sanofi-aventis

The following changes have been made;

section 4.2- following text added - For a full list of excipients, see section 6.1

section 4.4 of the SPC updated by specifying that nicorandil "should be" discontinued instead of "it is recommended" with regards to its discontinuation if ulcerations develop.

Section 10- date revised to 8/04/2011

NOTE: Only changes and section headings are listed here. Green shows deletions: Red shows insertions
Section 4.2       Posology and method of administration

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

Section 4.3       Contraindications 

Ikorel is contraindicated in patients with hypersensitivity to nicorandil or any of the excipients.

Nicorandil must not be used in the case of cardiogenic shock, hypotension or 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.

Concurrent Due to the risk of severe hypotension, the concomitant use of nicorandil Ikorel and phosphodiesterase 5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) is contraindicated since it can lead to a serious drop in blood pressure.

Scetion 4.4       Special warnings and precautions for use

Gastrointestinal ulcerations, skin and mucosal ulceration have been reported with nicorandil. These are refractory to treatment and most only respond to withdrawal of nicorandil treatment.   If ulcerations develop, it is recommended to discontinue the nicorandil treatment.

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

The use of Nnicorandil must be used with caution in should be avoided in patients with who may have depleted blood volume depletion or in those who present, low systolic blood pressure (e.g below 100 mm Hg), acute pulmonary oedema or acute myocardial infarction with acute left ventricular failure and low filling pressures.

            Caution is advised if nicorandil is used in combination with other medicinal products with blood pressure lowering effect (see section 4.5). 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.

The tablets are sensitive to moisture; hence the patients should be advised to keep the tablets in their blister until intake.   Besides the nicorandil tablets, each blister contains active substance-free silica gel tablets as desiccant in a separate blister segment which is marked accordingly.   The patients should be advised not to take these tablets.   Although any accidental intake of this desiccant is usually harmless, it may alter the scheduled intake of the active tablets.

Paediatric patient
Ikorel is not recommended in paediatric patients since its safety and efficacy have not been established in this patient group.

Section 4.5       Interaction with other medicinal products and other forms of interaction 

            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.

Concurrent use of nicorandil and phosphodiesterase 5 inhibitors, e.g. sildenafil, tadalfil, vardenafil, is contraindicated, since it can lead to a serious drop in blood pressure.

Therapeutic doses of nicorandil may lower the blood pressure of hypotensive patients.   If nicorandil is used concomitantly with antihypertensive agents or other medicinal products with blood-pressure-lowering effect (e.g vasodilators, tricyclic antidepressants, alcohol) the blood-pressure-lowering effect may be increased.

4.6       Pregnancy and lactation 

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.

Pregnancy:  Although animal studies have not shown any teratogenic effect of nicorandil, the medicinal product has not been studied in human pregnancy; therefore, Ikorel must only be used in pregnant women if the anticipated benefit outweighs any potential risks.

Lactation:  Animal studies have shown that nicorandil is excreted in small amounts into the breast milk.  It is not known whether nicorandil is excreted in human milk, therefore Ikorel is not recommended during breastfeeding.

4.7       Effects on ability to drive and use machines

4.8       Undesirable effects

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.

The following definitions apply to the frequency terminology used hereafter:

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)Additional Information

In addition, the following events have been reportedundesirable effects occurred at a different frequency in the IONA (Impact of Nicorandil in Angina) studytrial which was conducted in a study of subjects at high risk of cardiovascular events only.

Immune System disordersSkin and subcutaneous tissue disorders           

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.

Very rRare – abdominal pain

            The clinical expression of diverticular disease may possibly be increased with       nicorandil[1]

4.9       Overdose

Symptoms
In case of Aacute overdoseage, the is likely symptomatology may be to be associated with peripheral vasodilation with a fall in , decreased blood pressure and reflex tachycardia.

Management

Monitoring cCardiac function should be monitored and general supportive measures are recommendedemployed.   If not successful, necessary, increase in circulating plasma volume by substitution of fluid is recommended. should be increased by infusion of suitable fluid.   In life-threatening situations, administration of vasopressors should must be considered.    

Change in section 4.5 as highlighted

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.