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Isosorbide Mononitrate Trade name: Isosorbide Mononitrate International Nonproprietary Name: Isosorbide Mononitrate Dosage form: Prolonged-release film-coated tablet 1 tablet 40 mg contains: Active substance: Isosorbide mononitrate 60% - 66.67 mg, diluted in lactose, in terms of isosorbide mononitrate - 40.00 mg. Excipients: Hypromellose - 72.00 mg; Microcrystalline cellulose (MCC-102) - 63.65 mg; Stearic acid - 24.00 mg; Povidone-K25 - 9.60 mg; Magnesium stearate - 2.40 mg; Colloidal silicon dioxide - 1.68 mg. See also: Monosan 40 mg 30 tablets Shell composition: Hypromellose - 3.30 mg; Titanium dioxide - 1.80 mg; Macrogol-4000 - 0.90 mg. 1 tablet 60 mg contains: Active substance: Isosorbide mononitrate 60% - 100.00 mg, diluted in lactose, in terms of isosorbide mononitrate - 60.00 mg. Excipients: Hypromellose - 108.00 mg; Microcrystalline cellulose (MCC-102) - 95.48 mg; Stearic acid - 36.00 mg; Povidone-K25 - 14.40 mg; Magnesium stearate - 3.60 mg; Colloidal silicon dioxide - 2.52 mg. Shell composition: Hypromellose - 4.95 mg; Titanium dioxide - 2.70 mg; Macrogol-4000 - 1.35 mg. Description: Round biconvex tablets, film-coated white or almost white. On the tablet cut, the core is white or almost white. Pharmacotherapeutic group: Vasodilating agent, nitrate. ATC code: C01DA14 Pharmacological properties Pharmacodynamics Mechanism of action Peripheral vasodilator with a predominant effect on venous vessels. At the molecular level, it stimulates the formation of nitric oxide (endothelium-derived relaxing factor) in the vascular endothelium, which leads to activation of intracellular guanylate cyclase, resulting in an increase in cyclic guanosine monophosphate (cGMP) content (vasodilation mediator). Pharmacodynamic action It has a vasodilating and antianginal effect. Reduces preload (due to peripheral venous dilation) and afterload (due to reduced total peripheral vascular resistance). Reduces myocardial oxygen demand. Dilates coronary arteries and improves coronary blood flow. Promotes redistribution of coronary blood flow to areas of impaired circulation. Reduces left ventricular end-diastolic volume and reduces the systolic tension of its walls. Reduces blood flow to the right atrium, promotes a decrease in pulmonary circulation pressure and regression of symptoms in pulmonary congestion. Isosorbide mononitrate causes relaxation of the muscles of the bronchi, urinary tract, gallbladder, bile ducts and esophagus, small and large intestines, including sphincters. Dilates cerebral blood vessels, dura mater, which can manifest as headache. Clinical efficacy and safety Prevents the development of angina attacks and increases exercise tolerance in patients with coronary heart disease. The antianginal effect appears 15-30 minutes after administration and lasts up to 8-12 hours. Cross-tolerance develops towards isosorbide mononitrate, as well as other nitrates. After discontinuation of therapy (break in treatment), sensitivity to it is quickly restored. There is no data on the effect of isosorbide mononitrate on mortality and the incidence of cardiovascular complications in patients with coronary heart disease (stable angina) and chronic heart failure. The hypotensive effect develops by the end of the first week, lasts for 24 hours with a single dose. Pharmacokinetics Absorption After oral administration, isosorbide mononitrate is rapidly and completely absorbed from the gastrointestinal tract (GIT). It has absolute bioavailability (approximately 100%) as there is no "first-pass" effect through the liver. The release of isosorbide mononitrate from tablets is not dependent on the time of food intake, peristalsis, or pH in the lumen of the GIT. Distribution Isosorbide mononitrate has a high volume of distribution (0.6-0.7 L/kg); less than 4% is bound to plasma proteins. Therapeutic concentration (100 ng/mL) is achieved 30 minutes after administration. The time to reach maximum concentration (Tmax) in blood plasma is 1-1.5 hours. Metabolism Isosorbide mononitrate undergoes denitration to form isosorbide or conjugation with glucuronide. Metabolites have no pharmacological activity. Excretion Isosorbide mononitrate is excreted by the kidneys in the form of inactive metabolites; only about 2% of the drug is excreted unchanged in the urine. Renal clearance is 115 mL/min. The half-life (T1/2) is 4 to 10 hours (average about 5 hours). Special patient groups. In case of liver and kidney failure, the pharmacokinetics of isosorbide mononitrate does not change significantly. Isosorbide mononitrate is removed by hemodialysis. Indications for use Isosorbide mononitrate is indicated for use in adults. • Ischemic heart disease: prevention of angina attacks, including after myocardial infarction; • Chronic heart failure: as additional symptomatic therapy in combination with cardiac glycosides and/or diuretics, if they are not sufficiently effective. Contraindications • Hypersensitivity to the active substance or any of the excipients listed in the "Composition" section; • Severe arterial hypotension (systolic pressure below 90 mmHg); • Acute heart failure (shock, vascular collapse); • Cardiogenic shock, if correction of left ventricular end-diastolic pressure cannot be achieved by intra-aortic balloon counterpulsation or by using drugs with positive inotropic effect; • Severe aortic and/or severe mitral stenosis, hypertrophic obstructive cardiomyopathy (HOCM); • Cardiac tamponade; • Constrictive pericarditis; • Pulmonary toxic edema; • Severe hypovolemia; • Severe anemia; • Concomitant use with phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, vardenafil, tadalafil); • Concomitant use of soluble guanylate cyclase stimulators (such as riociguat) due to the high risk of arterial hypotension; • Lactation period; • Children under 18 years of age (efficacy and safety not established); • Lactose intolerance, lactase deficiency, glucose-galactose malabsorption (the product contains lactose). With caution: With caution: Prescribe for liver and/or kidney disorders, water-electrolyte balance disorders, hyperparathyroidism, patients with QT interval on ECG or in combination therapy with other antiarrhythmics, diabetes mellitus in the decompensation stage, hyperuricemia (especially when accompanied by gout and urate nephrolithiasis). Use during pregnancy and lactation Pregnancy Administration of the drug during pregnancy is not recommended, as there is currently insufficient data on the effect of isosorbide mononitrate in pregnant women. The drug can be used only as prescribed by a doctor when the expected benefit to the mother outweighs the potential risk to the fetus and/or child. Lactation period There is evidence that nitrates are excreted in breast milk and can cause methemoglobinemia in newborns. The amount of isosorbide mononitrate excreted in breast milk has not been studied, and therefore, the use of the drug during breastfeeding is contraindicated. If necessary, breastfeeding should be discontinued. Fertility Data on the effect of isosorbide mononitrate on fertility are not available. Dosage and administration Dosage regimen The dosage regimen is determined according to the patient's clinical response to treatment. The lowest effective dose of isosorbide mononitrate should be used. The duration of treatment is determined by the doctor. Do not stop taking the drug abruptly. If the drug needs to be discontinued, the dose and frequency of administration should be gradually reduced. Prolonged-release tablets should not be divided! Ischemic heart disease: prevention of angina attacks, including after myocardial infarction The recommended starting dose of isosorbide mononitrate is 1 prolonged-release tablet 40 mg once daily in the morning. If the effect is insufficient, the dose can be increased to 1 prolonged-release tablet 60 mg once daily, then to 2 prolonged-release tablets 40 mg or 60 mg once daily in the morning. The maximum daily dose is 120 mg (2 prolonged-release tablets 60 mg once daily in the morning). For patients who have not previously taken nitrates for the prevention of angina attacks, it is recommended to start therapy by prescribing isosorbide mononitrate at a dose of 10 mg once daily for 2 days, then 2-3 times daily for 2-3 days. To ensure the specified dosage regimen, it is necessary to prescribe isosorbide mononitrate preparations from other manufacturers in the dosage form of "20 mg tablets" with a scoring line. Chronic heart failure (CHF) In CHF, the recommended dose of isosorbide mononitrate is 20 mg twice or three times daily, depending on the patient's individual response to treatment. The optimal dose of the drug is preferably determined with continuous monitoring of hemodynamics. To ensure the specified dosage regimen, it is recommended to prescribe drugs from other manufacturers in the dosage form of "tablets 20 mg" or "tablets 40 mg" with a scoring line. The use of isosorbide mononitrate in chronic heart failure is not mandatory and should be considered only as additional symptomatic therapy along with standard treatment for heart failure (e.g., cardiac glycosides and/or diuretics) if it is insufficiently effective. Special patient groups Elderly patients Dose adjustment is not required. However, caution should be exercised when using the drug, as elderly patients are more sensitive to the effects of antihypertensive drugs. Patients with impaired renal function Dose adjustment is not required. Patients with impaired liver function Dose adjustment is not required. Children The safety and efficacy of the drug in children under 18 years of age have not been established. Data are not available. Method of administration Orally, whole, without chewing, with water, 1 hour before or 2 hours after meals. Side effects Classification of side effects by the World Health Organization (WHO): Very common -> 1/10; Common - > 1/100 to < 1/10; Uncommon - > 1/1000 to < 1/100; Rare - > 1/10000 to < 1/1000; Very rare - < 1/10000, including individual reports. Nervous system disorders Very common - "nitrate" headache; Common - dizziness, weakness, drowsiness, decreased ability for rapid mental and motor reactions (especially at the beginning of treatment); Rare - cerebral ischemia. Eye disorders Common - blurred vision. Cardiac disorders Common - tachycardia; Uncommon - paradoxical bradycardia, increased angina attacks. Vascular disorders Common - orthostatic hypotension; Uncommon - flushing of the skin of the face, feeling of heat, sharp decrease in blood pressure. Gastrointestinal disorders Uncommon - nausea, vomiting, mild burning sensation on the tongue, dry mucous membranes of the oral cavity; Very rare - heartburn (due to relaxation of the cardiac sphincter). Skin and subcutaneous tissue disorders Uncommon - skin rash, urticaria; Very rare - Stevens-Johnson syndrome; Frequency unknown - exfoliative dermatitis, angioneurotic edema. General disorders and administration site conditions Common - asthenia. Tolerance to the drug may develop during its use (including cross-tolerance with other nitrates). To prevent the development of tolerance, continuous use of high doses of isosorbide mononitrate should be avoided. Cases of sharp decrease in blood pressure, accompanied by nausea, vomiting, anxiety, pallor of the skin, and increased sweating, have been reported with the use of organic nitrates. Arterial hypotension may be accompanied by paradoxical bradycardia and an increase in angina attacks. Prolonged use of the drug can lead to transient hypoxemia due to redistribution of blood flow to poorly ventilated areas of the lungs. In patients with ischemic heart disease, this can lead to the development of myocardial ischemia. Overdose Symptoms Sharp decrease in blood pressure (systolic pressure below 90 mmHg), reflex tachycardia, and headache. Pallor or hyperemia of the skin, increased sweating, "thread-like" pulse, postural dizziness, general weakness, nausea, vomiting, diarrhea may occur. In some cases, increased intracranial pressure is observed (loss of consciousness, neurological symptoms). With the intake of high doses of isosorbide mononitrate (more than 20 mg/kg body weight), methemoglobinemia may develop as a result of the metabolism of isosorbide mononitrate with the formation of nitrite ions. Symptoms of methemoglobinemia: cyanosis, shortness of breath (dyspnea), and rapid breathing (tachypnea). In severe cases, anxiety, restlessness, seizures, arrhythmias, loss of consciousness, respiratory and cardiac arrest may occur. Treatment It is necessary to discontinue isosorbide mononitrate. General measures in case of development of nitrate-dependent arterial hypotension include placing the patient in a "lying" position with elevated legs, gastric lavage, oxygen therapy, and, if necessary, replenishment of circulating blood volume. If no more than one hour has passed since the overdose, oral administration of activated charcoal is possible. The patient's condition should be monitored for at least 12 hours after overdose, with regular monitoring of blood pressure, heart rate, and pulse. Patients with severe arterial hypotension and/or shock should be transferred to the intensive care unit for specific treatment. To increase blood pressure and circulating blood volume, plasma substitutes should be administered. In patients who do not respond to infusion therapy with plasma substitutes, in exceptional cases, vasopressors may be used (intravenous infusion of dobutamine or dopamine). Administration of epinephrine (adrenaline) and related compounds is contraindicated! In case of methemoglobinemia: ascorbic acid at a dose of 1 g orally or intravenously (as a sodium salt); oxygen therapy, artificial lung ventilation, hemodialysis, exchange transfusion. In case of seizures, intravenous administration of diazepam solution is indicated. If respiratory and cardiac arrest occurs, resuscitation measures should be initiated immediately. Interaction with other medicinal products Contraindicated combinations of medicinal products Phosphodiesterase-5 inhibitors (PDE-5) PDE-5 inhibitors used to treat erectile dysfunction (such as sildenafil, vardenafil, tadalafil, udenafil) have been shown to enhance the antihypertensive effect of nitric oxide donors (including isosorbide mononitrate). This can lead to life-threatening hypotension. In this regard, the simultaneous use of isosorbide mononitrate and PDE-5 inhibitors is contraindicated. Soluble guanylate cyclase stimulators Concomitant use of nitric oxide donors (including isosorbide mononitrate) can enhance the antihypertensive effect of soluble guanylate cyclase stimulators (such as riociguat) with the development of severe arterial hypotension. In this regard, the simultaneous use of isosorbide mononitrate and riociguat is contraindicated. Combinations to be considered Pharmacodynamic interactions With the simultaneous use of isosorbide mononitrate with vasodilators, beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, diuretics, procainamide, quinidine, antipsychotics (neuroleptics), tricyclic antidepressants, ethanol, alprostadil, the antihypertensive effect may increase. With the simultaneous use of amiodarone, propranolol, calcium channel blockers (verapamil, nifedipine, etc.), the antianginal effect of isosorbide mononitrate may be enhanced. With the simultaneous use of beta-agonists, alpha-blockers (dihydroergotamine, etc.), the severity of the antianginal effect may decrease (tachycardia, excessive decrease in blood pressure). With the simultaneous use of M-anticholinergics (atropine, etc.), the probability of increased intraocular pressure increases. With simultaneous use with nitrates, the therapeutic effect of norepinephrine may decrease. Sapropterin is a coenzyme of nitric oxide synthase. Concomitant use of drugs containing sapropterin is recommended with all vasodilators whose action is associated with nitric oxide (NO), including classical NO donors (such as nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, sodium nitroprusside, molsidomine). Pharmacokinetic interactions Isosorbide mononitrate increases the concentration of dihydroergotamine in blood plasma and may enhance the latter's hypertensive effect. Adsorbents, astringent and enveloping agents reduce the absorption of isosorbide mononitrate from the gastrointestinal tract. Barbiturates accelerate biotransformation and reduce the concentration of isosorbide mononitrate in the blood. Special instructions The drug isosorbide mononitrate cannot be used to stop angina attacks and treat acute myocardial infarction! Do not stop treatment with isosorbide mononitrate abruptly. If the drug needs to be withdrawn, the dose and frequency of administration should be gradually reduced to avoid the development of a "withdrawal" syndrome. Arterial hypotension Isosorbide mononitrate, even in low doses, can cause orthostatic hypotension and syncope in some patients. Symptoms of acute circulatory failure (vascular collapse) may occur after the first dose of the drug, especially in patients with labile hemodynamics. Arterial hypotension caused by isosorbide mononitrate intake may be accompanied by paradoxical bradycardia and worsening of angina. Blood pressure and heart rate should be monitored during therapy. Patients at high risk of developing arterial hypotension (e.g., those with reduced circulating blood volume during diuretic therapy or with low diastolic blood pressure) should be monitored carefully and require individual dose adjustment of the drug. Tolerance With prolonged use of isosorbide mononitrate, especially at high doses, tolerance may develop, which is manifested by a decrease in the duration and severity of action and the need to increase the dose of the drug to achieve a therapeutic effect. After a break in treatment, sensitivity to nitrates is restored. In case of tolerance development, isosorbide mononitrate intake should be discontinued for 24-48 hours. To prevent the development of tolerance, the drug should be used at the lowest effective doses, and prolonged intake of high doses should be avoided. After 3-6 weeks of regular intake, a break of 3-5 days is recommended, during which isosorbide mononitrate should be replaced with other antianginal agents. Hypoxemia In patients with alveolar hypoventilation, the use of nitrates (including isosorbide mononitrate) can cause vasoconstriction of poorly ventilated lung areas and redirection of blood flow to normally ventilated lungs (Euler-Liljestrand phenomenon). The latter can occur in lung diseases, as well as in patients with angina, myocardial infarction, and cerebral ischemia. The vasodilating effect of the drug can cause redistribution of blood flow to hypoventilated alveolar segments and the development of arterial hypoxemia. This can be a trigger for ischemia in patients with coronary heart disease. Alcohol consumption should be excluded during treatment with other isosorbide mononitrate preparations (as ethanol enhances the antihypertensive effect of isosorbide mononitrate). Isosorbide mononitrate contains lactose. Patients with rare hereditary diseases, such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption, should not take this drug. Effect on ability to drive vehicles and operate machinery Caution should be exercised when driving vehicles and operating complex technical equipment during the use of the drug due to the possibility of side effects. Dosage form Prolonged-release film-coated tablet 40 mg and 60 mg. 5, 10, 14, 25, 30 tablets in contour cell packaging made of PVC film and printed aluminum foil. 10, 20, 30, 40, 50, 60, 90 or 100 tablets in polyethylene terephthalate or polypropylene medicinal product containers, sealed with high-pressure polyethylene caps with first-opening control or polypropylene caps with a "push-and-turn" system or low-pressure polyethylene caps with tamper-evident control. One jar or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 contour cell packages with instructions for medical use (leaflet) are placed in a cardboard box (package). 1, 2, 3, 4, 5, 6, 8 or 10 contour cell packages with instructions for medical use (insert leaflet) are placed in a cardboard box (package). Storage conditions At a temperature not exceeding 25°C. Keep out of reach of children. Shelf life: 3 years. Do not use after the expiry date. Dispensing regime: Pharmaceutical product group - II, dispensed by prescription form №3
