Ventavis, 10 µg/ml 2 ml 30 pcs

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 microcirculatory bed level; stimulates endogenous fibrinolytic activity; has anti-inflammatory effects such as inhibition of leukocyte adhesion following endothelial damage and leukocyte infiltration in damaged tissues and reduction of tumor necrosis factor alpha release.

After inhalation of Ventavis, direct vasodilation of the pulmonary arterial bed is observed with subsequent significant improvement of such parameters as pulmonary arterial pressure, pulmonary vascular resistance, cardiac output, and oxygen saturation of mixed venous blood. Effects on systemic vascular resistance and systemic BP were minimal.

Pharmacokinetics

Absorption. When iloprost was inhaled in patients with pulmonary hypertension (dose of iloprost delivered through a mouthpiece – 5 mcg, duration of inhalation – 4.6 to 10.6 min), Cmax of the drug in serum was determined by the end of inhalation and was 100-200 pg/ml. The drug concentration decreases as the drug is eliminated (T1/2 is approximately 5 to 25 minutes). Between 30 minutes and 1 hour after the end of inhalation, iloprost is no longer detectable in the central chamber (the sensitivity limit of the method is 25 pg/ml).

Distribution. There are currently no studies performed with inhaled administration of the drug.

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

Metabolism. There are currently no studies performed with inhalation administration of the drug. Results of in vitro studies indicate similar metabolism of iloprost in the lungs after both IV and inhalation administration. After IV administration, iloprost is metabolized to a greater extent, mainly by β-oxidation of the side carboxyl chain. The drug is not excreted in unchanged form. The main metabolite is tetraniloprost, which is detected in urine in free and conjugated form. As experimental studies in animals have shown, tetranoriloprost is pharmacologically inactive.

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

Elimination. There are currently no studies performed with inhaled administration of the drug. The excretion of iloprost after IV infusion in subjects with normal renal and hepatic function is in most cases characterized by a biphasic profile with an average T1/2 of 3 to 5 min and 15 to 30 min. Total Cl of iloprost is approximately 20 ml/kg/min, indicating additional extrahepatic metabolism of iloprost.

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

Renal dysfunction

. In a study with IV administration of iloprost, it was shown that patients with end-stage renal failure who were on intermittent dialysis had significantly lower Cl of the drug (mean Cl = 5±2 mL/min/kg) than patients with renal failure who were not receiving intermittent dialysis (mean Cl =18±2 mL/min/kg).

Hepatic dysfunction

Because iloprost is metabolized to a greater extent in the liver, changes in hepatic function affect plasma concentrations of the drug. The results of a study with intravenous administration of the drug included data from 8 patients with cirrhosis. The mean Cl of iloprost was calculated to be 10 ml/min/kg.

Age and sex

Age and sex have no clinical relevance to the pharmacokinetics of iloprost.

Indications

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 action of drugs or toxins; pulmonary hypertension due to chronic pulmonary artery thrombosis and/or embolisms when surgical treatment is not possible.

Active ingredient

Composition

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

How to take, the dosage

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

Previous therapy should be adjusted according to the patient’s individual needs (see “Interactions”). Ventavis is used for long-term therapy.

Recommended doses

Adults. At the start of treatment with Ventavis, the first inhaled dose of iloprost should be 2.5 mcg (delivered through the mouthpiece of an inhaler). If the patient tolerates treatment well, the dose of iloprost should be increased to 5 mcg and maintained for subsequent inhalations. If the patient’s tolerance is poor, the dose should be returned to 2.5 mcg.

Iloprost inhalations should be given 6 to 9 times daily, according to individual patient need and tolerance of the drug.

Depending on the desired dose of medication 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. Cautious titration of the initial dose with an interval between injections of 3-4 hours is recommended.

The starting dose should be 2.5 mcg with an injection interval of 3-4 hours (which corresponds to a maximum of 6 times a day). Subsequently, a cautious reduction of the intervals between injections is possible, taking into account individual tolerance of the drug. If further dose increase up to 5 µg is indicated, the intervals between injections should initially be 3-4 h; thereafter they may be reduced taking into account individual tolerance. Further accumulation of the drug after several days of therapy seems unlikely due to overnight intervals of use.

Patients with impaired renal function. In patients with Cl creatinine >30 ml/min there is no need to adjust the drug dose. The use of the drug Ventavis in patients with creatinine cl cl <30 ml/min has not been studied in clinical trials. Iloprost elimination is reduced in patients with renal insufficiency requiring dialysis. For dosing recommendations, see “Patients with impaired renal function. “Patients with impaired liver function”.

Injection instructions

A new ampoule of Ventavis must be used for each inhalation. The entire contents of the ampoule must be poured into the nebulizer chamber immediately prior to use. The manufacturer’s instructions for hygiene and cleaning of the nebulizer must be strictly followed.

The nebulizer solution not used for inhalation must be discarded.

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

Nebulizers suitable for inhaled administration of iloprost must deliver iloprost through the mouthpiece at a dose of 2.5 or 5 mcg over a time period of approximately 4 to 10 minutes. The mass-median aerodynamic diameter of the aerosol particles is 1-5 μm.

In order to minimize accidental exposure to the drug, it is recommended that Ventavis be used in nebulizers equipped with a filter or inhalation trigger system and that the room be well ventilated.

Transition to another type of nebulizer should be done under the supervision of your doctor.

Interaction

Is no compatibility studies have been performed, Ventavis should not be mixed when administered with other drugs. Iloprost may increase the antihypertensive effect of vasodilators and other antihypertensive drugs. Caution should be exercised when using Ventavis concomitantly with vasodilators and antihypertensive drugs, since their doses may need to be adjusted.

Because iloprost inhibits platelet function, its use with anticoagulants (such as heparin, coumarin-derived anticoagulants), or other antiaggregants (such as acetylsalicylic acid, NSAIDs, phosphodiesterase inhibitors and nitrate vasodilators) may increase the risk of bleeding (see “Side effects”). “Side effects). Patients receiving anticoagulant therapy or other platelet aggregation inhibitors in accordance with accepted medical practice should be under constant monitoring of coagulation parameters. Prior administration of acetylsalicylic acid at a dose of up to 300 mg/day for 8 days has no effect on the pharmacokinetics of iloprost. In an animal study, it was found that administration of iloprost can lead to a decrease in plasma tissue plasminogen activator (TAP) Css. Results from human studies show that infusion of iloprost does not affect the pharmacokinetics of orally administered digoxin, and iloprost does not affect the pharmacokinetics of concomitantly administered TAP.

In animal experiments, the vasodilatory effect of iloprost was attenuated if GCS were administered beforehand, whereas the inhibitory 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 cytochrome P450 isoenzyme activity have shown that significant suppression of drug metabolism mediated through these isoenzymes by exposure to iloprost is unlikely.

Special Instructions

Contact of Ventavis in nebulizer solution form with skin and eyes should be avoided and swallowing should be avoided. A face mask is not used during nebulizer inhalation and only the mouthpiece should be used.

The risk of fainting. Vital signs should be monitored during the use of the drug. Patients with low systemic BP should be closely monitored to avoid worsening hypotension. Ventavis should not be administered to patients with BP less than 85 mm Hg. Physicians should be alert to patients’ comorbidities or use of other medications that may increase the risk of fainting.

Fainting is also a symptom that characterizes the course of pulmonary hypertension. Patients who have fainting due to pulmonary hypertension should avoid any overexertion, such as exercise. Performing inhalation before performing physical activity may be helpful. Iloprost for inhalation has a short-lived (1 to 2 hours) vasodilatory effect on pulmonary vessels. If fainting occurs with exercise, however, this reflects a failure in therapy, and in this case, you should consider adjusting and/or changing your therapy (see side effects).

Bronchospasm. Inhalation of Ventavis may increase the risk of bronchospasm, especially in patients with bronchial hyperresponsiveness. In patients with concomitant COPD and severe bronchial asthma a 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 when surgical treatment is possible.

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

The use of Ventavis is not recommended in patients with unstable pulmonary hypertension with concomitant severe right atrial insufficiency if right atrial insufficiency worsens. In this case it is reasonable to consider switching to other drugs.

Preliminary data from preclinical studies (pharmacological safety, chronic toxicity, genotoxicity and carcinogenicity studies) showed no particular risk to humans. Significant effects were found only when the drug was used in doses significantly higher than the maximum allowable doses in humans, which are not used in clinical practice.

There are currently no adequate data on the use of Ventavis in pregnant women. Reproductive toxicity has been shown in animal studies. For example, in studies in rats evaluating embryo- and fetotoxicity, prolonged IV administration of iloprost resulted in abnormalities of individual foreleg toe phalanges in several baby animals without the presence of dose-dependence. These abnormalities are not considered a consequence of true teratogenic exposure. Most likely, they are related to iloprost-induced growth retardation during late organogenesis due to hemodynamic abnormalities in the fetoplacental complex. No abnormalities in postnatal reproductive development were observed in the grown offspring. This indicates that growth retardation can be compensated in the postnatal period of development. No finger abnormalities or other apparent structural abnormalities were found in rabbits and monkeys in comparative embryotoxicity studies, even after administration of significantly higher doses of the drug, many times the human doses.

Contraindications

Pregnancy and lactation; pathological conditions in which the effect of the drug on platelets may increase the risk of bleeding (including gastric and duodenal ulcer in acute stages, trauma, intracranial hemorrhage); severe coronary heart disease or unstable angina; myocardial infarction within the previous 6 months; decompensated heart failure without proper medical supervision; severe arrhythmias; suspected pulmonary congestion; cerebrovascular complications (including transient ischemic attack).including transient ischemic attack, stroke) within the previous 3 months; pulmonary hypertension due to pulmonary veno-occlusive disease; congenital or acquired heart valve defects with clinically significant myocardial dysfunction that are not due to pulmonary hypertension; hypersensitivity to iloprost or other drug components; children and adolescents under 18 years of age.

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

Side effects

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

The adverse reactions noted with Ventavis are classified by organ system below.

The frequency of adverse reactions observed in clinical trials is as follows: very common ≥1/10; common ≥1/100 and < 1/10. For adverse effects detected only during post-registration observational programs and for which it is not possible to estimate the frequency, “frequency unknown” is indicated. In each adverse effect frequency group, adverse reactions are presented in decreasing order of importance.

The data on adverse reactions presented below are based on pooled data from phase II and III clinical trials (number of patients taking the drug – 131) and data from post-registration observational programs.

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

Immune system disorders: frequency unknown – hypersensitivity reactions.

Nervous system disorders: very common – headache; common – dizziness.

Vascular system disorders: very common – vasodilation; common – hypotension*, fainting.

Chronic disorders: often – tachycardia, palpitations.

Respiratory, chest and mediastinal disorders: very common – chest pain, cough; common – dyspnea, pharyngolaryngeal pain, throat irritation; common unknown – bronchospasm*/chewed breath, nasal congestion.

Gastrointestinal disorders: very common – nausea; common – diarrhea, vomiting, irritation of the mucosa of the mouth and tongue, including pain; frequency unknown – perversion of taste.

Skin and subcutaneous tissue disorders: often – rash.

Musculoskeletal and connective tissue disorders: very common – pain in the jaw/trism; common – back pain.

General disorders and disorders at the site of administration: very often – peripheral edema.

The terms from the Medical Dictionary of Standardized International Terminology (MedDRA, version 14.0) were used to describe certain reactions, synonyms and related conditions.

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

**Bleeding (mainly in the form of nasal bleeding 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 “Interactions”).

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

In clinical studies, peripheral edema was reported in 19.1% of patients treated with iloprost and in 22.2% of patients treated with placebo. Peripheral edema is a very common symptom of the disease itself; however, it may also be associated with the use of iloprost.

As expected for patients with pulmonary hypertension, dizziness and syncope were frequently reported, but there were no significant differences in their frequency between therapy groups (see “Special Precautions”).

Overdose

No cases of overdose have been reported.

Symptoms: in case of overdose, hypotensive reaction can be expected, as well as headache, hot flashes, nausea, vomiting, and diarrhea. BP elevation, bradycardia or tachycardia, and pain in the extremities or back may also occur in an overdose of the drug.

Treatment: interrupt use of iloprost, monitor patient’s condition and provide symptomatic therapy. A specific antidote is not known.

Pregnancy use

Women with pulmonary hypertension should avoid becoming pregnant, as this could lead to a life-threatening exacerbation of the disease. There are insufficient data on the use of Ventavis in pregnant women. If pregnancy occurs, Ventavis should be administered when the expected benefit to the mother outweighs the possible risk to the fetus.

If it is not known whether iloprost and its metabolites are excreted into the breast milk, breastfeeding should be stopped if it is necessary to use the drug during lactation.