Instruction for use: Ventavis

Dosage form: Inhalation solution

Active substance: Iloprostum

ATX

B01AC11 Iloprost

Pharmacological groups

Antiaggregants

Nosological classification (ICD-10)

I26 Pulmonary embolism: Recurrent thromboembolism of the pulmonary artery; Recurrent pulmonary embolism; Thromboembolism of the branches of the pulmonary artery; Thromboembolism of the lungs; Thromboembolism of the pulmonary artery (PE); Thrombosis of the pulmonary artery; Thromboembolism; Thromboembolism of the pulmonary artery; Thromboembolism; Pulmonary embolism; Thromboembolism of the pulmonary artery and its branches; Thromboembolism of pulmonary vessels; Embolism of the lung; Embolism of the pulmonary artery; Acute massive thromboembolism of the pulmonary artery

I27 Other forms of cardiopulmonary diseases: Chronic pulmonary heart disease; Hypertension pulmonary circulation; Pulmonary hypertension; Pulmonary heart disease; pulmonary heart disease; Cardio-pulmonary insufficiency; Secondary pulmonary hypertension; Chronic pulmonary heart; Eisenmenger syndrome

I27.0 Primary pulmonary hypertension

Structure and Composition

active substance: Iloprost - 10 mcg

Auxiliary substances: trometamol - 0,121 mg; Ethanol 96% - 0.81 mg; Sodium chloride - 9 mg; Hydrochloric acid 1M - 0.51 mg; Water for injection - 992.849 mg

Description of dosage form

Transparent, colorless or slightly colored, particle-free solution.

Pharmachologic effect

Mode of action - Antiaggregational, vasodilating with respect to the pulmonary arterial bed.

Pharmacodynamics

Iloprost, the active ingredient of the drug Ventasis, is a synthetic analogue of prostacyclin. The drug inhibits platelet aggregation, platelet adhesion, and release reactions of soluble adhesion molecules; Expands arterioles and venules; Increases the density of capillaries and reduces the increased vascular permeability caused by mediators such as serotonin or histamine at the microcirculatory level; Stimulates endogenous fibrinolytic activity; Has anti-inflammatory effects such as inhibition of leukocyte adhesion after endothelial damage and leukocyte infiltration in injured tissues, as well as a decrease in the release of tumor necrosis factor alpha.

After inhalation of the Ventasis preparation, direct vasodilation of the pulmonary arterial bed is observed, followed by a significant improvement in such parameters as pulmonary arterial pressure, pulmonary vascular resistance, cardiac output, and oxygen saturation of mixed venous blood. The effect on systemic vascular resistance and systemic BP was minimal.

Pharmacokinetics

Absorption. With inhalation administration of iloprost, patients with pulmonary hypertension (a dose of iloprost delivered via the mouthpiece - 5 μg, duration of inhalation - from 4.6 to 10.6 min) Cmax of the drug in the serum was determined by the end of the inhalation and was 100-200 pg / ml. The concentration of the drug decreases as the drug is withdrawn (T1 / 2 is about 5-25 minutes). In the interval from 30 minutes to 1 hour after the end of inhalation, iloprost is no longer detected in the central chamber (the sensitivity limit of the method is 25 pg / ml).

Distribution. At present, there are no studies performed with the inhalation application of the drug.

After IV infusion, the apparent Vss in healthy volunteers was 0.6 to 0.8 l / kg. In the concentration range from 30 to 3000 pg / ml, the total binding of iloprost to plasma proteins is independent of the concentration and is about 60%, of which 75% is binding to albumin.

Metabolism. At present, there are no studies performed with the inhalation application of the drug. The results of in vitro studies indicate a similar metabolism of iloprost in the lungs after both IV and after inhalation. After intravenous administration, iloprost is more metabolized, mainly by β-oxidation of the carboxyl side chain. In the unmodified form, the drug is not excreted. The main metabolite is tetranoriloprost, which is found in the urine in a free form and conjugated form. As shown by experimental studies in animals, tetranoriloprost is pharmacologically inactive.

According to the results of in vitro studies, the participation of cytochrome P450 in the metabolism of iloprost is minimal.

Excretion. At present, there are no studies performed with the inhalation application of the drug. Elimination of iloprost after IV infusion in subjects with normal renal and hepatic function in most cases is characterized by a two-phase profile with a mean T1 / 2 of 3 to 5 minutes and 15 to 30 minutes. The total Cl of iloprost is about 20 ml / kg / min, which indicates the presence of extra extrahepatic metabolism of iloprost.

A mass balance study using iloprost-labeled 3H was performed in healthy subjects. After intravenous infusion, excretion of the total radioactivity was 81%, with 68% being excreted in the urine and 12% being excreted in the feces. Elimination of metabolites occurs in two phases, for which the calculated T1 / 2 are about 2 and 5 hours (plasma) and about 2 and 18 hours (urine).

Impaired renal function

In a study with intravenous administration of iloprost, it was shown that in the patients with terminal stage of renal failure who are on periodic dialysis, Cl preparation (mean Cl = 5 ± 2 ml / min / kg) is significantly lower than in patients with renal insufficiency, Not receiving periodic dialysis (mean Cl = 18 ± 2 ml / min / kg).

Impaired liver function

Since iloprost is more likely to be metabolized in the liver, changes in liver function affect the concentration of the drug in the plasma. The results of the study with intravenous administration of the drug included data from 8 patients with cirrhosis of the liver. The average Cl of iloprost was calculated as 10 ml / min / kg.

Age and gender

Age and gender have no clinical significance for the pharmacokinetics of iloprost.

Indications of the drug Ventavis

Treatment of moderate to severe pulmonary hypertension in the following cases:

Idiopathic (primary) arterial pulmonary hypertension, familial arterial pulmonary hypertension;

Arterial pulmonary hypertension due to connective tissue disease or the effects of drugs or toxins;

Pulmonary hypertension due to chronic thrombosis and / or pulmonary embolism in the absence of the possibility of surgical treatment.

Contraindications

Hypersensitivity to iloprost or other components of the drug;

Pathological conditions in which the effect of the Ventasis preparation on platelets may increase the risk of bleeding (including gastric ulcer and duodenal ulcer in the acute stage, trauma, intracranial hemorrhage);

Severe ischemic heart disease or unstable angina;

Myocardial infarction in the previous 6 months;

Decompensated heart failure in the absence of proper medical control;

Severe arrhythmias;

Suspicion of stagnation of blood in the lungs;

Cerebrovascular complications (including transient ischemic attack, stroke) in the previous 3 months;

Pulmonary hypertension due to pulmonary veno-occlusive disease;

Congenital or acquired heart valve defects with clinically significant impairments in myocardial function that are not due to pulmonary hypertension;

Children and adolescents under 18 years of age (experience of use is limited).

CAREFULLY:

Impaired liver function and renal failure in patients requiring dialysis;

Arterial hypotension;

COPD;

Severe bronchial asthma.

Pregnancy and breast-feeding

Women suffering from pulmonary hypertension should avoid pregnancy, This can lead to life-threatening aggravation of the disease. There is insufficient data on the use of the drug Ventasis in pregnant women. When pregnancy occurs, Ventavis should be given if the expected benefit to the mother exceeds the possible risk to the fetus.

Since it is not established whether iloprost and its metabolites are excreted into breast milk, then if breastfeeding is necessary, breastfeeding should be discontinued.

Side effects

In addition to the local undesirable effects resulting from the inhalation route of administration of iloprost (an increasing cough), undesirable reactions to the drug are due to the pharmacological features of PG. The most frequent undesirable effects (> 20%) observed in clinical studies were vasodilation, headache and an intensifying cough. The most serious adverse effects were hypotension, bleeding, and bronchospasm.

The adverse reactions noted during the application of Ventavis are classified below in organ systems.

Characteristics of the frequency of adverse reactions observed in clinical trials are as follows: very often - ≥1 / 10; Often - ≥1 / 100 and <1/10. For undesirable effects revealed only during post-registration observation programs, and for which it is not possible to estimate the frequency, "frequency is unknown" is indicated. In each group of frequency of undesirable effects, undesirable reactions are presented in order of decreasing importance.

The data on adverse reactions presented below are based on the combined data of phase II and III clinical trials (the number of patients taking the drug-131) and the data obtained during post-registration surveillance programs.

Violations from the blood and lymphatic system: very often - bleeding **; Frequency unknown - thrombocytopenia.

Disorders from the immune system: the frequency is unknown - hypersensitivity reactions.

Disturbances from the nervous system: very often - headache; Often - dizziness.

Disorders from the vascular system: very often - vasodilation; Often - hypotension *, fainting.

Violations from the heart: often - tachycardia, a feeling of palpitations.

Disorders from the respiratory, thorax and mediastinal organs: very often - pain in the chest, cough; Often - shortness of breath, pharyngolaryngeal pain, irritation in the throat; Frequency unknown - bronchospasm * / wheezing, nasal congestion.

Disorders from the digestive tract: very often - nausea; Often - diarrhea, vomiting, irritation of the mucous membrane of the mouth and tongue, including pain; Frequency is unknown - perversion of taste.

Disturbances from the skin and subcutaneous tissues: often - rash.

Disturbances from the musculoskeletal system and connective tissue: very often - pain in the jaw / trismus; Often - pain in the back.

General disorders and disorders at the injection site: very often - peripheral edema.

To describe specific reactions, their synonyms and related states, the terms from the medical dictionary of the standardized international terminology (MedDRA, version 14.0) are used.

* These adverse effects were life-threatening and / or fatal.

** Bleeding (mainly in the form of nasal bleeding and hemoptysis) occurred very often, which is expected for a population with a high proportion of patients receiving concomitant anticoagulant therapy. The risk of bleeding may be increased in patients receiving anticoagulant therapy or inhibitors of platelet aggregation (see "Interaction").

Cases of cerebral hemorrhage and intracranial hemorrhage with a fatal outcome have been reported.

Clinical studies reported cases of peripheral edema in 19.1% of patients taking iloprost and in 22.2% of patients taking placebo. Occurrence of peripheral edema is a very frequent symptom of the disease itself, nevertheless, they can also be associated with the use of iloprost.

As expected for patients with pulmonary hypertension, dizziness and fainting were common, but there was no significant difference in frequency between treatment groups (see "Special instructions").

Interaction

Since compatibility studies have not been conducted, Ventasis should not be confused when administered with other drugs. Iloprost may enhance the antihypertensive effect of vasodilators and other antihypertensive drugs. Care should be taken when using VENTAVIS with vasodilators and antihypertensive drugs at the same time. May need to adjust their dose.

Since iloprost suppresses platelet function, its use in conjunction with anticoagulants (such as heparin, anticoagulants from the coumarin derivative group) or other antiplatelet agents (such as acetylsalicylic acid, NSAIDs, phosphodiesterase inhibitors and vasodilators from the nitrate group) may increase the risk of bleeding (see " Side effects"). Patients receiving anticoagulant therapy or other inhibitors of platelet aggregation in accordance with accepted medical practice should be under constant control of coagulation parameters. Previous use of acetylsalicylic acid in a dose up to 300 mg / day for 8 days does not affect the pharmacokinetics of iloprost. In a study in animals, it was found that the administration of iloprost can lead to a decrease in Css in the plasma tissue plasminogen activator (TAP). The results of human studies show that iloprost infusion does not affect the pharmacokinetics of digoxin administered internally, and iloprost does not affect the pharmacokinetics of concomitant TAP.

In experiments on animals, the vasodilating effect of iloprost was weakened, if the SCS was first introduced, while the suppressive effect on platelet aggregation remained unchanged. The significance of these data for the use of the drug Ventasis in humans is unknown. Although no clinical studies have been conducted, in vitro studies to assess the possible inhibitory effect of iloprost on the activity of cytochrome P450 isoenzymes have shown that it is unlikely to significantly suppress the metabolism of drugs mediated through these isozymes under the influence of iloprost.

Dosing and Administration

Inhalation. A ready-to-use solution is administered through an appropriate inhalation device (nebulizer).

The previous therapy should be adjusted in accordance with the individual needs of the patient (see "Interaction"). The drug Ventavis is used for long-term therapy.

Recommended doses

To adults. At the beginning of treatment with Ventavis, the first inhalation dose of iloprost should be 2.5 μg (delivered through the mouthpiece of the inhaler). If the patient tolerates treatment well, the dose of iloprost should be increased to 5 μg and maintained with subsequent inhalations. In case of poor tolerance, return to a dose of 2.5 μg.

Inhalation of iloprost should be carried out 6 to 9 times a day, according to the individual need of the patient and the tolerability of the drug.

Depending on the required dose of the drug delivered through the mouthpiece and the type of nebulizer, the duration of the inhalation session is approximately 4 to 10 minutes.

Patients with impaired liver function. Elimination of iloprost is reduced in patients with impaired liver function. To avoid undesirable accumulation of the drug during the day, when selecting the initial dose of the drug in these patients should take special precautions. Careful titration of the initial dose with an interval between administrations of 3-4 hours is recommended.

The initial dose should be 2.5 μg with an interval between administrations 3-4 hours (which corresponds to a maximum of 6 times a day). Subsequently, a cautious reduction in the intervals between administrations is possible, taking into account the individual tolerability of the preparation. If further increase in the dose to 5 μg is shown, the intervals between the administrations at the initial stage should be 3-4 hours; Then they can be reduced taking into account individual tolerance. Further accumulation of the drug after several days of therapy seems unlikely due to a night-time interruption in use.

Patients with impaired renal function. In patients with Cl creatinine> 30 ml / min, there is no need to correct the dose of the drug. The use of Ventavis in patients with Cl creatinine <30 ml / min in clinical studies has not been studied. Elimination of iloprost is reduced in patients with renal failure who need dialysis. Recommendations for dosing - see "Patients with impaired liver function".

Instructions for the introduction

To perform each inhalation, you need to use a new vial of the Centaur preparation. The contents of the ampoule must be completely poured into the nebulizer chamber immediately before use. It is necessary to strictly follow the instructions for hygiene and cleaning of the inhaler provided by the device manufacturer.

Solution for nebulizer, not used for inhalation, it is necessary to pour out.

In general, nebulizers that are suitable for inhalation therapy with the Ventavis solution are certified compressor-type nebulizers, ultrasound or nebulizers based on vibration technology.

Nebulizers suitable for inhalation administration of iloprost should provide iloprost delivery through the mouthpiece at a dose of 2.5 or 5 μg for a period of about 4 to 10 minutes. The mass median aerodynamic diameter of the aerosol particles is 1-5 μm.

To minimize the accidental effects of the drug, it is recommended to use Ventavis in nebulizers equipped with a filter or inhalation-starting system, and also to ventilate the room well.

Switch to another type of inhaler should be performed under the supervision of the attending physician.

Overdose

No cases of overdose have been reported.

Symptoms: In case of an overdose, it is possible to expect the development of an antihypertensive reaction, as well as headache, hot flushes, nausea, vomiting and diarrhea. A rise in blood pressure, a bradycardia or a tachycardia, pain in the extremities or back can also be noted during an overdose of the drug.

Treatment: interrupt the use of iloprost, monitor the patient's condition and conduct symptomatic therapy. The specific antidote is unknown.

Special instructions

Avoid contact of the Ventasis preparation in the form of a solution for the nebulizer with skin and eyes, and also its ingestion. During the inhalation from the nebulizer, the facial mask is not applied, and only the mouthpiece should be used.

Risk of fainting. During the use of the drug, it is necessary to monitor vital signs. It should be closely monitored for patients with low systemic BP to avoid aggravation of hypotension. Do not administer Ventasis to patients with a SAD level of less than 85 mm Hg. Art. Doctors should be wary of patients' concomitant diseases or the use of other medicines that may increase the risk of developing fainting.

Syncope is also a symptom that characterizes the course of pulmonary hypertension. Patients who experience syncope due to pulmonary hypertension should avoid any overexertion, for example, when performing physical exertion. Carrying out inhalation before exercise can be useful. Iloprost for inhalation has a short (1 to 2 h) vasodilating effect on the pulmonary vessels. The onset of syncope in physical activity reflects a failure in the therapy; In this case, the need for correction and / or modification of the selected therapy should be considered (see "Side effect").

Bronchospasm. With the inhalation of the drug Ventavis may increase the risk of bronchospasm, especially in patients with bronchial hyperreactivity. In patients with concomitant COPD and severe forms of bronchial asthma, the beneficial effect of Ventavis is not established. Patients with acute infectious processes in the lungs, COPD and severe bronchial asthma should be under close and constant supervision.

Pulmonary venous hypertension. Ventavis should not be used as a first-choice drug in the treatment of pulmonary hypertension caused by thromboembolism, with the possibility of surgical treatment.

If pulmonary edema occurs in patients with pulmonary hypertension when inhaling the iloprost, the likelihood of associated thrombosis of the pulmonary veins should be considered. The therapy in this case should be discontinued.

The use of the drug Ventasis is not recommended for patients with unstable pulmonary hypertension with concomitant severe right atrial failure in the event of aggravation of right atrial insufficiency. It is advisable to consider the possibility of switching to other drugs.

Additional safety information for physicians

The data obtained in preclinical studies (studies of pharmacological safety, chronic toxicity, genotoxicity and carcinogenicity), revealed no special risk for humans. Significant effects were detected only when the drug was used in doses significantly exceeding the maximum permissible doses in a person that are not used in clinical practice.

Currently, adequate data on the use of the drug Ventasis in pregnant women are absent. In studies in animals, the presence of reproductive toxicity was shown. Thus, in studies in rats on the evaluation of embryo and fetotoxicity, prolonged iv injection of iloprost led to anomalies of individual phalanges of fingers on the front paws of several young animals without the presence of dose-dependence. These anomalies are not considered as a consequence of a true teratogenic effect. Most likely, they are associated with the induced iloprost growth retardation during late organogenesis due to hemodynamic disorders in the fetoplacental complex. At the grown up offspring there were no disturbances of postnatal development of reproductive function. This indicates that a slowdown in growth can be compensated for in the postnatal period of development. In comparative studies on the evaluation of embryotoxicity in rabbits and monkeys, there was no abnormality of the fingers or other obvious structural abnormalities, even after administration of substantially higher doses of the drug, many times higher than the human dose.

Release Form

Solution for inhalation. In ampoules of 2 ml; In a pack of cardboard 30 amp. Or in a cardboard package of 30 amps; In a pack of cardboard 3 packs.

Manufacturer

Bayer Pharma AG, Germany.

For more information, please contact:

107113, Moscow, 3rd Rybinskaya St., 18, p. 2.

Conditions of supply of pharmacies

Without recipe.

Storage conditions of the drug Ventavis

At a temperature not exceeding 30 ° C.

Keep out of the reach of children.

The shelf life of the drug Ventavis

2 years.

Do not use beyond the expiration date printed on the package.