Nitrosorbide

I N S T R U C T I O N for medical use of the medicinal product NITROSORBID (NITROSORBIDUM)

Composition:

Active substance: isosorbide dinitrate;

1 tablet contains 10 mg (0.01 g) of diluted isosorbide dinitrate;

Excipients: calcium stearate, sugar, potato starch, lactose monohydrate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white-colored tablets, with flat surface and beveled edges.

Pharmacotherapeutic group. Vasodilators used in cardiology.

ATC code C01DA08.

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 relaxes vascular smooth muscle (primarily veins and systemic arteries) by stimulating guanylate cyclase and subsequent increase in intracellular cyclic guanosine monophosphate (cGMP) concentration. This activates cGMP-dependent protein kinase, altering phosphorylation of various proteins in smooth muscle cells. This leads to dephosphorylation of myosin light chains and reduced contractility.

The effect of isosorbide dinitrate is associated with reduced myocardial oxygen demand due to decreased preload (dilation of peripheral veins and reduced blood flow to the right atrium) and afterload (reduced total peripheral vascular resistance), as well as direct coronary vasodilatory 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 provoking 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 workload, 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, peak 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 course treatment. 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 component of the drug;
• Increased intracranial pressure (including in head trauma, hemorrhagic stroke), since venodilation may lead to its 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 (if adequate end-diastolic pressure is not maintained by appropriate measures);
• Angina caused by hypertrophic obstructive cardiomyopathy;
• Cardiac tamponade, aortic stenosis, mitral stenosis, constrictive pericarditis;
• Acute myocardial infarction;
• 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 types of interactions.

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 be administered no earlier than 72 hours after nitrate administration.

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

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

Disopyramide – possible reduction in efficacy of isosorbide dinitrate.

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

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

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

Heparin – possible reduction in its 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 activity (e.g., ethacizine, etmozine) – possible reduction in vasodilatory effect of isosorbide dinitrate and increase in intraocular pressure.

Sulfhydryl group donors (captopril, acetylcysteine, unithiol) restore reduced sensitivity to the drug.

Sapropterin (tetrahydrobiopterin, BH4) – a cofactor of nitric oxide synthase. Use with caution when administering sapropterin-containing products together with any medicinal agents exerting vasodilatory effects via nitric oxide metabolism or containing nitric oxide donors (e.g., nitroglycerin (NTG), isosorbide dinitrate (ISDN), isosorbide mononitrate).

Special precautions for use.

Do not use the drug for the relief of acute 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 Nitrosorbide for 24–48 hours, or after 3–6 weeks of regular use, to make a 3–5 day break, replacing Nitrosorbide during this period with other antianginal agents. Patients should be warned that the antianginal effect of isosorbide dinitrate is closely related to its dosing regimen, and therefore the prescribed dosing schedule must be strictly followed. Nitrosorbide should be prescribed with caution to patients with hypothyroidism, hypothermia, malnutrition, and also to elderly patients due to age-related changes in liver, kidney, and heart function, concomitant diseases, and use of other medications.

Nitrosorbide should be discontinued gradually by tapering the dose.

To prevent arterial hypotension and "nitrate-induced" headache, treatment should be initiated with the lowest possible dose. Aspirin and/or acetaminophen may be used to alleviate isosorbide dinitrate-induced headache without negatively affecting the antianginal effect of isosorbide nitrate. Treatment with the drug may lead to orthostatic reactions, which are more likely to occur when alcohol or other vasodilators are used concomitantly. Alcohol consumption should be avoided during Nitrosorbide therapy.

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

Isosorbide dinitrate may interfere with colorimetric determination of cholesterol.

Patients on maintenance therapy with the 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; therefore, the use of nitrosorbide is contraindicated.

Since the drug contains lactose, sucrose, and milk sugar, it should not be used in patients with rare hereditary conditions such as fructose intolerance, galactose intolerance, sucrase-isomaltase deficiency, 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. Nitrosorbide is contraindicated during the first trimester of pregnancy. During the second and third trimesters, the drug should be used only after careful consideration of the benefit-risk ratio to the mother and potential risk to the fetus.

If drug use is necessary, breastfeeding should be discontinued.

Effect on ability to drive or operate machinery.

Until individual response to the drug is established, patients should refrain from driving or operating machinery, considering that treatment may cause reduced concentration, slowed psychomotor reactions, dizziness, or 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 "nitrate-induced" 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.

For determining individual dosage in patients with chronic heart failure, hemodynamic monitoring is essential.

The interval between doses should be at least 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: decreased arterial pressure, pallor, increased sweating, weak pulse filling, dizziness, headache, orthostatic hypotension, weakness, reflex tachycardia, hyperthermia, nausea, vomiting, diarrhea, and stupor. Since nitrite ions are released during the biotransformation of isosorbide dinitrate, development of methemoglobinemia with cyanosis, anxiety, loss of consciousness, and cardiac arrest cannot be excluded.

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

Treatment: in case of arterial hypotension, the patient should be placed in a horizontal position with elevated lower limbs and provided with oxygen. If arterial pressure does not normalize, correction of circulating blood volume should be performed; 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, then according to severity), as well as oxygen therapy, hemodialysis, and transfusion therapy. If signs of respiratory or circulatory arrest occur, immediate resuscitation measures should be initiated.

Side effects.

Immune system side effects: allergic reactions such as fever, skin rashes, urticaria, itching, transient facial and trunk hyperemia; exfoliative dermatitis/Stevens-Johnson syndrome, angioedema; vasodilation of the skin with redness, sensation of warmth, diaphoresis, and flushing.

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

Nervous system side effects: dizziness, headache ("nitrate headache" at the beginning of treatment, which usually gradually decreases/disappears with continued use of the drug, but may be severe and persistent); intracranial hemorrhage in patients with undiagnosed pituitary tumors.

Cardiovascular system side effects: 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 blood pressure, pallor of the skin; collapse associated with bradycardia, cardiac rhythm disturbances, and syncope. Alveolar hypoventilation leading to subsequent hypoxemia and risk of hypoxia/myocardial infarction in patients with ischemic heart disease.

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

Eye-related side effects: blurred vision; closed-angle glaucoma; cases of visual hallucinations; narrowing of the visual field.

Other side effects: cases of development of tolerance to isosorbide dinitrate, as well as cross-tolerance to other nitrates, have been reported. Prolonged use of high doses and/or shortening of the dosing interval may lead to reduced or even complete loss of the drug's effect. Cases of significant increase in plasma renin and aldosterone levels associated with decreased glomerular filtration rate and osmotically free water clearance have been reported in patients with liver cirrhosis, especially those with ascites.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 15 °C.

Keep out of reach of children.

Packaging.

20 tablets in a blister; 2 or 3 blisters per cardboard pack.

Prescription status.

By prescription only.

Manufacturer: JSC "Monfarm".

Manufacturer's address and location of business activity:

8, Zavodska Street, Avramivka, Uman district, Cherkasy region, 19161, Ukraine.