Ventavis

General characteristics. Structure:

Active agent: 10 mkg of an iloprost.
Excipients: трометамол - 0,121 mg, ethanol of 96% - 0,810 mg, sodium chloride - 9,000 mg, Acidum hydrochloricum of 1 M - 0,510 mg, water for injections of-992,849 mg.
Description
Solution, transparent, colourless or slabookrashenny, free from particles.

Pharmacological properties:

Pharmacodynamics. Илопрост, active ingredient of drug Ventavis, represents a synthetic analog of prostacyclin. Drug inhibits aggregation of thrombocytes, adhesion of thrombocytes and reaction of release of soluble molecules of adhesion; expands arterioles and venules; increases density of capillaries and reduces the increased vascular permeability caused by such mediators as serotonin or a histamine at the level of a microcirculator bed; stimulates endogenous  fibrinolitic  activity;  renders  antiinflammatory effects, such as inhibition of adhesion of leukocytes after damage of an endothelium and leukocytic infiltration to the damaged fabrics, and also reduction of release of a factor of a necrosis of a tumor an alpha.
After drug inhalation Ventavis is observed a direct vazodilatation of a pulmonary arterial bed with the subsequent considerable improvement of such indicators as pressure in pulmonary arteries, the pulmonary vascular resistance, cordial emission, and also saturation by oxygen of the mixed venous blood. Influence on system vascular resistance and system arterial pressure was minimum.
Pharmacokinetics.

• Absorption
At inhalation purpose of an iloprost to patients with pulmonary hypertensia (the dose of an iloprost delivered through a mouthpiece: 5 mkg) the maximum concentration of drug in serum was defined by the time of the end of inhalation and made 100-200 pg/ml. Concentration of drug decreases in process of drug removal (elimination half-lives make about 5-25 min.). In the range from 30 min. to 1 h after completion of inhalation илопрост is not defined in the central camera any more (a test-sensitivity limit - 25 pg/ml).
• Distribution
  Now there are no researches executed with inhalation use of drug.
After intravenous infusion the seeming distribution volume in an equilibrium state at healthy volunteers made from 0.6 to 0.8 l/kg. In the range of concentration from 30 to 3000 pg/ml the general linkng of an iloprost with proteins of plasma does not depend on concentration and makes about 60% from which 75% are the share of linkng with albumine.
• Metabolism
  Now there are no researches executed with inhalation use of drug.
Results of the researches in vitro indicate similar metabolism of an iloprost in lungs both after intravenous, and after inhalation introduction.
After intravenous administration илопрост more is exposed to metabolism by R-oxidation of a side carboxyl chain. In not changed form drug is not removed. The main metabolite - тетранорилопрост which is found in urine in a free look and the conjugated form. As showed pilot studies at animals, тетранорилопрост pharmacological it is inactive.
By results of the researches in vitro participation of P450 cytochrome in metabolism of an iloprost is minimum.
• Removal
  Now there are no researches executed with inhalation use of drug.
Removal of an iloprost after intravenous infusion at subjects with normal function of kidneys and a liver is in most cases characterized by a two-phase profile with average elimination half-lives from 3 to 5 min. and from 15 to 30 min. The general clearance of an iloprost makes about 20 ml/kg/min. that indicates existence of additional extrahepatic metabolism of an iloprost.
The research of balance of weight with use of an iloprost, marked 3H, at healthy subjects was conducted. After intravenous infusion removal of the general radioactivity made 81%, at the same time 68% were removed with urine, and 12% - with excrements. Elimination of metabolites happens in two phases for which settlement elimination half-lives make about 2 h and 5 h (plasma) and about 2 h and 18 h (urine).
At a renal failure
In a research with intravenous administration of an iloprost it was shown that at the patients with an end-stage of a renal failure who are on periodic dialysis, clearance of drug (average clearance = 5 ± 2 ml/min.) is much lower, than at the patients with a renal failure who are not receiving periodic dialysis (average clearance =18 ± 2 ml/min.).
At an abnormal liver function
As илопрост more is exposed to metabolism in a liver, changes of function of a liver influence concentration of drug in plasma. Results of a research with intravenous administration of drug included data of 8 patients with cirrhosis. The average clearance of an iloprost made 10 ml/min. by calculations.
Age and floor
The age and floor have no clinical value for pharmacokinetics of an iloprost.

Indications to use:

Treatment of a medium-weight and heavy stage of pulmonary hypertensia in the following cases:
• idiopathic (primary) arterial pulmonary hypertension, family arterial pulmonary hypertension;
• the arterial pulmonary hypertension caused by a disease of connecting fabric or effect of medicines or toxins;
• pulmonary hypertensia owing to chronic thromboses and/or embolisms of a pulmonary artery in the absence of a possibility of surgical treatment.

Route of administration and doses:

Drug Ventavis is used for long therapy.
Solution, ready to use, is appointed via the corresponding device for inhalations (nebulizer). The previous therapy should be corrected according to individual needs of the patient (see. "Interaction with other medicines and other forms of interaction").
The recommended doses:
• Adults
In an initiation of treatment Ventavis the first inhalation dose of an iloprost has to make 2.5 mkg (delivered through an inhaler mouthpiece). If the patient transfers treatment well, it is necessary to increase a dose of an iloprost to 5 mkg and to support this dose at the subsequent inhalations. In case of bad portability it is necessary to return to a dose of 2,5 mkg.
Inhalation of an iloprost should carry out from 6 to 9 times a day according to individual need of the patient and portability of drug.
Depending on the required dose of drug delivered through a mouthpiece and like the nebulizer duration of a session of inhalation makes from about 4 to 10 min.
• Patients with an abnormal liver function
Elimination of an iloprost decreases at patients with an abnormal liver function. In order to avoid undesirable accumulation of drug during the day, at selection of an initial dose of drug at these patients it is necessary to take special precautionary measures. Careful titration of an initial dose with an interval between introductions of 3-4 hours is recommended.
The initial dose has to make 2.5 mkg with an interval between introductions of 3-4 h (that corresponds to purpose of at most 6 times a day). Afterwards perhaps carefully to reduce intervals between introductions, taking into account individual portability of drug. If further increase in a dose up to 5 mkg is shown, intervals between introductions at the initial stage have to make 3-4 h; then they can be reduced taking into account individual portability. Further accumulation of drug after several days of therapy is represented improbable thanks to a night break in appointment.
• Patients with a renal failure
Patients with clearance of creatinine> have 30 ml/min. no need to korrigirovat a drug dose. Drug use Ventavis at patients with clearance of creatinine <30 ml/min. in clinical trials was not studied. Elimination of an iloprost decreases at the patients with a renal failure needing carrying out dialysis. Recommendations about dosing see. "Patients with an abnormal liver function".
Instructions for introduction
For performance of each inhalation it is necessary to use a new ampoule of drug Ventavis. Contents of an ampoule need to be poured completely in the nebulizer camera just before use. It is necessary to observe strictly the instructions on hygiene and cleaning of an inhaler provided by the producer of the device.
The solution for the nebulizer which is not used for inhalation needs to be poured out.
In general, nebulizers which are suitable for performing inhalation therapy by drug solution Ventavis are the certified nebulizers of compressor type, ultrasonic or the nebulizers based on vibration technology.
The nebulizers suitable for inhalation introduction of an iloprost have to provide delivery of an iloprost through a mouthpiece in a dose of 2.5 mkg or 5 mkg during a span from about 4 to 10 min. Mass and median aerodynamic diameter of particles of an aerosol makes 1 - 5 micron.
To minimize accidental influence of drug, Ventavis in the nebulizers supplied with the filter or inhalation and starting system is recommended to use and also it is good to air the room.
Transition to other type of an inhaler should be made under observation of the attending physician.

Features of use:

It is necessary to avoid drug contact Ventavis in the form of solution for the nebulizer with integuments and eyes, and also its proglatyvaniye. During performing inhalation from the nebulizer the front mask is not applied, and it is necessary to use only a mouthpiece.
Risk of a faint
During use of drug it is necessary to monitorirovat indicators of the vital functions. It is necessary to watch attentively patients with initially low system arterial pressure in order to avoid aggravation of hypotension. It is not necessary to appoint Ventavis to patients with the level of systolic arterial pressure less than 85 mm hg.
Doctors have to show vigilance concerning the associated diseases which are available for patients or use of other medicines which can strengthen risk of development of a faint.
The syncope is also the symptom characterizing the course of pulmonary hypertensia. Patients at whom faints in connection with pulmonary hypertensia are observed have to avoid any overstrain, for example, when performing exercise stresses. Performing inhalation before performance of an exercise stress can be useful. Илопрост for inhalation use renders short (from one to two hours) vasodilating action on pulmonary vessels. Developing of faints at an exercise stress reflects "failures" in the carried-out therapy; in this case it is necessary to consider need of correction and/or change of the chosen therapy (see. "Side effect").
Bronchospasm
At drug inhalation Ventavis can raise risk of development of a bronchospasm, especially at patients with hyperreactivity of bronchial tubes. At patients with the accompanying chronic obstructive pulmonary disease (COPD) and severe forms of bronchial asthma positive effect of drug Ventavis is not established. Patients with acute infectious processes in lungs, a chronic obstructive pulmonary disease and heavy bronchial asthma have to be under careful constant observation.
Pulmonary venous hypertensia
Ventavis should not be used as drug of the first choice in treatment of the pulmonary hypertensia caused by a thromboembolism at a possibility of surgical treatment.
If at inhalation introduction of an iloprost patients with pulmonary hypertensia have fluid lungs symptoms, it is necessary to consider probability of the associated thrombosis of pulmonary veins. Therapy in this case has to be stopped.
Drug use Ventavis is not recommended to patients with unstable pulmonary hypertensia with the accompanying heavy right atrial insufficiency in case of aggravation of right atrial insufficiency. At the same time it is reasonable to consider the possibility of transition to other medicines.
Additional information on safety for doctors
The data obtained in preclinical trials (a research of pharmacological safety, chronic toxicity, genotoxicity and carcinogenicity) did not reveal any extra risk for the person. Significant effects were found only at use of drug in the doses considerably exceeding the maximum admissible doses at the person which are not applied in clinical practice.
Now adequate data on drug use Ventavis at pregnant women are absent. In researches at animals existence of reproductive toxicity was shown. So, in researches at rats by assessment embrio-and fetotoksichnost long intravenous administration of an iloprost resulted in anomalies of separate phalanxes of fingers on forelegs at several fruits of the been born animals without existence of a dozozavisimost. These anomalies are not considered as a result of true teratogenic influence. Most possibly, they are connected with the delay of growth induced iloprosty during a late organogenesis because of hemodynamic disturbances in a fetoplacental complex. At the grown-up posterity disturbances of post-natal development and reproductive function were not observed. It indicates that delay of growth can be compensated during the post-natal period of development. In comparative researches on embriotoxity assessment at rabbits and monkeys anomalies of fingers or other explicit structural anomalies, even after introduction of significantly higher doses of drug many times exceeding doses for the person were not revealed.

Influence on ability to driving of motor transport and to control of mechanisms
It is necessary to be careful at control of vehicles and mechanisms during the beginning of therapy, features of individual reaction to drug will not be defined yet. Ability to manage vehicles and other mechanisms at patients who test the symptoms connected with hypotension such as dizziness can be broken.

Side effects:

In addition to the local undesirable effects which are result of an inhalation way of introduction of an iloprost (cough), undesirable reactions to drug are caused by pharmacological    features    of prostaglandins.        The vazodilatation, a headache and cough were the most frequent undesirable effects (> 20%) observed in clinical trials. The most serious undesirable effects were hypotension, bleedings and a bronchospasm.
The undesirable reactions noted at Ventavis's use are classified below by systems of bodies.
The characteristic of frequency of the undesirable reactions observed in clinical trials, following: very often - more than 1/10; often - more than 1/100 and less than 1/10. For the undesirable effects revealed only during post-registration observation programs and for which it is not possible to estimate frequency it is specified "frequency is unknown". In each group of frequency of undesirable effects undesirable reactions are presented as reduction of their importance.
Data on the undesirable reactions given below are based on the integrated data of clinical trials II and III phases (the number of the patients accepting drug - 131) and the data obtained during post-registration observation programs. 

System                   Very often more than 1/10     it is frequent - more than 1/100        Frequency are unknown
organ class                                                         and less than 1/10
Disturbances from               Bleeding                                                             Thrombocytopenia
parties of blood and         
lymphatic
systems 
Disturbances with
parties immune
systems 
Disturbances with               the Headache                                   Reaction Dizziness
parties of nervous                                                                                               hypersensitivity
systems 
Disturbances from               Vazodilatation                Gipotenziya *, a syncope
parties
vascular
systems 
Disturbances from               Pain in chest               the Asthma,                              the Bronchospasm * / whistling
parties of bodies           to a cell                              pharyngolaryngeal        breath
breath, chest                                                  pain,
cells and                                                                irritation in a throat
mediastinums        
Disturbances with               Nausea                           Diarrhea, vomiting, irritation      the Food faddism
sides                                                                 of a mucous membrane of a mouth and
gastro                                                            language, including pain
intestinal path
Disturbances about                                                         Rash
sides of skin and
hypodermic fabrics
Disturbances from               Bol in a jaw/lockjaw       the Dorsodynia
parties bone
muscular system
and connecting
fabrics

* These undesirable effects represented life-threatening and/or fatal cases.
For the description of certain reactions, their synonyms and the connected states the most preferable terms from the medical dictionary for regulatory activity of MedDRA, version 14.0 are used.
# Bleedings (mainly in the form of nasal bleedings and a pneumorrhagia) met very often that is expected for population with a high share of the patients receiving the accompanying anticoagulating therapy. The risk of development of bleedings can be increased at the patients receiving anticoagulating therapy or inhibitors of aggregation of thrombocytes (see. "Interaction with other medicines and other forms of interaction").
As well as it is expected for patients with pulmonary hypertensia, faints were often noted, however between groups therapy of significant distinctions on their frequency was not (see. "Special instructions").

Interaction with other medicines:

As researches on studying of compatibility were not conducted, Ventavis it is not necessary to mix at introduction with other medicines.
Илопрост can strengthen anti-hypertensive effect of vazodilatator and other anti-hypertensive drugs. It is necessary to be careful at simultaneous use of Ventavis with vasodilating and anti-hypertensive drugs since correction of their dose can be required.
As илопрост suppresses function of thrombocytes, its use together with anticoagulants (such as heparin, anticoagulants of group of derivatives of coumarin), or other antiagregant (such as acetylsalicylic acid, non-steroidal anti-inflammatory drugs, inhibitors of phosphodiesterase and vazodilatator of group of nitrates) can increase risk of bleeding (see. "Side effects"). The patients receiving anticoagulating therapy or other inhibitors of aggregation of thrombocytes according to the accepted medical practice have to be under constant control of parameters of coagulation.
The previous purpose of acetylsalicylic acid inside in a dose to 300 mg a day within 8 days does not influence pharmacokinetics of an iloprost. In a research at animals it was revealed that purpose of an iloprost can lead to decrease in equilibrium concentration in plasma of the fabric plasminogen activator (FPA). Results of researches at the person show that infusion of an iloprost does not influence pharmacokinetics of the digoxin appointed inside and илопрост does not influence pharmacokinetics at the same time appointed TAPAS.
In experiments on animals vasodilating action of an iloprost was weakened if glucocorticosteroids while overwhelming influence on aggregation of thrombocytes remains invariable were entered previously. Value of these data for drug use Ventavis at people is unknown.
Though clinical trials were not conducted, the researches in vitro according to the possible inhibiting influence of an iloprost on activity of isoenzymes of P450 cytochrome showed that essential suppression of the metabolism of medicines mediated through these isoenzymes under the influence of an iloprost on them is improbable.

Contraindications:

• Morbid conditions at which drug influence Ventavis on thrombocytes can increase risk of bleeding (including a peptic ulcer of a stomach and duodenum in an aggravation stage, an injury, intracraneal hemorrhage).
• Heavy coronary heart disease or unstable stenocardia.
• A myocardial infarction in the last 6 months.
• Dekompensirovanny heart failure in the absence of appropriate medical control.
• Heavy arrhythmias.
• Suspicion on stagnation of blood of lungs.
• Cerebrovascular complications (including the tranzitorny ischemic attack, a stroke) in the last 3 months.
• Pulmonary hypertensia owing to a pulmonary veno-occlusal disease.
• The inborn or acquired defects of valves of heart with clinically significant dysfunctions of a myocardium which are not caused by pulmonary hypertensia.
• Hypersensitivity to an iloprost or other components of drug. Children and teenagers up to 18 years (because experience of use is limited).

With care
• An abnormal liver function and a renal failure at the patients needing carrying out dialysis.
• Arterial hypotension.
• HOBL.
• Heavy bronchial asthma.

Use during pregnancy and feeding by a breast
The women having pulmonary hypertensia have to avoid pregnancy approach as it can lead to a life-threatening exacerbation of a disease.
Pregnant women have an insufficient number of data on drug use Ventavis. At pregnancy approach, Ventavis it is necessary to appoint in that case when the expected advantage for mother exceeds possible risk for a fruit.
As it is not established whether it is allocated илопрост and its metabolites in breast milk, in need of use of drug in the period of a lactation breastfeeding should be stopped.

Overdose:

About cases of overdose it was not reported.
• Symptoms
In case of overdose it is possible to expect development of hypotensive reaction, and also a headache, "inflows" of blood, nausea, vomiting and diarrhea. Rise in arterial pressure, bradycardia or tachycardia, extremity or spin pain can be also noted at drug overdose.
• Therapy
The specific antidote is unknown.
It is recommended having rummaged in use of an iloprost, monitoring of a condition of the patient and performing symptomatic therapy.

Storage conditions:

Period of validity 2 years. Not to use after a period of validity. To store at a temperature not above 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for inhalations of 10 mkg/ml.
On 2 ml in ampoules from colourless glass of type 1 volume of 3 ml with a point of a break and
two rings - white and pink color. 6 ampoules in the pallet, 5 pallets together with
the application instruction place in a cardboard pack (30 ampoules).
6 ampoules in the pallet, place 5 pallets in primary cardboard packaging, 3 such packagings (on 30 ampoules) together with the application instruction place in a cardboard pack (90 ampoules).