MORE @ WWW. PHARMACY For references, go to www RX FOCUS DRUG INTERACTIONS TIMES.COM .PharmacyTimes.com/ publications/issue. Another Thiopurine- Allopurinol Tragedy John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD

reduce toxicity. Thiopurines can produce been “rediscovered” repeatedly, often with hepatotoxic metabolites, and there is evi- fatal results. Some of the disasters occurred dence that allopurinol can shunt more of when the thiopurine was prescribed by the metabolism to the metabolites that one physician, and the allopurinol was provide efficacy (6-thioguanine nucleo- prescribed by another. For this reason, it is tides) and away from those that produce necessary that the patient be advised about hepatotoxicity.2 If the combination is used, the dangers of adding allopurinol to thio- however, it is absolutely necessary to sub- purine therapy unless it is done properly. stantially reduce the dose of thiopurine and The published case reports are likely to John R. Horn, PharmD, Philip D. Hansten, monitor the patient carefully for evidence represent only a small fraction of the actual FCCP PharmD of bone marrow suppression. There is cases. The drug interaction may not be substantial person-to-person variability in recognized as the cause of the reaction, and recent news headline read, the magnitude of all drug interactions, and even when it is recognized by prescribers, “Pharmacists’ failure to check drug a rule-of-thumb dosage reduction may well they may be reluctant to publish a fatal Arisks leads to ‘horrible’ death.”1 be too much for one patient and not enough drug error that they committed. According to the CBC News report, a for another. In 2009, the New Zealand Health 76-year-old woman on mercaptopurine Department issued a safety notice after for colitis was started on allopurinol. Six Is This an Old Interaction? a patient on azathioprine and allopurinol weeks later, she developed a blister on her Very old. It was described in 1963 by died of pancytopenia.7 The patient was foot and went to the hospital; the hospital Gertrude Elion, the scientist who won the on azathioprine as an outpatient and upon physicians recognized the problem as a Nobel Prize in 1988, partly for the devel- admission to a hospital was given allopuri- drug interaction, but the patient died of opment of all 3 of the drugs involved: nol by the physicians. The interaction was severe infection and respiratory failure. mercaptopurine, azathioprine, and allopu- not detected by the pharmacy computer Apparently, the interacting rinol. She reported in 1963 because the patient’s azathioprine prescrip- drugs were prescribed by Giving a that allopurinol, as expec- tion was not on the system. the same physician, and ted, reduced the metabo- they were filled at the same xanthine oxidase lism of mercaptopurine Recommendations pharmacy. by xanthine oxidase.3 By • When thiopurines are intentionally used inhibitor with a 1966, others warned that with xanthine oxidase inhibitors (allopu- What Is the the mercaptopurine dose rinol or febuxostat) to improve efficacy Interaction? thiopurine can should be reduced to about and reduce toxicity of thiopurines, there The thiopurines (mercap- 25% of the usual dose if must be both a dosage reduction of the topurine and azathioprine) substantially allopurinol is given con- thiopurine and regular monitoring for have complex metabolism, currently.4 bone marrow depression. but one important path- increase the • Every patient taking thiopurines alone way is via xanthine oxi- effect of the Are There Other (without allopurinol or febuxostat) should dase, leading to an inactive Case Reports? be warned specifically about the dangers metabolite. Giving a xan- thiopurine, In 1970, a clinicopatho- of taking allopurinol or febuxostat con- thine oxidase inhibitor such logic conference was pub- currently. as allopurinol or febuxostat leading to bone lished in which a 61-year- • Whenever allopurinol or febuxostat use with a thiopurine can sub- old man on azathioprine is initiated in a patient, prescribers and stantially increase the effect marrow died of pancytopenia, pharmacists should investigate to ensure of the thiopurine, leading to bleeding, and sepsis after that the patient is not already taking aza- bone marrow suppression. suppression. starting allopurinol ther- thioprine or mercaptopurine. n apy.5 Even though numer- Is Allopurinol Contraindicated ous theories were proposed to explain the with Thiopurines? fatality, over a year later, the true cause Not at all. In fact, allopurinol is used was discovered and published: an interac- Drs. Horn and Hansten are both professors of pharmacy at the University of Washington with thiopurines in selected patients with tion between azathioprine and allopuri- School of Pharmacy. For an electronic version inflammatory bowel disease and other dis- nol.6 Since this index case, the interaction of this article, including references, if any, visit eases in order to improve efficacy and between allopurinol and thiopurines has www.hanstenandhorn.com.

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