Ikorel^TM Tablets 10mg and 20mg

Nicorandil 10mg or 20mg

Tablets, off-white, round, with faceted edges, scored on one side and bearing the inscription IK10 (10mg) or IK20 (20mg).

Ikorel tablets are indicated for the following:

• The prevention and long term treatment of chronic stable angina pectoris

• A reduction in the risk of acute coronary syndromes in patients with chronic stable angina and at least one of the following risk factors:

Previous MI

Previous CABG

CHD on angiography or a positive exercise test together with one of the following: LVH on ECG, left ventricular dysfunction, Age 65, diabetes mellitus (type I or II excluding those on sulphonylureas, see section 5.1), hypertension or documented vascular disease

Route of administration: oral.

Adults: The recommended starting dose is 10mg nicorandil twice daily, although 5mg twice daily may be employed in patients particularly susceptible to headache. Subsequently the dosage should be titrated upward depending on the clinical response. The usual therapeutic dosage is in the range 10 to 20mg nicorandil twice daily, although up to 30mg twice daily may be employed if necessary.

Elderly: There is no special requirement for dosage reduction in elderly patients. As with all medicines, the lowest effective dosage should be used.

Children:A paediatric dosage has not been established and use of nicorandil is not recommended.

Ikorel is contraindicated in patients with cardiogenic shock, left ventricular failure with low filling pressures and in hypotension. It is also contraindicated in patients who have demonstrated an idiosyncratic response or hypersensitivity to nicorandil. Due to the risk of severe hypotension, the concomitant use of Ikorel and phosphodiesterase 5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) is contraindicated.

The use of nicorandil should be avoided in patients with depleted blood volume, low systolic blood pressure, acute pulmonary oedema or acute myocardial infarction with acute left ventricular failure and low filling pressures.

Therapeutic doses of nicorandil may lower the blood pressure of hypertensive patients and therefore nicorandil, as with other antianginal agents, should be used with care when prescribed with antihypertensive drugs.

Gastrointestinal ulceration, skin ulceration, and ulcers of the mucosal membranes have been reported with nicorandil (see Section 4.8). These tend to be refractory to treatment and most only respond to withdrawal of nicorandil treatment.

No pharmacological or pharmacokinetic interactions have been observed in humans or animals with beta-blockers, digoxin, rifampicin, cimetidine, acenocoumarol, a calcium antagonist or a combination of digoxin and furosemide. Nevertheless, there is the possibility that nicorandil may potentiate the hypotensive effects of other vasodilators, tricyclic antidepressants or alcohol.

As the hypotensive effects of nitrates or nitric oxide donors are potentiated by phosphodiesterase 5 inhibitors, the concomitant use of Ikorel and phosphodiesterase 5 inhibitors is contraindicated.

Gastrointestinal perforations in the context of concomitant use of nicorandil and corticosteroids have been reported. Caution is advised when concomitant use is considered.

Pregnancy: Animal studies have not revealed any harmful effect of nicorandil on the foetus although there is no experience in humans. It should not be used in pregnant patients unless there is no safer alternative.

Lactation: As it is not known whether nicorandil is excreted in human milk, breastfeeding should be avoided by lactating patients who require therapy.

Patients should be warned not to drive or operate machinery until it is established that their performance is unimpaired by nicorandil.

The following undesirable effects have been reported from the original clinical trials for the prevention and long-term treatment of chronic stable angina and post-marketing experience.

Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports.

The following additional adverse reactions have been reported during postmarketing experience; they are derived from spontaneous reports, and therefore the frequency of these adverse reactions is not known:

Skin and subcutaneous tissue disorders

Skin and mucosal ulcerations (mainly peri-anal, genital, and para-stomal ulcerations).

Other Clinical Trials – IONA (Impact of Nicorandil in Angina)

In addition, the following undesirable effects occurred at a different frequency in the IONA trial which was a study of subjects at high risk of cardiovascular events.

Immune System disorders

Uncommon – angioedema

Gastrointestinal disorders

Common – rectal bleeding.

Uncommon -Cases of gastritis and oesophagitis were noted in the IONA study, but the difference in incidence between the nicorandil group and the placebo group was not statistically significant.

Uncommon – mouth ulcers

Very Rare – abdominal pain

The clinical expression of diverticular disease may possibly be increased with nicorandil¹

Musculoskeletal & connective tissue disorders

Uncommon - myalgia

¹ A statistically significant difference (p=0.039) has been found between the nicorandil (20 cases = events) and the placebo group (5 cases = events) in the IONA study, with enrolement of 5126 patients.

Acute overdosage is likely to be associated with peripheral vasodilation, decreased blood pressure and reflex tachycardia. Cardiac function should be monitored and general supportive measures employed. If necessary, circulating plasma volume should be increased by infusion of suitable fluid. In life-threatening situations, administration of vasopressors should be considered. There is no experience of massive overdosage in humans, although the LD₅₀ in dogs is in the range 62.5 to 125 mg/kg and in rodents it is in the order of 1200 mg/kg.

Nicorandil provides a dual mode of action leading to relaxation of vascular smooth muscle. A potassium channel opening action provides arterial vasodilation, thus reducing afterload, while the nitrate component promotes venous relaxation and a reduction in preload. Nicorandil has a direct effect on coronary arteries without leading to a steal phenomenon. The overall action improves blood flow to post-stenotic regions and the oxygen balance in the myocardium.

A reduction of coronary heart disease complications has been shown in patients suffering from angina pectoris who were treated with nicorandil in the IONA study.

The study was a randomised, double blind, placebo controlled, cardiovascular endpoint study carried out in 5126 patients to determine if Nicorandil could reduce the frequency of coronary events in men and women with chronic stable angina and standard anti anginal treatment at high risk of cardiovascular events defined by either: 1) previous myocardial infarction, or 2) coronary artery bypass grafting , or 3) coronary artery disease confirmed by angiography, or a positive exercise test in the previous two years, together with one of the following: left ventricular hypertrophy on the ECG, left ventricular ejection fraction 45%, or an end diastolic dimension of>55 mm, age 65, diabetes (either type 1 or type 2), hypertension, peripheral vascular disease, or cerebrovascular disease. Patients were excluded from the study if they were receiving a sulphonylurea as it was felt these patients may not benefit; (sulphonylurea agents have the potential to close potassium channels and may thus antagonise some of the effects of nicorandil). Study follow up for endpoint analysis was between 12 and 36 months with a mean of 1.6 years.

The primary endpoint of coronary heart disease (CHD) death, non-fatal myocardial infarction, or unplanned hospital admission for cardiac chest pain, occurred in 13.1% of patients treated with nicorandil compared with 15.5% of patients receiving placebo (hazard ratio 0.83, p=0.014). The rate of acute coronary syndrome (CHD death, non fatal MI or unstable angina) was 6.1% in patients treated with nicorandil compared with 7.6% in patients receiving placebo (hazard ratio 0.79, p=0.028). All cardiovascular events were significantly less in the nicorandil than placebo group 14.7% vs 17.0% (hazard ratio 0.86 p=0.027). The validity of these findings was confirmed by re-analysing the primary endpoint using all cause rather than cardiovascular mortality (nicorandil 14.9% compared with placebo 17.3%, hazard ratio 0.85, p=0.021). The study was not expressly powered to, nor did it detect any statistically significant reduction in any individual component endpoints.

Nicorandil is well absorbed with no significant first-pass metabolism. Maximum plasma concentrations are achieved in 30 to 60 minutes and are directly related to the dosage. Metabolism is mainly by denitration of the molecule into the nicotinamide pathway with less than 20% of an administered dose being excreted in the urine. The main phase of elimination has a half-life of about 1 hour. Nicorandil is only slightly bound to plasma proteins.

No clinically relevant modifications in the pharmacokinetic profile have been seen in the elderly or in patients with liver disease or chronic renal failure.

There are no preclinical data of relevance to the prescriber which are additional to that included in other sections of the SPC.

Maize starch, croscarmellose sodium, stearic acid and mannitol.

None stated.

18 months.

Each blister strip should be used within 30 days of opening.

Store in a dry place below 25^oC.

Ikorel tablets 10mg and 20mg are presented in hard tempered aluminium foil/ (Polyamide/aluminium/PVC) blister strips of 10 tablets, in which each tablet is linked to a silica gel capsule dessicant.

The blister strips are packaged in cartons of 60 tablets.

None stated.

Sanofi-aventis

One Onslow Street

Guildford

Surrey, GU1 4YS, UK

Ikorel tablets 10mg: PL 04425/0327

Ikorel tablets 20mg: PL 04425/0328

24 February 2009

February 2009

Legal category: POM