Instructions Izo-mic sublingual spray 1.25 mg/1 dose bottle 15 ml 300 doses
Composition
active ingredient: isosorbide dinitrate;
1 dose of spray contains isosorbide dinitrate aqueous (calculated as 100% isosorbide dinitrate) – 1.25 mg;
Excipients: macrogol-400; ethanol 96%.
Dosage form
Sublingual metered spray.
Main physicochemical properties: clear colorless liquid with an alcohol odor.
Pharmacotherapeutic group
Vasodilators used in cardiology. Organic nitrates. ATX code C01D A08.
Pharmacological properties
Pharmacodynamics
Isosorbide dinitrate relaxes vascular smooth muscle, causing vasodilation. Both peripheral arteries and veins relax. This effect promotes venous pooling of blood and reduces venous return to the heart; thus, ventricular end-diastolic pressure and volume (preload) are reduced. The action on arteries, and at higher doses on arterioles, leads to a decrease in systemic vascular resistance (afterload). This, in turn, facilitates the work of the heart.
The effects on both preload and afterload lead to a further reduction in cardiac oxygen consumption.
Isosorbide dinitrate also causes a redistribution of blood flow to the subendocardial regions of the heart when the coronary circulation is partially obstructed by atherosclerotic lesions. This effect is probably due to selective dilatation of the large coronary vessels. The dilatation of collateral arteries caused by nitrates may improve perfusion of the poststenotic myocardium. In addition, nitrates counteract the appearance and eliminate coronary spasms.
In patients with congestive heart failure, nitrates improve hemodynamics at rest and during exercise. This beneficial effect is due to a number of pathogenetic mechanisms, including improvement in valvular regurgitation (due to ventricular reduction) and reduction in myocardial oxygen demand.
By reducing oxygen demand and increasing oxygen supply, nitrates limit myocardial damage during infarction. Thus, the use of isosorbide dinitrate may be beneficial for patients who have had a myocardial infarction.
Effects on other organ systems include relaxation of bronchial muscles, as well as muscles of the digestive, 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 nitric oxide (NO) donor. Nitric oxide causes relaxation of vascular smooth muscle by stimulating guanylyl cyclase and a subsequent increase in the concentration of intracellular cyclic guanosyl monophosphate (cGMP). This stimulates cGMP-dependent protein kinase and, as a result, changes in protein phosphorylation in smooth muscle cells. This, in turn, causes dephosphorylation of myosin light chains and a decrease in contractility.
Pharmacokinetics
After spraying in the oral cavity, the active substance - isosorbide dinitrate - is absorbed very quickly. The drug begins to act 1-3 minutes after application, the maximum concentration in the blood plasma is reached within 3-6 minutes. The half-life is 30-60 minutes. Within 90-120 minutes, the concentration in the blood plasma returns to the initial level. Isosorbide dinitrate is metabolized to form isosorbide-2-mononitrate and isosorbide-5-mononitrate with half-lives of 1.5-2 hours and 4-6 hours, respectively. Both metabolites have pharmacological activity.
When isosorbide dinitrate is administered orally, it undergoes rapid metabolism in the liver, resulting in significantly higher bioavailability of 60–100% (15–30% when administered orally).
Indication
Assigned to adults:
– for the treatment of angina attacks, except for cases caused by hypertrophic obstructive cardiomyopathy;
– for the prevention of angina attacks;
– in acute myocardial infarction;
– in acute left ventricular heart failure.
Contraindication
The drug is contraindicated in:
– hypersensitivity to isosorbide dinitrate, other nitrate compounds or other components of the drug;
– acute vascular insufficiency (shock, vascular collapse);
– cardiogenic shock, if it is impossible to correct the end-diastolic pressure of the left ventricle using 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 outflow and cause fainting);
– severe anemia;
– head injuries;
– bleeding;
– with aortic and/or mitral stenosis;
– angle-closure glaucoma;
– hemorrhagic stroke;
– hypothermia;
– severe liver and kidney disorders.
The soluble guanylate cyclase stimulator riociguat should not be used during nitrate therapy (see section “Interaction with other medicinal products and other types of interactions”).
Interaction with other medicinal products and other types of interactions
When used simultaneously with other vasodilators, such as β-blockers, calcium channel blockers, vasodilators, neuroleptics or tricyclic antidepressants, ethanol, the hypotensive effect of the drug may be enhanced. Angiotensin-converting enzyme (ACE) inhibitors, monoamine oxidase (MAO) inhibitors, phenothiazines, other nitrates/nitrites, quinidine, novocainamide, narcotic analgesics potentiate the hypotensive effect of isosorbide dinitrate, orthostatic collapse may develop.
Interactions with concomitant use of isosorbide dinitrate with ACE inhibitors or arterial vasodilators may be desirable if the antihypertensive effect is not excessive and when a dose reduction of one or both drugs is required.
The hypotensive effect of the drug is enhanced when used simultaneously with phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil) (see sections "Special instructions" and "Interaction with other medicinal products and other types of interactions"). This may lead to life-threatening cardiovascular complications. Patients receiving isosorbide dinitrate therapy should not use phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil).
Patients receiving phosphodiesterase inhibitor therapy (e.g. sildenafil, vardenafil, tadalafil) should not use isosorbide dinitrate for the treatment of acute conditions within 24 hours of discontinuing sildenafil and vardenafil and within 48 hours of discontinuing tadalafil.
There are reports indicating an increase in the concentration of dihydroergotamine in the blood when used together with isosorbide dinitrate, which may enhance the hypertensive effect of dihydroergotamine.
The use of isosorbide dinitrate with the guanylate cyclase stimulator riociguat is contraindicated (see section "Contraindications"), as concomitant use may cause hypotension.
Sapropterin (tetrahydrobiopterin, BH4) is a cofactor of nitric oxide synthase. Sapropterin-containing drugs should be used with caution with any drugs that have a vasodilating effect due to nitric oxide metabolism or contain nitric oxide donors (including nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, and others).
Noradrenaline, acetylcholine, histamine – weakening of their effects when used with nitrates, since isosorbide dinitrate may be their physiological antagonist.
With simultaneous use of sympathomimetic agents (adrenaline, ephedrine, noradrenaline, naphthyzine, mezaton, isadrin), the antianginal effect of isosorbide dinitrate may be reduced.
Application features
The drug should be used with extreme caution and under the constant supervision of a doctor:
- with hypothyroidism;
- with increased intracranial pressure (including brain injuries, hemorrhagic shock) - due to the fact that the expansion of cerebral vessels can cause its further increase. Although a further increase in pressure was observed only with intravenous administration of large doses of nitroglycerin;
- with reduced filling pressure, for example in acute myocardial infarction, impaired left ventricular function (left ventricular failure). A decrease in systolic blood pressure below 90 mm Hg should be avoided;
- with orthostatic dysfunction;
- in hypoxemia and ventilation-perfusion imbalance associated with lung diseases or ischemic heart disease;
- with insufficient nutrition;
- elderly patients – due to age-related changes in liver, kidney and heart function, concomitant diseases and taking other medications.
Tolerance to other nitrate-containing drugs may develop when using isosorbide dinitrate. To prevent this, high doses of the drug should be avoided.
Patients should be warned that the antianginal effect of isosorbide dinitrate is closely related to its dosage regimen, so the proposed dosage schedule should be carefully followed. To prevent arterial hypotension and "nitrate" headache, treatment should be started with a minimum dose. Treatment with the drug may cause the development of orthostatic reactions, which are more likely to occur with simultaneous use of alcohol or other vasodilators.
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 can lead to increased perfusion of poorly ventilated areas, worsening ventilation/perfusion imbalance, and further reduction in arterial partial oxygen pressure.
Patients with glucose-6-phosphate dehydrogenase deficiency may develop acute hemolysis (favism) when using isosorbide dinitrate. Taking isosorbide dinitrate may affect the results of colorimetric cholesterol determination.
As an emergency treatment, the drug is not used in patients who have recently used phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil). In case of using the drug as an emergency treatment, patients should be aware that phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil) should not be used simultaneously (see sections "Contraindications" and "Interaction with other medicinal products and other types of interactions")).
Patients on maintenance therapy with the drug should be informed that they are prohibited from using drugs containing phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil) due to the risk of angina attacks.
The drug contains a small amount of ethanol (alcohol), less than 100 mg/dose of 85% alcohol by volume.
The drug should be discontinued by gradually reducing the dose. Avoid contact with the eyes. If the drug gets on a large area of skin, it should be washed off immediately. As a result of absorption of the drug through the skin, severe adverse reactions may develop (see section "Adverse reactions").
Use during pregnancy or breastfeeding
Pregnancy.
The drug is contraindicated in the first trimester of pregnancy. In the second and third trimesters of pregnancy, the drug should be used only if the expected benefit to the mother outweighs the potential risk to the fetus.
Animal reproduction studies have not shown any harmful effects of isosorbide dinitrate on the fetus. However, there are no adequate and well-controlled studies in pregnant women.
Breast-feeding.
The risk to infants during breastfeeding cannot be determined based on available data. 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 milk is not known, therefore, if necessary, the use of the drug should be discontinued.
Fertility.
There are no data on the effect of isosorbide dinitrate on fertility in humans.
Ability to influence reaction speed when driving vehicles or other mechanisms
The drug may reduce the speed of reaction or cause dizziness, so you should refrain from driving or using other mechanisms during treatment. This effect is enhanced by alcohol consumption.
Method of administration and doses
The drug is prescribed only to adults. For spraying in the oral cavity. The dose should be adapted to the individual characteristics of the patient.
To stop an attack of angina or before physical or emotional stress that may cause an attack, the medicine should be injected into the oral cavity 1–3 times with an interval of 30 seconds between injections.
A single dose (up to 3 injections) to stop an angina attack can be increased only on the recommendation of a doctor.
In acute myocardial infarction or acute heart failure, start with 1–3 injections. If there is no effect within 5 minutes, another injection can be given. If there is no improvement in the next 10 minutes, the spray can be repeated, carefully monitoring blood pressure.
No dose adjustment is required for elderly patients.
Tolerance (reduced efficacy) and cross-tolerance with other nitrate drugs (reduced efficacy in the case of previous therapy with another nitrate) have been described. To prevent reduced or lost efficacy, frequent administration of high doses should be avoided.
Method of application.
Before using the medicine for the first time, press the sprayer several times, directing the spray into the air, until a uniform cloud of spray is formed. The medicine is now ready for use.
If more than a day has passed since the last use of the drug, the first spray should be done in the air to prevent the use of an incomplete dose.
When using, the bottle should be held vertically, with the sprayer facing upwards.
Bring the bottle close to your mouth and, pressing the sprayer, inject the solution into your mouth as follows:
– take a deep breath;
– hold your breath;
– by pressing the sprayer, spray the solution into your mouth (this may cause a slight burning sensation on your tongue);
– close your mouth and breathe only through your nose for the next 30 seconds.
The solution should not be inhaled. To ensure perfect performance, press the sprayer all the way down and release. The sprayer should be checked from time to time, especially if it has not been used for a long time.
Children
Do not apply.
Overdose
Symptoms:
– Decrease in blood pressure to a level of systolic blood pressure < 90 mm Hg, orthostatic hypotension.
– Pallor.
– Increased sweating.
– Weak pulse filling.
– Tachycardia.
– Dizziness.
– Headache.
– Weakness.
– Nausea.
– Vomiting.
– Methemoglobinemia. Cases of methemoglobinemia have been reported in patients receiving other nitrates. The biotransformation of isosorbide dinitrate releases nitrite ions, which can induce methemoglobinemia and cyanosis, followed by tachypnea, anxiety, loss of consciousness and cardiac arrest. The possibility of this adverse reaction in case of overdose with isosorbide dinitrate cannot be excluded.
– Excessive doses can cause increased intracranial pressure, sometimes leading to cerebral symptoms.
Treatment:
– stop using the medicine.
General measures in case of hypotension caused by nitrates:
– place the patient in a horizontal position with the head down and legs raised above the head level;
– ensure the supply of oxygen;
– increase the volume of circulating blood plasma;
– perform specific anti-shock therapy (the patient must be in the intensive care unit).
Special events:
– increase in blood pressure if it is too low;
– additional use of vasoconstrictors in the absence of an adequate response to fluid therapy.
Treatment of methemoglobinemia:
– restorative therapy with vitamin C, methylene blue or toluidine blue;
– use of oxygen (if necessary);
– artificial lung ventilation;
– hemodialysis (if necessary);
– if signs of respiratory or circulatory arrest appear, immediately take resuscitation measures.
Adverse reactions
The frequency of undesirable effects is defined as: very common (more than 10%), common (1% to 10%), uncommon (0.1% to 1%), rare (0.01% to 0.1%), and unknown (frequency cannot be estimated from the available data).
The following undesirable effects may occur when using the medicine.
Nervous system: very common - headache (so-called "nitrate" headache, which occurs at the beginning of treatment, usually gradually decreases/disappears with continued use of the drug, but may be severe and persistent); common - dizziness, drowsiness; frequency unknown - hemorrhage into the pituitary gland in patients with undiagnosed pituitary tumor.
Cardiac disorders: common: tachycardia; rare: increased symptoms of angina; frequency unknown: peripheral edema (usually in patients with left ventricular failure).
Vascular disorders: common: orthostatic hypotension; uncommon: vascular collapse (sometimes accompanied by bradyarrhythmia, cardiac arrhythmias and loss of consciousness); frequency unknown: hypotension.
On the part of the digestive system: infrequent - nausea; vomiting; rare - heartburn.
Skin and subcutaneous tissue disorders: uncommon – allergic skin reactions (e.g. rash), transient facial flushing, flushing; rare – angioedema, Stevens-Johnson syndrome; frequency unknown – exfoliative dermatitis, pruritus.
General disorders: common – asthenia (feeling of weakness), redness of the tongue at the injection site
Hematological side effects may occur, including methemoglobinemia; a case of isosorbide dinitrate-induced hemolytic anemia in a patient with concomitant glucose-6-phosphate dehydrogenase deficiency has been reported.
Cases of tolerance to isosorbide dinitrate, as well as cross-tolerance to other nitrates, have been described. Prolonged use of high doses and/or shortening the interval between doses may lead to a decrease 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 temporary hypoxemia due to relative redistribution of blood flow to alveolar areas with hypoventilation. In patients with ischemic heart disease, this may lead to temporary myocardial hypoxia.
Expiration date
5 years.
Storage conditions
Store at a temperature not exceeding 30 °C in the original packaging, away from fire.
Keep out of reach of children.
Packaging
15 ml (300 doses) in bottles with a sprayer in a cardboard pack.
Vacation category
According to the recipe.
Producer
JSC "Farmak" (responsible for production and batch control/testing, not including batch release)
LLC NVF "MICROCHEM" (responsible for batch release, not including batch control/testing).
Location of the manufacturer and address of its place of business
Ukraine, 04080, Kyiv, Kyrylivska St., 74.
Ukraine, 01013, Kyiv, Budindustrii St., 5.
You can report an adverse event when using a medicinal product by calling +38 (050) 309-83-54 (24 hours a day).
