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Crohn's Disease Forum » Treatment » Imuran/Azathioprine/6-MP » Overview of Azathioprine & 6-MP


11-26-2011, 10:08 PM   #1
DustyKat
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Overview of Azathioprine & 6-MP

Immuno-modulator medications

Immuno-modulators are medications that affect the body's immune system. The immune system is composed of immune cells and the proteins that they produce. These cells and proteins serve to protect the body against harmful bacteria, viruses, fungi, and other foreign invaders. Activation of the immune system causes inflammation within the tissues where the activation occurs. (Inflammation is, in fact, an important mechanism used by the immune system to defend the body.) Normally, the immune system is activated only when the body is exposed to foreign invaders. In patients with Crohn's disease and ulcerative colitis, however, the immune system is abnormally and chronically activated in the absence of any known invader.

Immuno-modulators decrease tissue inflammation by reducing the population of immune cells and/or by interfering with their production of proteins. Decreasing the activity of the immune system with immuno-modulators increases the risk of infections; however, the benefits of controlling moderate to severe Crohn's disease usually outweigh the risks of infection due to weakened immunity.

Azathioprine (Imuran) and 6-mercaptopurine (6-MP, Purinethol)

Azathioprine (Imuran) and 6-mercaptopurine (6-MP, Purinethol) are medications that weaken the body's immune system by reducing the population of a class of immune cells called lymphocytes. Azathioprine and 6-MP are related chemically. (Actually, azathioprine is converted into 6-MP within the body.) In high doses, these two drugs have been useful in preventing rejection of transplanted organs and in treating leukemia. In low doses, they have been used for many years to treat patients with moderate to severe Crohn's disease and ulcerative colitis.

Azathioprine and 6-MP are increasingly recognized by doctors as valuable drugs in treating Crohn's disease and ulcerative colitis. Some 70% of patients with moderate to severe disease will benefit from these drugs. Azathioprine and 6-MP are used primarily in the following situations:

Severe Crohn's disease and ulcerative colitis not responding to corticosteroids.

The presence of undesirable corticosteroid-related side effects.

Corticosteroid dependency, a condition in which patients are unable to discontinue corticosteroids without developing relapses of their disease.

Maintenance of remission.

When azathioprine and 6-MP are added to corticosteroids in the treatment of Crohn's disease not responding to corticosteroids alone, there may be an improved response. Also, smaller doses and shorter courses of corticosteroids may be able to be used. Some patients can discontinue corticosteroids altogether without experiencing relapses of their disease. This corticosteroid-lowering effect has earned azathioprine and 6-MP their reputation as "steroid-sparing" medications.

In Crohn's disease patients with severe disease who suffer frequent relapses, 5-ASA may not be sufficient, and the more potent azathioprine and 6-MP will be necessary to maintain remissions. In the lower doses used to treat Crohn's disease, the long-term side effects of azathioprine or 6- MP are less serious than those of long-term corticosteroids or repeated courses of corticosteroids.

Patients with Crohn's disease may undergo surgery to remove a segment of the intestine that is obstructed or contains a fistula. After surgical removal of the diseased segments, the patients often will be free of disease and symptoms for a while, but many eventually will have their disease recur. During these recurrences, previously healthy intestine can become inflamed. Long-term 5-ASA (such as Pentasa) and 6-MP both are effective in reducing the chances of recurrence after surgery.

Anal fistulae can develop in some patients with Crohn's disease. Anal fistulae are abnormal tracts (tunnels) that form between the small intestine or colon and the skin around the anus. Drainage of fluid and mucous from the opening of the fistula is a troublesome problem. These fistulae are difficult to treat and do not heal readily. Metronidazole (Flagyl) has been used with some success in promoting healing of these fistulae. In difficult cases, azathioprine and 6-MP may be successful in promoting healing.

Side effects of azathioprine and 6-MP

Side effects of azathioprine and 6-MP include increased vulnerability to infections, inflammation of the liver (hepatitis) and the pancreas (pancreatitis), and bone marrow toxicity (interference with the formation of cells that circulate in the blood).

The goal of treatment with azathioprine and 6-MP is to lower the body's production of certain types of white blood cells (lymphocytes) in order to decrease the inflammation in the intestines; however, lowering the number of lymphocytes may increase vulnerability to infections. For example, in a group of patients with severe Crohn's disease unresponsive to standard doses of azathioprine, raising the dose of azathioprine helped to control the disease, but two patients developed cytomegalovirus (CMV) infection. (CMV typically infects individuals with weakened immune systems such as patients with AIDS and cancer patients receiving chemotherapy).

Azathioprine and 6-MP can induce inflammation of the liver (hepatitis) and pancreas (pancreatitis). Pancreatitis typically causes severe abdominal pain and sometimes vomiting. Pancreatitis due to azathioprine or 6-MP occurs in 3% to 5% of patients, usually during the first several weeks of treatment. Patients who develop pancreatitis should not receive either of these two medications again.

Azathioprine and 6-MP also suppress the bone marrow. The bone marrow is where the red blood cells, white blood cells, and platelets are made. Actually, a slight reduction in the white cell count during treatment is desirable since it suggests that the dose of azathioprine or 6-MP is high enough to have an effect; however, excessively low red or white blood cell counts indicates bone marrow toxicity. Therefore, patients on azathioprine or 6-MP should have periodic blood counts (usually every two weeks initially and then every three months during maintenance) to monitor the effect of the drugs on the bone marrow.

Patients on long-term, high dose azathioprine to prevent rejection of the kidney after kidney transplantation have an increased risk of developing lymphoma, a malignant disease of lymph cells. There is no evidence at present that long term use of azathioprine or 6-MP, in the lower doses used in Crohn's disease, increases the risk of lymphoma, leukemia or other malignancies.

The use of azathioprine and 6-MP in pregnant women must be carefully considered. There are reports suggesting that the use of azathioprine or 6-MP in pregnancy is safer than once thought. The risk of continuing azathioprine or 6-MP during conception and pregnancy must be weighed against the risk of worsening disease if they are stopped. On the other hand, worsening disease has been shown clearly to be a significant risk to the fetus.

Other issues with azathioprine and 6-MP

One problem with 6-MP and azathioprine is their slow onset of action. Typically, full benefit of these drugs is not realized for three months or longer. During this time, corticosteroids frequently have to be maintained at high levels to control inflammation.

The reason for this slow onset of action is partly due to the way doctors prescribe these drugs. For example, 6-MP is typically started at a dose of 50 mg daily. The blood count is then checked two weeks later. If the lymphocytes are not reduced, the dose of 6-MP is increased. This cautious, stepwise approach helps reduce bone marrow and liver toxicity but also delays benefit from the drug.

Studies have shown that giving higher doses of 6-MP early can hasten the benefit of 6-MP without increasing the toxicity in most patients, but some patients do develop severe bone marrow toxicity. Scientists now believe that an individual's vulnerability to 6-MP toxicity is genetically inherited. Blood tests can be performed to identify those individuals with increased vulnerability to 6-MP toxicity. Blood tests also can be performed to measure the levels of certain by-products of 6-MP. The levels of these by-products in the blood help doctors more quickly determine whether the dose of 6-MP is right for the patient.

TPMT genetics and safety of azathioprine and 6-MP

Azathioprine is converted into 6-MP in the body and 6-MP then is partially converted in the body into inactive and non-marrow toxic chemicals by an enzyme called thiopurine methyltransferase (TPMT). These chemicals then are eliminated from the body. The activity of TPMT enzyme (the ability of the enzyme to convert 6-MP into inactive and non-marrow toxic chemicals) is genetically determined, and approximately 10% of the population in the Untied States has a reduced or absent TPMT activity. In this 10% of patients, 6-MP accumulates and is converted into chemicals that are toxic to the bone marrow where blood cells are produced. Thus, when given normal doses of azathioprine or 6-MP, these patients with reduced or absent TPMT activities can develop seriously low white blood cell counts for prolonged periods of time, exposing them to serious life-threatening infections.

The U.S. Food and Drug Administration now recommends that doctors check TPMT levels prior to starting treatment with azathioprine or 6-MP. Patients found to have genes associated with reduced or absent TPMT activity are treated with alternative medications or are prescribed substantially lower than normal doses of 6-MP or azathioprine.

A word of caution is in order, however. Having normal TPMT genes is no guarantee against azathioprine or 6-MP toxicity. Rarely, a patient with normal TPMT genes can develop severe toxicity in the bone marrow and a low white blood cell count even with normal doses of 6-MP or azathioprine. Also, hepatotoxicity in the presence of normal TPMT levels been reported15. Therefore, all patients taking 6-MP or azathioprine (regardless of TPMT genetics) have to be closely monitored by periodic blood counts and liver enzyme tests for as long as the medication is taken.

Another cautionary note, allopurinol (Zyloprim), used in treating high blood uric acids levels, can induce bone marrow toxicity when used together with azathioprine or 6-MP. Allopurinol (Zyloprim) used together with azathioprine or 6-MP has similar effect as having reduced TPMT activity, causing increased accumulation of the 6-MP metabolite that is toxic to the bone marrow.

6-MP metabolite levels

In addition to monitoring blood cell counts and liver tests, doctors also may measure blood levels of the chemicals that are formed from 6-MP (6-MP metabolites), which can be helpful in several situations such as if a patient's disease:

is not responding to standard doses of 6-MP or azathioprine and his/her 6-MP blood metabolite levels are low, doctors may increase the 6-MP or azathioprine dose;

is not responding to treatment and his/her 6-MP blood metabolite levels are zero, he/she is not taking his/her medication. The lack of response in this case is due to patient non-compliance.
Duration of treatment with azathioprine and 6-MP

Patients have been maintained on 6-MP or azathioprine for years without important long-term side effects. Patients on long-term azathioprine or 6-MP, however, should be closely monitored by their doctors. There are data suggesting that patients on long-term maintenance fare better than those who stop these medications. Thus, those who stop azathioprine or 6-MP are more likely to experience recurrence of their disease and are more likely to need corticosteroids or undergo surgery.

http://www.medicinenet.com/crohns_disease/page10.htm
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11-27-2011, 04:55 AM   #2
ormsklad
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DustyKat Thanks for this info its been very helpful to me as I have been switched from AZA to 6MP due to adverse effects. The info on the part of the TPMT is true I think if the doc sees its normal they just go with it. Thanks for sharing with us
05-11-2012, 04:13 PM   #3
DustyKat
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Initiating Azathioprine for Crohn's Disease: Management Strategies

Interesting and informative article presented as a case study.

An insite as to when serious side effects are likely to occur...

It is pragmatic to note to patients that approximately 15% of patients cannot tolerate AZA. These dose-independent adverse reactions include drug fever, pancreatitis, arthralgias, nausea, and rash. Drug fever usually presents within 2 weeks of initiating therapy as a flu-like illness, and requires immediately stopping AZA. The risk of pancreatitis is approximately 3%, typically occurs within the first few weeks of therapy, and requires stopping AZA as well. It is useful to instruct patients to have a low threshold for reporting new symptoms, especially in the first month of therapy. Dose-dependent reactions include leukopenia and hepatotoxicity. Although leukopenia most often occurs within the first month, it may occur at any time during therapy.

http://www.medscape.com/viewarticle/763051_4
Dusty.
09-17-2012, 10:46 AM   #4
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What is considered a high dose and a low dose of Azathioprine?
09-17-2012, 12:09 PM   #5
IAmTheWalrus
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50mg is considered low and 250mg is considered high for someone with IBD, although I'm sure transplant patients take higher doses.
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28 y/o male from Dublin, Ireland, Dx with Crohn's Colitis in January 09.

Current Meds: Remicade, Imuran.

Risk/Benefits of treating Crohn's. Link below

http://www.ccfa.org/assets/pdfs/risk...transcript.pdf
09-17-2012, 12:52 PM   #6
spingirl
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So I just checked my dose and I am taking 3 of the 50 mgs per day so I guess that puts me right in the middle for the Aza. Darn. I guess I'm still at risk? I have to say - I do notice infections taking longer to heal. I had a hangnail. I bit the skin on my finger and in less than 12 hours I had to go to doctor and he put me on very heavy antibiotic. I got freaked out. He almost sent me to a surgeon. Now that is just odd I've been a nail biter all my life!!! I wash my hands like crazy. I want to read up though on it. I am wondering if I should be taking things to heighten my immunity in other ways. Ways that won't harm my intestines at the same time. Or is it futile? I don't want to contradict what I am trying to do with the medicine. This is also just for bacterial infections right? Does it weaken my ability to fight a virus too? I will be getting the flu shot but...so much is out there. Maybe Michael Jackson wasn't such a weirdo after all wearing the mask in public!!! I might be doing it soon!
01-07-2013, 01:49 AM   #7
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The overview with respect to Imuran, while generally useful, is misleading in one respect when it says : "There is no evidence at present that long term use of azathioprine or 6-MP, in the lower doses used in Crohn's disease, increases the risk of lymphoma, leukemia or other malignancies." - In case of the increased occurence of Hepatosplenic T-cell lymphoma noted in those using Biologics, the FDA have notice co-/prior use of Imuran in the case histories. Subsequently, on review, it decided to place a warning on Imuran itself.

On the FDA site, the warning concerning imuran is reported in its use for inflammatory Bowel Disease as follows:


"Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with Imuran. These cases have had a very aggressive disease course and have been fatal. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Some of the patients were treated with Imuran as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis.

The safety and efficacy of Imuran for the treatment of Crohn's disease and ulcerative colitis have not been established."

The link is at http://www.fda.gov/Safety/MedWatch/S.../ucm258794.htm

The fact that such a rare cancer shows up in such numbers in a relatively small sub-population with a specific set of common factors is significant. Obviously the FDA thought so. It should be noted that while this notice pertains to Imuran, it does not preclude the possibility that the biologics may be an indepenent risk factor. Indeed, the FDA have a similar concern, because they have a similar warning for Remicade, where they noted : " It is uncertain whether the occurrence of HSTCL is related to Remicade or Remicade in combination with these other immunosuppressants. "

Given, the legal position on such information it is in everyone's interest that this warning be repeated wherever appropriate.

Last edited by SMSIRL; 01-07-2013 at 01:26 PM. Reason: Additional suppoing refrences
01-07-2013, 03:39 AM   #8
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Just as a general comment about medicine : there are few medicines without significant issues for at least some people. For example, it was once thought that paracetamol/acetaminophen, outside of overdose, was quite safe. It is now known that in use >6mnths there can be significant renal toxicity. So, for those at great risk of renal disorders such drugs represent a less than attractive option. However, for people with renaud's, aspirin and similar drugs would not be appropriate, and short-term paracetamol would be superior.

While this may be true, it is also true, that untreated many diseases have significant/fatal impact on people's lives. Hence, while no one in their right mind should take any drug unless it is needed, some drugs, even ones under-studied and dangerous may be the lesser of two evils. For example, many cancer drugs themselves can cause can. However, if you happen to be a person with a cancer that such a drug treats, you would be mad not to take it.

This is a balancing act. However, it is most important that decisions we make are based on the totallity of the evidence available, and taking into account the individual's particular circumstances.

What we as individuals can do to make these decisions better is to fully engage in the decision making process, educating ourselves, and insisting that research be done to address the blind spots in the medical literature with integrity and honesty.

To that end, we must also be active in insisting that government, through its agencies insist on total disclosure of ALL research findings, both positive and negative. Pharma companies have repeatedly been found wanting in this regards which means drugs that are ineffective and dangerous have been licienced, and even some useful drugs have not been appropriately assessed vis-a-vis indications, warnings, contra-indication, and dosing.

Another dimension is that, while drugs tha are threating disease are useful, drugs that cure a disease would be more useful. However, the fnancial practicalities make treatments more appealing for pharma companies that would cures. A lifetime of treatment accrues more revenues than a two week cure. So, in the absence of a market imperative for a cure, other funding must be sourced to provide for research into cures.Therefore, we as a community should actively seek to raise money to fund research into the under-lying causes and potential cures for IBD.

Last edited by SMSIRL; 01-07-2013 at 04:09 AM.
03-28-2013, 12:28 PM   #9
Paul Cronk
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I have been taking Humira but the effect has diminished and I now need 10mg Prednisone a day as well. My doc will do another coloscopy but may then prescribe Imuran. At first I was disapointed that he was not considering Cimzia instead, but he does not have that available. However, as I seem to be generally very drug tolerant, and having read the intro, I am getting more comfortable about Imuran, as long as the Pred goes at the same time!
03-30-2013, 01:49 PM   #10
spingirl
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Does Humira have fewer or less dangerous issues than Imuran? I thought they were all about the same with the risks...???

Makes me sad to hear that one is working and then stops...I guess the body is just remarkable as it adjusts and compensates for medications. Amazing really.

Prednesone I just don't like. That one just scares me. I've used it and it works wonders...but...well...you all know...
03-31-2013, 09:53 AM   #11
Paul Cronk
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50mg is considered low and 250mg is considered high for someone with IBD, although I'm sure transplant patients take higher doses.
I note you are on Humira and Imuran. Did the H stop working alone or was the Imuran first? I am welcoming Imuran as a safer alternative to pred but I will still need H as well. Interested in all feedback from anyone on both drugs.
04-24-2013, 11:56 PM   #12
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I see that this is an old post. I am new to this forum and had seen that you at one point were on Humira and going to start taking Imuran on top of that. Just all wanted to ask if that helped at for you? I was on Humira, Apriso and Entocort. About a week ago I was taken off of Entocort and had Imuran and Prednisone added.So now I am on Humira, Imuran, Apriso, and Prednisone. Like I said, I'm just to get info or feedback on this combo.

Thanks
06-19-2015, 04:53 PM   #13
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I feel obligated to make parents aware of the dangers of using 6mp to treat Crohn's Disease. My son has been treated for Crohns since he was 5. When he was 14 his doctors switched him to 6mp. I didn't like this med and even got a second opinion about him taking it. He took it for 15 months and was just switching over to Remicade when the labs showed a drop in his blood counts. Four weeks later leukemia cells were detected in his blood. He was diagnosed with treatment-related Acute Myeloid Leukemia and it is deadly. He has been through 7 different rounds of chemo and not one of the regimens put him in remission. He tried an investigational drug-no success. Just went through a bone marrow transplant and about 30 days after transplant leukemia cells still showing in his blood. We are going to lose our son because of the use of 6mp for his Crohns Disease (which was never debilitating for him). I realize this risk is small and many take 6mp with no issues. Please don't take this drug without carefully considering other options. I wish I turn back the clock and never have my son on this medication but it's too late. My heart is broken and my world forever changed. He is currently receiving supportive care because it would appear a cure is not possible.
06-19-2015, 06:43 PM   #14
Caitlin84
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That is absolutely awful, I'm so sorry for what you and your son are going through.
06-19-2015, 11:30 PM   #15
spingirl
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I am so so very sorry Crohnsmom1999. This is a very important post for all of us to read and I am truly grateful that you took the time to write it.
11-30-2015, 01:49 PM   #16
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There is definitely a documented increased risk of cancer associated with the doses of azathioprine used in IBD. It is not confined solely to the higher doses used in transplantation:

http://aje.oxfordjournals.org/conten.../1296.full.pdf

http://www.ncbi.nlm.nih.gov/pmc/arti...ut05401121.pdf
11-30-2015, 11:51 PM   #17
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I guess the reason I wasnt allowed yo continue with Pentasa was because of the rxprnde. I had a resection in 2010.
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