Brand name Iso-mik® 5 mg

Form tablets, sublingual

Active substance / Dosage

isosorbide dinitrate · 5 mg

Prescription type prescription only

ATC code

C01DA08

Registration number UA/3186/03/01

Manufacturer NPF Microkhim LLC (production unit (all stages of manufacturing process); responsible for batch release, excluding batch control/testing)

Table of Contents

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ISO-MIK® 5 MG (ISO-MIK 5 MG)
Composition:
Pharmacological properties.
Clinical characteristics.
Special precautions.
Administration and Dosage
Adverse Reactions
Composition:
Pharmacological properties.
Clinical characteristics.
Special precautions.
Administration and Dosage.
Adverse Reactions.

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ISO-MIK® 5 MG (ISO-MIK 5 MG)

Composition:

Active ingredient: isosorbide dinitrate;

Each tablet contains 5 mg of isosorbide dinitrate;

Excipients: maize starch; lactose monohydrate; sorbitol (E 420); magnesium stearate.

Pharmaceutical form. Sublingual tablets.

Main physico-chemical properties.

White-colored tablets with a flat surface and beveled edges.

Pharmacotherapeutic group. ATC code.

Agents acting on the cardiovascular system. Cardiological preparations. Vasodilators used in cardiology. Organic nitrates. Isosorbide dinitrate. ATC code C01DA08.

Pharmacological properties.

Pharmacodynamics.

A peripheral vasodilator with predominant effect on venous vessels. An antianginal agent. The mechanism of action is associated with the release of the active substance – nitrogen oxide. In vascular smooth muscle, nitrogen oxide activates guanylate cyclase and increases the level of cyclic 3′,5′-guanosine monophosphate, leading to relaxation of smooth muscles. Under the influence of isosorbide dinitrate, arterioles and precapillary sphincters relax to a lesser extent than large arteries and veins. The action of isosorbide dinitrate is primarily related to reducing myocardial oxygen demand by decreasing preload (dilation of peripheral veins and reduction of blood flow to the right atrium) and afterload (reduction of total peripheral vascular resistance), as well as due to a direct coronary vasodilating effect. Isosorbide dinitrate promotes redistribution of coronary blood flow to areas with reduced perfusion. It increases exercise tolerance in patients with ischemic heart disease and angina pectoris. In heart failure, the drug facilitates myocardial unloading by reducing preload and decreases pulmonary circulation pressure.

Pharmacokinetics.

When administered sublingually, isosorbide dinitrate is rapidly absorbed and produces hemodynamic and antianginal effects within 2–5 minutes (i.e., angina attack relief occurs within 2–5 minutes after administration, due to the specific manufacturing characteristics of the sublingual dosage form). Maximum plasma concentration of the active substance is achieved within 5–6 minutes. The peak effect of isosorbide dinitrate tablets after sublingual administration occurs at 10–15 minutes. The duration of therapeutic action lasts 60–120 minutes. The drug has a short duration of action. Isosorbide dinitrate is metabolized to form the active metabolite isosorbide-5-mononitrate, which has a half-life of 5 hours, as well as isosorbide-2-mononitrate with a half-life of 2.5 hours. The half-life of isosorbide dinitrate after sublingual administration is 1 hour. Between 80 and 100% of a single administered dose is excreted in the urine within 24 hours, predominantly as metabolites. This formulation is particularly important in patients with low systemic bioavailability of orally administered isosorbide dinitrate tablets.

Clinical characteristics.

Indications.

For the relief and prevention of angina attacks.

To prevent angina attacks, the drug is administered prior to anticipated physical or emotional exertion.

Contraindications.

Hypersensitivity to the components of the drug;
marked arterial hypotension (systolic blood pressure – less than 90 mm Hg, diastolic blood pressure – less than 60 mm Hg);
acute circulatory failure (collapse, shock);
hypertrophic obstructive cardiomyopathy;
constrictive pericarditis;
cardiac tamponade;
toxic pulmonary edema;
conditions associated with increased intracranial pressure (including hemorrhagic stroke, traumatic brain injury);
closed-angle glaucoma with high intraocular pressure;
bleeding, hypovolemia (isosorbide dinitrate, by reducing venous return, may provoke syncope);
primary pulmonary diseases (due to the risk of developing hypoxemia caused by blood flow redistribution in areas of hyperventilation), cor pulmonale;
severe anemia;
acute myocardial infarction with low ventricular filling pressure;
severe impairment of liver and/or kidney function, hyperthyroidism;
concomitant use of phosphodiesterase inhibitors, such as sildenafil, tadalafil, vardenafil.

Interaction with other medicinal products and other types of interactions.

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

Disopyramide – possible reduction in the effectiveness of isosorbide dinitrate.

Heparin – possible reduction in its anticoagulant effect.

Hydralazine – improved cardiac output in heart failure when used concomitantly with isosorbide dinitrate.

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

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

Phosphodiesterase inhibitors (sildenafil) – concomitant use with nitrates is contraindicated due to the possible development of uncontrolled arterial hypotension.

Sympathomimetic agents (adrenaline, ephedrine, noradrenaline, histamine, acetylcholine, naphazoline, mesaton, isadrine, and other antihypertensive drugs) – possible reduction in the antianginal effect of isosorbide dinitrate.

Special precautions.

Use with caution when treating patients with cerebral circulation disorders, aortic and/or mitral stenosis; patients prone to orthostatic hypotension; and patients with symptoms of ischemia in various vascular beds occurring against a background of reduced arterial pressure. During treatment, especially when gradually increasing the dose, monitoring of arterial pressure and heart rate is required. Frequent administration of high doses may lead to development of "nitrate" tolerance to isosorbide dinitrate or cross-tolerance to other nitrates. To overcome tolerance to isosorbide dinitrate (if possible – discontinuation of nitrates), it is recommended not to increase the frequency of administration or dose of the drug, but to abstain from taking it for 16–24 hours, replacing it during this time with other antianginal agents. Then continue treatment either as monotherapy at usual doses or in combination with other drugs (intervals during regular administration of the drug should be made every 4–6 weeks). The occurrence of "nitrate" headache at the beginning of treatment can be prevented by gradual dose escalation or administration of valeridol and non-narcotic analgesics (acetylsalicylic acid, paracetamol, metamizole). Alcohol consumption should be avoided during treatment with this drug.

The drug should be prescribed with caution to patients with hypothyroidism, hypothermia, poor nutrition, concomitant diseases, and during concomitant use of other medications.

The drug should be discontinued gradually by reducing the dose. To prevent arterial hypotension and "nitrate" headache, treatment should be initiated with the lowest possible dose. Treatment with the drug may cause orthostatic reactions, which occur more frequently when alcohol or other vasodilators are used concomitantly. In patients with glucose-6-phosphate dehydrogenase deficiency, acute hemolysis (favism) may occur during administration of isosorbide dinitrate.

Administration of isosorbide dinitrate may affect the results of colorimetric determination of cholesterol.

Use during pregnancy or breastfeeding.

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

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

Ability to influence reaction rate while driving or operating machinery.

During treatment, driving vehicles and engaging in other potentially hazardous activities is not recommended, as regular use of isosorbide dinitrate may reduce the ability to concentrate and slow psychomotor reaction speed.

Administration and Dosage

IZO-MIK® 5 MG should be administered sublingually (under the tongue). The single dose is 5–10 mg.

To relieve an angina attack or before anticipated emotional or physical exertion that usually triggers an attack, place 1 tablet under the tongue and hold it in the mouth until completely dissolved. If necessary, the dose may be repeated after 10–15 minutes.

Children

There is no experience of use in children.

Overdose

Symptoms: pallor, increased sweating, weak pulse, hyperthermia, diarrhea, reflex tachycardia, headache, episodes of weakness, dizziness, rapid heartbeat, nausea, vomiting, arterial hypotension, and stupor.

Methemoglobin formation is possible, accompanied by tachypnea, anxiety, loss of consciousness, and cardiac arrest.

Excessive doses may lead to increased intracranial pressure with the appearance of cerebral symptoms, including seizures.

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

In cases of methemoglobinemia, antidotes may be used depending on the severity of the condition: 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, transfusion therapy, and hemodialysis.

Adverse Reactions

Cardiovascular system: possible reflex tachycardia, transient facial hyperemia, arterial hypotension; in individual cases – increased frequency of angina attacks, bradycardia, cardiac arrhythmias, and syncope; alveolar hypoventilation followed by hypoxemia and risk of hypoxia/myocardial infarction in patients with ischemic heart disease.

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

Central nervous system: possible dizziness, drowsiness, headache (during continuous treatment usually disappears within 1–2 weeks after initiation of therapy), collapse, hemorrhage into the pituitary gland in patients with undiagnosed pituitary tumor.

Allergic reactions: possible skin rash, pruritus, pallor of the skin, Stevens-Johnson syndrome, Quincke's edema (angioedema).

Eyes: blurred vision, closed-angle glaucoma. Cases of visual hallucinations and narrowing of the visual field have been reported.

General disorders: sweating, weakness, flushing, peripheral edema, hematological adverse effects including methemoglobinemia, a case of hemolytic anemia induced by isosorbide dinitrate in a patient with concomitant glucose-6-phosphate dehydrogenase deficiency.

Cases of development of tolerance to isosorbide dinitrate, as well as cross-tolerance to other nitrates, have been described.

Prolonged use of high doses and/or shortening of the interval between doses may lead to a decrease or even 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 in patients with liver cirrhosis, especially with ascites, have been reported.

Shelf life.

4 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

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

Or 40 tablets in a bottle, 1 bottle in a cardboard box.

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

Prescription status.

By 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.

INSTRUCTIONS

for medical use of the medicinal product

ISO-MIK® 5 MG

(ISO-MIK 5 MG)

Composition:

Active ingredient: isosorbide dinitrate;

1 tablet contains isosorbide dinitrate 5 mg;

Excipients: maize starch; lactose monohydrate; sorbitol (E 420); magnesium stearate.

Pharmaceutical form. Sublingual tablets.

Main physicochemical properties.

White, flat-surfaced tablets with bevelled edges.

Pharmacotherapeutic group. ATC code.

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

Pharmacological properties.

Pharmacodynamics.

A peripheral vasodilator with predominant effect on venous vessels. An antianginal agent. The mechanism of action is associated with the release of the active substance – nitrogen oxide. In vascular smooth muscles, nitrogen oxide activates guanylate cyclase and increases the level of cyclic 3′,5′-guanosine monophosphate, leading to relaxation of smooth muscles. Under the influence of isosorbide dinitrate, arterioles and precapillary sphincters relax to a lesser extent than large arteries and veins. The action of isosorbide dinitrate is primarily related to reducing myocardial oxygen demand by decreasing preload (due to dilation of peripheral veins and reduced blood flow to the right atrium) and afterload (reduction in total peripheral vascular resistance), as well as due to its direct coronary vasodilating effect. Isosorbide dinitrate promotes redistribution of coronary blood flow to areas with reduced perfusion. It increases exercise tolerance in patients with ischemic heart disease and angina. In heart failure, the drug facilitates myocardial unloading by reducing preload and decreases pressure in the pulmonary circulation.

Pharmacokinetics.

After sublingual administration, isosorbide dinitrate is rapidly absorbed and produces hemodynamic and antianginal effects within 2–5 minutes (i.e., angina attack relief occurs within 2–5 minutes after administration, which is due to the specific manufacturing characteristics of the sublingual dosage form). Maximum plasma concentration of the active substance is achieved within 5–6 minutes. The peak effect of sublingual isosorbide dinitrate tablets occurs at 10–15 minutes. The duration of therapeutic action ranges from 60 to 120 minutes. The drug has a short duration of action. Isosorbide dinitrate undergoes metabolism to form the active metabolite isosorbide-5-mononitrate, which has a half-life of 5 hours, and isosorbide-2-mononitrate, with a half-life of 2.5 hours. The half-life of isosorbide dinitrate after sublingual administration is 1 hour. Between 80 and 100% of a single administered dose is excreted in the urine within 24 hours, primarily as metabolites. This formulation is particularly important in patients with low systemic bioavailability of orally administered isosorbide dinitrate tablets.

Clinical characteristics.

Indications.

Relief and prevention of angina attacks.

To prevent angina attacks, the drug is administered before anticipated physical or emotional exertion.

Contraindications.

Hypersensitivity to the components of the drug;
marked arterial hypotension (systolic blood pressure – less than 90 mm Hg, diastolic blood pressure – less than 60 mm Hg);
acute circulatory failure (collapse, shock);
hypertrophic obstructive cardiomyopathy;
constrictive pericarditis;
cardiac tamponade;
toxic pulmonary edema;
conditions associated with increased intracranial pressure (including hemorrhagic stroke, head trauma);
closed-angle glaucoma with high intraocular pressure;
bleeding, hypovolemia (isosorbide dinitrate, by reducing venous return, may provoke syncope);
primary pulmonary diseases (due to the risk of developing hypoxemia caused by redistribution of blood flow to areas of hyperventilation), cor pulmonale;
severe anemia;
acute myocardial infarction with low ventricular filling pressure;
severe impairment of liver and/or kidney function, hyperthyroidism;
concomitant use of phosphodiesterase inhibitors, e.g., sildenafil, tadalafil, vardenafil.

Interaction with other medicinal products and other types of interactions.

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 – potentiation of the hypotensive effect of isosorbide dinitrate, possible development of orthostatic collapse.

Disopyramide – possible reduction in the effectiveness of isosorbide dinitrate.

Heparin – possible reduction in its anticoagulant effect.

Hydralazine – improved cardiac output in heart failure when used in combination with isosorbide dinitrate.

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

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

Phosphodiesterase inhibitors (sildenafil) – concomitant use with nitrates is contraindicated due to the possible development of uncontrolled arterial hypotension.

Sympathomimetic agents (adrenaline, ephedrine, noradrenaline, histamine, acetylcholine, naphazoline, mesaton, isadrine, and other antihypertensive drugs) – possible reduction in the antianginal effect of isosorbide dinitrate.

Special precautions.

Use with caution in patients with cerebral circulation disorders, aortic and/or mitral stenosis; in patients prone to orthostatic hypotension; and in patients with symptoms of ischemia in various vascular beds occurring against a background of reduced arterial pressure. During treatment, especially when gradually increasing the dose, monitoring of arterial pressure and heart rate is required. Frequent administration of high doses may lead to the development of "nitrate" tolerance to isosorbide dinitrate or cross-tolerance to other nitrates. To overcome tolerance to isosorbide dinitrate (if possible – withdrawal of nitrates), it is recommended not to increase the frequency of administration or dosage, but to abstain from taking the drug for 16–24 hours, replacing it during this time with other antianginal agents. Then continue treatment either as monotherapy at usual doses or in combination with other drugs (intervals during regular administration of the drug are recommended every 4–6 weeks). The occurrence of "nitrate" headache at the beginning of treatment can be prevented by gradual dose escalation or administration of valeridol and non-narcotic analgesics (acetylsalicylic acid, paracetamol, analgin). Alcohol consumption should be avoided during treatment with this drug.

The drug should be prescribed with caution in patients with hypothyroidism, hypothermia, malnutrition, concomitant diseases, and during concomitant use of other medications.

The drug should be discontinued gradually by reducing the dose. To prevent arterial hypotension and "nitrate" headache, treatment should be initiated with the lowest possible dose. Treatment with the drug may cause orthostatic reactions, which occur more frequently with concomitant alcohol intake or use of other vasodilators. In patients with glucose-6-phosphate dehydrogenase deficiency, acute hemolysis (favism) may occur during administration of isosorbide dinitrate.

Isosorbide dinitrate intake may affect the results of colorimetric determination of cholesterol.

Use during pregnancy or breastfeeding.

Data regarding the safety of isosorbide dinitrate use during pregnancy are insufficient. The use of the drug is contraindicated in the first trimester of pregnancy. In the second and third trimesters of pregnancy, 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 influence reaction rate while driving or operating machinery.

During treatment, driving vehicles and engaging in other potentially hazardous activities is not recommended, as regular use of isosorbide dinitrate may impair concentration and psychomotor reaction speed.

Administration and Dosage.

Sublingual administration (under the tongue) of ISOMIK® 5 MG is recommended. The single dose is 5–10 mg.

To relieve an angina attack or before anticipated emotional or physical exertion that usually triggers an attack, place 1 tablet under the tongue and retain in the mouth until dissolved. If necessary, the dose may be repeated after 10–15 minutes.

Children.

Experience with use in children is lacking.

Overdose.

Symptoms: pallor, increased sweating, weak pulse, hyperthermia, diarrhea, reflex tachycardia, headache, episodes of weakness, dizziness, rapid heartbeat, nausea, vomiting, arterial hypotension, and stupor.

Methemoglobin formation is possible, accompanied by tachypnea, anxiety, loss of consciousness, and cardiac arrest.

Excessive doses may increase intracranial pressure, leading to cerebral symptoms, including seizures.

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

In cases of methemoglobinemia, depending on severity, antidotes may include: 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, transfusion therapy, and hemodialysis.

Adverse Reactions.

Cardiovascular system: possible reflex tachycardia, transient facial hyperemia, arterial hypotension; in individual cases – increased frequency of angina attacks, bradycardia, cardiac arrhythmias, and syncope; alveolar hypoventilation with subsequent hypoxemia and risk of hypoxia/myocardial infarction in patients with ischemic heart disease.

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

Central nervous system: possible dizziness, drowsiness, headache (with continuous treatment usually disappears within 1–2 weeks after the start of therapy), collapse, hemorrhage into the pituitary gland in patients with undiagnosed pituitary tumor.

Allergic reactions: possible skin rash, pruritus, pallor of the skin, Stevens–Johnson syndrome, Quincke's edema.

Eye disorders: blurred vision, closed-angle glaucoma. Cases of visual hallucinations and narrowing of visual fields have been reported.

General disorders: sweating, weakness, flushing, peripheral edema, hematological adverse effects including methemoglobinemia, a case of isosorbide dinitrate-induced hemolytic anemia in a patient with concomitant glucose-6-phosphate dehydrogenase deficiency.