Instructions for use Nicorel tablets 20mg No. 60
Composition
active ingredient: nicorandil;
1 tablet contains 10 mg or 20 mg of nicorandil;
excipients: cetyl alcohol, mannitol (E 421), croscarmellose sodium, povidone, sodium stearyl fumarate.
Dosage form
Pills.
Main physicochemical properties:
10 mg tablets: round tablets of white or almost white color, with a score on one side and engraving "10" on the other side.
20 mg tablets: round tablets of white or almost white color, with a score on one side and engraving "20" on the other side.
The 10 mg and 20 mg tablets can be divided into two halves.
Pharmacotherapeutic group
Other vasodilators used in heart disease.
ATX code C01D X16.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Nicorandil, a nicotinamide ester, is a vasodilator with a dual mechanism of action that causes relaxation of vascular smooth muscle tone in both venous and arterial vessels.
It has the effect of opening potassium channels. Such activation of potassium channels causes hyperpolarization of vascular cell membranes with the effect of relaxing the muscles of the arteries, thereby leading to dilation of the arteries and a decrease in pressure after exercise. In addition, activation of potassium channels causes a cardioprotective effect, which mimics the previous adaptation to ischemic disease.
Due to the nitrate moiety of the molecule, nicorandil also relaxes vascular smooth muscle, particularly in the venous system, by increasing intracellular cyclic guanosine monophosphate (cGMP). This results in an increase in total vascular capacity with a decrease in preload.
Pharmacodynamic effects
Nicorandil has been shown to have a direct effect on coronary arteries, both in normal and stenotic segments, without causing a steal phenomenon. In addition, the reduction in end-diastolic pressure and wall tension reduces the extravascular component of vascular resistance. Ultimately, this leads to improved myocardial oxygen balance and improved blood flow in post-stenotic myocardial regions.
Moreover, nicorandil has antispasmodic effects in both in vitro and in vivo studies, and it also relieves coronary spasm induced by methacholine and noradrenaline.
Nicorandil has no direct effect on myocardial contractility.
Clinical efficacy and safety
The IONA study, a randomised, double-blind, placebo-controlled trial, enrolled 5,126 patients aged 45 years and older with chronic stable angina, who were receiving standard antianginal therapy and had a high risk of cardiovascular disease as defined by the following: 1) previous myocardial infarction or 2) coronary artery bypass grafting or 3) coronary artery disease confirmed by angiography or a positive exercise stress test within the last two years together with one of the following: left ventricular hypertrophy on ECG, left ventricular ejection fraction ≤ 45% or end-diastolic dimension > 55 mm, age ≥ 65 years, diabetes mellitus, hypertension, peripheral vascular disease, or cerebrovascular disease.
Patients were excluded from the study if they were receiving a sulfonylurea, as it was considered that such patients might not benefit from treatment (sulfonylureas have the ability to block potassium channels and may therefore antagonize some of the effects of nicorandil). Post-study follow-up for the analysis of the endpoint ranged from 2 to 36 months, with a median of 1.6 years.
The combined primary endpoint (fatal coronary heart disease (CHD) event, non-fatal myocardial infarction, or unplanned hospitalization for cardiac chest pain) occurred in 337 patients (13.1%) receiving nicorandil 20 mg twice daily compared with 389 patients (15.5%) receiving placebo (hazard ratio 0.83; 95% confidence interval (CI) 0.72 to 0.97; p = 0.014).
Pharmacokinetics
The pharmacokinetics of nicorandil are linear - from 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 about 75%. There is no significant effect of first-pass metabolism. Maximum plasma concentration (Cmax) is reached after approximately 30-60 minutes. Plasma concentration and area under the pharmacokinetic curve (AUC) show linear dose proportionality.
With repeated oral administration (twice daily), steady state is rapidly achieved (within 4-5 days). At steady state, the accumulation rate (based on AUC) is about 2 for the 20 mg tablet and 1.7 for the 10 mg tablet twice daily.
Distribution
The distribution of the drug throughout the body remains stable within the therapeutic range, regardless of dose.
The volume of distribution of nicorandil after intravenous administration is 1.04 l/kg body weight. Nicorandil is only slightly bound to human plasma proteins (bound fraction is approximately 25%).
Nicorandil is metabolized primarily in the liver by denitration to a number of compounds that have no cardiovascular effects. In plasma, unchanged nicorandil accounts for 45.5% of the radioactive AUC, and the alcohol metabolite, N-(20-hydroxyethyl)-nicotinamide, accounts for 40.5%. Other metabolites account for 20% of the radioactive AUC.
Nicorandil is excreted primarily in the urine as metabolites, with parent drug accounting for less than 1% of the administered dose (0-48 hours) in human urine. The most abundant metabolite is N-(2-hydroxyethyl)-nicotinamide (approximately 8.9% of the administered dose over 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 route of nicorandil transformation.
Breeding
The decrease in plasma concentration occurs in two stages:
- the main elimination phase: the half-life is about 2 hours;
- slow elimination phase: occurs approximately 12 hours after taking an oral dose of 20 mg twice a day.
After intravenous administration of 4-5 mg (5 min infusion), total body clearance was approximately 40-55 L/hour.
Nicorandil and its metabolites are excreted mainly in the urine, with the faecal route accounting for a minor portion.
Special patient groups
In risk groups (elderly people, patients with liver disease and patients with chronic renal failure) no clinically significant changes in the pharmacokinetic profile of nicorandil are observed.
Pharmacokinetic interaction
The metabolism of nicorandil is not significantly altered by cimetidine or rifampicin, an inhibitor and inducer of mixed-function hepatic microsomal oxidases, respectively.
Indication
Nicorandil is indicated in adult patients for the symptomatic treatment of stable angina pectoris when first-line antianginal medicinal products (such as beta-blockers and/or calcium antagonists) are ineffective or poorly tolerated, or when there are contraindications to their use.
Contraindication
- Hypersensitivity to nicorandil or to any of the excipients of the drug.
- Patients with shock (including cardiogenic shock), severe hypotension or left ventricular dysfunction with low filling pressure or cardiac decompensation.
- Use of phosphodiesterase 5 inhibitors, as this may lead to a serious drop in blood pressure (see section “Interaction with other medicinal products and other types of interactions”).
- Use of soluble guanylate cyclase stimulators (e.g. riociguat), as this may lead to a serious drop in blood pressure (see section "Interaction with other medicinal products and other types of interactions").
- Hypovolemia.
- Acute pulmonary edema.
- Children under 18 years of age.
- Pregnancy and breastfeeding.
- Acute myocardial infarction.
- Collapse.
- Unstable angina, including Prinzmetal's angina.
- Chronic heart failure of class III or IV according to the NYHA classification.
- Severe bradycardia (heart rate less than 50 beats/min).
- AV block of the 2nd and 3rd degree.
- Severe anemia.
- Refractory hyperkalemia.
Interaction with other drugs and other types of interactions
The concomitant use of nicorandil and phosphodiesterase type 5 inhibitors such as sildenafil, tadalafil, vardenafil is contraindicated as this may lead to a severe 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 serious drop in blood pressure.
Therapeutic doses of nicorandil may lower blood pressure in patients with hypotension (see section "Contraindications").
If nicorandil is used concomitantly with antihypertensive drugs or other drugs that lower blood pressure (e.g. vasodilators, tricyclic antidepressants, alcohol), the drop in blood pressure may be increased.
Dapoxetine should be prescribed with caution to patients taking nicorandil due to possible reduction in orthostatic tolerance.
There have been reports of gastrointestinal perforation with concomitant use of nicorandil and corticosteroids. It is recommended that their concomitant use be considered with caution if necessary (see section 4.4).
Patients who are concomitantly taking non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid, both in prophylactic doses for the prevention of cardiovascular diseases and for the purpose of achieving an anti-inflammatory effect, are at increased risk of serious complications such as ulceration, perforation and bleeding of the gastrointestinal tract (see section "Special warnings and precautions for use").
It is recommended to use nicorandil with caution in combination with other drugs that may increase potassium levels (see sections "Special warnings and precautions for use" and "Adverse reactions").
Cimetidine (CYP inhibitor) or rifampicin (CYP3A4 inducer) have no significant effect on the metabolism of nicorandil. Nicorandil does not affect the pharmacodynamics of acenocoumarol.
Application features
Gastrointestinal, skin and mucous membrane ulcers have been reported with the use of nicorandil (see section 4.8).
Ulceration in the gastrointestinal tract
Some patients may develop ulcers as a result of taking nicorandil. These are not curable and most respond only to discontinuation of nicorandil. If ulcers develop, nicorandil should be discontinued (see section 4.8). Physicians should be aware of the importance of early diagnosis of nicorandil-induced ulcers and the need to promptly discontinue nicorandil if such ulcers develop. Based on available information, the time between the start of nicorandil use and the onset of ulcers varies from a short time after starting nicorandil treatment to several years.
Gastrointestinal bleeding due to gastrointestinal ulceration has been reported with nicorandil. Patients taking acetylsalicylic acid or NSAIDs are at increased risk of serious complications such as gastrointestinal bleeding. Therefore, acetylsalicylic acid or NSAIDs should be administered with caution when co-administered with nicorandil (see section 4.5).
Ulcers may progress to perforation, fistula or abscess. Patients with diverticular disease may be at increased risk of intestinal fistula or perforation during treatment with nicorandil.
There have been reports of gastrointestinal perforation with concomitant use of nicorandil and corticosteroids. Therefore, their concomitant use should be considered with caution.
Eye ulcers
Conjunctivitis, conjunctival and corneal ulcers have been reported very rarely with the use of nicorandil. Patients should be informed about the signs and symptoms of corneal ulcers and be closely monitored. If ulcers develop, nicorandil should be discontinued (see section 4.8).
Lowering blood pressure
Nicorandil should be used with caution in combination with other medicinal products that have a blood pressure-lowering effect (see sections “Interaction with other medicinal products and other types of interactions” and “Adverse reactions”).
Heart failure
Due to lack of data, it is recommended to use nicorandil with caution in patients with heart failure, NHYA class III or IV.
Hyperkalemia
Serious cases of hyperkalaemia have been reported very rarely with nicorandil. 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 4.5 and 4.8).
Children
Nicorandil tablets are not recommended for use in children as the safety and efficacy of its use 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. The metabolism of organic nitrates can lead to the formation of nitriles, which can cause methemoglobinemia in patients with glucose-6-phosphate dehydrogenase deficiency.
This medicine contains the excipient mannitol, which may have a mild laxative effect.
Use during pregnancy or breastfeeding
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.
The use of nicorandil should be avoided as a precautionary measure during pregnancy.
Breastfeeding: Animal studies have shown that nicorandil passes into breast milk in small amounts. It is not known whether nicorandil is excreted in human milk, so its use is not recommended during breastfeeding.
Reproductive function: There are insufficient reproductive data to assess the risk to humans.
Ability to influence reaction speed when driving vehicles or other mechanisms
Nicorandil affects the ability to drive and use machines. Of course, as with other vasodilators, the blood pressure-lowering effect, as well as dizziness and weakness caused by nicorandil, may impair the ability to drive and use machines. This effect may be increased when combined with alcohol or other drugs that lower blood pressure (e.g. vasodilators, tricyclic antidepressants) (see section “Interaction with other medicinal products and other forms of interaction”). Therefore, patients should not drive or use machines if they experience these symptoms.
Method of administration and doses
The usual therapeutic dose is 10-20 mg twice daily. The usual starting dose is 10 mg twice daily, preferably in the morning and evening. If necessary, an increase in the dose to 40 mg twice daily is recommended according to the patient's needs, response and tolerability. A lower starting dose of 5 mg twice daily may be used in patients prone to headache.
Elderly patients
There are no special dosage requirements for elderly patients, but as with all drugs, it is recommended to use the lowest effective dose.
Patients with impaired liver and/or kidney function
There are no special dosage requirements for patients with impaired liver and/or kidney function.
Method of application
Nicorandil tablets are taken orally.
The tablets should be taken in the morning and evening with a glass of water. The tablets should not be crushed or chewed.
The tablet can be divided into two halves.
Taking the drug does not depend on food intake.
Children
Nicorandil tablets are not recommended for use in pediatric patients, as the safety and efficacy of its use in this group of patients have not been established.
Overdose
Symptoms
In case of acute overdose, the likely symptoms may be peripheral vasodilation with a fall in blood pressure and reflex tachycardia.
Treatment
Cardiac monitoring and general supportive measures are recommended. If this is not effective, volume expansion with blood substitutes is recommended. In life-threatening situations, vasoconstrictors should be considered.
Adverse reactions
The most common adverse reaction reported in clinical trials was headache, which occurred in more than 30% of patients, especially in the first days of treatment, and was the cause of most drug withdrawals in the studies.
Gradual dose titration may reduce the frequency of headaches (see section "Method of administration and dosage").
In addition, serious adverse reactions, including ulcers and their complications, have been reported during post-marketing surveillance of nicorandil (see section 4.4).
Adverse reactions reported with nicorandil are listed in the table below by system organ class and frequency. The frequency is defined as follows:
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); frequency unknown (cannot be estimated from the available data).
Within each grouping, the frequency of adverse reactions is presented in order of decreasing seriousness.
Metabolic and nutritional disorders:
very rarely - hyperkalemia (see sections "Special instructions for use" and "Interaction with other medicinal products and other types of interactions").
From the nervous system: very often - headache; often - dizziness.
On the part of the organs of vision:
very rarely - corneal ulcers, conjunctiva, conjunctivitis (see section "Special warnings and precautions for use"); frequency unknown - diplopia.
Cardiac disorders: often - increased heart rate.
Vascular disorders:
often - dilation of skin vessels with hot flashes; infrequently - decrease in blood pressure ("Special instructions").
From the gastrointestinal tract:
often - nausea, vomiting; rarely - formation of gastrointestinal ulcers (stomatitis, aphthosis, mouth ulcers, tongue ulcers, small intestinal ulcers, large intestinal ulcers, anal ulcers) (see below and the section "Special instructions for use"); frequency unknown - gastrointestinal bleeding (see the section "Special instructions for use").
Hepatobiliary system: very rarely - liver dysfunction, such as hepatitis, cholestasis or jaundice.
Skin and subcutaneous tissue disorders:
rarely - rash, itching; very rarely - angioedema, skin and mucous membrane ulcers (mainly perianal ulcers, genital ulcers and parastomal ulcers) (see section "Special instructions").
Musculoskeletal and connective tissue disorders: rarely – myalgia.
General disorders and local complications at the injection site: often - feeling of weakness.
Description of selected adverse reactions
Ulceration in the gastrointestinal tract
Complications of gastrointestinal ulcers, such as perforation, fistula or abscess formation, sometimes leading to gastrointestinal bleeding and weight loss, have been reported (see section 4.4).
Additional information
In addition, in the IONA study (Effect of Nicorandil on Angina Pectoris), where nicorandil was used in addition to standard therapy in patients with stable angina and high risk of cardiovascular events, the following adverse reactions were observed with varying frequencies:
Gastrointestinal: often - rectal bleeding; infrequently - mouth ulcers; very rarely - abdominal pain.
Skin and subcutaneous tissue disorders: uncommon – angioedema.
Musculoskeletal and connective tissue disorders: uncommon – myalgia.
Expiration date
18 months.
Storage conditions
Store out of the reach of children in the original packaging, to protect from moisture, at a temperature not exceeding 25 °C.
Packaging
10 tablets in a blister; 3 or 6 blisters in a cardboard pack.
Vacation category
According to the recipe.
Producer
Dexcel Ltd./Dexcel Ltd.
Location of the manufacturer and address of its place of business
1 Dexcel St., Or Akiva, 3060000, Israel/1 Dexcel St., Or Akiva, 3060000, Israel.
In case of side effects and questions regarding the safety of the drug, please contact the Pharmacovigilance Department of ASINO UKRAINE LLC at the address: Vaclav Havel Boulevard, 8, Kyiv, 03124
phone/fax: +38 044 281 2333.
