Ventavis, ampoules 10 µg/ml, 2ml, 30pcs

Composition

In ampoules of 2 ml,1 ml of the solution contains 10 micrograms of iloprost.

Pharmacological action

Iloprost, the active ingredient in Ventavis, is a synthetic analog of prostacyclin. The drug inhibits platelet aggregation, platelet adhesion and release reactions of soluble adhesion molecules; dilates arterioles and venules; increases capillary density and reduces increased vascular permeability caused by mediators such as serotonin or histamine at the level of the microcirculatory bed; stimulates endogenous fibrinolytic activity; has anti-inflammatory effects, such as inhibition of leukocyte adhesion after endothelial damage and leukocytic activation. infiltration in damaged tissues, as well as a decrease in the release of tumor necrosis factor alpha.

After inhalation of Ventavis, direct vasodilation of the pulmonary arterial bed is observed, followed by a significant improvement in such indicators 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. When iloprost is administered by inhalation to patients with pulmonary hypertension (the dose of iloprost delivered through a mouthpiece is 5 micrograms, the duration of inhalation is from 4.6 to 10.6 minutes) Cmax of the drug in serum was determined by the end of inhalation and was 100-200 pg / ml. The concentration of the drug decreases as the drug is eliminated (T1 / 2 is approximately 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. Currently, there are no studies performed with the inhaled use of the drug.

After intravenous infusion, the apparent Vss in healthy volunteers ranged from 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 does not depend on the concentration and is approximately 60%, of which 75% is due to binding to albumin.

Metabolism. Currently, there are no studies performed with the inhaled use of the drug. The results of in vitro studies indicate a similar metabolism of iloprost in the lungs after both intravenous and inhaled use. After intravenous use, iloprost is more metabolized, mainly by beta-oxidation of the carboxyl side chain. The drug is not excreted in unchanged form. The main metabolite is tetranoriloprost, which is found in the urine in free form and conjugated form. Experimental studies in animals have shown that tetranoriloprost is pharmacologically inactive.

According to the results of in vitro studies, the involvement of cytochrome P 450 in the metabolism of iloprost is minimal.

Output. Currently, there are no studies performed with the inhaled use of the drug. Elimination of iloprost after intravenous infusion in subjects with normal renal and hepatic function in most cases is characterized by a two-phase profile with an average 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 additional extrahepatic metabolism of iloprost.

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

Impaired renal function

In a study with IV use of iloprost, it was shown that in patients with end-stage renal insufficiency who are on periodic dialysis, the Cl of the drug (average Cl = 5±2 ml/min/kg) is significantly lower than in patients with renal insufficiency who do not receive periodic dialysis (average Cl =18±2 ml/min/kg).

Impaired liver function

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

Age and gender

Age and gender are not clinically relevant for the pharmacokinetics of iloprost.

Indications

Treatment of moderate and severe pulmonary hypertension in the following cases: idiopathic (primary) arterial pulmonary hypertension, familial arterial pulmonary hypertension; arterial pulmonary hypertension caused by connective tissue disease or the action of drugs or toxins; pulmonary hypertension due to chronic thrombosis and/or pulmonary embolism in the absence of surgical treatment.

Use during pregnancy and lactation

Women suffering from pulmonary hypertension should avoid pregnancy, as this can lead to a life-threatening exacerbation of the disease. There are insufficient data on the use of Ventavis in pregnant women. When pregnancy occurs, Ventavis should be prescribed when the expected benefit to the mother exceeds the possible risk to the fetus.

Since it has not been established whether iloprost and its metabolites are excreted in breast milk, breast-feeding should be discontinued if necessary during lactation.

Contraindications

pregnancy and lactation; pathological condition in which the effects of the drug on platelets may increase the risk of bleeding (including gastric ulcer and duodenal ulcer in the acute stage, trauma, intracranial hemorrhage), severe coronary artery disease or unstable angina; myocardial infarction in the previous 6 months; decompensated heart failure in the absence of adequate medical supervision; severe arrhythmia; suspicion of the stagnation of blood in the lungs; cerebrovascular events (including transient ischemic attack, stroke) in the previous 3 months; pulmonary hypertension due to pulmonary veno-occlusive disease; congenital or acquired valvular heart with clinically significant dysfunction of the myocardium, which is not due to pulmonary hypertension; hypersensitivity to iloprost or other components of the drug; children and adolescents under 18 years.

With caution: impaired liver function and renal failure in patients requiring dialysis; hypotension; COPD; severe bronchial asthma.

Side effects

In addition to local undesirable effects resulting from the inhaled route of use of iloprost (increased cough), adverse reactions to the drug are due to the pharmacological characteristics of PH. The most common adverse events (>20%) observed in clinical trials were vasodilation, headache, and worsening cough. The most serious adverse events were hypotension, bleeding, and bronchospasm.

Adverse reactions reported with the use of Ventavis are classified below by organ system.

Characteristics of the frequency of adverse reactions observed in clinical studies are as follows: very often – ≥1/10; often – ≥1/100; and For undesirable effects identified only during post-marketing surveillance programs, and for which it is not possible to estimate the frequency, “frequency unknown”is indicated. In each group, the frequency of undesirable effects is presented in order of decreasing significance.

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

Blood and lymphatic system disorders: very common — bleeding**; frequency unknown-thrombocytopenia.

Immune system disorders: frequency unknown-hypersensitivity reactions.

Nervous system disorders: very often — headache; often-dizziness.

Vascular disorders: very often — vasodilation; often-hypotension*, syncope.

Cardiac disorders: often-tachycardia, palpitation sensation.

Respiratory, thoracic and mediastinal disorders: very common — chest pain, cough; often — shortness of breath, pharyngolaryngeal pain, throat irritation; frequency unknown-bronchospasm*/wheezing, nasal congestion.

Gastrointestinal disorders: very often — nausea; often-diarrhea, vomiting, irritation of the oral mucosa and tongue, including pain; frequency unknown-taste distortion.

Skin and subcutaneous tissue disorders: often-rash.

Musculoskeletal and connective tissue disorders: very common — jaw pain/trismus; often-back pain.

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

Terms from the medical Dictionary of Standardized International Terminology (MedDRA, version 14.0) are used to describe certain reactions, their synonyms, and related conditions.

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

** Bleeding (mainly in the form of nosebleeds and hemoptysis) was very common, which is expected in 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 platelet aggregation inhibitors (see Interaction).

Cases of brain hemorrhage and fatal intracranial hemorrhage have been reported.

In clinical trials, peripheral edema was reported in 19.1% of patients treated with iloprost and in 22.2% of patients treated with placebo. The occurrence of peripheral edema is a very common symptom of the disease itself, however, they can also be associated with the use of iloprost.

As expected for patients with pulmonary hypertension, dizziness and fainting were often noted, but there were no significant differences in their frequency between the treatment groups (see “Special instructions”).

Interaction

Since compatibility studies have not been conducted, Ventavis should not be mixed with other drugs when administered. Iloprost may enhance the antihypertensive effect of vasodilators and other antihypertensive drugs. Caution should be exercised when using Ventavis concomitantly with vasodilators and antihypertensive drugs, as dose adjustment may be required.

Since iloprost suppresses platelet function, its use in combination with anticoagulants (such as heparin, coumarin-derived anticoagulants), or other antiplatelet agents (such as acetylsalicylic acid, NSAIDs, phosphodiesterase inhibitors, and nitrate vasodilators) may increase the risk of bleeding (see “Side Effects”). Patients receiving anticoagulant therapy or other platelet aggregation inhibitors in accordance with accepted medical practice should be constantly monitored for coagulation parameters. Previous use of acetylsalicylic acid at a dose of 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 use of iloprost can lead to a decrease in Css in the plasma of the tissue plasminogen activator (TAP). The results of human studies show that iloprost infusion does not affect the pharmacokinetics of digoxin administered orally, and iloprost does not affect the pharmacokinetics of concomitantly administered TAP.

In animal experiments, the vasodilating effect of iloprost was weakened if corticosteroids were previously administered, while the suppressive effect on platelet aggregation remained unchanged. The significance of these data for the use of Ventavis in humans is unknown. Although no clinical studies have been conducted, in vitro studies evaluating the possible inhibitory effect of iloprost on the activity of cytochrome P 450 isoenzymes have shown that significant suppression of drug metabolism mediated through these isoenzymes under the influence of iloprost is unlikely.

How to take, course of use and dosage

By inhalation. The ready-to-use solution is prescribed through an appropriate inhalation device (nebulizer).

Previous therapy should be adjusted according to the individual needs of the patient (see “Interaction”). The drug Ventavis is used for long-term therapy.

Recommended doses

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

Inhalation of iloprost should be carried out from 6 to 9 times a day, in accordance with the individual patient’s needs and 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. Iloprost elimination is reduced in patients with impaired liver function. In order to avoid undesirable accumulation of the drug during the day, special precautions should be taken when selecting the initial dose of the drug in these patients. Careful titration of the initial dose with an interval between injections of 3-4 hours is recommended.

The initial dose should be 2.5 mcg with an interval between injections of 3-4 hours (which corresponds to the appointment of a maximum of 6 times a day). Subsequently, it is possible to carefully reduce the intervals between injections, taking into account the individual tolerability of the drug. If a further increase in the dose to 5 mcg is indicated, the intervals between injections should initially be 3-4 hours; then they can be reduced taking into account individual tolerability. Further accumulation of the drug after several days of therapy seems unlikely due to the night break in use.

Patients with impaired renal function. In patients with creatinine clearance >30 ml / min, there is no need to adjust the dose of the drug. Use of Ventavis in patients with creatinine clearance Iloprost elimination is reduced in patients with renal insufficiency requiring dialysis. Dosage recommendations-see “Patients with impaired liver function”.

Introduction Instructions

For each inhalation, a new ampoule of Ventavis must be used. The contents of the ampoule must be completely poured into the nebulizer chamber immediately before use. The inhaler manufacturer’s instructions for hygiene and cleaning must be strictly followed.

The nebulizer solution that was not used for inhalation should be emptied.

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

Nebulizers suitable for inhaling iloprost should allow delivery of 2.5 or 5 micrograms of iloprost through the mouthpiece over a period of approximately 4 to 10 minutes. The mass-median aerodynamic diameter of aerosol particles is 1-5 microns.

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

Switching to a different type of inhaler should be done under the supervision of the attending physician.

Overdose

No overdose cases have been reported.

Symptoms: in case of overdose, you can expect to develop a hypotensive reaction, as well as headache, hot flashes, nausea, vomiting and diarrhea. An increase in blood pressure, bradycardia or tachycardia, pain in the extremities or back can also occur with an overdose of the drug.

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

Special instructions

Avoid contact of Ventavis as a nebulizer solution with the skin and eyes, as well as its ingestion. During nebulizer inhalation, the face mask is not used, and only the mouthpiece should be used.

Risk of fainting. During the use of the drug, it is necessary to monitor vital signs. Patients with low systemic blood pressure should be closely monitored to avoid worsening hypotension. Ventavis should not be prescribed to patients with a blood pressure level of less than 85 mm Hg. Doctors should be wary of concomitant diseases or the use of other drugs that may increase the risk of syncope.

Syncope is also a symptom that characterizes the course of pulmonary hypertension. Patients who experience syncope due to pulmonary hypertension should avoid any overexertion, such as when performing physical activities. Taking an inhalation before exercising can be helpful. Iloprost for inhalation use has a short-term (from 1 to 2 hours) vasodilating effect on the pulmonary vessels. The occurrence of syncope during physical exertion reflects failures in the therapy performed; in this case, the need for correction and/or modification of the chosen therapy should be considered (see “Side effect”).

Bronchospasm. Inhalation of Ventavis may increase the risk of bronchospasm, especially in patients with hyperreactivity of the bronchi. In patients with concomitant COPD and severe forms of bronchial asthma, the positive effect of Ventavis has not been established. Patients with acute lung infections, COPD, and severe bronchial asthma should be closely monitored at all times.

Pulmonary venous hypertension. Ventavis should not be used as the drug of first choice in the treatment of pulmonary hypertension caused by thromboembolism, if surgical treatment is possible.

If symptoms of pulmonary edema occur during inhaled use of iloprost in patients with pulmonary hypertension, the possibility of associated pulmonary vein thrombosis should be considered. Therapy in this case should be discontinued.

Ventavis is not recommended for patients with unstable pulmonary hypertension and concomitant severe right-atrial insufficiency in case of exacerbation of right-atrial insufficiency. At the same time, it is advisable to consider the possibility of switching to other medicines.

Additional safety information for doctors

Data obtained in preclinical studies (studies of pharmacological safety, chronic toxicity, genotoxicity and carcinogenicity) did not reveal any particular risk to humans. Significant effects were found only when the drug was administered at doses significantly higher than the maximum permissible doses in humans, which are not used in clinical practice.

Currently, there are no adequate data on the use of Ventavis in pregnant women. Animal studies have shown the presence of reproductive toxicity. Thus, in studies in rats evaluating embryoand fetotoxicity, prolonged intravenous use of iloprost led to anomalies of individual phalanges of the fingers on the forelegs in 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 iloprost-induced growth retardation during late organogenesis due to hemodynamic disorders in the fetoplacental complex. The raised offspring did not show any postnatal development of reproductive function. This indicates that growth retardation can be compensated for in the postnatal period of development. In comparative studies evaluating embryotoxicity in rabbits and monkeys, no finger abnormalities or other obvious structural abnormalities were found, even after significantly higher doses of the drug were administered, many times higher than the human dose.

Form of production

Solution for inhalation

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

2 years

Active ingredient

Iloprost

Conditions of release from pharmacies

By prescription

Dosage form

inhalation solution