Normocor®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NORMOCOR® (NORMOCOR®)

Composition:

Active substance: nicorandil;

1 tablet contains 10 mg or 20 mg of nicorandil;

Excipients: stearic acid, pregelatinized corn starch, sodium croscarmellose, mannite (E 421).

Pharmaceutical form. Tablets.

Main physicochemical properties:

10 mg tablets: white, round tablets with a score line on one side and embossing "10" on the other side;

20 mg tablets: white, round tablets with a score line on one side and embossing "20" on the other side.

Pharmacotherapeutic group. Vasodilators used in cardiovascular diseases. ATC code C01D X16.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Nicorandil, a nicotinamide ester, is a vasodilating agent with a dual mechanism of action, causing relaxation of the smooth muscles of both venous and arterial vessels.

It has the ability to open potassium channels. As a result, hyperpolarization of vascular cell membranes occurs, leading to arterial muscle relaxation, arterial dilation, reduction of afterload, and lowering of arterial blood pressure. In addition, activation of potassium channels exerts a cardioprotective effect through preconditioning and adaptation of cardiomyocytes to ischemia.

Furthermore, due to the nitrate moiety of the nicorandil molecule, it relaxes vascular smooth muscle, particularly in venous vessels, by increasing intracellular cyclic guanosine monophosphate (cGMP). This leads to blood pooling in capacitance vessels and reduction of preload.

Pharmacodynamic effects

Nicorandil has been shown to directly affect coronary arteries, acting on both normal and stenotic vascular segments, thus avoiding the "steal" phenomenon. Additionally, reduction of end-diastolic pressure and myocardial wall tension decreases the extravascular component of vascular resistance. Ultimately, this results in improved myocardial oxygen balance and enhanced blood flow in post-stenotic myocardial regions.

Moreover, both in vitro and in vivo studies have demonstrated nicorandil's spasmolytic effect—relieving coronary spasm induced by methacholine and noradrenaline.

Nicorandil does not exert a direct effect on myocardial contractile activity.

Clinical efficacy and safety

In the IONA study and a randomized, double-blind, placebo-controlled trial, 5126 patients aged 45 years and older with chronic stable angina receiving standard antianginal therapy and at high cardiovascular risk were enrolled. High risk was defined by the following criteria: 1) previous myocardial infarction, or 2) coronary artery bypass grafting, or 3) documented coronary artery disease by angiography or a positive exercise stress test within the past two years, plus at least one of the following: left ventricular hypertrophy on ECG, left ventricular ejection fraction ≤ 45%, end-diastolic dimension > 55 mm, age ≥ 65 years, diabetes mellitus, arterial hypertension, peripheral vascular disease, or cerebrovascular disease.

Patients were excluded from the study if they were receiving sulfonylureas, as it was considered that treatment might not be beneficial in these patients (sulfonylureas have the ability to close potassium channels and thus may act as antagonists of certain nicorandil effects). Follow-up for endpoint analysis lasted from 12 to 36 months, with a mean duration of 1.6 years.

The primary composite endpoint (death due to ischemic heart disease (IHD), non-fatal myocardial infarction, or unplanned hospitalization for chest pain) occurred in 337 patients (13.1%) receiving 20 mg of nicorandil twice daily, compared to 389 patients (15.5%) receiving placebo (risk ratio 0.83; 95% confidence interval (CI) – 0.72 to 0.97; p = 0.014).

Pharmacokinetics.

Nicorandil pharmacokinetics are linear within the dose range of 5 to 40 mg.

Absorption

After oral administration, nicorandil is rapidly and completely absorbed from the gastrointestinal tract, regardless of food intake. Absolute bioavailability is approximately 75%. There is no significant first-pass metabolism. Maximum plasma concentration (C_max) is reached within approximately 30–60 minutes. Plasma concentration and area under the pharmacokinetic curve (AUC) demonstrate linear dose proportionality.

With repeated oral dosing (twice daily), steady-state is rapidly achieved (within 4–5 days). At steady-state, the accumulation ratio (based on AUC) is approximately 2 for the 20 mg tablet and 1.7 for the 10 mg tablet given twice daily.

Distribution

Drug distribution throughout the body remains stable within the therapeutic range, independent of dose.

The volume of distribution of nicorandil after intravenous administration is 1.04 L/kg body weight. Nicorandil binds only minimally to human plasma proteins (the bound fraction is approximately 25%).

Biological transformation

Nicorandil is primarily metabolized in the liver via denitration, forming several metabolites that lack cardiovascular activity. Unchanged nicorandil accounts for 45.5% of the radioactive AUC in plasma, while the alcohol metabolite, N-(2-hydroxyethyl)-nicotinamide, accounts for 40.5%. Other metabolites account for 20% of the radioactive AUC.

Nicorandil is primarily excreted in urine as metabolites, as less than 1% of the administered dose is excreted unchanged in human urine (0–48 hours). The most prevalent metabolite is N-(2-hydroxyethyl)-nicotinamide (approximately 8.9% of the administered dose within 48 hours), followed by nicotinic acid (5.7%), nicotinamide (1.34%), N-methyl-nicotinamide (0.61%), and nicotinic acid (0.40%). These metabolites represent the main products of nicorandil transformation.

Elimination

Plasma concentration decline occurs in two phases:

• Rapid elimination phase: elimination half-life is approximately 1 hour, accounting for 96% of plasma exposure;
• Slow elimination phase: begins approximately 12 hours after oral administration of 20 mg twice daily.

After intravenous administration of 4–5 mg (5-minute infusion), total clearance was approximately 40–55 L/hour.

Nicorandil and its metabolites are primarily excreted in urine; fecal excretion accounts for a very minor portion.

Special patient groups

No clinically significant changes in the pharmacokinetic profile of nicorandil have been observed in at-risk groups (elderly individuals, patients with hepatic disease, and patients with chronic renal insufficiency).

Pharmacokinetic interactions

Nicorandil metabolism is not significantly altered by cimetidine or rifampicin, which are an inhibitor and an inducer, respectively, of hepatic microsomal oxidases.

Clinical characteristics.

Indications.

Nicorandil is indicated in adults for the symptomatic treatment of stable angina pectoris when first-line antianginal medications (such as beta-blockers and/or calcium antagonists) are insufficiently effective, poorly tolerated, or contraindicated.

Contraindications.

• Hypersensitivity to nicorandil or to any of the excipients.
• Patients with shock (including cardiogenic shock), severe arterial hypotension, or left ventricular dysfunction with low filling pressure or cardiac decompensation.
• Concomitant use of phosphodiesterase-5 inhibitors, as this may lead to severe hypotension (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of soluble guanylate cyclase stimulators (e.g., riociguat), as this may lead to severe hypotension (see section "Interaction with other medicinal products and other forms of interaction").
• Hypovolemia.
• Acute pulmonary edema.

Interaction with other medicinal products and other forms of interaction.

Concomitant administration of nicorandil and phosphodiesterase-5 inhibitors, such as sildenafil, tadalafil, or vardenafil, is contraindicated, as it may result in a significant drop in blood pressure (synergistic effect) (see section "Contraindications").

Concomitant use of soluble guanylate cyclase stimulators (such as riociguat) is contraindicated, as it may lead to a significant drop in blood pressure.

Therapeutic doses of nicorandil may reduce blood pressure in patients with arterial hypotension (see section "Contraindications").

When nicorandil is used concomitantly with antihypertensive agents or other medicinal products that lower blood pressure (e.g., vasodilators, tricyclic antidepressants, alcohol), the blood pressure-lowering effect may be enhanced.

Dapoxetine should be used with caution in patients taking nicorandil due to a potential decrease in orthostatic tolerance.

There have been reports of gastrointestinal perforation with concomitant use of nicorandil and corticosteroids. Concomitant use should therefore be considered cautiously if necessary.

In patients concurrently taking nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid, both at prophylactic doses for prevention of cardiovascular events and at doses aimed at achieving anti-inflammatory effect, there is an increased risk of severe complications such as gastrointestinal ulcers, perforations, and bleeding (see section "Special precautions for use").

Concomitant use of nicorandil with other medicinal products that may increase potassium levels should be approached with caution (see sections "Special precautions for use" and "Undesirable effects").

Cimetidine (a CYP inhibitor) or rifampicin (a CYP3A4 inducer) do not have a significant effect on the metabolism of nicorandil. Nicorandil does not affect the pharmacodynamics of acenocoumarol.

Special precautions for use.

Ulcer formation

Gastrointestinal ulcers, skin ulcers, and mucosal ulcers have been reported during nicorandil therapy (see section "Adverse reactions").

Gastrointestinal ulceration

Ulcers may develop in some patients taking nicorandil. These ulcers are often refractory to treatment, and most resolve only after discontinuation of nicorandil. If ulcers develop, nicorandil should be discontinued (see section "Adverse reactions"). Physicians should be aware of the importance of timely diagnosis of nicorandil-induced ulcers and the need for prompt discontinuation of nicorandil therapy if such ulcers occur. Based on available data, the time between initiation of nicorandil therapy and onset of ulceration ranges from shortly after starting treatment to several years.

Gastrointestinal bleeding due to formation of gastrointestinal ulcers has been reported with nicorandil use. Patients who are concurrently taking acetylsalicylic acid or other NSAIDs have an increased risk of severe complications, including gastrointestinal bleeding. Therefore, acetylsalicylic acid or other NSAIDs should be co-administered with nicorandil with caution (see section "Interaction with other medicinal products and other forms of interaction").

Gastrointestinal ulcers may progress to perforations, fistulas, or abscesses. Patients with diverticular disease have an increased risk of intestinal fistula or perforation during nicorandil therapy.

There have been reports of gastrointestinal perforations with concomitant use of nicorandil and corticosteroids. Therefore, these agents should be used together with caution.

Ocular ulcers

Conjunctivitis, conjunctival ulcers, and corneal ulcers have been reported during nicorandil therapy. Therefore, patients should be informed about the signs and symptoms of corneal ulceration prior to initiating treatment. Patients should be closely monitored. If ulceration occurs, nicorandil therapy should be discontinued (see section "Adverse reactions").

Reduction in blood pressure

Nicorandil should be used with caution in combination with other medicinal products that lower blood pressure (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Heart failure

Due to lack of data, nicorandil should be used with caution in patients with heart failure, NYHA class III or IV.

Hyperkalaemia

Very rare cases of serious hyperkalaemia have been reported during nicorandil therapy. Nicorandil should be used with caution in combination with other medicinal products that may increase potassium levels, especially in patients with moderate to severe renal impairment (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Desiccant

The tablets are moisture-sensitive; therefore, patients should be advised to keep the tablets in the blister pack until the time of administration. In addition to the nicorandil tablets, each blister contains a molecular sieve desiccant in a separate compartment of the blister pack, clearly marked. Patients should not take this desiccant. Although accidental ingestion of the desiccant is generally harmless, it may interfere with the intended intake of active tablets.

Children

Nicorandil tablets are not recommended for use in children, as safety and efficacy have not been established in this patient group.

Glucose-6-phosphate dehydrogenase deficiency

Nicorandil tablets should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency. Nicorandil acts partly through the organic nitrate component of the molecule. Metabolism of organic nitrates may lead to the formation of nitriles, which may cause methaemoglobinaemia in patients with glucose-6-phosphate dehydrogenase deficiency.

The product contains mannitol, which may have a mild laxative effect.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no or limited data on the use of nicorandil in pregnant women. Reproductive toxicity studies in animals did not show direct or indirect adverse effects.

Nicorandil should be avoided (as a precaution during pregnancy).

Breastfeeding.

Animal studies have shown that nicorandil passes into breast milk in small amounts. It is unknown whether nicorandil is excreted in human breast milk; therefore, Normocor should not be used during breastfeeding.

Fertility.

There is insufficient data on the effect of nicorandil on reproductive function to assess risk in humans.

Ability to affect reaction speed when driving or operating machinery.

Nicorandil affects the ability to drive and operate machinery. The blood pressure-lowering effect, as well as dizziness and weakness caused by nicorandil, may negatively affect the ability to drive or operate machinery. This effect may be enhanced when nicorandil is used concomitantly with alcohol or other medicinal products that lower blood pressure (e.g., vasodilators, tricyclic antidepressants) (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, patients should refrain from driving or operating machinery if such symptoms occur.

Dosage and Administration

Dosing

The usual therapeutic dose is 10–20 mg twice daily. The usual initial dose is 10 mg twice daily, preferably taken in the morning and evening. If necessary, the dose may be increased to 40 mg twice daily according to the patient's needs, response, and tolerability. For patients prone to headaches, a lower initial dose of 5 mg twice daily may be used.

Elderly Patients

There are no specific dosage requirements for elderly patients. However, as with all medicinal products, it is recommended to use the lowest effective dose.

Patients with Hepatic and/or Renal Impairment

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

Route of Administration

Nicorandil tablets are for oral use.

The tablets should be taken in the morning and evening with a glass of water. The tablets must not be crushed or chewed.

The tablet may be divided into two equal parts.

The administration of the drug is not affected by food intake.

Children

Nicorandil tablets are not recommended for use in pediatric patients, as the safety and efficacy in this age group have not been established.

Overdose

Symptoms

In acute overdose, likely symptoms include peripheral vasodilation leading to a drop in arterial blood pressure and reflex tachycardia.

Treatment

Cardiac function should be monitored and general supportive measures applied. If this is ineffective, expansion of circulating plasma volume with blood substitutes is recommended. In life-threatening situations, the use of vasoconstrictor agents should be considered.

Side effects

The most commonly reported adverse reaction in clinical trials was headache, occurring in more than 30% of patients, particularly during the first days of treatment, and was the main reason for drug discontinuation in most cases in the studies.

Gradual dose titration can reduce the frequency of headache (see section "Dosage and administration").

Additionally, serious adverse reactions have been reported from post-marketing surveillance of nicorandil, including ulcers and their complications (see section "Special precautions").

Adverse reactions observed with nicorandil are listed in the table below by organ class and frequency. Adverse reactions are categorized by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and infestations:
Common – abscess (skin abscess)* (see section "Special precautions");
Uncommon – abscess (genital, anal, or other gastrointestinal fistulae)* (see section "Special precautions").

Metabolism and nutrition disorders:
Very rare – hyperkalemia (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Nervous system disorders:
Very common – headache;
Common – dizziness;
Frequency not known – paralysis of the 3rd cranial nerve, paralysis of the 6th cranial nerve (often associated with headache).

Eye disorders:
Very rare – corneal ulcers*, conjunctival ulcers, conjunctivitis* (see section "Special precautions");
Frequency not known – diplopia, ophthalmoplegia (often associated with headache).

Cardiac disorders:
Common – increased heart rate.

Vascular disorders:
Common – cutaneous vasodilation with flushing;
Uncommon – hypotension (see section "Special precautions").

Gastrointestinal disorders:
Common – diverticulitis*, gastrointestinal hemorrhage*, nausea, vomiting, gastrointestinal ulceration (stomatitis, aphthae, oral ulcers, tongue ulcers, small intestinal ulcers, large intestinal ulcers, anal ulcers)* (see below and section "Special precautions");
Uncommon – gastrointestinal perforation*, fistula (anal, genital, gastrointestinal, or cutaneous fistula)* (see section "Special precautions").

Hepatobiliary disorders:
Very rare – liver function disorders such as hepatitis, cholestasis, or jaundice.

Skin and subcutaneous tissue disorders:
Common – skin and mucosal ulcers (mainly perianal ulcers, genital ulcers, and parastomal ulcers) (see section "Special precautions");
Rare – rash, pruritus;
Very rare – angioneurotic edema.

Musculoskeletal and connective tissue disorders:
Rare – myalgia.

General disorders and administration site conditions:
Common – feeling of weakness.

* Frequency was calculated based on results from a post-authorization retrospective cohort safety study using the UK Clinical Practice Research Datalink (CPRD) database. The stated frequency represents the incidence of adverse reactions in the UK population.

Description of selected adverse reactions

Gastrointestinal ulceration

Complications of gastrointestinal ulcers have been reported, including perforation, fistula formation, or abscess development, sometimes leading to gastrointestinal bleeding and weight loss (see section "Special precautions").

Additional information

In addition, during the IONA study ("Impact of Nicorandil on Angina"), in which nicorandil was added to standard therapy in patients with stable angina and high risk of cardiovascular disease, the following adverse reactions were observed at varying frequencies:

Gastrointestinal disorders:
Common – rectal bleeding;
Uncommon – oral ulcers;
Very rare – abdominal pain.

Skin and subcutaneous tissue disorders:
Uncommon – angioneurotic edema.

Musculoskeletal and connective tissue disorders:
Uncommon – myalgia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Each blister should be used within 30 days after opening.

Storage conditions

Store at temperatures not exceeding 25 °C, in the original packaging, in a place protected from moisture. Keep out of reach of children.

Packaging

10 tablets per blister with integrated desiccant; 6 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

RivoPharm SA

Manufacturer's location and address of place of business

Centro Insema, 6928 Manno, Switzerland.