Allopurinol with Azathioprine Interaction Details

Brand Names Associated with Allopurinol

Brand Names Associated with Azathioprine

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Feb 27, 2024

Interaction Effect

Azathioprine toxicity (nausea, vomiting, leukopenia, anemia)

Interaction Summary

Allopurinol may prolong the activity of azathioprine via inhibition of xanthine oxidase[1]. Bone marrow suppression has occurred with concomitant use [2][3]. If coadministration is required, reduce the azathioprine dose to one-third to one-fourth of the usual dose. Monitor closely and adjust subsequent doses based on response to therapy and presence of toxicities [1][4]. Further dose reduction or alternative therapy may be required for patients with low or absent thiopurine S-methyltransferase (TPMT) activity [5][4].

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Allopurinol inhibits one of the pathways of inactivation of azathioprine. If coadministration is required, reduce the dose of azathioprine to one-third to one-fourth of the usual dose. Monitor closely and adjust subsequent doses based on response to therapy and presence of toxicities[1]. Further dose reduction or alternative therapy may be required for patients with low or absent thiopurine S-methyltransferase (TPMT) activity [5][4]. Consider continuous monitoring as interaction may take several months to appear [6].

Mechanism Of Interaction

Inhibition of xanthine oxidase

Literature Reports

A) Concomitant allopurinol and azathioprine therapy has been reported to impair the conversion of 6-mercaptopurine (the first metabolite of azathioprine) to inactive products by inhibiting xanthine oxidase, resulting in higher blood levels of 6-mercaptopurine. Increased blood levels of 6-mercaptopurine may exert serious toxic effects on bone marrow and other tissues [7][8].

B) Several patients receiving azathioprine developed reversible anemia, leukopenia, and thrombocytopenia after allopurinol therapy was added. After discontinuation of concomitant therapy, the hematocrit, hemoglobin, red blood cells, white blood cells and platelets increased [9][10].

C) A 63-year-old heart transplant patient was hospitalized for pancytopenia six weeks after his local physician prescribed allopurinol for wrist pain thought to be gout related. The patient had been maintained on azathioprine 200 mg daily, along with other medications. After the allopurinol was started, the patient developed progressive dizziness and weakness. Six days before admission to the hospital, the patient had a syncopal episode which resulted in a fall. Upon admission to the hospital, the allopurinol and azathioprine were held, and the patient required packed red blood cells and regramostim (GM-CSF). The therapy was successful and the patient left the hospital eight days after admission. Azathioprine was titrated back to the patient's previous dose [2].

D) Twenty-four transplant patients receiving azathioprine and allopurinol were retrospectively studied. At the initiation of allopurinol therapy, the mean reduction of azathioprine was 73.3%, but ranged from 0% to 90%. Within three months of concurrent therapy, 46% of the patients became leukopenic, 30% became moderately anemic, and 22% became thrombocytopenic. The risk of myelotoxicity was not eliminated in patients who had their dose of azathioprine reduced by two-thirds or more at the start of allopurinol therapy. This study highlighted the need for careful and continuous monitoring of patients on concurrent azathioprine and allopurinol regimens, since some patients did not develop myelotoxicity until the second or third month of combined therapy [6].

E) Five cases of allopurinol and azathioprine interactions causing bone marrow suppression are reported. In all of the cases, bone marrow suppression occurred within one to three months after starting combination therapy with allopurinol and azathioprine. These observations again reiterate the dangers of this drug interaction. Frequent monitoring of blood parameters and initial reduction of the azathioprine dose by 75% in the presence of allopurinol is reinforced [3].

F) A case report described a 68-year-old male who had persistent thrombocytopenia and leukopenia that responded to steroid treatment. A trial of azathioprine was started at 150 mg daily. Two weeks later, the patient presented with new petechiae on the lower extremities and large purpura on the arms. At that time, it became known that allopurinol 300 mg daily had been prescribed by a different physician. Both azathioprine and allopurinol were discontinued and the patient required red cell and platelet transfusions. The platelet count began to recover by the 15th day after the discontinuation of the offending agents [11].

References

1 ) Product Information: DUZALLO(R) oral tablets, lesinurad, allopurinol oral tablets. Ironwood Pharmaceuticals, Inc (per manufacturer), Cambridge, MA, 2017.

2 ) Kennedy DT, Hayney MS, & Lake KD: Azathioprine and allopurinol: the price of an avoidable drug interaction. Ann Pharmacother 1996; 30:951-954.

3 ) Venkat Raman G, Sharman VL, & Lee HA: Azathioprine and allopurinol: a potentially dangerous combination. J Intern Med 1990; 228:69-71.

4 ) Product Information: IMURAN(R) oral tablets, azathioprine oral tablets. Prometheus Laboratories Inc. (per FDA), San Diego, CA, 2014.

5 ) Product Information: IMURAN(R) intravenous injection, azathioprine intravenous injection. Prometheus Laboratories Inc. (per FDA), San Diego, CA, 2014.

6 ) Cummins D, Muthasamy S, Halil O, et al: Myelosuppression associated with azathioprine-allopurinol interaction after heart and lung transplantation. Transplantation 1996; 61:1661-1662.

7 ) Rundles RW, Wyngaarden JB, & Hitchings GH: Effects of a xanthine oxidase inhibitor on thiopurine metabolism, hyperuricemia and gout. Trans Assoc Am Physicians 1963; 76:126.

8 ) Zimm S, Collins JM, O'Neill D, et al: Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol. Clin Pharmacol Ther 1983; 34:810-817.

9 ) Zazgornik J, Kopsa H, Schmidt P, et al: Increased danger of bone marrow damage in simultaneous azathioprine-allopurinol therapy. Int J Clin Pharmacol Ther Toxicol 1981; 19:96-97.

10 ) Boyd IW: Allopurinol-azathioprine interaction (letter). J Intern Med 1991; 229:386.

11 ) Brooks RJ, Dorr RT, & Durie BGM: Interaction of allopurinol with 6-mercaptopurine and azathioprine. Biomed Pharmacother 1982; 36:217-222.

Allopurinol Overview

• Allopurinol is used to treat gout (a type of arthritis in which uric acid, a naturally occurring substance in the body, builds up in the joints and causes sudden attacks of redness, swelling, pain, and heat in one or more joints). Allopurinol is also used to treat high levels of uric acid that builds up in the blood as tumors break down in people with certain types of cancer who are being treated with chemotherapy medications. It is also used to treat kidney stones that have come back in people who have high levels of uric acid in their urine. Allopurinol is in a class of medications called xanthine oxidase inhibitors. It works by reducing the production of uric acid in the body. High levels of uric acid may cause gout attacks or kidney stones. Allopurinol is used to prevent gout attacks, not to treat them once they occur.

Azathioprine Overview

• Azathioprine is used with other medications to prevent transplant rejection (attack of the transplanted organ by the immune system) in people who received kidney transplants. It is also used to treat severe rheumatoid arthritis (a condition in which the body attacks its own joints, causing pain, swelling, and loss of function) when other medications and treatments have not helped. Azathioprine is in a class of medications called immunosuppressants. It works by decreasing the activity of the body's immune system so it will not attack the transplanted organ or the joints.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.