Isoket

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ISOKET® (ISOKET®)

Composition:

Active substance: isosorbide dinitrate;

1 dose (1 spray pump actuation) delivers 0.05 ml of solution containing 1.25 mg of isosorbide dinitrate;

1 bottle with 15 ml (12.7 g) of solution contains 375 mg of isosorbide dinitrate;

Excipients: anhydrous ethanol, macrogol 400.

Pharmaceutical form. Oromucosal spray.

Main physicochemical characteristics: clear, colorless, mobile solution.

Pharmacotherapeutic group. Vasodilators used in cardiology. Organic nitrates. ATC code C01DA08.

Pharmacological Properties

Pharmacodynamics

Isosorbide dinitrate causes relaxation of vascular smooth muscle, resulting in vasodilation.

This leads to relaxation of both peripheral arteries and veins. This effect promotes venous pooling of blood and reduces venous return to the heart; thus, left ventricular end-diastolic pressure and volume (preload) are reduced.

The effect on arteries, and at higher doses on arterioles, causes a decrease in systemic vascular resistance (afterload). This, in turn, reduces the workload of the heart. The impact on both preload and afterload leads to further reduction in myocardial oxygen demand.

Isosorbide dinitrate also redistributes blood flow to the subendocardial regions of the heart in cases where coronary circulation is partially impaired by atherosclerotic lesions. This effect is likely explained by selective dilation of large coronary vessels. Nitrate-induced dilation of collateral arteries may improve perfusion of post-stenotic myocardium. In addition, nitrates prevent and relieve coronary spasms.

In patients with congestive heart failure, nitrates improve hemodynamics at rest and during exercise. This beneficial effect is mediated by several pathogenetic mechanisms, including improvement in valvular regurgitation (due to reduced ventricular dilation) and decreased myocardial oxygen demand.

Due to reduced oxygen demand and increased oxygen supply, nitrates limit myocardial damage during infarction. Thus, the use of isosorbide dinitrate may be beneficial in patients who have suffered myocardial infarction.

Isosorbide dinitrate affects other organ systems, including relaxation of bronchial smooth muscle, as well as muscles of the gastrointestinal tract, biliary and urinary tracts. There are also reports of relaxation of uterine smooth muscle.

Mechanism of Action

Like all organic nitrates, isosorbide dinitrate acts as a donor of nitric oxide (NO). Nitric oxide induces relaxation of vascular smooth muscle by stimulating guanylyl cyclase and subsequently increasing intracellular cyclic guanosine monophosphate (cGMP) levels. This activates cGMP-dependent protein kinase, leading to changes in protein phosphorylation within smooth muscle cells. As a result, dephosphorylation of myosin light chains occurs, reducing contractility.

Pharmacokinetics

After sublingual administration, the active substance—isosorbide dinitrate—is rapidly absorbed. The effect of the drug begins within 1–3 minutes after administration, and maximum plasma concentration is achieved within 3–6 minutes. The elimination half-life is 30–60 minutes. Plasma concentrations return to baseline levels within 90–120 minutes. Isosorbide dinitrate is metabolized to isosorbide-2-mononitrate and isosorbide-5-mononitrate, with elimination half-lives of approximately 1.5–2 hours and 4–6 hours, respectively. Both metabolites are pharmacologically active.

When administered sublingually, isosorbide dinitrate bypasses the first-pass hepatic metabolism, resulting in significantly higher bioavailability—60–100% (compared to 15–30% with oral administration).

Clinical characteristics.

Indications.

For use in adults:

• for the treatment of angina attacks, except in cases caused by hypertrophic obstructive cardiomyopathy;
• for prevention of angina attacks;
• in acute myocardial infarction;
• in acute left ventricular heart failure.

Contraindications.

The medicinal product is contraindicated in:

• hypersensitivity to isosorbide dinitrate, other nitrate compounds, or any of the excipients of the medicinal product;
• acute circulatory failure (shock, vascular collapse);
• cardiogenic shock, if left ventricular end-diastolic pressure cannot be corrected by appropriate measures;
• hypertrophic obstructive cardiomyopathy;
• constrictive pericarditis;
• cardiac tamponade;
• severe arterial hypotension (systolic pressure below 90 mm Hg);
• severe hypovolemia (isosorbide dinitrate may reduce venous return and cause syncope);
• severe anemia;
• head trauma;
• hemorrhage;
• aortic and/or mitral stenosis;
• closed-angle glaucoma;
• hemorrhagic stroke;
• hypothermia;
• severe hepatic and renal disorders.

The medicinal product must not be used during therapy with phosphodiesterase-5 inhibitors (e.g., sildenafil, vardenafil, tadalafil) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Soluble guanylate cyclase stimulator riociguat must not be used during nitrate therapy (see section "Interaction with other medicinal products").

Interaction with other medicinal products and other forms of interaction.

When used concomitantly with other vasodilating agents such as beta-blockers, calcium channel blockers, vasodilators, neuroleptics, or tricyclic antidepressants, and ethanol, the hypotensive effect of the medicinal product may be enhanced. Angiotensin-converting enzyme (ACE) inhibitors, monoamine oxidase (MAO) inhibitors, phenothiazines, other nitrates/nitrites, quinidine, procainamide, and narcotic analgesics potentiate the hypotensive effect of isosorbide dinitrate, and orthostatic collapse may occur.

The interaction when isosorbide mononitrate is used concomitantly with ACE inhibitors or arterial vasodilators may be desirable, provided the antihypertensive effect is not excessive and provided dose reduction of one or both agents is considered.

The hypotensive effect of the medicinal product is enhanced when used concomitantly with phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil) (see section "Special precautions for use"). This may lead to life-threatening cardiovascular complications. Patients receiving therapy with isosorbide dinitrate must not use phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil).

Patients receiving therapy with phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil) must not be treated with isosorbide dinitrate for 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 of dihydroergotamine when administered concomitantly with isosorbide dinitrate, which may enhance the hypertensive effect of dihydroergotamine.

Concomitant use of isosorbide dinitrate with the guanylate cyclase stimulator riociguat is contraindicated (see section "Contraindications") because simultaneous use may cause arterial hypotension.

Sapropterin (tetrahydrobiopterin, BH4) – a cofactor of nitric oxide synthase. Medicinal products containing sapropterin should be used with caution in combination with any medicinal products exerting vasodilatory effects via nitric oxide metabolism or containing nitric oxide donors (including nitroglycerin (GTN), isosorbide dinitrate (ISDN), isosorbide mononitrate, and others).

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

Concomitant use of sympathomimetic agents (adrenaline, ephedrine, noradrenaline, naphazoline, mesaton, isadrine) may reduce the antianginal effect of isosorbide dinitrate.

Special precautions for use.

The drug should be used with special caution and under constant medical supervision in the following cases:

• in hypothyroidism;
• in increased intracranial pressure (including brain trauma, hemorrhagic shock), since cerebral vasodilation may lead to a further increase in pressure. Although such an increase has been observed only after intravenous administration of high doses of nitroglycerin;
• in reduced filling pressure, for example, in acute myocardial infarction or impaired left ventricular function (left ventricular failure). Systolic arterial pressure below 90 mm Hg should be avoided;
• in orthostatic dysfunction;
• in hypoxemia and ventilation/perfusion imbalance associated with lung diseases or ischemic heart disease;
• in malnutrition;
• in elderly patients due to age-related changes in liver, kidney, and heart function, concomitant diseases, and use of other medications;
• in severe liver diseases.

Tolerance to other drugs containing nitrates may develop during treatment with isosorbide dinitrate. To prevent this phenomenon, the use of high doses of the drug should be avoided.

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

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

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

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

Acute hemolysis (favism) may occur in patients with glucose-6-phosphate dehydrogenase deficiency during treatment with isosorbide dinitrate. Isosorbide dinitrate may interfere with colorimetric determination of cholesterol.

The drug should not be used as emergency treatment in patients who have recently taken phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil). When the drug is used as emergency treatment, patients must be informed that concomitant use of phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil) is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Patients on maintenance therapy with the drug should be informed that they must not use medications containing phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil) due to the risk of developing an angina attack.

The drug contains a small amount of ethanol (alcohol), less than 100 mg per dose of 85% v/v alcohol.

The drug should be discontinued gradually by tapering the dose. Avoid contact of the solution with the eyes. If the solution comes into contact with a large area of skin, it should be washed off immediately. Systemic adverse reactions may develop due to absorption of the drug through the skin (see section "Adverse reactions").

Use during pregnancy or breastfeeding.

Pregnancy
The drug is contraindicated during the first trimester of pregnancy. In the second and third trimesters of pregnancy, the drug should be used only after careful assessment of the benefit to the mother versus the potential risk to the fetus.

Reproductive studies in animals have not shown any harmful effects of isosorbide dinitrate on the fetus. However, adequate and well-controlled studies in pregnant women have not been conducted.

Breastfeeding

Based on available data, the risk to infants during breastfeeding cannot be determined. There is evidence that nitrates pass into breast milk and may cause methemoglobinemia in infants. The amount of isosorbide dinitrate and its metabolites excreted in human breast milk has not been determined; therefore, if use of the drug is necessary, breastfeeding should be discontinued.

Fertility
There are no data on the effect of isosorbide dinitrate on fertility in humans.

Ability to affect reaction speed when driving or operating machinery.

The drug may reduce reaction speed or cause dizziness; therefore, patients should refrain from driving or operating machinery during treatment. This effect is intensified by alcohol consumption.

Method of Administration and Dosage

The dosage should be adjusted according to individual patient characteristics and depends on the severity of the disease and individual need for nitrates.

For terminating an angina attack or prior to physical or emotional exertion that may provoke an attack, administer 1–3 sprays into the oral cavity, with a 30-second interval between sprays.

The single dose (up to 3 sprays) for terminating an angina attack may be increased only upon physician's recommendation.

In acute myocardial infarction or acute heart failure, start with 1–3 sprays. If no effect is observed within 5 minutes, an additional spray may be administered. If improvement is still not observed within the following 10 minutes, repeat administration of the spray may be considered, with careful monitoring of arterial blood pressure.

Dose adjustment is not required for elderly patients.

Tolerance (reduced effectiveness) has been reported, as well as cross-tolerance with other nitrate group drugs (reduced effect in case of prior therapy with another nitrate). To prevent reduced or lost efficacy, frequent administration of high doses should be avoided.

Method of Administration

For oral spray use only — the medicinal product is not intended for inhalation!

Before first use, press the spray pump several times into the air until a uniform mist is produced. The product is now ready for use.

If more than 24 hours have passed since the last use of the medicinal product, the first spray should be administered into the air to prevent delivery of an incomplete dose.

When using, hold the bottle vertically with the spray nozzle pointing upwards.

Bring the bottle close to the mouth and administer the solution as follows:

• Take a deep breath;
• Hold your breath;
• While pressing the spray pump, administer the solution into the mouth (a slight burning sensation on the tongue may occur);
• Close the mouth and breathe through the nose only for the next 30 seconds.

Avoid contact of the spray with the eyes. Do not spray near open flames or hot objects (e.g., glowing surfaces).

The solution should not be inhaled. To ensure optimal delivery, press the spray pump fully and without interruption, then release. The spray pump should be tested periodically, especially after prolonged non-use.

The medicinal product should be stored at room temperature. A mark in the form of an arrow is printed on the label at the bottom of the bottle. When the liquid level reaches the top edge of the arrow, it is recommended to obtain a new bottle of the product. However, continued use is still possible as long as, in a slightly tilted bottle, the tip of the tube remains submerged in the liquid.

Children: Do not use.

Overdose

Symptoms:

• Decrease in arterial blood pressure to systolic levels <90 mm Hg, orthostatic hypotension;
• Pallor;
• Profuse sweating;
• Weak pulse;
• Tachycardia;
• Headache;
• Dizziness;
• Weakness;
• Nausea;
• Vomiting;
• Diarrhea;
• Methemoglobinemia. Cases of methemoglobinemia have been reported in patients using other nitrates. During biotransformation of isosorbide dinitrate, nitrite ions are released, which may induce methemoglobinemia and cyanosis, followed by tachypnea, anxiety, loss of consciousness, and cardiac arrest. The possibility of this adverse reaction cannot be excluded in case of isosorbide dinitrate overdose;
• Increased intracranial pressure, which may occasionally lead to cerebral symptoms.

Treatment: Discontinue the medicinal product.

General measures in case of nitrate-induced hypotension:

• Place the patient in a horizontal position with the head down and legs elevated above the level of the head;
• Ensure oxygen supply;
• Increase circulating plasma volume;
• Initiate specific anti-shock therapy (the patient should be managed in an intensive care unit).

Specific measures:

• Increase arterial blood pressure if it is excessively low;
• Additional use of vasoconstrictive agents — in case of inadequate 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);
• In case of signs of respiratory or circulatory arrest, initiate resuscitation measures immediately.

Adverse Reactions

The following adverse events may occur during administration of the medicinal product. The frequency of adverse effects is defined as follows: very common (more than 10%), common (1% to 10%), uncommon (0.1% to 1%), rare (0.01% to 0.1%), very rare (less than 0.01%), frequency not known (cannot be estimated from available data).

From the nervous system:

very common – headache (so-called "nitrate" headache, which occurs at the beginning of treatment and usually gradually decreases/disappears with continued use of the drug, but may be severe and persistent);

common – dizziness, somnolence;

frequency not known – hemorrhage into the pituitary gland in patients with undiagnosed pituitary tumors.

From the heart:

common – tachycardia;

rare – worsening of angina symptoms;

frequency not known – peripheral edema (usually in patients with left ventricular insufficiency).

From the vascular system:

common – orthostatic hypotension;

uncommon – vascular collapse (sometimes accompanied by bradycardia, cardiac arrhythmia, and loss of consciousness);

frequency not known – hypotension.

From the gastrointestinal system:

uncommon – nausea, vomiting;

rare – heartburn.

From the skin and subcutaneous tissue:

uncommon – allergic skin reactions (e.g., rash), transient facial hyperemia, flushing;

rare – angioedema, Stevens-Johnson syndrome;

frequency not known – exfoliative dermatitis, pruritus.

General disorders:

common – asthenia (feeling of weakness), redness of the tongue at the site of administration.

Hematological adverse effects may occur, including methemoglobinemia; a case of isosorbide dinitrate-induced hemolytic anemia has been reported 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 reduction or even loss of the therapeutic effect of the drug.

Severe hypotensive reactions, accompanied by nausea, vomiting, restlessness, pallor, and increased sweating, have been reported with the use of organic nitrates.

The use of the drug may cause transient hypoxemia due to relative redistribution of blood flow to alveolar areas with hypoventilation. In patients with ischemic heart disease, this may lead to transient myocardial hypoxia.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows continuous monitoring of the benefit-risk ratio of the drug. Physicians should report any suspected adverse reactions.

Shelf life. 5 years.

Storage conditions.

No special storage conditions required.

Keep out of reach of children.

Packaging.

15 ml (300 doses) in a bottle. 1 bottle in a cardboard box.

Prescription status.

Prescription only.

Marketing Authorization Holder.

Zentiva, k.s.

Address of the Marketing Authorization Holder.

Praha-10 Dolni Měcholupy, U kabelovny 130, postal code 10237, Czech Republic.

Manufacturer.

Acicapharmaceuticals GmbH, Germany.

Address of the manufacturer and site of its operations.

Alfred-Nobel-Str. 10, 40789 Monheim am Rhein, Germany.