4.1. Therapeutic indications

Nicorandil 20mg Tablets are indicated in adults for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or have a contraindication or intolerance to first-line antianginal therapies (such as beta-blockers and/or calcium antagonists).

4.2. Posology and method of administration

Posology

The usual therapeutic range is 10 to 20 mg twice daily. The usual starting dose is 10 mg twice daily (bid), in the morning and in the evening preferably. It is recommended that the dose be titrated upwards in accordance with the patient's needs, response and tolerance up to 40 mg twice daily, if necessary. A lower starting dose of 5 mg twice daily may be used in patients particularly prone to headache.

Elderly: There are no special dose requirements for elderly patients, but as with all medicine, use of the lowest effective dose is recommended.

Patients with liver and/or renal impairment

There are no special dosage requirements for patients with liver and/or renal impairment.

Paediatric population: Nicorandil Tablets are not recommended in paediatric patients since its safety and efficacy have not been established in this patient group.

Method of administration

Nicorandil Tablets are administered by oral route.

The tablets are to be swallowed in the morning and in the evening with a glass of water. The tablets should not be crushed or chewed.

The tablet can be divided into equal doses.

Administration is independent of food intake.

4.3. Contraindications

• Hypersensitivity to nicorandil or to any of the excipients listed in section 6.1.

• Patients with shock (including cardiogenic shock), severe hypotension, or left ventricular dysfunction with low filling pressure or cardiac decompensation.

• Use of phosphodiesterase 5 inhibitors, since this can lead to a serious drop in blood pressure (see section 4.5).

• Use of soluble guanylate cyclase stimulator(s) (such as riociguat) since it can lead to a serious fall in blood pressure (see section 4.5).

• Hypovolaemia.

• Acute pulmonary oedema.

4.4. Special warnings and precautions for use

Ulcerations

Gastrointestinal ulcerations, skin and mucosal ulceration have been reported with nicorandil (see section 4.8).

Gastrointestinal ulcerations

Nicorandil induced ulceration may occur at different locations in the same patient. They are refractory to treatment and most only respond to withdrawal of nicorandil treatment. If ulcerations develop, nicorandil should be discontinued (see section 4.8). Healthcare professionals should be aware of the importance of a timely diagnosis of nicorandil-induced ulcerations and of a rapid withdrawal of nicorandil treatment in case of occurrence of such ulcerations. Based on available information, the time between starting nicorandil use and the onset of ulceration ranges from shortly after initiating nicorandil treatment to several years after starting nicorandil.

Gastrointestinal haemorrhage secondary to gastrointestinal ulceration has been reported with nicorandil. Patients taking acetylsalicylic acid or NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) concomitantly are at increased risk for severe complications such as gastrointestinal haemorrhage. Therefore caution is advised when concomitant use of acetylsalicylic acid or NSAIDs and nicorandil is considered (see section 4.5).

If advanced, gastrointestinal ulcerations may evolve into perforation, fistula, or abscess formation. Patients with diverticular disease may be at particular risk of fistula formation or bowel perforation during nicorandil treatment.

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

Eye ulcerations

Conjunctivitis, conjunctival ulcer and corneal ulcer have been reported with nicorandil. Patients should be advised of the signs and symptoms and monitored closely for corneal ulcerations. If ulceration(s) develops, nicorandil should be discontinued (see section 4.8).

Decrease of blood pressure

Caution is advised if nicorandil is used in combination with other medicinal products with blood pressure lowering effect (see sections 4.5 and 4.8).

Heart failure

Due to lack of data, caution is advised to use nicorandil in patients with heart failure class NHYA III or IV.

Hyperkalaemia

Severe hyperkalaemia has been reported very rarely with nicorandil. Nicorandil should be used with care in combination with other medical products that may increase potassium levels especially in patients with moderate to severe renal impairment (see sections 4.5 and 4.8).

Paediatric population

Nicorandil Tablets are not recommended in paediatric patients since its safety and efficacy have not been established in this patient group.

G6PD deficiency

Nicorandil Tablets should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency. Nicorandil acts in part through its organic nitrate moiety. The metabolism of organic nitrates can result in the formation of nitrites which may trigger methemoglobinaemia in patients with glucse-6-phosphate dehydrogenase deficiency.

Nicorandil Tablets contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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

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 (synergic effect).

Concomitant use of soluble guanylate cyclase stimulators (such as riociguat) 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.

Dapoxetine should be prescribed with caution in patients taking nicorandil due to possible reduced orthostatic tolerance.

Gastrointestinal perforations in the context of concomitant use of nicorandil and corticosteroids have been reported. Caution is advised when concomitant use is considered (see section 4.4).

In patients concomitantly receiving NSAIDs including acetylsalicylic acid for both cardiovascular prevention and anti-inflammatory doses, there is an increased risk for severe complications such as gastrointestinal ulceration, perforation and haemorrhage (see section 4.4).

Caution is advised when nicorandil is used in combination with other medical products that may increase potassium levels (see sections 4.4 and 4.8).

The metabolism of nicorandil is not significantly affected by cimetidine (a CYP inhibitor), or rifampicin (a CYP3A4 inducer). Nicorandil does not affect the pharmacodynamics of acenocoumarol.

4.6. Fertility, pregnancy and lactation

Pregnancy: There are no or limited amount of data from the use of nicorandil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Nicorandil Tablets during pregnancy.

Breast-feeding: 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 Tablets are not recommended during breastfeeding.

Fertility: There are insufficient data on fertility to estimate the risk for humans (see section 5.3).

4.7. Effects on ability to drive and use machines

Nicorandil Tablets have an influence on the ability to drive and use machines. Indeed, as with other vasodilators, blood pressure-lowering effects as well as dizziness and feeling weakness induced by nicorandil can reduce the ability to drive or to use machines. This effect can be increased in conjunction with alcohol or other medicinal products with blood pressure lowering effect (e.g. vasodilators, tricyclic antidepressants) (see section 4.5). Therefore, patients should be advised not to drive or use machines if these symptoms occur.

4.8. Undesirable effects

Summary of safety profile

The most common adverse reaction reported in clinical trials is headache occurring in more than 30% of patients, particularly in the first days of treatment and responsible for most of study withdrawal.

Progressive dose titration may reduce the frequency of these headaches (see section 4.2).

In addition, serious adverse reactions including ulcerations and their complications (see section 4.4) were reported during the post marketing surveillance of nicorandil.

Tabulated list of adverse reactions

The frequencies of adverse reactions reported with nicorandil are summarised in the following table by system organ class (in MedDRA) and by frequency. Frequencies are defined as:

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); Not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Very common

Common

Uncommon

Rare

Very rare

Not known

Infections and infestations

Abscess (skin abscess)*(see section 4.4)

Abscess (genital, anal or other gastrointestinal locations)* (see section 4.4)

Metabolism and nutrition disorders

Hyperkalaemia (see sections 4.4 and 4.5)

Nervous system disorders

Headache

Dizziness

IIIrd nerve paralysis, VIth nerve paralysis (often associated with headache)

Eye disorders

Corneal ulcer, conjunctival ulcer, conjunctivitis (see section 4.4)

Diplopia Ophthalmoplegia (often associated with headache)

Cardiac disorders

Heart rate increased

Vascular disorders

Cutaneous vasodilation with flushing

Decrease in blood pressure (see section 4.4)

Gastrointestinal disorders

Diverticulitis*, gastrointestinal haemorrhage*, gastrointestinal ulcerations (stomatitis, aphthosis, mouth ulcer, tongue ulcer, small intestinal ulcer, large intestinal ulcer, anal ulcer)* (see section 4.4), vomiting, nausea

Gastrointestinal perforation*, fistula (anal, genital, gastrointestinal and skin fistula)* (see section 4.4)

Hepatobiliary disorders

Liver disorders such as hepatitis, cholestasis, or jaundice

Skin and subcutaneous tissue disorders

Skin and mucosal ulcerations (mainly peri-anal ulcerations, genital ulcerations and parastomal ulcerations) (see section 4.4)

Rash, pruritus

Angioedema

Musculoskeletal and connective tissue disorders

Myalgia

General disorders and administration site conditions

Feeling of weakness

*The frequencies were calculated on the basis of the results of the Post Authorisation Safety Study (PASS), which is a retrospective cohort study which was conducted using the UK Clinical Practice Research Datalink (CPRD) database. Therefore, the frequencies represent those of the UK population.

Description of selected adverse reactions

Gastrointestinal ulcerations

Complications of gastrointestinal ulceration such as perforation, fistula, or abscess formation sometimes leading to gastrointestinal haemorrhage and weight loss have been reported (see section 4.4).

Additional information

In addition, the following adverse reactions have been reported with different frequencies in the IONA (Impact of Nicorandil in Angina) study, where nicorandil has been used on top of standard therapy in patients with stable angina and at high risk of cardiovascular events (see section 5.1).

Common

Uncommon

Very rare

Gastrointestinal disorders

Rectal bleeding

Mouth ulcer

Abdominal pain

Skin and subcutaneous tissue disorders

Angioedema

Musculoskeletal & connective tissue disorders

Myalgia

Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

In case of acute overdose, the likely symptomatology may be peripheral vasodilation with a fall in blood pressure and reflex tachycardia.

Management

Monitoring cardiac function and general supportive measures are recommended. If not successful, increase in circulating plasma volume by fluid substitution is recommended. In life-threatening situations, administration of vasopressors must be considered.