6-Mercaptopurine in the Management of Inflammatory Bowel Disease: Short- and Long-Term Toxicity

Abstract

We assess toxicity related to 6-mercaptopurine in the treatment of inflammatory bowel disease by reporting our experience with 396 patients (120 patients with ulcerative colitis, 276 with Crohn disease) observed over 18 years. Follow-up data for a mean period of 60.3 months were obtained for 90% of the patients. Toxicity directly induced by 6-mercaptopurine included pancreatitis in 13 patients (3.3%), bone marrow depression in 8 (2%), allergic reactions in 8 (2%), and drug hepatitis in 1 (0.3%). These complications were reversible in all cases with no mortality. Most cases of marrow depression occurred earlier in our experience, when the initial drug doses used were higher. Infectious complications were seen in 29 patients (7.4%), of which 7 (1.8%) were severe, including one instance of herpes zoster encephalitis. All infections were reversible with no deaths. Twelve neoplasms (3.1%) were observed, but only 1 (0.3%), a diffuse histiocytic lymphoma of the brain, had a probable association with the use of 6-mercaptopurine. Our data, showing a low incidence of toxicity in 396 patients, coupled with the previously demonstrated efficacy of 6-mercaptopurine in the treatment of inflammatory bowel disease, indicate that the drug is a reasonable alternative in the management of patients with intractable inflammatory bowel disease.

Tioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine

“…The overall frequency of side-effects with AZA/MP has been reported to affect 10-15% of patients. 8 Among these side-effects, pancreatitis was observed in about 3.3% of patients. 8 Pancreatitis recurs upon re-introduction of AZA or MP 8,9 and requires a definitive withdrawal of these drugs.…”

“…Among 21 of them, remission was achieved without corticosteroids or infliximab during the follow-up period (median duration 7 months, range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The probability of remission without corticosteroids or infliximab was 46% (95% CI, 37-55%) and 79% (95% CI, 70-88%) at 6 and 12 months, respectively ( Figure 2).…”

“…[5][6][7] About 15% of inflammatory bowel disease patients do not tolerate AZA/MP due to side-effects. 8 Some of these side-effects are clearly idiosyncratic in nature, e.g. pancreatitis, fever, rash, joint pain, and diarrhoea, whereas others are usually dose dependent, e.g.…”

“…nausea, vomiting, liver toxicity and leucopenia. 8,9 In the latter, the role of imidazole derivatives 10 as well as methylated derivatives 7 or high 6-TGN levels 11 is evoked. Approximately 40% of inflammatory bowel diseases patients fail to achieve a complete clinical response under AZA/MP.…”

Improving pharmacovigilance in Europe: TPMT genotyping and phenotyping in the UK and Spain

“…1 -6 However, severe leukopenia was reportedly less frequent in a study of 396 IBD patients who were receiving 6-MP, 2% of the cases developed clinical severe bone marrow suppression that required hospitalization. 21 Examination of the online records for reports on adverse drug reactions (ADRs) in patients prescribed AZA on the UK Medicines Control Agency website (http://www.mhra. gov.uk) provides a detailed account of AZA-related ADRs during the reporting period of 1 July 1963 to 19 May 2006.…”