What are the potential side effects of nicorandil?

Side Effects of Nicorandil

The main adverse effects of nicorandil are headache, reflux, tachycardia, facial flushing, and hypotension, with rare but serious skin, mucosal, and eye ulceration that can occur anywhere from the mouth to the perineum. 1

Common Side Effects

Cardiovascular and Vasodilatory Effects

• Headache is the most frequently reported adverse effect, occurring in approximately one-third of patients receiving the recommended therapeutic regimen of 10-20 mg twice daily 2
• Headaches are typically mild to moderate in severity, occur most frequently during the first days of treatment, and usually resolve within a few days if treatment is continued 3
• The incidence of headache with nicorandil is similar to that produced by isosorbide mononitrate and isosorbide dinitrate 2
• Approximately 5% of patients in European trials withdrew due to headache, though this rate can be reduced by starting with a lower dose of 5 mg twice daily 2
• Facial flushing and hypotension occur due to the vasodilatory properties of the drug 1
• Tachycardia can develop as a compensatory response to vasodilation 1

Gastrointestinal Effects

• Reflux is a recognized common adverse effect 1
• Dizziness and other gastrointestinal disorders have been reported as mild to moderate in severity 3

Serious and Rare Side Effects

Ulcerative Complications

• Serious skin, mucosal, and eye ulceration have been reported, though these are rare 1
• Gastrointestinal ulceration can occur anywhere from the mouth to the perineum, including oral ulcerations (sometimes quite large), painful anal ulceration, and chronic ulceration of the colon and small intestine 4
• Painful parastomal ulceration has been reported in patients with ileostomies or colectomies 4
• In some cases, lesions are sufficiently extensive and refractory to warrant surgery (colostomy) or immunosuppressant treatment 4
• Simply withdrawing nicorandil generally leads to recovery within a few weeks 4
• Ulceration is sometimes associated with skin ulcers 4

Drug Interaction Risks

• Concomitant use of nicorandil with aspirin may increase the risk of gastrointestinal ulcers, perforations, and hemorrhage 1

Clinical Context and Tolerability

Treatment Withdrawal Rates

• In the IONA outcome study, 39% of patients in the treatment group withdrew, with headache being the primary reason 1
• At the end of a 1-year safety study, 70% of patients were maintained on nicorandil 3
• Study withdrawals due to clinical intolerance were 9.6% overall, but this was substantially reduced to 2.7% when using a progressive titration scheme 3

Safety Profile Compared to Other Agents

• The overall incidence of adverse events with nicorandil is no different from beta-blockers, calcium antagonists, or nitrates in comparative studies, although the safety profile differs according to drug category 3
• The incidence of adverse events is not modified when nicorandil is given in combination with a beta-blocker, calcium antagonist, or both agents 3
• Cardiovascular safety is satisfactory and laboratory parameters (including lipid profile and glucose levels) are not adversely affected 3, 5

Important Clinical Pitfalls

Avoiding Ulcerative Complications

• Maintain high clinical suspicion for ulcerative complications in any patient on nicorandil who develops painful lesions anywhere from the mouth to the perineum 4
• If cutaneous or gastrointestinal ulceration occurs, nicorandil must be withdrawn immediately 4
• Consider alternative antianginal therapy such as beta-blockers rather than continuing nicorandil if ulceration develops 4

Minimizing Headache

• Start with a lower dose (5 mg twice daily) in patients prone to headache, then titrate upward 2
• Counsel patients that headaches typically occur early in treatment and usually resolve with continued therapy 3
• Use progressive titration schemes to substantially reduce withdrawal rates due to headache 3