Ventavis (Ventavis)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceIloprostIloprost
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  • Ventavis
    solution d / inhal. 
    Bayer Pharma AG     Germany
  • Ilomedin®
    concentrate d / infusion 
    Bayer Pharma AG     Germany
    • Dosage form: & nbspinhalation solution
    Composition:

    1 ml of the solution contains 10 μg of iloprost.

    Excipients: trometamol 0.121 mg, ethanol 96% 0.810 mg, sodium chloride 9,000 mg, hydrochloric acid 1 M 0.510 mg, water for injection 992.849 mg.

    Description:Transparent, colorless or lightly colored, particle-free solution.
    Pharmacotherapeutic group:Antiaggregant agent
    ATX: & nbsp

    B.01.A.C.11   Iloprost

    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 such mediators 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 damaged 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 saturation with mixed venous blood. The effect on systemic vascular resistance and systemic blood pressure was minimal.

    Pharmacokinetics:

    Absorption

    With inhalation administration of iloprost, patients with pulmonary hypertension or healthy volunteers (iloprost dose delivered via the mouthpiece: 5 μg, duration of inhalation from 4.6 to 10.6 min), the mean peak concentration 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 The concentration of the drug decreases as the drug is withdrawn (half-life is about 5-25 minutes). In the interval from 30 minutes to 2 hours after the end of the 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 intravenous infusion, the apparent volume of distribution in the equilibrium state 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.

    Research results in vitro indicate a similar metabolism of iloprost in the lungs after both intravenous and after inhalation administration.

    After intravenous administration iloprost is more exposed to metabolism 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.

    Based on research results in vitro the involvement 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 following intravenous infusion in subjects with normal kidney and liver function in most cases is characterized by a two-phase profile with an average half-life of 3 to 5 minutes and 15 to 30 minutes. The total clearance 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, in healthy volunteers. After intravenous infusion, the excretion of total radioactivity was 81%, with 68% being excreted by the kidneys and 12% by the intestine. Elimination of metabolites occurs in two phases, for which the calculated half-lives are about 2 hours and 5 hours (plasma) and about 2 hours and 18 hours (urine).

    In case of impaired renal function

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

    When a violation of liver function

    Because the iloprost is more exposed to metabolism in the liver, changes in liver function affect the concentration of the drug in the plasma. Results of the study with intravenous administration of the drug included data from 8 patients with cirrhosis of the liver. The average clearance of iloprost was calculated as 10 ml / min / kg.

    Age and gender

    Sex has no clinical significance for the pharmacokinetics of iloprost.

    Pharmacokinetics in elderly patients has not been studied.

    Indications:

    Treatment of moderate and 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 surgical treatment.

    Contraindications:

    - Pathological conditions, in which the effect of the drug Ventasis on platelets may increase the risk of bleeding (incl.peptic ulcer of the stomach and duodenum in the stage of exacerbation, 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;

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

    - Pincreased sensitivity to iloprost or other components of the drug;

    - children and adolescents under 18 years of age (due to the limited experience).

    Carefully:

    - Dysfunction of the liver and renal failure in patients in need of dialysis;

    - arterial hypotension;

    - COPD;

    - severe bronchial asthma.

    Pregnancy and lactation:

    Women suffering from pulmonary hypertension should avoid pregnancy, as this can lead to a 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, does iloprost and its metabolites into breast milk, then if you need to use the drug during lactation, breastfeeding should be discontinued.

    Dosing and Administration:

    The drug Ventavis is used for long-term therapy.

    Ready-to-use solution is used through an appropriate device for inhalation (nebulizer). The previous therapy should be adjusted in accordance with the individual needs of the patient (see "Interaction with other drugs and other forms of interaction").

    Recommended doses:

    Adults

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

    Inhalation of iloprost should be performed 6 to 9 times a day in accordance with the individual patient's need 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 hepatic 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, you must 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, it is possible to carefully reduce the intervals between administrations, taking into account the individual tolerability of the drug. 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 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. The use of Ventavis in patients with creatinine clearance <30 ml / min in clinical studies has not been studied. Elimination of iloprost is reduced in patients with renal failure who need dialysis. For recommendations on dosing, see the subsection "Patients with impaired hepatic function".

    Instructions for the introduction of

    To perform each inhalation, you need to use a new vial of Ventasis. 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.

    The solution not used for inhalation should be poured out.

    For carrying out inhalation therapy with a solution of the drug Ventas, certified nebulizers of compressor type, ultrasonic nebulizers and nebulizers, based on vibration technology, are suitable.

    Nebulizers suitable for inhalation administration of iloprost should provide iloprost delivery through the mouthpiece at a dose of 2.5 μg 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 effect 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.

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

    Side effects:

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

    The adverse reactions noted with the use of the Ventasis preparation are classified below in organ systems.

    The adverse reactions presented below are based on pooled phase II or III clinical data, involving 131 patients who received Ventasis 10 μg / mL and post-marketing follow-up data.

    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 reactions 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 frequencies, unwanted reactions are presented in order of decreasing importance.

    System-Organ Class

    Very often - ≥1 / 10

    Often - ≥1 / 100 and <1/10

    Frequency unknown

    Violations of the blood and lymphatic system

    Bleeding *#

    Thrombocytopenia

    Immune system disorders

    Hypersensitivity reactions

    Disturbances from the nervous system

    Headache

    Dizziness

    Disorders from the vascular system

    Vasodilation

    Arterial hypotension *, fainting#

    Heart Disease

    Tachycardia, palpitation

    Disturbances from the respiratory, thoracic and mediastinal organs

    Pain in the chest, cough

    Shortness of breath, pharyngolaryngeal pain, irritation in the throat

    Bronchospasm * / wheezing, nasal congestion

    Disorders from the gastrointestinal tract

    Nausea

    Diarrhea, vomiting, irritation of the oral mucosa and tongue, including pain

    Perversion of taste

    Disturbances from the skin and subcutaneous tissues

    Skin rash

    Disturbances from the musculoskeletal system and connective tissue

    Pain in the jaw / trismus

    Backache

    General disorders and disorders at the site of administration

    Peripheral edema#

    * These cases were life-threatening and / or fatal.

    To describe specific reactions, their synonyms and bound states, the most preferable terms from the medical vocabulary for regulatory activity MedDRA, version 14.0.

    # Description of certain undesirable reactions

    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 with other drugs and other forms of interaction"). Cases of cerebral hemorrhage and intracranial hemorrhage with a fatal outcome have been reported.

    In clinical trials, cases of peripheral edema in 12.2% of patients receiving iloprost, and in 16.2% 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, fainting, but there was no significant difference between the treatment groups (see "Special instructions").

    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 flashes" of blood, nausea, vomiting and diarrhea. Raising blood pressure, aetiology, or tachycardia, pain in the extremities or back can also be noted with an overdose of the drug.

    Therapy

    The specific antidote is unknown.

    It is recommended to break the application of iloprost, monitor the patient's condition and perform symptomatic therapy.

    Interaction:

    Since compatibility studies have not been conducted, the Ventavis preparation should not be mixed with other drugs.

    Iloprost can enhance the antihypertensive effect of vasodilators and antihypertensive drugs. Care should be taken when using the drug Ventavis with vasodilators and antihypertensive drugs at the same time. may need to adjust their dose.

    Because the iloprost suppresses the function of platelets, its use in conjunction with anticoagulants (such as heparin, anticoagulants from the group of coumarin derivatives), or other antiplatelet agents (such as acetylsalicylic acid, non-steroidal anti-inflammatory drugs, non-selective phosphodiesterase inhibitors [such as theophylline, pentoxifylline, dipyridamole, trapidil or ibudilast], selective inhibitors of phosphodiesterase-3 [FDEZ] [such as amrinone, enoximone, milrinone, cilostazol, anagrelide], and vasodilators from the nitrate group) can enhance iloprost-induced platelet inhibition and thus 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 supervision.

    The previous appointment of acetylsalicylic acid inside at a dose of up to 300 mg per 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 the equilibrium concentration in the plasma of the tissue plasminogen activator (TAP). The results of studies in humans show that iloprost infusion does not affect the pharmacokinetics of digoxin administered orally, and iloprost does not affect the pharmacokinetics of concomitant TAP.

    In animal experiments, the vasodilating effect of iloprost was weakened if glucocorticosteroids were previously introduced, while the inhibitory effect on platelet aggregation remains unchanged.The significance of these data for the use of the drug Ventasis in humans is unknown.

    Although no clinical studies have been conducted, studies in vitro to assess the possible inhibitory effect of iloprost on the activity of cytochrome P450 isoenzymes showed that it is unlikely to significantly suppress the metabolism of drugs mediated through these isoenzymes under the influence of iloprost.

    Special instructions:

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

    Risk of syncope

    Doctors should be wary of patients' concomitant diseases or the use of other medicines that may increase the risk of developing syncope.

    Syncope is also a symptom that characterizes the course of pulmonary hypertension. Patients who have fainting 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 (from one to two hours) vasodilating effect on pulmonary vessels. An increased frequency of fainting can indicate "failures" in ongoing therapy and / or progression of the disease; in this case, the need for correction and / or modification of the selected therapy should be considered (see "Side effect").

    Arterial hypotension

    During the application of the drug, it is necessary to monitor vital signs. It is necessary to closely monitor patients with initially low systemic blood pressure in order to avoid aggravation of hypotension. Do not prescribe the drug Ventasis to patients with a systolic blood pressure less than 85 mm Hg. Art.

    Bronchospasm

    With the inhalation of the drug Ventavis may increase the risk of bronchospasm, especially in patients with hyperreactivity of the bronchi (see section "Side effect"). In patients with concomitant chronic obstructive pulmonary disease (COPD) and severe forms of bronchial asthma, the beneficial effect of Ventavis is not established.Patients with acute infectious processes in the lungs, chronic obstructive pulmonary disease and severe bronchial asthma should be under close and constant supervision.

    Pulmonary venous hypertension

    The Ventavis preparation 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 patients with inhaled use of iloprost have signs of pulmonary edema, the probability of associated pulmonary veno-occlusive disease should be considered. Treatment should be discontinued.

    The use of Ventavis is not recommended for patients with unstable pulmonary hypertension with concomitant severe right atrial fibrillation if right atrial insufficiency worsens. It is advisable to consider the possibility of switching to other medicines.

    Additional safety information for physicians

    Data obtained in preclinical studies (studies on pharmacological safety, chronic toxicity, genotoxicity and carcinogenicity) did not reveal any particular risk to 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 intravenous administration of iloprost led to abnormalities of the fingers in several born 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 due to hemodynamic disorders in the fetoplacental complex. These anomalies were not detected in other animal species.

    Effect on the ability to drive transp. cf. and fur:

    Care should be taken when driving vehicles and mechanisms during the initiation of therapy, until the individual response to the drug is determined.The ability to drive vehicles and other mechanisms in patients who experience symptoms associated with hypotension, such as dizziness, may be compromised.

    Form release / dosage:

    Solution for inhalation, 10 mcg / ml.

    Packaging:

    To 2 ml in ampoules of colorless glass type 1 with a capacity of 3 ml with a break point and two rings - white and pink. 6 ampoules per pallet, 5 pallets along with instructions for use are placed in a cardboard box (30 ampoules).

    6 ampoules per pallet, 5 pallets are placed in a primary cardboard package, 3 such packages (30 ampoules each) along with the instructions for use are placed in a cardboard box (90 ampoules).

    Storage conditions:

    Store at a temperature not exceeding 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after expiry date.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-005775/10
    Date of registration:23.06.2010 / 11.09.2012
    Expiration Date:Unlimited
    The owner of the registration certificate:Bayer Pharma AGBayer Pharma AG Germany
    Manufacturer: & nbsp
    Representation: & nbspBAYER, AOBAYER, AO
    Information update date: & nbsp02.02.2017
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