Nitro-mik®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NITRO-MIK® (NITRO-MIK)

Composition:

Active substance: glyceryl trinitrate;

1 dose contains diluted nitroglycerin, calculated as 100% nitroglycerin – 0.4 mg;

Excipients: propylene glycol, ethanol 96%, purified water.

Pharmaceutical form. Sublingual metered spray.

Main physicochemical properties: clear, colorless liquid with a characteristic alcoholic odor.

Pharmacotherapeutic group.

Vasodilators used in cardiology. Organic nitrates. Glyceryl trinitrate. ATC code C01DA02.

Pharmacological Properties.

Pharmacodynamics.

Nitroglycerin is an organic nitrate compound that exerts a dilating effect on arteries and veins.

Postcapillary segments of peripheral vessels, large arteries, and particularly those portions of coronary vessels that remain reactive, are more sensitive to nitroglycerin than resistant (precapillary) vessels. Vasodilation in the systemic circulation increases venous capacitance and consequently reduces venous return to the heart (preload), ventricular size, and cardiac filling pressure. As a result, myocardial energy and oxygen demand decrease, and blood supply to the subendocardial layers of the walls, which are most vulnerable to ischemia, improves. Regional wall motion and cardiac stroke volume are also enhanced. Vasodilation of large arteries adjacent to the heart reduces systemic and pulmonary vascular resistance.

Nitroglycerin also exerts a myorelaxant effect on smooth muscles of the bronchi, bile and urinary tracts, gallbladder, small and large intestine, and sphincters.

It is believed that nitroglycerin produces these effects by binding to so-called nitrate receptors located on the membranes of smooth muscle cells. Within smooth muscles, nitroglycerin undergoes enzymatic transformation, producing nitric oxide (NO), which stimulates soluble guanylate cyclase, leading to the formation of cyclic guanosine-3'5'-monophosphate (cGMP), resulting in smooth muscle relaxation.

Pharmacokinetics.

After sublingual administration, nitroglycerin is rapidly absorbed from the oral cavity and enters directly into the systemic circulation (thus avoiding the first-pass liver effect). Bioavailability shows significant individual variability and averages approximately 39%. The onset of nitroglycerin action is very rapid; the effect develops within 1–1.5 minutes and lasts for about 30 minutes. Peak plasma concentrations are reached within 4 minutes. After sublingual administration, the elimination half-life of nitroglycerin is approximately 2.5–4.4 minutes. Nitroglycerin entering the bloodstream binds to erythrocytes and accumulates in vessel walls; plasma protein binding is nearly 60%. The primary route of elimination is via urine as metabolites; less than 1% of the administered dose is excreted unchanged.

Clinical Characteristics.

Indications.

• For the treatment of angina attacks;
• for the prevention of angina attacks induced by physical exertion or emotional stress;
• for adjunctive therapy in emergencies requiring immediate intervention in acute left ventricular failure (cardiac asthma);
• for reducing blood pressure in acute myocardial infarction;
• for prevention of coronary vasospasm caused by cardiac catheterization during coronary angiography.

Contraindications.

• Hypersensitivity to the active substance, other nitrate derivatives, or to any component of the medicinal product;
• acute circulatory failure (shock, collapse);
• arterial hypotension (systolic blood pressure (BP) below 100 mm Hg, diastolic BP below 60 mm Hg);
• cardiogenic shock;
• acute myocardial infarction with low filling pressure;
• left ventricular failure with low filling pressure;
• angina caused by hypertrophic obstructive cardiomyopathy;
• constrictive pericarditis;
• pericardial tamponade;
• cerebral ischemia;
• closed-angle glaucoma with elevated intraocular pressure;
• bradycardia (less than 50 beats/min);
• concomitant use with compounds that generate nitric oxide and nitrates due to the effect of Nitro-Mik® on the nitric oxide/cyclic guanosine monophosphate (cGMP) metabolic pathway; phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil) may potentiate the antihypertensive effects of nitrates;
• any condition associated with increased intracranial pressure (cerebral hemorrhage, traumatic brain injury);
• primary pulmonary hypertension (since hyperemia of poorly ventilated alveolar areas may lead to hypoxia); patients with cardiovascular disorders and a predisposition to orthostatic circulatory disturbances are at particular risk;
• severe anemia;
• concomitant use with riociguat and stimulators of soluble guanylate cyclase.

Interaction with other medicinal products and other forms of interaction.

Concomitant administration of Nitro-Mik® with cGMP-specific phosphodiesterase type 5 inhibitors used for the treatment of erectile dysfunction (e.g., sildenafil, vardenafil, tadalafil) is contraindicated due to the potential for enhanced antihypertensive effects of Nitro-Mik®.

Nitro-Mik® should be used with caution when administered concomitantly with:

• other vasodilators and antihypertensive agents (β-blockers, calcium channel blockers), neuroleptics, tricyclic antidepressants (possible enhancement of nitroglycerin’s antihypertensive effect);
• dihydroergotamine (increased serum levels and effect of dihydroergotamine);
• heparin (reduced heparin effect).

Patients previously treated with nitrates (e.g., isosorbide dinitrate, isosorbide mononitrate) may require higher doses of nitroglycerin.

Nitro-Mik® may be used concomitantly with other nitrate-containing medications, but caution should be exercised to avoid overdose. Sublingual nitroglycerin tablets should not be used as adjunctive therapy with Nitro-Mik® for the treatment of angina attacks.

Phenobarbital enhances hepatic metabolism of nitrates.

α-adrenergic agonists, histamine, pituitary extract (pituitrin), corticosteroids, central nervous system (CNS) stimulants, bee venom, snake venom, and exposure to sunlight reduce the antianginal effect of nitroglycerin.

Salicylates increase nitroglycerin blood levels, while barbiturates accelerate its metabolism. Sulfhydryl group donors (captopril, acetylcysteine, unithiol) restore reduced sensitivity to nitroglycerin.

Alcohol consumption during use of the medicinal product is strictly prohibited.

N-acetylcysteine may potentiate the vasodilatory effect of nitroglycerin.

Concomitant use with dihydroergotamine may increase its serum concentration and enhance vasoconstrictive effects, potentially reducing the efficacy of nitroglycerin. This requires special attention when treating patients with ischemic heart disease, as combined use of dihydroergotamine and nitroglycerin may lead to coronary vasoconstriction.

Nonsteroidal anti-inflammatory drugs (NSAIDs), except acetylsalicylic acid, may reduce the therapeutic effect of nitroglycerin.

Concomitant administration of nitroglycerin with amifostine and acetylsalicylic acid may increase arterial blood pressure and reduce the effect of nitroglycerin.

The possibility of developing tolerance to the effects of nitroglycerin should be considered when it is used concomitantly with long-acting nitrate preparations.

Concomitant use of nitroglycerin with riociguat and stimulators of soluble guanylate cyclase may cause hypotension.

Special precautions for use.

Particular caution and careful medical monitoring should be exercised in patients predisposed to postural hypotension and in those with increased intracranial pressure.

The medicinal product should be administered with caution to patients suffering from migraine.

Individual sensitivity of patients to nitrates may vary significantly; therefore, this should always be taken into account when determining the dosage.

Dose escalation may lead to tolerance.

Alcohol consumption during treatment with this medicinal product is strictly prohibited.

Nitroglycerin enhances the urinary excretion of catecholamines and vanillylmandelic acid.

The medicinal product contains alcohol. Its use may be hazardous in patients with liver disease, alcoholism, epilepsy, brain injury, and other CNS disorders, as well as in pregnant women and children. Nitroglycerin may alter or enhance the effects of other drugs.

The medicinal product contains propylene glycol and may cause irritation of the mucous membranes.

The medicinal product should be used with caution, taking into account the risk-benefit ratio, in the following conditions: primary pulmonary hypertension (with hyperemia of alveolar areas with reduced ventilation, which may lead to hypoxia); uncontrolled hypovolemia; heart failure with normal or low pulmonary artery pressure; toxic pulmonary edema; severe anemia; hyperthyroidism; impaired cerebral circulation; severe renal insufficiency (risk of methemoglobinemia development). Patients with coronary artery disease are at particular risk.

Caution is advised in patients with marked cerebral atherosclerosis, elderly patients, and patients with aortic or mitral stenosis.

During treatment, visiting saunas, steam baths, or taking hot showers is contraindicated.

Nitroglycerin should be used cautiously in patients with cerebrovascular disease, as symptoms of such conditions may be induced by hypotension.

Arterial hypotension with bradycardia may occur in patients with myocardial infarction; this phenomenon is considered to be reflex-mediated.

Particular caution is required when administering nitroglycerin to patients with severe liver or kidney disease, hypothyroidism, mitral valve prolapse, hypothermia, malnutrition, or with a recent history of myocardial infarction.

In cases of myocardial infarction or acute heart failure, treatment with nitroglycerin should be carried out cautiously, under strict medical supervision and/or hemodynamic monitoring.

Caution is necessary when treating patients with arterial hypoxia due to severe anemia (including G6PD deficiency-induced forms), as biotransformation of glyceryl trinitrate is reduced in such patients.

Patients with angina, myocardial infarction, or cerebral ischemia often suffer from lower respiratory tract abnormalities (particularly alveolar hypoxia). Caution is required when administering the drug to patients with hypoxemia and ventilation/perfusion imbalance due to lung disease. In patients with alveolar hypoventilation, pulmonary vasoconstriction occurs to redirect perfusion away from areas of alveolar hypoxia to better-ventilated lung regions (Euler-Liljestrand mechanism).

As a potent vasodilator, glyceryl trinitrate may alter this protective vasoconstriction, thereby increasing perfusion to poorly ventilated areas, worsening ventilation/perfusion imbalance, and further reducing arterial partial oxygen pressure.

Nitroglycerin may reduce blood oxygen levels in patients with pulmonary diseases or cor pulmonale.

If angina symptoms do not resolve after administration of three doses, emergency medical assistance should be sought immediately.

Use during pregnancy or breastfeeding.

Pregnancy.

The use of this medicinal product during pregnancy is permissible only if the expected benefit to the mother outweighs the potential risk to the fetus or infant.

Breastfeeding.

It is unknown whether nitroglycerin metabolites are excreted in breast milk.

Therefore, the benefit and risk to both mother and infant should be carefully weighed before initiating nitroglycerin therapy. If the risk outweighs the benefit, breastfeeding should be discontinued.

Fertility.

Animal studies do not indicate any harmful effect of nitroglycerin on fertility. However, there are no data available on its effects in humans.

Ability to affect reaction speed when driving or operating machinery.

At the beginning of treatment – for a period individually determined – driving vehicles or operating complex machinery is prohibited. Later, these restrictions may be reduced depending on the patient's individual response to the medicinal product.

Glyceryl trinitrate, especially at the beginning of treatment or during dose titration, may impair reaction speed or, rarely, may cause orthostatic hypotension and dizziness (and, in exceptional cases, syncope may occur following overdose). Patients experiencing these effects should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage

Treatment of angina attacks.

During an angina attack, administer 1 dose (1 spray equals 400 mcg) sublingually.

If symptoms do not resolve, the dose may be repeated at 5-minute intervals, but no more than 3 doses should be administered.

If the attack persists after this, immediate medical attention is required. The patient should be in a sitting position to prevent symptoms of postural hypotension.

Prevention of angina attacks.

To prevent angina attacks during exertion or other anticipated situations, it is recommended to administer 1 dose (1 spray) (400 mcg) sublingually shortly before the anticipated exertion.

Acute left ventricular failure (cardiac asthma).

For treatment of non-hypotensive patients with acute left ventricular failure (i.e., arterial systolic pressure > 100 mm Hg), administer 400 mcg of nitroglycerin, i.e., 1 dose (1 spray) sublingually, and repeat administration every 5–10 minutes. The total number of sprays should not exceed 3 doses, with careful monitoring of the patient's clinical condition, including arterial pressure. Subsequently, the patient may be switched to intravenous therapy or another vasodilator depending on the clinical condition.

Prior to coronary angiography.

To prevent coronary vasospasm, a dose of 1–2 sprays (0.4–0.8 mg) is recommended.

Reduction of blood pressure in acute myocardial infarction.

The recommended dose is 0.4–1.2 mg, i.e., 1–3 sprays, with monitoring of circulation (arterial systolic pressure should exceed 100 mm Hg).

Dosage adjustment in patients with renal or hepatic insufficiency is not required.

Elderly patients.

Hypotension and dizziness may be particular concerns when using nitrates in elderly patients. Patients are advised to sit while administering the sublingual spray.

Method of Administration.

Before first use, press the spray pump several times into the air until a uniform spray mist is produced. The medication is now ready for use.

If more than 24 hours have passed since the last use, the first spray should be administered into the air to prevent delivery of an incomplete dose.

When using the spray, hold the bottle vertically with the nozzle pointing upwards.

Bring the bottle close to the mouth and, while pressing the spray pump, administer the solution into the mouth as follows:

• take a deep breath;
• hold the breath;
• while pressing the spray pump, spray the solution into the mouth (a slight stinging sensation on the tongue may occur);
• close the mouth and breathe through the nose only for the next 30 seconds.

The solution should not be inhaled. To ensure optimal efficacy, press the spray pump fully and without interruption, then release. The spray pump should be checked periodically, especially after prolonged periods of non-use.

Children.

There is no experience with the use of this medication in pediatric practice; therefore, Nitro-Mik® should not be used in children (under 18 years of age).

Overdose.

Overdose of the medication may intensify known adverse reactions (headache, marked arterial hypotension, tachycardia, dizziness, flushing, vomiting, diarrhea). With very high doses, increased intracranial pressure with cerebral symptoms, methemoglobinemia, cyanosis, dyspnea, and tachypnea may occur. Additional gastrointestinal effects such as colic and diarrhea have also been reported.

Treatment of overdose.

In case of overdose, the patient's clinical condition, including vital signs and mental status, should be assessed, and cardiovascular and respiratory functions should be supported. For mild hypotension, lying down with elevated legs may be sufficient.

In cases of severe overdose, general measures for intoxication and shock should be implemented (fluid administration, norepinephrine and/or dopamine). Epinephrine (adrenaline) is contraindicated.

In case of methemoglobinemia, the following antidotes and measures are indicated:

1. Vitamin C: 1 g orally as tablets or 1 g intravenously as sodium ascorbate solution.
2. Methylene blue: 1–2 mg/kg body weight of a 1% solution, administered intravenously over 5 minutes, if the patient does not have G-6-PD deficiency.
3. Toluidine blue: initial dose 2–4 mg/kg intravenously, followed by a repeat dose of 2 mg/kg.
4. Oxygen therapy, hemodialysis, blood transfusion.

Adverse reactions.

Blood and lymphatic system disorders: methemoglobinemia.

Psychiatric disorders: may experience feelings of excitement, anxiety, and restlessness.

Nervous system disorders: headache, dizziness, drowsiness, syncope, cerebral ischemia, blurred vision, psychotic reactions, lethargy, disorientation.

Cardiovascular system disorders: occasionally, the first dose, especially an increased initial dose, may cause a decrease in arterial blood pressure and/or postural hypotension with marked tachycardia, dizziness, or weakness. With excessive reduction of arterial pressure, treatment with Nitro-Mik® may exacerbate symptoms of angina (paradoxical reaction to nitrates). Occasionally, collapse accompanied by bradyarrhythmia and loss of consciousness, sensation of warmth, cyanosis, pallor may occur.

Respiratory system disorders: breathing difficulties.

Gastrointestinal disorders: nausea, vomiting, dry mouth, abdominal pain, diarrhea, heartburn, halitosis.

Skin and subcutaneous tissue disorders: flushing, skin allergic reactions, hypersensitivity reactions, exfoliative dermatitis.

Immune system disorders: allergic reactions, including skin rash, itching, anaphylactic shock.

General disorders: mild transient burning sensation in the throat, taste disturbances (metallic taste in the mouth), headache, postural hypotension, flushing, palpitations, hypothermia, glaucoma exacerbation, asthenia. These symptoms are transient and disappear within a few minutes.

Shelf life.

5 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging, away from fire.

Keep out of reach of children.

Packaging.

15 ml (300 doses) in spray bottles in cardboard boxes.

Prescription status.

Prescription only.

Manufacturer.

LLC NVP "MIKROKHIM" (responsible for batch release excluding batch control/testing)

Manufacturer's address and location of business activity.

5, Budyndustrії Str., Kyiv, 01013, Ukraine.

To report adverse events during the use of the medicinal product, please call +38 (050) 309-83-54 (24/7).

INSTRUCTIONS

for medical use of the medicinal product

NITRO-MIK®

(NITRO-MIK)

Composition:

Active substance: glyceryl trinitrate;

1 dose contains diluted nitroglycerin, calculated as 100% nitroglycerin – 0.4 mg;

Excipients: propylene glycol, ethanol 96%, purified water.

Pharmaceutical form. Dosage sublingual spray.

Main physicochemical properties: clear, colorless liquid with a characteristic alcoholic odor.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

Nitroglycerin is an organic nitrate compound that exerts a dilating effect on arteries and veins.

Postcapillary segments of peripheral vessels, large arteries, and particularly reactive areas of coronary vessels are more sensitive to nitroglycerin than resistant (precapillary) vessels. Vasodilation in the systemic circulation increases venous capacity and consequently reduces venous return to the heart (preload), ventricular size, and cardiac filling pressure. As a result, myocardial energy and oxygen demand are reduced, and blood supply to the subendocardial layers of the walls, which are most vulnerable to ischemia, is improved. Regional wall motion and cardiac stroke volume are also enhanced. Dilation of large arteries adjacent to the heart reduces systemic and pulmonary vascular resistance.

Nitroglycerin also exerts a myorelaxant effect on smooth muscles of the bronchi, biliary and urinary tracts, gallbladder, small and large intestines, and sphincters.

It is believed that nitroglycerin produces these effects by binding to so-called nitrate receptors located on the membranes of smooth muscle cells. Within smooth muscles, nitroglycerin undergoes enzymatic transformation, producing nitric oxide (NO), which stimulates soluble guanylyl cyclase, leading to the formation of cyclic guanosine-3',5'-monophosphate (cGMP), resulting in smooth muscle relaxation.

Pharmacokinetics.

When administered sublingually, nitroglycerin is rapidly absorbed from the oral cavity and enters directly into the systemic circulation (first-pass hepatic metabolism is avoided). Bioavailability shows significant individual variability and averages approximately 39%. The onset of action of nitroglycerin is very rapid; the effect develops within 1–1.5 minutes and lasts for about 30 minutes. Maximum plasma concentration is reached within 4 minutes. After sublingual administration, the elimination half-life of nitroglycerin is approximately 2.5–4.4 minutes. Nitroglycerin entering the bloodstream binds to erythrocytes and accumulates in vessel walls; plasma protein binding is nearly 60%. The primary route of elimination is via urine as metabolites; less than 1% of the administered dose is excreted unchanged.

Clinical characteristics.

Indications.

• For the treatment of angina attacks;
• for the prevention of angina attacks provoked by physical exertion or emotional stress;
• for adjunctive therapy in emergency situations of acute left ventricular failure (cardiac asthma);
• for reducing blood pressure in acute myocardial infarction;
• for prevention of coronary vessel spasm caused by cardiac catheterization during coronary angiography.

Contraindications.

• Hypersensitivity to the active substance, other nitrate derivatives, or any component of the medicinal product;
• acute circulatory failure (shock, collapse);
• arterial hypotension (systolic blood pressure (BP) below 100 mm Hg, diastolic BP below 60 mm Hg);
• cardiogenic shock;
• acute myocardial infarction with low filling pressure;
• left ventricular failure with low filling pressure;
• angina caused by hypertrophic obstructive cardiomyopathy;
• constrictive pericarditis;
• pericardial tamponade;
• cerebral ischemia;
• closed-angle glaucoma with high intraocular pressure;
• bradycardia (less than 50 beats/min);
• concomitant use with compounds that produce nitric oxide and nitrates, as the medicinal product Nitro-Mik® affects the metabolic pathway of nitric oxide/cyclic guanosine monophosphate (cGMP); phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil) may potentiate the antihypertensive effects of nitrates;
• any condition associated with increased intracranial pressure (cerebral hemorrhage, head trauma);
• primary pulmonary hypertension (since hyperemia of poorly ventilated alveolar areas may lead to hypoxia); patients with cardiovascular disorders and a predisposition to orthostatic circulatory disturbances are at particular risk;
• severe anemia;
• concomitant use with riociguat and stimulators of soluble guanylate cyclase.

Interaction with other medicinal products and other forms of interaction.

It is contraindicated to administer Nitro-Mik® simultaneously with cGMP-specific phosphodiesterase type 5 inhibitors used for the treatment of erectile dysfunction (e.g., sildenafil, vardenafil, tadalafil), as this may enhance the antihypertensive effect of Nitro-Mik®.

Nitro-Mik® should be used with caution when administered concomitantly with:

• other vasodilators and antihypertensive agents (β-blockers, calcium channel blockers), neuroleptics, tricyclic antidepressants (possible enhancement of nitroglycerin's antihypertensive effect);
• dihydroergotamine (increased serum levels and effect of dihydroergotamine);
• heparin (reduced heparin effect).

Patients previously treated with nitrates (e.g., isosorbide dinitrate, isosorbide mononitrate) may require higher doses of nitroglycerin.

Nitro-Mik® may be used together with other nitrate-containing preparations, but caution should be exercised to avoid overdose. Sublingual nitroglycerin tablets should not be used as adjunctive therapy with Nitro-Mik® for the treatment of angina attacks.

Phenobarbital enhances hepatic metabolism of nitrates.

α-adrenergic agonists, histamine, pituitary, corticosteroids, central nervous system (CNS) stimulants, bee and snake venom, and sunlight reduce the antianginal effect of nitroglycerin.

Salicylates increase nitroglycerin blood levels, while barbiturates accelerate its metabolism. Sulfhydryl group donors (captopril, acetylcysteine, unithiol) restore reduced sensitivity to nitroglycerin.

Alcohol consumption during use of the medicinal product is strictly prohibited.

N-acetylcysteine may potentiate the vasodilatory effect of nitroglycerin.

Concomitant use with dihydroergotamine may increase its serum concentration and enhance vasoconstrictive effects, potentially reducing the efficacy of nitroglycerin. This requires special attention when treating patients with ischemic heart disease, as combined use of dihydroergotamine and nitroglycerin may lead to coronary vasoconstriction.

Non-steroidal anti-inflammatory drugs (NSAIDs), except acetylsalicylic acid, may reduce the therapeutic effect of nitroglycerin.

Concomitant administration of nitroglycerin with amifostine and acetylsalicylic acid may increase arterial pressure and reduce the effect of nitroglycerin.

The possibility of developing tolerance to the effects of nitroglycerin should be considered when it is used concomitantly with long-acting nitrate preparations.

Concomitant use of nitroglycerin with riociguat and stimulators of soluble guanylate cyclase may cause hypotension.

Special precautions for use.

Particular caution and careful medical monitoring should be exercised in patients predisposed to postural hypotension and in those with increased intracranial pressure.

The medicinal product should be administered with caution in patients suffering from migraine.

Individual sensitivity of patients to nitrates may vary significantly; therefore, this should always be taken into account when selecting the dosage.

Dose escalation may lead to tolerance development.

Alcohol consumption during treatment with this medicinal product is strictly prohibited.

Nitroglycerin enhances the urinary excretion of catecholamines and vanillylmandelic acid.

The medicinal product contains alcohol. Its use may be hazardous in patients with liver disease, alcoholism, epilepsy, brain injury, and other CNS disorders, as well as in pregnant women and children. Nitroglycerin may alter or enhance the effects of other drugs.

The medicinal product contains propylene glycol and may cause irritation of mucous membranes.

The medicinal product should be used with caution, taking into account the risk-benefit ratio, in the following conditions: primary pulmonary hypertension (with hyperemia of alveolar areas with reduced ventilation, which may lead to hypoxia); uncontrolled hypovolemia; heart failure with normal or low pulmonary artery pressure; toxic pulmonary edema; severe anemia; hyperthyroidism; impaired cerebral circulation; severe renal insufficiency (risk of methemoglobinemia development). Patients with coronary artery disease are at particular risk.

Caution should be exercised when administering the drug to patients with marked cerebral atherosclerosis, elderly patients, and those with aortic or mitral stenosis.

During treatment, visiting saunas, steam baths, or taking hot showers is contraindicated.

Nitroglycerin should be used cautiously in patients with cerebrovascular disease, as symptoms of such conditions may be triggered by hypotension.

Arterial hypotension with bradycardia may occur in patients with myocardial infarction; this phenomenon is considered to be reflex-mediated.

Particular caution is required when administering nitroglycerin to patients with severe liver or kidney disease, hypothyroidism, mitral valve prolapse, hypothermia, malnutrition, or with a recent history of myocardial infarction.

In cases of myocardial infarction or acute heart failure, treatment with nitroglycerin should be carried out cautiously, under strict medical supervision and/or hemodynamic monitoring.

Caution is necessary when treating patients with arterial hypoxia due to severe anemia (including G6PD deficiency-induced forms), as biotransformation of glyceryl trinitrate is reduced in such patients.

Patients with angina, myocardial infarction, or cerebral ischemia often suffer from lower respiratory tract abnormalities (particularly alveolar hypoxia). Caution is required when administering the drug to patients with hypoxemia and ventilation/perfusion imbalance due to lung disease. In patients with alveolar hypoventilation, vasoconstriction occurs in the lungs to redirect perfusion away from areas of alveolar hypoxia to better-ventilated lung regions (Euler-Liljestrand mechanism).

As a potent vasodilator, glyceryl trinitrate may interfere with this protective vasoconstriction, thereby increasing perfusion to poorly ventilated areas, worsening ventilation/perfusion imbalance, and further reducing arterial partial oxygen pressure.

Nitroglycerin may reduce blood oxygen levels in patients with pulmonary diseases or cor pulmonale.

If angina symptoms do not resolve after administration of three doses, emergency medical assistance should be sought immediately.

Use during pregnancy or breastfeeding.

Pregnancy.

The use of this medicinal product during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus or child.

Breastfeeding.

It is unknown whether nitroglycerin metabolites are excreted in breast milk.

Therefore, the benefit and risk to both mother and child should be carefully weighed before initiating nitroglycerin therapy. If the risk outweighs the benefit, breastfeeding should be discontinued.

Fertility.

Animal studies do not indicate harmful effects of nitroglycerin on fertility. However, there are no data available on its effects in humans.

Effects on ability to drive and use machines.

At the beginning of treatment – for a period individually determined – driving vehicles or operating complex machinery is prohibited. Later, these restrictions may be reduced depending on the patient's individual response to the medicinal product.

Glyceryl trinitrate, particularly at the start of treatment or during dose titration, may impair reaction speed or, rarely, may cause orthostatic hypotension and dizziness (and, exceptionally, syncope may occur following overdose). Patients experiencing these effects should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage

Treatment of angina attacks.

During an angina attack, administer 1 dose (1 spray equals 400 mcg) sublingually.

If symptoms do not resolve, the dose may be repeated at 5-minute intervals, but no more than 3 doses should be administered.

If the attack persists after this, immediate medical attention is required. The patient should be in a sitting position to prevent symptoms of postural hypotension.

Prevention of angina attacks.

To prevent angina attacks during exertion or other anticipated situations, it is recommended to administer 1 dose (1 spray) (400 mcg) sublingually shortly before the anticipated exertion.

Acute left ventricular failure (cardiac asthma).

For treatment of non-hypotensive patients with acute left ventricular failure (i.e., systolic arterial pressure > 100 mm Hg), administer 400 mcg of nitroglycerin (1 dose, 1 spray) sublingually, and repeat administration every 5–10 minutes. The total number of sprays should not exceed 3 doses, with careful monitoring of the patient's clinical condition, including arterial pressure. Subsequently, the patient may be switched to intravenous therapy or another vasodilator depending on the clinical condition.

Prior to coronary angiography.

To prevent coronary vasospasm, a dose of 1–2 sprays (0.4–0.8 mg) is recommended.

Reduction of arterial pressure in acute myocardial infarction.

The recommended dose is 0.4–1.2 mg (i.e., 1–3 sprays), with hemodynamic monitoring (systolic arterial pressure should remain above 100 mm Hg).

Dosage adjustment in patients with renal or hepatic impairment is not required.

Elderly patients.

Hypotension and dizziness may be particular concerns when using nitrates in elderly patients. Patients are advised to sit while administering the sublingual spray.

Method of Administration.

Before first use, press the spray pump several times into the air until a uniform mist is produced. The medication is now ready for use.

If more than 24 hours have passed since the last use, the first spray should be administered into the air to prevent delivery of an incomplete dose.

When using the spray, hold the bottle vertically with the nozzle pointing upward.

Bring the bottle close to the mouth and spray the solution into the mouth as follows:

• take a deep breath;
• hold the breath;
• while pressing the spray pump, administer the solution into the mouth (a slight burning sensation on the tongue may occur);
• close the mouth and breathe through the nose only for the next 30 seconds.

The solution should not be inhaled. To ensure optimal effectiveness, press the spray pump fully and continuously until the end, then release. The spray pump should be checked periodically, especially after prolonged periods of non-use.

Children.

There is no experience with the use of this medication in pediatric practice; therefore, Nitro-Mik® should not be used in children (under 18 years of age).

Overdose.

Overdose of the medication may intensify known adverse reactions (headache, marked arterial hypotension, tachycardia, dizziness, flushing, vomiting, diarrhea). With very high doses, increased intracranial pressure with cerebral symptoms, methemoglobinemia, cyanosis, dyspnea, and tachypnea may occur. Additional gastrointestinal effects such as colic and diarrhea have also been reported.

Treatment of overdose.

In case of overdose, the patient's clinical status—including vital signs and mental status—should be assessed, and cardiovascular and respiratory functions should be supported. In cases of mild hypotension, lying down with elevated legs may be sufficient.

In cases of severe overdose, general measures for intoxication and shock should be implemented (administration of fluids, norepinephrine and/or dopamine). Epinephrine (adrenaline) is contraindicated.

In the event of methemoglobinemia, the following antidotes and measures are indicated:

1. Vitamin C: 1 g orally in tablet form or 1 g intravenously as a solution of sodium ascorbate.
2. Methylene blue: 1–2 mg/kg body weight of a 1% solution, administered intravenously over 5 minutes, if the patient does not have G-6-PD deficiency.
3. Toluidine blue: initial dose 2–4 mg/kg intravenously, followed by a repeat dose of 2 mg/kg.
4. Oxygen therapy, hemodialysis, blood transfusion.

Adverse reactions.

Blood and lymphatic system disorders: methemoglobinemia.

Psychiatric disorders: feelings of excitement, anxiety, and uneasiness may occur.

Nervous system disorders: headache, dizziness, drowsiness, syncope, cerebral ischemia, blurred vision, psychotic reactions, inhibition, disorientation.

Cardiovascular system disorders: sometimes the first dose, especially an increased initial dose, may cause a decrease in arterial blood pressure and/or postural hypotension with pronounced tachycardia, dizziness, or weakness. With excessive reduction of arterial blood pressure, treatment with Nitro-Mik® may exacerbate symptoms of angina pectoris (paradoxical reaction to nitrates). Occasionally collapse may occur, accompanied by bradyarrhythmia and loss of consciousness, sensation of warmth, cyanosis, pallor.

Respiratory system disorders: breathing difficulties.

Gastrointestinal disorders: nausea, vomiting, dry mouth, abdominal pain, diarrhea, heartburn, halitosis.

Skin and subcutaneous tissue disorders: flushing, skin allergic reactions, hypersensitivity reactions, exfoliative dermatitis.

Immune system disorders: allergic reactions, including skin rash, pruritus, anaphylactic shock.

General disorders: mild transient sensation of burning in the throat, taste disturbances (metallic taste in the mouth), headache, postural hypotension, hot flushes, palpitations, hypothermia, worsening of glaucoma, asthenia. These symptoms are transient and disappear within a few minutes.

Shelf life.

5 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging, away from fire.

Keep out of reach of children.

Packaging.

15 ml (300 doses) in spray bottles in a cardboard box.

Prescription status.

By prescription only.

Manufacturer.

LLC NPF "MIKROKHEM" (production unit (all stages of the manufacturing process)).

Manufacturer's address and location of business activity.

33 Lenin Street, Rubizhne, Luhansk Oblast, 93000, Ukraine.

To report an adverse event associated with the use of this medicinal product, please call +38 (050) 309-83-54 (24/7).