Nicorandil can cause serious skin ulceration

Nicorandil has been associated with skin and mucosal ulceration, and although rare, this has restricted its use to the 2nd line treatment of angina..
Islam M. Eid, BS Pharm, PGDipClinPharm

INTRODUCTION ã…¡ Angina is a pain that comes from the heart. It is usually caused by narrowing of one or more of the arteries that supply blood to your heart. This narrowing reduces the blood supply to parts of heart muscle. When heart needs more blood and oxygen than it can get through the narrowed arteries (for example, when patient walk fast or climb stairs, he feels angina pain).

Nicorandil (Adancor, Randil) is a nitrate derivative of nicotinamide and acts as a vasodilator. It is a potassium-channel opener providing vasodilatation of arterioles and large coronary arteries and its nitrate component produces venous vasodilatation through stimulation of guanylate cyclase. It thus reduces both preload and afterload, and improves coronary blood flow. Nicorandil is given orally for the treatment of angina pectoris, when first-line drugs cannot be used or tolerated, or do not provide adequate control. It is usual to take one tablet (either 10 mg or 20 mg) twice daily, in the morning and evening. Cardiologist may prescribe a smaller dose (such as half a tablet) and then increase dose after a short while. This will help avoiding any unwanted side-effects, particularly headache The usual initial oral dose is 10 mg twice daily (or 5 mg twice daily in patients susceptible to headache), increased as necessary to a maximum of 40 mg twice daily; the usual therapeutic dose is in the range of 10 to 20 mg twice daily.

Pharmacokinetics

Nicorandil is well absorbed from the gastrointestinal tract and peak plasma concentrations occur 30 to 60 minutes after oral doses. Metabolism is mainly by denitration and about 20% of a dose is excreted in the urine mainly as metabolites. The elimination half-life is about 1 hour. Nicorandil is only slightly bound to plasma proteins.

Side effects

Adverse effects reported with nicorandil are headache (which is usually transitory and seen at the start of therapy), cutaneous vasodilatation and flushing, nausea, vomiting, dizziness, and weakness. Some patients who take nicorandil tablets have developed ulcers - particularly mouth, eye or skin ulcers. Although this is a rare side-effect, nicorandil should be recognized as an etiological factor for non-healing wounds or ulcers once other inflammatory and malignant causes have been excluded (see section of ulceration).

Nicorandil is contra-indicated in patients with cardiogenic shock, cardiac decompensation, left ventricular failure with low filling pressures, and severe hypotension. It is also contra-indicated in patients with hypovolemia or acute pulmonary edema. Caution is advised when using nicorandil in patients with heart failure (class III and IV) or G6PD deficiency.

Ulceration from nicorandil

Nicorandil has been associated with serious skin and mucosal ulceration, and although rare, this has restricted its use to the second-line treatment of angina. Gastrointestinal ulcers are reported most frequently, and can lead to perforation, hemorrhage, fistula, or abscess. Ulceration of the skin or other mucous membranes, including the eye, is very rare. Ulcers may develop at different locations simultaneously; their onset is varied, and can occur several years after starting treatment. Treatment with conventional therapy, including surgery, is usually ineffective although improvement is generally seen after nicorandil is withdrawn.

  • Painful, large aphthous ulcers on the tongue and oral mucosa have been reported in patients receiving nicorandil for angina. The ulcers were usually resistant to treatment but all healed when nicorandil was withdrawn.
  • Colchicine or thalidomide treatment has improved ulcers associated with nicorandil in a few patients, but relapse occurred when the colchicine or thalidomide was stopped.
  • Anal ulceration has been reported in patients taking nicorandil. Healing of the ulcers occurred in those patients in whom nicorandil was withdrawn.
  • Multiple ulcers of the upper and lower gastrointestinal tract, in addition to oral and anal ulceration, have been reported in a patient taking nicorandil; all of the ulcers healed when nicorandil was stopped. There have also been several cases of peristomal ulceration, which resolved after stopping nicorandil. Patients with diverticular disease were found to be at particular risk
  • Perivulval and vaginal ulceration has also been reported, and may be associated with cutaneous or inguinal ulceration. Another patien developed both perianal and leg ulcers, both of which improved rapidly when nicorandil was stopped.
  • As with conventional nitrates, the vasodilatory effects of nicorandil are mediated in part via the stimulation of guanylate cyclase, and it is considered likely to interact with other vasodilators that act on this pathway. Licensed product information for nicorandil contra-indicates its use with phosphodiesterase type-5 inhibitors such as sildenafil, and the guanylate cyclase stimulator riociguat, as the hypotensive effect of nicorandil may be significantly enhanced.

Drug interaction

Concomitant use of nicorandil and NSAIDs or corticosteroids may increase the risk of ulceration. Rarely, cases of severe hyperkalemia have been seen with nicorandil, and caution is advised if it is used with other drugs that may increase potassium levels.

References