Nicorandil‐induced ulcerations: a 10‐year observational study of all cases spontaneously reported to the French pharmacovigilance network

Abstract

Nicorandil-induced ulcers remain often poorly recognised, with a late diagnosis and an inadequate management. We aimed to provide a clinical overview of the 148 spontaneously reported cases of nicorandil-induced ulcers to the French pharmacovigilance network between 2005 and 2014 and to complete this picture with worldwide published cases over the same period. Spontaneously reported nicorandil-induced ulcers were mainly mucosal (oral and anal) with a previous trauma in 23·0% of patients, revealed by a severe complication in 12·8% of cases. The mean cumulative dose of nicorandil was higher in serious cases. The median delay between the start of nicorandil use and the onset of the ulcer was 23·4 months, and after the ulcer was diagnosed, the median time to incriminate nicorandil was still 3·3 months, being shorter for mucosal ulcerations than for cutaneous ulcerations (5·2 versus 14·0 months, P = 0·001). The anatomic distribution in the 199 published cases differed slightly, but delays were similar. The hypothesis of mechanism becomes more precise, leaving no doubt about the necessity to discontinue the treatment. Practitioners need to be aware that nicorandil-induced ulcers can occur in many locations, possibly multiple and complicated, and should be simply managed by discontinuing treatment with no further reintroduction of nicorandil.

Genetic Risk of Diverticular Disease Predicts Early Stoppage of Nicorandil

“…In 1997, the first reports appeared of gastrointestinal ulceration and fistulation in association with nicorandil use. 3,8,9 General consensus from these initial case reports and observational studies was that the adverse effects cannot be predicted. However, more recent data have shown that individuals with diverticular disease are at an increased risk of bowel perforation 10 and are seven times more likely to develop a fistula.…”

“…It is hypothesized that in these outpouchings, nicorandil's toxic metabolites accumulate causing epithelial proliferation and subsequent tissue ulceration. 8 Additionally, it has been postulated that nicorandil releases proinflammatory nitric oxide, which may also trigger the development of fistulas among sigmoidal diverticula. 3 The main clinical implication of our study is the potential for the use of a GRS to predict adverse side effects with nicorandil use.…”

“…Nicorandil was first prescribed in Japan in 1984. In 1997, the first reports appeared of gastrointestinal ulceration and fistulation in association with nicorandil use 3,8,9 . General consensus from these initial case reports and observational studies was that the adverse effects cannot be predicted.…”

“…Diverticula most often occur at vulnerable sites where blood vessels cross the colon muscle wall. It is hypothesized that in these outpouchings, nicorandil's toxic metabolites accumulate causing epithelial proliferation and subsequent tissue ulceration 8 . Additionally, it has been postulated that nicorandil releases proinflammatory nitric oxide, which may also trigger the development of fistulas among sigmoidal diverticula 3 …”

Painful perianal ulcers with nicorandil

“…Patients may present with ulcers, which are usually painful, in the mouth, around the anus, or on the cornea, skin, or genitalia 214151617. Those with ulcers in the bowel may present with gastrointestinal haemorrhage.…”