Nicorandil 10mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Nicorandil 10mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 10mg of nicorandil.
For a full list of excipients, see Section 6.1
3 PHARMACEUTICAL FORM
Tablet
White, round, scored on one side and embossed on the other side with ’10’.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
- Prevention and long term treatment of chronic stable angina pectoris
- 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
4.2 Posology and method of administration
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: For elderly patients use of the lowest effective dose is recommended.
Children: A paediatric dosage has not been established and use of nicorandil is not recommended.
4.3 Contraindications
Nicorandil 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 pressure.
Concurrent use of nicorandil and phosphodiesterase 5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) is contraindicated since it can lead to a serious drop in blood pressure.
4.4 Special warnings and precautions for use
Gastrointestinal ulcerations, skin and mucosal ulceration have been reported with nicorandil (see section 4.8 Undesirable Effects). These are refractory to treatment and most only respond to withdrawal of nicorandil treatment. If ulcerations develop, nicorandil should be discontinued.
Gastrointestinal perforations in context of concomitant use of nicorandil and corticosteroids have been reported. Caution is advised when concomitant use is considered.
Nicorandil must be used with caution in patients who may have blood volume depletion or in those who present acute pulmonary oedema.
Caution is advised if nicorandil is used in combination with other medicinal products with blood pressure lowering effect (see section 4.5).
The tablets are sensitive to moisture; hence the patients should be advised to keep the tablets in their blister until intake (see section 6.4)
4.5 Interaction with other medicinal products and other forms of interaction
Gastrointestinal perforations in the context of concomitant use of nicorandil and corticosteroids have been reported. Caution is advised when concomitant use is considered.
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 Fertility, pregnancy and lactation
Pregnancy: Although animal studies have not shown any teratogenic effect of nicorandil, the medicinal product has not been studied in human pregnancy; therefore, Nicorandil 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 Nicorandil is not recommended during breastfeeding.
4.7 Effects on ability to drive and use machines
Blood pressure-lowering effects of nicorandil can reduce the ability to drive or to use machines. This effect can be increased in conjunction with alcohol or other products with blood-pressure-lowering effect (e.g. vasodilators, tricyclic antidepressants). (see section 4.5). Patients should be warned not to drive or operate machinery until it is established that their performance is unimpaired by nicorandil.
4.8 Undesirable effects
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).
|
SOC |
FREQUENCY |
ADR |
|
Nervous system disorders |
Very common |
Headache, particularly during the first few days of treatment. |
|
Common |
Dizziness | |
|
Cardiac disorders |
Common |
Increase in heart rate, following the administration of high doses |
|
Vascular disorders |
Common |
Cutaneous vasodilation with flushing |
|
Uncommon |
Decrease in blood pressure. | |
|
Gastrointestinal disorders |
Common |
Nausea and vomiting |
|
Rare |
Gastrointestinal ulcerations such as stomatitis, mouth ulcers, tongue ulcers, intestinal and anal ulcers. These ulcers, if advanced, may develop into perforation, fistula, or abscess formation. (see section 4.4). | |
|
Hepato-biliary disorders |
Very rare |
Liver disorders such as hepatitis, cholestasis, or jaundice. |
|
Skin and subcutaneous tissue disorders |
Rare |
Different types of rash, pruritus. |
|
Very rare |
Angio-oedema. Skin and mucosal ulcerations (mainly peri-anal ulcerations, genital ulcerations and parastomal ulcerations (see section 4.4). | |
|
Musculoskeletal & connective tissue disorders |
Rare |
Myalgia |
|
General disorders and administration site |
Common |
Feeling of weakness |
conditions
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.
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 nicorandil[1] [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 enrolment of 5126 patients.
Immune system disorders
Uncommon - angioedema
Musculoskeletal & connective tissue disorders
Uncommon - myalgia
4.9 Overdose
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 not 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other vasodilators used in cardiac diseases ATC code: C01DX16
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 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 infraction, 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 fallowing: 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 reanalysing 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.
5.2 Pharmacokinetic properties
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.
5.3 Preclinical safety data
There are no preclinical data of relevance to the prescriber which are additional to that included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Maize starch croscarmellose sodium stearic acid mannitol.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months.
Each blister strip should be used within 30 days of opening.
6.4 Special precautions for storage
Do not store above 25°C. Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Alu/Alu blister strips of 10 tablets. In each blister each tablet is linked to a molecular sieve desiccant. The blisters strips are packed in cartons of 60 tablets.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Rivopharm UK Limited, 6th floor, 28 Kingsway, London WC2B 6JR - UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 33155/0001
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
18/11/2010
10
DATE OF REVISION OF THE TEXT
21/06/2013