Nitrosorbide

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NITROSORBIDE (NITROSORBIDE)

Composition:

Active substance: isosorbide dinitrate;

1 tablet contains 10 mg of isosorbide dinitrate;

Excipients: potato starch; calcium stearate; sucrose; lactose monohydrate.

Pharmaceutical form. Tablets.

Main physico-chemical properties.

Tablets are white or white with a creamy shade, with a flat surface and beveled edges.

Pharmacotherapeutic group. ATC code.

Cardiovascular agents. Cardiological preparations. Vasodilators used in cardiology. Organic nitrates. Isosorbide dinitrate. ATC code C01D A08.

Pharmacological properties.

Pharmacodynamics.

Isosorbide dinitrate is one of the main antianginal agents from the group of organic nitrates, a peripheral vasodilator that primarily affects venous vessels.

Like all organic nitrates, isosorbide dinitrate acts as a donor of nitric oxide (NO). NO causes relaxation of vascular smooth muscles (mainly veins and systemic arteries) by stimulating guanylate cyclase and subsequent increase in intracellular cyclic guanosine monophosphate (cGMP) concentration. This leads to activation of cGMP-dependent protein kinase and altered phosphorylation of various proteins in smooth muscle cells. As a result, dephosphorylation of myosin light chains occurs, reducing contractility.

The effect of isosorbide dinitrate is associated with reduced myocardial oxygen demand due to decreased preload (by dilating peripheral veins and reducing blood flow to the right atrium) and afterload (by reducing total peripheral vascular resistance), as well as due to its direct coronary vasodilating action. Isosorbide dinitrate promotes redistribution of coronary blood flow to areas with impaired perfusion. It increases exercise tolerance in patients with ischemic heart disease and angina pectoris.

Administration of isosorbide dinitrate improves coronary perfusion without inducing a "coronary steal" syndrome. It exhibits antihypertensive effects. In severe forms of heart failure, due to reduced tone of peripheral venous vessels, the drug reduces cardiac load, pressure in pulmonary circulation vessels, and dyspnea.

Pharmacokinetics.

Bioavailability after oral administration is 22% (first-pass liver effect). Onset of action occurs within 15–40 minutes, maximum effect develops within 1.5–2 hours, and the total duration of action is 4–6 hours or longer. It is metabolized in the liver. Elimination half-life is 4 hours and may be prolonged during repeated administration. It is excreted in urine almost entirely as metabolites.

Clinical characteristics.

Indications.

• Prevention and treatment of angina attacks, including post-infarction angina.
• Treatment of chronic congestive heart failure – in combination with cardiac glycosides and diuretics.

Contraindications.

• Hypersensitivity to isosorbide dinitrate, other nitrates, or any other component of the drug.
• Increased intracranial pressure (including due to head trauma, hemorrhagic stroke) – since venodilation may lead to further increase.
• Severe arterial hypotension (systolic blood pressure below 90 mm Hg), hemorrhage, hypovolemia (isosorbide dinitrate, by reducing venous return, may provoke syncope).
• Acute circulatory failure (shock, vascular collapse).
• Cardiogenic shock (unless adequate end-diastolic pressure is maintained by appropriate measures).
• Angina caused by hypertrophic obstructive cardiomyopathy.
• Cardiac tamponade, aortic stenosis, mitral stenosis, constrictive pericarditis.
• Acute myocardial infarction with low filling pressure.
• Primary pulmonary diseases (due to risk of hypoxemia caused by redistribution of blood flow to areas of hyperventilation), toxic pulmonary edema, cor pulmonale.
• Severe anemia.
• Closed-angle glaucoma.
• Severe impairment of liver and/or kidney function, hyperthyroidism.
• Concomitant use with phosphodiesterase inhibitors (e.g. sildenafil, tadalafil, vardenafil).

Interaction with other medicinal products and other forms of interaction.

Phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil) – concomitant use of isosorbide dinitrate with these agents for treatment of erectile dysfunction is contraindicated due to potential risk of uncontrolled hypotension and life-threatening cardiovascular complications. If necessary, phosphodiesterase inhibitors should not be administered earlier than 72 hours after nitrate intake.

Alcohol – severe disulfiram-alcohol type reactions may occur, including severe hypotension and collapse.

Antihypertensive agents (e.g. β-blockers, angiotensin-converting enzyme inhibitors, calcium antagonists, vasodilators), phenothiazines, other nitrates/nitrites, quinidine, procainamide, cyclic antidepressants, monoamine oxidase inhibitors, narcotic analgesics – enhanced hypotensive effect of isosorbide dinitrate, possible development of orthostatic collapse.

Disopyramide – possible reduction in effectiveness of isosorbide dinitrate.

Dihydroergotamine – plasma concentration of dihydroergotamine may increase, leading to enhanced hypertensive effect.

Noradrenaline, acetylcholine, histamine – their effects may be diminished when used with nitrates, as isosorbide dinitrate may act as a physiological antagonist.

Sympathomimetic agents (including adrenaline, ephedrine, noradrenaline, naphazoline, mesaton, isadrine) – possible reduction in antianginal effect of nitrates.

Heparin – possible reduction in anticoagulant effect.

Hydralazine – combined use with isosorbide dinitrate improves cardiac output in heart failure.

Miotics – isosorbide dinitrate reduces their effectiveness.

Atropine and other drugs with M-cholinolytic action (e.g. etacizin, etmozine) – possible reduction in vasodilatory effect of isosorbide dinitrate and increase in intraocular pressure.

Donors of sulfhydryl groups (captopril, acetylcysteine, unithiol) – restore reduced sensitivity to the drug.

Sapropterin (tetrahydrobiopterin, BH4) – a cofactor of nitric oxide synthase. Use with caution any medicinal products containing sapropterin together with drugs causing vasodilation via nitric oxide metabolism or containing nitric oxide donors (e.g. nitroglycerin (GTN), isosorbide dinitrate (ISDN), isosorbide mononitrate).

Special precautions for use

The drug must not be used to relieve angina attacks.

To prevent reduction or loss of effect, prolonged administration of high doses should be avoided. In case of nitrate tolerance, it is recommended to discontinue the drug for 24–48 hours or, after 3–6 weeks of regular use, to take a break for 3–5 days, replacing it during this period with other antianginal medications. Patients should be informed that the antianginal effect of isosorbide dinitrate is closely related to its dosing regimen, and therefore the prescribed dosing schedule must be strictly followed.

The drug should be prescribed with caution to patients predisposed to orthostatic reactions, as well as to patients with hypothyroidism, hypothermia, malnutrition, and elderly patients due to age-related changes in liver, kidney, and heart function, concomitant diseases, and use of other medications.

During treatment, especially with gradual dose escalation, monitoring of blood pressure and heart rate is necessary.

The drug should be discontinued gradually by reducing the dose.

To prevent arterial hypotension and nitrate-induced headache, treatment should be initiated at the lowest possible dose. Concomitant use of aspirin and/or acetaminophen may help reduce isosorbide dinitrate-induced headache without negatively affecting the antianginal effect.

Treatment with the drug may cause orthostatic reactions, which are more likely to occur when alcohol or other vasodilators are used concomitantly. Alcohol consumption should be avoided during treatment with this drug.

In patients with glucose-6-phosphate dehydrogenase deficiency, administration of isosorbide dinitrate may lead to acute hemolysis (favism).

Isosorbide dinitrate may interfere with colorimetric determination of cholesterol levels.

Patients receiving maintenance therapy with this drug should be informed not to take medications containing phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil) due to the risk of developing uncontrolled hypotension.

In patients with closed-angle glaucoma, intraocular pressure may increase.

The drug contains lactose and therefore is contraindicated in patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

There is insufficient data on the safety of isosorbide dinitrate use during pregnancy. Use of the drug is contraindicated during the first trimester of pregnancy. In the second and third trimesters, the drug should be used only after careful consideration of the benefit-risk ratio for the mother and potential risk to the fetus.

If use of the drug is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery

Until individual response to the drug is established, patients should refrain from driving or operating machinery due to possible adverse effects such as reduced attention, slowed psychomotor reactions, dizziness, and visual disturbances.

Dosage and Administration

The dosage and duration of therapy are determined individually by a physician. The drug is recommended to be taken on an empty stomach; however, to reduce the intensity of "nitrate-related" headache, the drug may be taken with food.

For oral administration in adults: 10–20 mg (1–2 tablets) 3–4 times daily, 30 minutes before meals, without chewing, and with sufficient fluid. If the therapeutic effect is insufficient, the dose may be gradually increased up to the maximum dose of 120 mg per day.

In patients with congestive heart failure, hemodynamic monitoring is essential for determining individual dosage.

The interval between doses should be no less than 4 hours.

Elderly patients: The dose may be reduced, especially in cases of impaired renal and/or hepatic function.

Children: Experience with use in children is lacking.

Overdose

Symptoms:

• Pallor
• Increased sweating
• Weak pulse filling
• Hyperthermia
• Diarrhea
• Reflex tachycardia
• Headache
• Episodes of weakness
• Dizziness
• Orthostatic hypotension
• Nausea
• Vomiting
• Stupor
• Arterial hypotension

Since nitrite ions are released during the biotransformation of isosorbide dinitrate, methemoglobinemia may develop, leading to tachypnea, cyanosis, anxiety, loss of consciousness, and cardiac arrest.

Excessive doses may increase intracranial pressure, resulting in cerebral symptoms, including seizures.

Treatment: Gastric lavage.

In case of arterial hypotension, the patient should be placed in a horizontal position with slightly elevated lower limbs. If blood pressure does not normalize, circulating blood volume should be corrected. In severe cases, administration of dopamine and sympathomimetics is indicated. Epinephrine (adrenaline) is contraindicated.

In cases of methemoglobinemia, depending on severity, antidotes may be used: vitamin C – 1 g orally; methylene blue – up to 50 ml of a 1% solution intravenously; toluidine blue – initially 2–4 mg/kg body weight intravenously, followed by further doses depending on severity. Additionally, oxygen therapy, hemodialysis, and transfusion therapy may be required.

Adverse Reactions.

Cardiovascular system: tachycardia, arterial hypotension; rarely – cerebral ischemia and collapse; orthostatic hypotension with reflex tachycardia, palpitations, and symptoms of cerebral ischemia (including drowsiness, dizziness, weakness, blurred vision), mostly at the beginning of treatment and when increasing the dose; peripheral edema, usually in patients with left ventricular insufficiency; exacerbation or increased frequency of angina attacks associated with reduction of arterial pressure, pallor of the skin; collapse associated with bradycardia, cardiac arrhythmias, and syncope. Alveolar hypoventilation with subsequent hypoxemia and risk of developing hypoxia/myocardial infarction in patients with ischemic heart disease.

Gastrointestinal system: nausea, vomiting, sensation of mild burning of the tongue, dry mouth, heartburn, constipation.

Central nervous system: dizziness, drowsiness, headache ("nitrate headache" at the beginning of treatment, which usually gradually decreases or disappears with continued use of the drug, but may be severe and persistent), general weakness, blurred vision.

Immune system: possible allergic reactions such as fever, skin rashes, urticaria, itching, transient facial and trunk hyperemia; exfoliative dermatitis/Stevens-Johnson syndrome, Quincke's edema; cutaneous vasodilation with flushing, sensation of warmth, diaphoresis, hot flashes.

Blood and lymphatic system: hematological adverse effects, including methemoglobinemia; a case of hemolytic anemia induced by isosorbide dinitrate in a patient with concomitant glucose-6-phosphate dehydrogenase deficiency.

Other: cases of development of tolerance to isosorbide dinitrate, as well as cross-tolerance to other nitrates, have been reported. Hypophyseal hemorrhage in patients with undiagnosed pituitary tumors.

Prolonged use of high doses and/or shortened intervals between doses may lead to reduced or even complete loss of drug efficacy. Closed-angle glaucoma. Cases of visual hallucinations, narrowing of visual fields, significant increase in plasma renin and aldosterone levels associated with decreased glomerular filtration rate and osmotically free water clearance in patients with liver cirrhosis, especially with ascites, have been reported.

Shelf life.

4 years. Do not use after the expiry date stated on the package.

Storage conditions.

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

Keep out of reach of children.

Packaging.

50 tablets in a bottle, 1 bottle in a cardboard box.

Or 50 tablets (10×5) in blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM LLC (responsible for batch release, excluding batch control/testing).

Manufacturer's address and location of business activity.

5 Budynstriji St., Kyiv, 01013, Ukraine.

INSTRUCTION

for medical use of medicinal product

NITROSORBIDE

(NITROSORBIDE)

Composition:

Active substance: isosorbide dinitrate;

1 tablet contains 10 mg of isosorbide dinitrate;

Excipients: potato starch; calcium stearate; sucrose; lactose monohydrate.

Pharmaceutical form. Tablets.

Main physicochemical properties.

White or almost white tablets with a creamy hue, flat surface, beveled edges.

Pharmacotherapeutic group. ATC code.

Medicinal products affecting the cardiovascular system. Cardiological preparations. Vasodilators used in cardiology. Organic nitrates. Isosorbide dinitrate. ATC code C01D A08.

Pharmacological properties.

Pharmacodynamics.

Isosorbide dinitrate is one of the main antianginal agents from the group of organic nitrates and a peripheral vasodilator that primarily affects venous vessels.

Like all organic nitrates, isosorbide dinitrate acts as a donor of nitric oxide (NO). NO causes relaxation of vascular smooth muscles (mainly veins and systemic arteries) by stimulating guanylate cyclase and subsequently increasing the concentration of intracellular cyclic guanosine monophosphate (cGMP). This leads to activation of cGMP-dependent protein kinase and altered phosphorylation of various proteins in smooth muscle cells. This results in dephosphorylation of myosin light chains and reduced contractility.

The effect of isosorbide dinitrate is associated with reduced myocardial oxygen demand due to decreased preload (by dilation of peripheral veins and reduced blood flow to the right atrium) and afterload (by reduction of total peripheral vascular resistance), as well as due to its direct coronary vasodilating action. Isosorbide dinitrate promotes redistribution of coronary blood flow to areas with impaired perfusion. It increases exercise tolerance in patients with ischemic heart disease and angina.

Administration of isosorbide dinitrate improves coronary perfusion without development of the "coronary steal syndrome." It exhibits antihypertensive effects. In severe forms of heart failure, due to reduced tone of peripheral venous vessels, the drug reduces cardiac load, pressure in pulmonary circulation vessels, and dyspnea.

Pharmacokinetics.

Bioavailability after oral administration is 22% (first-pass effect in the liver). Onset of action occurs within 15–40 minutes, maximum effect develops within 1.5–2 hours, and the total duration of action is 4–6 hours or longer. It is metabolized in the liver. Elimination half-life is 4 hours and may be prolonged during repeated administration. It is excreted in urine almost entirely as metabolites.

Clinical characteristics.

Indications.

• Prevention and treatment of angina attacks, including post-infarction angina.
• Treatment of chronic congestive heart failure – in combination with cardiac glycosides and diuretics.

Contraindications.

• Hypersensitivity to isosorbide dinitrate, other nitrates, or any other component of the drug.
• Increased intracranial pressure (including due to head injury, hemorrhagic stroke) – since venodilation may lead to further increase in pressure.
• Severe arterial hypotension (systolic blood pressure below 90 mm Hg), hemorrhage, hypovolemia (isosorbide dinitrate, by reducing venous return, may provoke syncope).
• Acute circulatory failure (shock, vascular collapse).
• Cardiogenic shock (unless adequate end-diastolic pressure is maintained by appropriate measures).
• Angina caused by hypertrophic obstructive cardiomyopathy.
• Cardiac tamponade, aortic stenosis, mitral stenosis, constrictive pericarditis.
• Acute myocardial infarction with low filling pressure.
• Primary pulmonary diseases (due to risk of hypoxemia caused by redistribution of blood flow to areas of hyperventilation), toxic pulmonary edema, cor pulmonale.
• Severe anemia.
• Closed-angle glaucoma.
• Severe impairment of liver and/or kidney function, hyperthyroidism.
• Concomitant use with phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil).

Interaction with other medicinal products and other forms of interactions.

Phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil) – treatment of erectile dysfunction with these agents is contraindicated during isosorbide dinitrate therapy due to potential risk of uncontrolled hypotension and life-threatening cardiovascular complications. If necessary, phosphodiesterase inhibitors should not be administered earlier than 72 hours after nitrate administration.

Alcohol – severe disulfiram-like alcohol reactions are possible, including severe hypotension and collapse.

Antihypertensive agents (e.g., β-blockers, angiotensin-converting enzyme inhibitors, calcium antagonists, vasodilators), phenothiazines, other nitrates/nitrites, quinidine, procainamide, tricyclic antidepressants, monoamine oxidase inhibitors, opioid analgesics – enhanced hypotensive effect of isosorbide dinitrate, possible development of orthostatic collapse.

Disopyramide – possible reduction in the effectiveness of isosorbide dinitrate.

Dihydroergotamine – plasma concentration of dihydroergotamine may increase, leading to potentiation of its hypertensive effect.

Noradrenaline, acetylcholine, histamine – their effects may be diminished when used with nitrates, as isosorbide dinitrate may act as a physiological antagonist.

Sympathomimetic agents (including adrenaline, ephedrine, noradrenaline, naphazoline, mesaton, isadrine) – possible reduction in the antianginal effect of nitrates.

Heparin – possible reduction in anticoagulant effect.

Hydralazine – combined use with isosorbide dinitrate improves cardiac output in heart failure.

Miоtic agents – isosorbide dinitrate reduces their effectiveness.

Atropine and other drugs with M-cholinolytic action (e.g., etacizine, etmozine) – possible reduction in vasodilatory effect of isosorbide dinitrate and increase in intraocular pressure.

Donors of sulfhydryl groups (captopril, acetylcysteine, unithiol) restore reduced sensitivity to the drug.

Sapropterin (tetrahydrobiopterin, BH4) – a cofactor of nitric oxide synthase. Use with caution any medicinal products containing sapropterin together with drugs that exert vasodilatory action via nitric oxide metabolism or contain nitric oxide donors (e.g., nitroglycerin (GTN), isosorbide dinitrate (ISDN), isosorbide mononitrate).

Special precautions for use.

The drug must not be used to relieve angina attacks.

To prevent reduction or loss of effect, prolonged use of high doses should be avoided. In case of "nitrate" tolerance, it is recommended to discontinue the drug for 24–48 hours or, after 3–6 weeks of regular use, to take a break for 3–5 days, replacing the drug during this period with other antianginal medications. Patients should be informed that the antianginal effect of isosorbide dinitrate is closely related to its dosing regimen; therefore, the prescribed dosing schedule must be strictly followed.

The drug should be prescribed with caution to patients prone to orthostatic reactions, those with hypothyroidism, hypothermia, malnutrition, and elderly patients due to age-related changes in liver, kidney, and heart function, concomitant diseases, and use of other medications.

During treatment, especially when gradually increasing the dose, monitoring of blood pressure and heart rate is necessary.

The drug should be discontinued gradually by reducing the dose.

To prevent arterial hypotension and "nitrate-induced" headache, treatment should be initiated with the lowest possible dose. Concomitant use of aspirin and/or acetaminophen may help reduce isosorbide dinitrate-induced headache without negatively affecting the antianginal effect.

Treatment with the drug may cause orthostatic reactions, which are more likely to occur when alcohol or other vasodilators are used concomitantly. Alcohol consumption should be avoided during treatment with this drug.

In patients with glucose-6-phosphate dehydrogenase deficiency, administration of isosorbide dinitrate may lead to acute hemolysis (favism).

Isosorbide dinitrate intake may interfere with the results of colorimetric cholesterol determination.

Patients receiving maintenance therapy with this drug should be informed that they must not take medications containing phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil) due to the risk of developing uncontrolled hypotension.

In patients with closed-angle glaucoma, intraocular pressure may increase.

The drug contains lactose and therefore should not be used in patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

There is insufficient data on the safety of isosorbide dinitrate use during pregnancy. The use of the drug is contraindicated during the first trimester of pregnancy. In the second and third trimesters, the drug should be used only after careful assessment of the benefit-risk ratio for the mother and potential risk to the fetus.

If use of the drug is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

Until individual response to the drug is known, patients should refrain from driving or operating machinery due to possible decrease in attention, delayed psychomotor reactions, dizziness, and visual disturbances.

Dosage and Administration.

The dosage and duration of therapy are determined individually by a physician. The drug is recommended to be taken on an empty stomach; however, to reduce the intensity of "nitrate" headache, the drug may be taken with food.

For adults, the recommended dose is 10–20 mg (1–2 tablets) taken orally 3–4 times daily, 30 minutes before meals. The tablets should be swallowed whole with sufficient amount of liquid. If therapeutic response is inadequate, the dose may be gradually increased up to the maximum daily dose of 120 mg.

In patients with chronic heart failure, hemodynamic monitoring is essential for determining individual dosage.

The interval between doses should be at least 4 hours.

Elderly patients: The dose may be reduced, especially in the presence of renal and/or hepatic impairment.

Children: There is no experience with use in pediatric patients.

Overdose.

Symptoms:

• Pallor;
• Increased sweating;
• Weak pulse volume;
• Hyperthermia;
• Diarrhea;
• Reflex tachycardia;
• Headache;
• Episodes of weakness;
• Dizziness;
• Orthostatic hypotension;
• Nausea;
• Vomiting;
• Stupor;
• Arterial hypotension.

Since nitrite ions are released during biotransformation of isosorbide dinitrate, development of methemoglobinemia cannot be excluded, manifesting as tachypnea, cyanosis, sense of anxiety, loss of consciousness, and cardiac arrest.

With excessive doses, increased intracranial pressure may occur, leading to cerebral symptoms including seizures.

Treatment: Gastric lavage.

In case of arterial hypotension, the patient should be placed in a horizontal position with slightly elevated lower limbs. If blood pressure does not normalize, circulating blood volume should be corrected. In severe cases, administration of dopamine and sympathomimetics is indicated. Epinephrine (adrenaline) is contraindicated.

In case of methemoglobinemia, depending on severity, antidotes may be used: vitamin C – 1 g orally; methylene blue – up to 50 ml of a 1% solution intravenously; toluidine blue – initially 2–4 mg/kg body weight intravenously, followed by additional doses depending on clinical severity. Additionally, oxygen therapy, hemodialysis, and transfusion therapy may be required.

Adverse Reactions.

Cardiovascular system: tachycardia, arterial hypotension; rarely – cerebral ischemia and collapse; orthostatic hypotension with reflex tachycardia, palpitations, and symptoms of cerebral ischemia (including drowsiness, dizziness, weakness, blurred vision), mostly at the beginning of treatment and when increasing the dose; peripheral edema, usually in patients with left ventricular insufficiency; worsening or increased frequency of angina attacks associated with decreased arterial pressure, pallor of the skin; collapse associated with bradycardia, cardiac arrhythmias, and syncope. Alveolar hypoventilation leading to subsequent hypoxemia and risk of hypoxia/myocardial infarction in patients with ischemic heart disease.

Gastrointestinal system: nausea, vomiting, sensation of mild burning of the tongue, dry mouth, heartburn, constipation.

Central nervous system: dizziness, drowsiness, headache ("nitrate headache" at the beginning of treatment, which usually gradually decreases or disappears with continued use of the drug, but may be severe and persistent), general weakness, blurred vision.

Immune system: possible allergic reactions such as fever, skin rashes, urticaria, itching, transient facial and trunk hyperemia; exfoliative dermatitis/Stevens-Johnson syndrome, angioedema (Quincke's edema); cutaneous vasodilation with flushing, sensation of warmth, diaphoresis, hot flashes.

Blood and lymphatic system: hematological adverse effects, including methemoglobinemia; a case of hemolytic anemia induced by isosorbide dinitrate in a patient with concomitant glucose-6-phosphate dehydrogenase deficiency.

Other: cases of development of tolerance to isosorbide dinitrate, as well as cross-tolerance to other nitrates, have been reported. Hemorrhage into the pituitary gland in patients with undiagnosed pituitary tumors.

Prolonged use of high doses and/or shortened intervals between doses may lead to reduced or even complete loss of drug efficacy. Closed-angle glaucoma. Cases of visual hallucinations, visual field constriction, significant increase in plasma renin and aldosterone levels associated with decreased glomerular filtration rate and osmotically free water clearance in patients with liver cirrhosis, especially with ascites, have been reported.

Shelf life.

4 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of reach of children.

Packaging.

50 tablets in a bottle, 1 bottle in a cardboard box.

Or 50 tablets (10×5) in blisters in a cardboard box.

Prescription category.

By prescription only.

Manufacturer.

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

Manufacturer's address and location of business activity.

33 Lenin Street, Rubizhne, Luhansk region, 93009, Ukraine.

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