Iso-mik®

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

Composition:

Active substance: isosorbide dinitrate;

1 ml of concentrate contains 1 mg of isosorbide dinitrate;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

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

Pharmacological Properties.

Pharmacodynamics.

Isosorbide dinitrate is an antianginal agent and a vasodilator that primarily affects venous vessels, but also relaxes arteries. As a result, it reduces venous return to the heart, thereby decreasing ventricular end-diastolic pressure and volume (preload). Its effect on arteries, and at higher doses on arterioles, leads to a reduction in systemic vascular resistance (afterload). This, in turn, reduces the workload of the heart. The combined effect on both preload and afterload further decreases the heart's oxygen demand. Additionally, isosorbide dinitrate promotes redistribution of blood flow to subendocardial regions of the heart when coronary circulation is partially impaired by atherosclerotic lesions. This effect may be explained by selective dilation of large coronary vessels. Nitrate-induced dilation of collateral arteries may improve perfusion of ischemic areas. Nitrates dilate the lumen at sites of eccentric stenosis, as they counteract possible constrictive factors affecting the partially preserved smooth musculature of coronary vessels at the site of narrowing. Furthermore, nitrates relieve coronary spasm.

In patients with congestive heart failure, nitrates improve hemodynamics both at rest and during exertion. This beneficial effect involves several mechanisms, including improvement of valvular regurgitation (due to reduced ventricular dilation) and decreased myocardial oxygen consumption. By reducing oxygen demand and increasing oxygen supply, the area of myocardial impairment is reduced. Thus, isosorbide dinitrate may be beneficial in patients with myocardial infarction.

Effects on other organ systems include relaxation of bronchial smooth muscles, gastrointestinal tract muscles, and muscles of the biliary and urinary tracts. There are reports of a relaxing effect on uterine smooth musculature.

Mechanism of Action

Isosorbide dinitrate acts as a donor of nitric oxide (NO), leading to smooth muscle relaxation in blood vessels by stimulating guanylyl cyclase and subsequently increasing intracellular levels of cyclic guanosine monophosphate (cGMP); cGMP is considered the mediator of relaxation. cGMP-dependent protein kinase is thus activated, resulting in altered phosphorylation of various proteins in smooth muscle cells. Ultimately, this leads to dephosphorylation of the myosin light chain and reduced contractility.

Pharmacokinetics.

The elimination half-life of isosorbide dinitrate after intravenous infusion is 10 minutes. Isosorbide dinitrate is metabolized in the liver to form isosorbide-2-mononitrate and isosorbide-5-mononitrate, with elimination half-lives of 1.5–2 hours and 4–6 hours, respectively. Both metabolites are pharmacologically active. The bioavailability of isosorbide dinitrate solution is 100%, as is typical for all intravenously administered drugs.

Clinical characteristics.

Indications.

• Symptomatic treatment of unstable angina pectoris as an adjunct to standard therapy; long-term treatment of vasospastic angina (Prinzmetal's angina);
• acute left ventricular heart failure of various etiologies (myocardial weakness with impaired left ventricular function);
• acute myocardial infarction.

Contraindications.

• Hypersensitivity to isosorbide dinitrate, other nitrate compounds, or any other component of the drug;
• acute circulatory failure (shock, collapse);
• cardiogenic shock (except in cases where the left ventricular end-diastolic pressure is maintained at an adequate level by appropriate measures);
• hypertrophic obstructive cardiomyopathy;
• constrictive pericarditis;
• cardiac tamponade;
• severe arterial hypotension (systolic blood pressure below 90 mm Hg);
• severe hypovolemia;
• severe anemia;
• the drug must not be used during therapy with phosphodiesterase-5 inhibitors (e.g., sildenafil, vardenafil, tadalafil). See sections "Special precautions" and "Interaction with other medicinal products and other forms of interactions";
• soluble guanylate cyclase stimulator riociguat must not be used during nitrate therapy (see section "Interaction with other medicinal products and other forms of interactions");
• hemorrhagic stroke;
• head trauma;
• conditions associated with increased intracranial pressure (however, to date, additional increase in intracranial pressure has been observed only after intravenous administration of high doses of glyceryl trinitrate);
• aortic and/or mitral stenosis;
• closed-angle glaucoma;
• hypothermia.

Interaction with other medicinal products and other forms of interactions.

When used concomitantly with other medicinal products that lower blood pressure, such as vasodilators, antihypertensive agents (e.g., beta-blockers, diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors), neuroleptics, tricyclic antidepressants, or ethanol, the hypotensive effect of the drug may be enhanced. The interaction between isosorbide dinitrate and ACE inhibitors or arterial vasodilators may be beneficial, provided the antihypertensive effect is not excessive and dosage reduction of one or both agents may be required.

ACE inhibitors, phenothiazines, other nitrates/nitrites, quinidine, procainamide, monoamine oxidase inhibitors (MAO), and narcotic analgesics may potentiate the hypotensive effect of isosorbide dinitrate, with possible development of orthostatic collapse.

The hypotensive effect of the drug is enhanced when used concomitantly with phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil) (see sections "Contraindications" and "Special precautions"). This may lead to life-threatening cardiovascular complications.

Concomitant use of the medicinal product ISOMIK® with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see section "Contraindications"), as simultaneous administration of these agents may cause arterial hypotension.

Patients who have recently received therapy with phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil) must not be administered isosorbide dinitrate for the treatment of acute conditions within 24 hours after discontinuation of sildenafil and vardenafil, and within 48 hours after discontinuation of tadalafil.

There have been reports indicating increased blood concentration and enhanced effects of dihydroergotamine when used concomitantly with the medicinal product.

Sapropterin (tetrahydrobiopterin, BH4) – a cofactor of nitric oxide synthase. Medicinal products containing sapropterin should be used with caution when administered concomitantly with any vasodilators whose mechanism of action is also related to the influence on nitric oxide metabolism or which are classical nitric oxide donors (including nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, and others).

The effects of noradrenaline, acetylcholine, and histamine are diminished when used with nitrates, as isosorbide dinitrate may act as their physiological antagonist.

Special precautions for use.

The medicinal product should be administered with special caution and under continuous medical supervision in the following cases:

• Low filling pressure, particularly in acute myocardial infarction, impaired left ventricular function (left ventricular failure). A reduction in systolic arterial pressure below 90 mm Hg should be avoided;
• Orthostatic dysfunction;
• Poor nutrition;
• Hypothyroidism;
• Age-related changes in liver, kidney, and heart function, concomitant diseases, and use of other medications in elderly patients;
• Hypoxemia and ventilation/perfusion imbalance associated with lung disease or ischemic heart disease;
• Severe liver impairment.

For drug infusion, administration sets made of polyethylene, polypropylene, or polytetrafluoroethylene may be used. It has been shown that infusion systems made of polyvinyl chloride or polyurethane lead to loss of the active substance due to adsorption. In case of urgent need for their use, the drug dose must be adjusted accordingly.

Since the drug is a supersaturated solution of isosorbide dinitrate, a crystalline precipitate may occasionally be observed when using the undiluted preparation. In the presence of crystals, it is safer not to use the solution, although under normal conditions its efficacy does not change.

Development of tolerance (reduced effectiveness) and cross-tolerance to other drugs of the nitrate class (reduced effect in case of prior treatment with other nitrate-containing drugs) has been reported. To prevent reduction or loss of effect, prolonged use of ISOMIK® at high doses should be avoided.

Patients receiving maintenance therapy with isosorbide dinitrate should be informed that they must not use drugs containing phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil). Therapy with isosorbide dinitrate should not be interrupted to take drugs containing phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil), as this increases the risk of angina attack (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Emergency therapy with isosorbide dinitrate should not be used in patients who have recently taken phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil), i.e., within 24 hours (48 hours after discontinuation of tadalafil).

Patients receiving isosorbide dinitrate as emergency therapy should be warned about the danger of using drugs containing phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil) (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Patients should be informed that the antianginal effect of isosorbide dinitrate is closely related to its dosing regimen, and therefore the recommended dosing schedule must be strictly followed. To prevent arterial hypotension and "nitrate" headache, treatment should be initiated at the lowest dose. Treatment with the drug may lead to orthostatic reactions, which occur more frequently when alcohol or vasodilators are used concomitantly.

Precautions should be taken in patients with hypoxemia and ventilation/perfusion imbalance due to lung disease or ischemic heart failure.

As a potent vasodilator, isosorbide dinitrate may increase perfusion of poorly ventilated areas, thereby worsening ventilation/perfusion imbalance and further reducing arterial partial oxygen pressure.

Alcohol consumption should be avoided during treatment with isosorbide dinitrate, as it may enhance the hypotensive effect of the drug.

In patients with glucose-6-phosphate dehydrogenase deficiency, acute hemolysis (favism) may occur during treatment with isosorbide dinitrate. Administration of isosorbide dinitrate may affect the results of colorimetric cholesterol determination. The drug should be discontinued gradually by tapering the dose.

ISOMIK® contains 0.15 mmol (3.54 mg) of sodium per 1 ml; therefore, patients receiving isosorbide dinitrate should monitor their dietary sodium intake.

The infusion tubing should be replaced whenever the perfusion needle is changed.

Use during pregnancy or breastfeeding.

Contraindicated.

Fertility

Data on the effect of ISOMIK® on human fertility are lacking.

Ability to affect reaction speed when driving or operating machinery.

During treatment, driving and engaging in other potentially hazardous activities are not recommended, as regular use of isosorbide dinitrate may impair concentration and psychomotor reaction speed. This effect is intensified by alcohol.

Administration and Dosage

The drug should be administered intravenously for intensive therapy in adults only under hospital conditions!

The dosage is determined individually based on the clinical picture and patient's condition, with continuous monitoring of clinical and hemodynamic parameters.

Intravenous infusion

Begin therapy at a dose of 1–2 mg/hour, gradually increasing it to the required level to achieve optimal therapeutic effect. The maximum dose usually does not exceed 8–10 mg/hour; however, in patients with heart failure, this dose may be increased up to 10 mg/hour, and in individual cases—up to 50 mg/hour. For patients previously treated with organic nitrates, such as isosorbide dinitrate or isosorbide-5-mononitrate, higher doses of the drug may be required to achieve the desired hemodynamic effect.

Elderly patients

There are no data regarding the need for dose adjustment in elderly patients.

Pediatric population

The safety and efficacy of isosorbide dinitrate in children have not been established to date.

Administration method

0.1% solution of the drug should be administered:

• Diluted, as a continuous intravenous infusion using automated infusion systems;
• Undiluted, using a syringe pump, under hospital conditions with continuous monitoring of cardiovascular parameters. Depending on the disease and its severity, in addition to routine monitoring (symptoms, arterial pressure, heart rate, diuresis), invasive methods should be used to determine hemodynamic parameters.

Depending on the clinical picture, hemodynamic status, and ECG parameters, treatment may last 3 days or longer.

Ampoules must be opened under aseptic conditions immediately before use. The diluted solution should be used immediately.

• Use of diluted solutions

Preparation of solutions of different concentrations:

0.1 mg/mL (0.01%): dilute 50 mL of the drug (5 ampoules of 10 mL each) to a final volume of 500 mL with one of the diluents listed below.

0.2 mg/mL (0.02%): dilute 100 mL of the drug (10 ampoules of 10 mL each) to a final volume of 500 mL with one of the diluents listed below.

Diluents: physiological saline, 5–30% glucose solution, Ringer's solution, albumin-containing solutions.

Dosage of diluted solutions (1 mL of solution equals 20 drops)

• Administration of undiluted solutions

The drug may also be administered undiluted using an infusion pump: 1 mL of the solution contains 1 mg of isosorbide dinitrate.

During administration, the recommendations specified in this instruction must be followed.

Children.

The safety and efficacy of isosorbide dinitrate in children (under 18 years of age) have not been studied.

Overdose.

Experience obtained from animal studies

In mice, significant lethality (LD50) was observed after a single intravenous administration of the drug at a dose of 33.4 mg/kg.

Experience from human use of the drug

Symptoms:

• drop in blood pressure to systolic arterial pressure ≤ 90 mm Hg;
• pallor;
• increased sweating;
• weak pulse filling;
• tachycardia;
• headache;
• dizziness;
• postural dizziness;
• weakness;
• nausea;
• vomiting;
• diarrhea;
• methemoglobinemia. Cases of methemoglobinemia have been observed in patients treated with other organic nitrates. During biotransformation of isosorbide mononitrate, nitrite ions are released, which may induce methemoglobinemia and cyanosis, followed by tachypnea, anxiety, loss of consciousness, and cardiac arrest. This adverse reaction cannot be excluded in cases of isosorbide dinitrate overdose;
• excessive doses may cause increased intracranial pressure, which sometimes leads to cerebral symptoms.

Treatment:

• discontinue administration of the drug.

General measures in nitrate-induced hypotension:

• place the patient in a horizontal position with legs elevated above the level of the head;
• ensure oxygen supply;
• increase circulating plasma volume (intravenous fluid administration);
• initiate specific anti-shock therapy (the patient must be admitted to an intensive care unit!).

Specific measures:

• elevate blood pressure if it is too low;
• use vasoconstrictive agents additionally if there is no adequate response to fluid therapy.

Treatment of methemoglobinemia:

• reductive therapy with vitamin C, methylene blue, or toluidine blue;
• oxygen administration (if needed);
• mechanical ventilation;
• hemodialysis (if required).

Resuscitation measures:

• in case of signs of respiratory or circulatory arrest, immediate resuscitation measures must be initiated.

Adverse Reactions

The frequency of adverse effects is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), not known (cannot be estimated from the available data).

The following adverse effects may occur during administration of isosorbide dinitrate.

Disorders of the nervous system

Very common: headache ("nitrate headache");

Common: dizziness, somnolence;

Not known: haemorrhage into the pituitary gland in patients with undiagnosed pituitary tumour.

Disorders of the cardiac system

Common: tachycardia;

Uncommon: worsening of angina symptoms;

Not known: peripheral oedema (usually in patients with left ventricular failure).

Disorders of the vascular system

Common: orthostatic hypotension;

Uncommon: vascular collapse (sometimes accompanied by bradycardia and syncope);

Not known: hypotension.

Disorders of the gastrointestinal system

Uncommon: nausea, vomiting;

Very rare: heartburn.

Disorders of the skin and subcutaneous tissue

Uncommon: allergic skin reactions (e.g. rash), transient facial hyperaemia (flushing);

Very rare: angioneurotic oedema (Quincke's oedema), Stevens–Johnson syndrome;

Not known: exfoliative dermatitis, pruritus.

General disorders and administration site conditions

Common: asthenia.

Haematological adverse effects may occur, including methaemoglobinaemia. There is a report of a case of haemolytic anaemia induced by isosorbide dinitrate in a patient with concomitant glucose-6-phosphate dehydrogenase deficiency.

If the first signs of hypersensitivity occur, administration of the drug should be discontinued.

Severe hypotensive reactions, including nausea, vomiting, restlessness, pallor, and excessive sweating, have been reported with organic nitrates.

Transient hypoxaemia may occur during treatment with isosorbide dinitrate due to a relative redistribution of blood flow to hypoventilated alveolar areas. This may lead to myocardial hypoxia, particularly in patients with coronary artery disease.

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 reduced dosing intervals may lead to a reduction or even complete loss of the therapeutic effect of the drug.

Shelf life.

3 years.

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

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of the reach of children.

Incompatibilities.

Materials made of polyethylene (PE), polypropylene (PP), or polytetrafluoroethylene (PTFE) are suitable for use with this drug. Loss of active substance due to adsorption has been demonstrated when using infusion systems made of polyvinyl chloride (PVC) or polyurethane (PU). If such materials (PVC, PU) are used, monitoring of the patient's response to the drug is recommended, and the dose should be adjusted as necessary.

The solution does not contain ethanol, propylene glycol, or potassium ions.

The drug should not be mixed with other medicinal products, except those specifically recommended.

Packaging.

10 ml in ampoules, 10 ampoules (5 × 2) in blisters or cassettes in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

JSC "PHARMAC".

LLC NPF "MIKROKHEM" (responsible for batch release, excluding batch control/testing).

Manufacturer's address and location of manufacturing activities.

74, Kyrylivska Street, Kyiv, 04080, Ukraine (JSC "PHARMAC").

5, Budynstustriyi Street, Kyiv, 01013, Ukraine.

(LLC NPF "MIKROKHEM").

Marketing Authorisation Holder.

LLC NPF "MIKROKHEM".

Address of the Marketing Authorisation Holder.

5, Budynstustriyi Street, Kyiv, 01013, Ukraine.