white blood cell count to rebound back to normal. If the white blood cell count drops very low then this can increase the risk for severe infections.
While you are using thiopurines, your doctor will check your white blood cell count every 1 to 3 months to make sure it is not going too low. It is very important to have the regular blood tests as requested by your doctor.

Complications

Pancreatitis: About 1 in 50 people (2%) will develop painful inflammation of the pancreas, called acute pancreatitis. This develops usually within 1 month of starting a thiopurine. This condition can cause severe pain and nausea, and may need for you to be admitted to hospital. The inflammation usually quickly improves when you stop the drug.
Infections: Users of thiopurines may have a higher risk of developing infections. Most of the time, these infections can be treated with antibiotics.
Lymphoma: Approximately 1 in 2000 people using thiopurines may develop a type of blood cancer called non-Hodgkin lymphoma. This is slightly more than the normal risk of developing lymphoma (around 1 in 5000).
Skin cancer: Thiopurines may also increase the risk of skin cancers. Therefore, persons using thiopurines should avoid excessive sun exposure and regularly use sunscreen
Females: If you are female, thiopurines may also increase the risk of developing abnormal cells in your cervix as detected on Pap smear tests. You should have Pap smears at least every 3 years if you are using a thiopurine. Your doctor may want you to have Pap smears more regularly if you have had abnormal Pap smears before.

References

Bernstein CN. Treatment of IBD: Where we are and where we are going. American Journal of Gastroenterology 2015; 110:114-126.

Khan KJ, Dubinsky MC, Ford AC, Ullman TA, Talley NJ, Moayyedi P. Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2011 Apr;106(4):630-42.

Lemaitre M, Kirchgesner J, Rudnichi A, Carrat F, Zureik M, Carbonnel F, Dray-Spira R. Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease. JAMA. 2017 Nov 7;318(17):1679-1686.

Last reviewed: March 2020

For more information about IBD and its treatment please visit: www.crohnsandcolitis.ca

Disclaimer: This information is provided for educational purposes only. Always consult a qualified health care professional for your specific care.

Source: This summary provides scientifically accurate information. It was prepared in a research review by researchers with the IBD Clinical and Research Centre, University of Manitoba with assistance from colleagues in Canada and internationally.

Acknowledgement: Preparation of this material was supported by funding from the Canadian Institutes of Health Research.

2017 Charles N. Bernstein, John R. Walker on behalf of Manitoba IBD Clinical and Research Centre. This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License. You are free to copy and distribute this material in its entirety, as long as it is not altered in any way (no derivative works).