BETAFERON

INSTRUCTIONS for medical use of the medicinal product NITROMAX (NITROMAX)

Composition

active substance: glyceryl trinitrate; 1 tablet contains 0.3 mg, 0.4 mg or 0.5 mg of nitroglycerin; excipients: lactose monohydrate; potato starch; spherical sugar; crospovidone; magnesium stearate.

Pharmaceutical form.

Sublingual tablets.

Main physical and chemical properties:

Tablets are white or white with a yellowish tint, with a flat, possibly rough surface.

Pharmacotherapeutic group.

Vasodilators used in cardiology. Organic nitrates. ATC code C01D A02.

Pharmacological properties.

Pharmacodynamics.

Nitroglycerin is a peripheral vasodilator with a predominant effect on peripheral vessels.

Nitroglycerin acts directly on the smooth muscles of predominantly venous and arterial vessels through the nitrate receptor, which is located in the smooth muscle layer of the vessel wall. Nitroglycerin in smooth muscles is enzymatically converted, forming nitric oxide (NO), which stimulates soluble guanylate cyclase, which is responsible for the formation of cyclic guanosine-3',5'-monophosphate (cGMP), which is a mediator of relaxation.

Affects the processes of central regulation of vascular tone and heart activity. Contributes to the release of catecholamines in the brain and heart, which causes central suppression of sympathetic and vasomotor tone, indirect sympathomimetic effect on the myocardium, changes in the conformation of the troponin-tropomyosin complex. The nature and intensity of the action of nitroglycerin on the heart and peripheral vessels depend on the interaction of central and peripheral processes. Inhibition of vasoconstrictor reflexes on coronary vessels, which is a result of central inhibition of pain impulses, contributes to the relief of pain attacks in angina pectoris. The antianginal effect of nitroglycerin is due to its normalizing effect on the exchange of electrolytes and energy of the myocardium, namely, on key indicators of the respiratory chain - the ratio of oxidized and reduced forms of nicotinamide coenzymes, the activity of NAD-dependent dehydrogenases. Affects heart activity and systemic hemodynamics. Under the influence of nitroglycerin, retrograde blood flow increases due to the expansion and increase in the number of functioning collaterals. Indirect sympathomimetic effect, as well as the accumulation of cyclic adenosine monophosphate (AMP) in the myocardium, leads to an increase in its contractility. In addition, nitric oxide effectively inhibits both aggregation and adhesion of platelets. Decrease in peripheral resistance and reduction of venous return - effects associated with relaxation of smooth muscles of vessels, reduction of pre- and post-load on the heart. Venous dilation leads to a decrease in the amount of blood entering the heart, a decrease in preload, and arterial dilation - to a decrease in total peripheral resistance and a decrease in post-load, which ultimately facilitates the work of the heart and improves coronary blood flow.

There is a redistribution of blood flow in the myocardium in favor of the ischemic focus, and the ionotropic function of the myocardium is enhanced. The end-diastolic pressure in the left ventricle and the size of the heart decrease, which improves blood supply to the most vulnerable to ischemia subendocardial region of the myocardium. Weakening of peripheral venous and arterial resistance and pressure filling the heart with blood contributes to a decrease in energy expenditure of the left ventricle and the need for oxygen in the myocardium. The pressure in the pulmonary capillaries decreases, which makes it possible to prescribe nitroglycerin in case of myocardial infarction with pulmonary edema, as well as in case of heart failure. In ischemic hypokinesia of individual areas of the myocardium, its contractility is restored. Meningeal vessels dilate, vessels of internal organs constrict, and blood pressure in the pulmonary artery system decreases due to vasodilation and systemic effects of nitroglycerin. Nitroglycerin relaxes the smooth muscles of the bronchi, bile ducts, digestive tract, and urinary tract. In experimental studies, no teratogenic or toxic effects on the embryo were found.

Pharmacokinetics.

After sublingual administration, the effect occurs within 0.5-2 minutes; 75% of patients note an improvement within the first 3 minutes, and another 15% - within 4-15 minutes.

Nitroglycerin, taken sublingually, is absorbed by the mucous membrane and enters the systemic bloodstream. 60-75% of the administered dose is absorbed. Within 2-4 minutes after administration, the maximum concentration in plasma is reached - 2.3 μg/l, by the 8th minute it decreases by 50%, and within 20 minutes, nitroglycerin is almost not detected in the blood. It is rapidly metabolized in the liver. Nitroesters of polyatomic alcohols are quickly denitrated. Denitrated metabolites, such as 1,2- and 3,4-dinitrates, act weaker and have a longer half-life compared to nitroglycerin. The half-life of nitroglycerin is almost 30 minutes. The cleavage of nitro groups occurs sequentially both by the formation of inorganic nitrites and by the formation of nitrates. From the organic part of the molecule of nitroesters, alcohols, aldehydes, and organic acids are formed. Within 4 hours after administration of the drug, nitroesters (the initial product) are almost not detected. The most active metabolism occurs in the liver, kidneys, and blood. Nitroesters are cleaved by two pathways: with the help of glutathione-dependent reductase, which is localized mainly in the soluble fraction of hepatocytes, and with the help of an enzyme that does not require reduced glutathione. The drug is metabolized, first of all, in the arteriovenous vascular bed, diffuses into the cells of smooth muscles, where it is converted into nitric oxide. A small part of the drug, mainly under the influence of glutathione-S-reductase, is biotransformed in the liver into di- and mononitrates and glycerin. When taken orally, a larger part of the drug is metabolized in the liver (the "first pass" effect). A significant part of dinitrate and mononitrate forms conjugates with glucuronic acid. Metabolites of nitroglycerin are excreted mainly by the kidneys, and some metabolites are excreted through the lungs with exhaled air. The total clearance of nitroglycerin is 25-30 liters.

The half-life is 4-5 minutes. The half-life of metabolites is 4 hours.

Clinical characteristics.

Indications.

Relief and short-term prevention of angina attacks.

Contraindications.

Increased sensitivity to nitrates and auxiliary components of the medicinal product; cerebral ischemia, hemorrhagic stroke, cerebral hemorrhage, increased intracranial pressure, recent head trauma, bradycardia (less than 50 beats/min), arterial hypotension (systolic blood pressure below 100 mmHg, diastolic blood pressure below 60 mmHg), shock, collapse, hypertrophic obstructive cardiomyopathy, aortic stenosis, conditions accompanied by a decrease in left ventricular filling pressure (acute myocardial infarction, isolated mitral stenosis, constrictive pericarditis), cardiac tamponade, toxic pulmonary edema, closed-angle glaucoma with high intraocular pressure, simultaneous use of phosphodiesterase-5 inhibitors (PDE-5) (sildenafil, tadalafil, vardenafil), pronounced anemia.

Interaction with other medicinal products and other types of interactions.

When used simultaneously with other vasodilators, antihypertensive agents, angiotensin-converting enzyme inhibitors (ACE), calcium channel blockers, diuretics, neuroleptics, tricyclic antidepressants, sapropterin, monoamine oxidase inhibitors, ethanol, and ethanol-containing products, beta-blockers, procainamides, acetylcysteine, quinidine, novocainamides, the hypotensive effect of nitroglycerin is enhanced.

Phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil) - simultaneous use of nitroglycerin with these drugs is contraindicated, as there is a risk of uncontrolled arterial hypotension, life-threatening cardiovascular complications.

It is possible to develop tolerance to nitroglycerin when used simultaneously with long-acting nitrate preparations.

Simultaneous use with drugs that cause dryness in the mouth (anticholinergic, antimuscarinic, tricyclic antidepressants) reduces the effectiveness of sublingual nitrates.

Simultaneous sublingual use of nitroglycerin and apomorphine can enhance the hypotensive effect.

Atropine and other drugs that have M-cholinolytic action can reduce the effect of nitroglycerin due to decreased secretion and bioavailability of the drug.

The use of dihydroergotamine may lead to an increase in its concentration in the blood plasma and an increase in blood pressure (due to increased bioavailability of dihydroergotamine).

When used simultaneously with heparin, a decrease in the anticoagulant effect of the latter is possible (after withdrawal of the drug, a significant decrease in blood coagulation may occur, which may require a decrease in the dose of heparin, early and frequent laboratory monitoring of blood coagulation).

Phenobarbital activates the metabolism of nitrates in the liver. Alpha-adrenomimetics, histamine, pituitrin, corticosteroids, central nervous system stimulants, bee venom, snake venom, sunlight reduce the antianginal effect of nitroglycerin. Salicylates increase the level of nitroglycerin in the blood, barbiturates accelerate its metabolism. Donors of sulfhydryl groups (captopril, acetylcysteine, unithiol) restore reduced sensitivity to nitroglycerin.

Features of use.

Should be used with caution in patients with uncontrolled hypovolemia, heart failure with normal or low blood pressure in the pulmonary artery, severe anemia, hyperthyroidism, hypoxia, hypothermia, history of myocardial infarction, inadequate nutrition, and severe renal and/or hepatic disorders (risk of developing methemoglobinemia).

Should be used with caution in patients with pronounced cerebral atherosclerosis, elderly patients. During treatment, it is not recommended to consume alcohol; visits to the bath, sauna, hot shower are contraindicated.

The tablet cannot be chewed, as an excessive amount of the active substance may enter the systemic bloodstream through the mucous membrane of the oral cavity.

As with other organic nitrates, tolerance (tolerance) to nitroglycerin may develop with frequent use, which requires an increase in the dose. With prolonged use, to prevent the development of tolerance, it is recommended to take the drug intermittently during the day (with an interval of 10-12 hours) or simultaneously with calcium antagonists, ACE inhibitors, or diuretics. In case of development of tolerance, it is sometimes necessary to temporarily cancel the use of nitroglycerin (for several days) and replace it with antianginal drugs of other pharmacotherapeutic groups.

Before using the drug for the first time, you should consult a doctor!

The patient must inform the doctor about the previous reaction to the use of drugs of this group.

When taking nitroglycerin, a significant decrease in blood pressure and dizziness may occur when suddenly changing from a lying or sitting position to a vertical position, when using alcohol, when performing physical exercises in hot weather.

If blurred vision or dryness in the mouth persists or is severely pronounced, treatment should be discontinued.

The severity of headache when taking the drug can be reduced by reducing its dose and/or simultaneous use of valerian.

The risk of developing methemoglobinemia, which is manifested by cyanosis and a change in blood color, increases with prolonged uncontrolled use of nitroglycerin, use of high doses of the drug in patients with liver failure. In case of development of methemoglobinemia, nitroglycerin should be immediately canceled and an antidote - methylene blue - should be used. If there is a need for further use of nitrates, it is necessary to control the content of methemoglobin.

The drug contains lactose. If the patient has a known intolerance to some sugars, it is necessary to consult a doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

The use of the drug NITROMAX during pregnancy or breastfeeding is contraindicated.

Ability to affect the speed of reaction when driving vehicles or other mechanisms.

When driving vehicles and other mechanisms that require increased attention, it should be remembered that taking nitroglycerin can lead to a decrease in the speed of reaction.

Method of use and doses.

In case of angina, NITROMAX should be taken sublingually immediately after the onset of an attack. The usual dose of the drug is 0.5 mg, and for many patients with stable angina, a smaller dose of 0.3 mg or 0.4 mg is effective. If there is no antianginal effect within the first 5 minutes, another tablet should be taken.

In the absence of a therapeutic effect after taking 1-1.5 mg of the drug, a doctor should be called immediately (likely development of myocardial infarction)!

NITROMAX acts for 30 minutes. In case of frequent angina attacks, it is advisable to prescribe prolonged-release nitroglycerin preparations. However, if an angina attack develops during treatment with prolonged-release nitrates, NITROMAX should be used to relieve the acute attack. Tolerance to sublingual forms of nitrates develops rarely, but if it occurs in some patients, the dose of the drug should be gradually increased to 1.0-1.5 mg.

Children.

Experience with the use of the drug in children is limited, so it is not recommended to use it in this age group of patients.

Overdose.

Symptoms: decrease in blood pressure (below 90 mmHg) with orthostatic dysregulation, headache, severe dizziness, fainting, frequent heartbeat, colic, diarrhea, nausea and vomiting, shortness of breath, pronounced weakness, drowsiness, increased body temperature, feeling of heat, arterial hypotension, increased sweating, chills.

When using high doses (more than 20 μg/kg) - collapse, cyanosis of the lips, nails, or palms, methemoglobinemia, dyspnea, and tachypnea.

Treatment: the patient should be placed in a horizontal position with elevated lower limbs, in severe cases, plasma substitutes, sympathomimetics, oxygen, and in case of methemoglobinemia, methylene blue should be prescribed, if the patient does not have a deficiency of glucose-6-phosphate dehydrogenase. Saturation should be assessed. If the saturation level is 1-2 mg/kg of body weight, oxygen therapy should be prescribed.

Side effects.

When using the medicinal product, the following side effects were reported.

From the central nervous system: blurred vision, psychotic reactions, retardation, disorientation.

From the gastrointestinal tract: dryness in the mouth, abdominal pain.

From the immune system: allergic reactions, including urticaria, itching; hyperemia of the skin, pallor, anaphylactic shock.

Others: irritability, vision disturbances, exacerbation of glaucoma, hypothermia, feeling of heat.

There were also reports of single cases of side effects: exacerbation of ischemic heart disease due to hypoxia, complete block, asystole, angioneurotic edema.

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging.

Store in a place inaccessible to children.

Packaging.

50 tablets in a glass bottle, 4 bottles in a cardboard box.

100 tablets in a glass bottle in a cardboard box.

50 tablets in a glass bottle, 3 bottles in a blister pack, 1 blister pack in a cardboard box.

50 tablets in a glass bottle, 3 bottles in a blister pack with foil, 1 blister pack in a cardboard box.

Release category.

Without a prescription.

Manufacturer.

LTD NPF "MICROCHEM" (production site (all stages of the production process))

Location of the manufacturer and address of the place of its activity.

Ukraine, 93000, Luhansk region, Rubizhne, Lenin Street, building 33.

You can report an adverse event when using the medicinal product by phone +38 (050) 309-83-54 (around the clock).