Ilomedin – antiagregatsionnoe
Iloprost is a synthetic analogue of prostacyclin inhibits the aggregation, adhesion and platelet release reaction; expanding arterioles and venules; increases the density of capillaries (restores the microcirculation by induction of vasodilation, inhibition of platelet activation, restoring and protecting the endothelium, activate endogenous fibrinolysis and correcting imbalance in cytokine system) and reduces the increased vascular permeability caused by mediators such as serotonin or histamine in the microcirculation system; activates the endogenous fibrinolysis; exhibits an anti-inflammatory effect: inhibits adhesion and migration of leukocytes after endothelial injury and accumulation of leukocytes into damaged tissue, reduces production of tumor necrosis factor (TNF-alpha;)
distribution. Css in plasma is reached very quickly, within 10-20 minutes after the start in / vinfuzii. The time to achieve linearly dependent on infusion rate at infusion rates of 3 ng / kg / min, is achieved the concentration is approximately equal to (135 ± 24) pg / ml. After the end of infusion iloprost concentration in plasma rapidly reduced (this is due to a very high intensity of its metabolism). Metabolic clearance is approximately (20 ± 5) ml / kg / min. T1 / 2 from the blood plasma in the terminal phase of the distribution is about 0.5 hours. After 2 hours, after termination of the drug infusion content is less than 10% of Css. Communication with albumin in blood plasma is 60%.
The metabolism and elimination. Iloprost metabolizirueteya mainly through the B-oxidation side chain carboxyl. In unaltered substance from the body are released. The main metabolite – tetranoriloprost – found in urine in free form and in conjugated forms of 4 diastereoisomers. As shown by experiments on animals, tetranoriloprost pharmacologically inactive. Studies in vitro results indicate the similar nature of the metabolism of iloprost in the lungs after the in / or administration of inhalation.
Withdrawal. Excretion iloprost after i / v infusion in subjects with normal renal function and liver in most cases it is characterized by a biphasic profile with average T1 / 2prodolzhitelnostyu respectively 3-5 and 15-30 min. Total clearance iloprost is about 20 ml / kg / min, indicating that metabolism iloprost is partly outside the liver.
It was carried out a mass balance study using iloprost labeled with 3 H, in healthy subjects. After the on / in infusion excretion of total radioactivity was 81%, while 68% was excreted in the urine and 12% – faeces. Elimination from the plasma metabolites and their renal excretion are biphasic, the T1 / 2 from the plasma in the first phase is about 2 hours, in the second – about 5 hours and for urine -, respectively, 2 and 18 h
Kidney failure. The study using in / infusion iloprost has been shown that patients with end stage renal failure, periodically receiving dialysis treatment, a clearance is considerably lower (average clearance = (5 ± 2) mL / min / kg) than in patients with renal patients failure who do not receive treatment by dialysis (average clearance = (18 ± 2) mL / min / kg).
liver dysfunction. Since iloprost is extensively metabolized in the liver, hepatic function changes affect the concentration of drug in blood plasma. Results from studies in / drug administration data included 8 patients with cirrhosis. Middle iloprost clearance calculations made at 10 ml / min / kg.
Age and nol. The pharmacokinetics of iloprost does not depend on the age and sex of the patient.
Berlimed SA, Spain
Active substance: iloprost trometamol0,027 mg (corresponding to 0.02 mg (20 ug) iloprost);
Other ingredients: trometamol – 0,235 mg; ethanol 96% – 1.62 mg; Sodium chloride – 9 mg; 1M hydrochloric acid – 0.76 mg; Water for Injection – 990.758 mg
- thromboangiitis obliterans (Buerger’s disease) in the later stages with critical limb ischemia in cases where no indications revaekulyarizatsii;
- severe forms of peripheral arterial occlusive disease, especially when the risk of amputation and the impossibility of surgical vascular surgery or angioplasty;
- severe Raynaud’s syndrome, leading to disability is not amenable to other drug therapy.
- Hypersensitivity to iloprost or to other components of the drug;
- pathological condition in which the action on platelets iloprost may increase the risk of bleeding (e.g. gastric ulcer or duodenal ulcer in the acute stage, trauma, intracranial bleeding);
- severe coronary heart disease or unstable angina; myocardial infarction within the past 6 months; acute heart failure or chronic congestive heart failure stage II-IV (according to the classification of New York Heart Association); severe violations of heart rate;
- suspicion of congestion in the pulmonary circulation;
With care: patients with ischemic attack within the last 3 months (eg transient ischemic attack, stroke). Such patients need careful evaluation of potential advantages and risks of the treatment (see also “Contra.” – the risk of bleeding, such as intracranial bleeding). In renal failure requiring dialysis, liver cirrhosis and elimination of Iloprost reduced (see. “Dosage and Administration”). It is necessary to take measures against the further reduction of blood pressure (pre-treatment Ilomedinom) in patients with initially low numbers of blood pressure; Patients with severe heart disease should be closely monitoring control. Should consider the possibility of orthostatic hypotension when switching patients from a horizontal position to a vertical after the introduction Ilomedina.
From the side of nervous system and sensory organs: common (more than 1% but less than 10%) – dizziness, headache, paresthesia, hyperesthesia, tinnitus, anxiety, agitation, confusion, lethargy, drowsiness; less frequently (more than 0.1% but less than 1%) – tremors, cerebrovascular disorders, depression, hallucinations, headache, fainting, prolonged loss of consciousness, disturbance of clarity of vision, irritation and pain in the eyes; slowly (over 0.01% but less than 0.1%) – vestibular disorders; the frequency is unknown – confusion
From the CCC: common (more than 1% but less than 10%) – decreased blood pressure, bradycardia, a rush of blood to the skin and the sensation of heat; less frequently (more than 0.1% but less than 1%) – arrhythmia (including arrythmia), myocardial ischemia, myocardial infarction, deep vein thrombosis, pulmonary embolism; frequency is unknown – increase in blood pressure, tachycardia; in a few cases (elderly patients with severe atherosclerosis) – pulmonary edema
The respiratory system: less often (more than 0.1% but less than 1%) – asthma; rare (more than 0.01% but less than 0.1%) – cough; in a few cases (elderly patients with severe atherosclerosis) – heart failure
From the digestive system: more often (10%) – nausea, vomiting; common (more than 1% but less than 10%) – anorexia, diarrhea, abdominal discomfort, abdominal pain; less frequently (more than 0.1% but less than 1%) – dry mouth, taste change, tenesmus, constipation, regurgitation, dysphagia, diarrhea, melena, rectal bleeding, jaundice
From the musculoskeletal system: often (more than 1% but less than 10%) – pain in the masticatory muscles, trismus, myalgia, arthralgia, muscle weakness; less frequently (more than 0.1% but less than 1%) – tetany, jerking muscle hypertonicity
From the urinary system: back pain, renal colic, a change in the cellular composition of urine, dysuria
Local reactions: often (more than 1% but less than 10%) – skin redness, pain, phlebitis at the injection site
The other: more often (10%) – sweating; common (more than 1% but less than 10%) – the local pain, generalized pain, pyrexia, pruritus, fatigue, thirst; the frequency is unknown – allergic reactions
How to accept, acceptance rate and dosage
intravenously by infusion (using infusomats or automatic syringe).
Ilomedin should be used only under conditions of careful monitoring and patient monitoring in hospitals or outpatient facilities, with relevant technical capabilities.
Pregnancy should be excluded before the start of treatment in women.
Duration of treatment – up to 4 weeks
Ilomedin should be used only after dilution. The solution should be freshly prepared. The contents of the ampoule and the solvent to be mixed thoroughly.
must be strictly observed dilution method depending on the mode of administration solution.
1. Using infusomats (infusion pump)
The contents of the ampoule with 1 ml concentrate for solution for infusion is diluted with sterile 0.9% sodium chloride or 5% glucose solution (dextrose) for injection to a volume of 100 ml; contents of the vial with 2.5 mL concentrate for solution for infusion – to a volume of 250 ml
The contents of the ampoule with 1 ml concentrate for solution for infusion is diluted with sterile 0.9% sodium chloride or 5% glucose solution (dextrose) for injection to a volume of 10 ml; contents of the vial with 2.5 mL concentrate for solution for infusion – to a volume of 25 ml
After dilution Ilomedin administered daily in a 6-hour infusion into a peripheral vein or a central vein mounted catheter. The rate of administration (dosage) depends on individual tolerance and 0.5-2 ng / kg / min.
It is necessary to control blood pressure and heart rate at the beginning of the infusion, and with each increase in dose.
During the first 2-3 days, the individual tolerability – treatment is initiated with the introduction rate of 0.5 ng / kg / min for 30 min. Thereafter the dosage is increased stepwise by 0.5 ng / kg / min, about every 30 minutes. Precise infusion rate was calculated based on the body weight at the maximum tolerated dose in the range of 0.5 to 2 ng / kg / min (see. Infusion rate below table using infusomats or automatic syringe).
Depending on the frequency of side effects such as headache, nausea, or decreased blood pressure, the infusion rate should be reduced until the maximum tolerated. With the development of serious side effects of the infusion should be interrupted. Treatment usually continues for 4 weeks, using doses that were well tolerated in the first 2-3 days of the previous course of treatment.
At a temperature of not higher than 30 ° C.
Due to the possible interactions Ilomedin not be mixed in the same solution with other drugs.
Iloprost enhances the antihypertensive effect of β-blockers, and all BPC vasodilators and ACE inhibitors. If there is significant hypotension, BP will be able to adjust by reducing the dose of iloprost.
Since iloprost inhibits platelet function, its use in combination with heparin or anticoagulant indirect (coumarin derivatives), or other platelet aggregation inhibitors (acetylsalicylic acid, NSAIDs, inhibitors of PDE, and vasodilators from the group consisting of nitrates, e.g. molsidomine), can increase the risk of bleeding . In this case, the infusion should be discontinued Ilomsdina.
The use of acetylsalicylic acid in a dose of 300 mg / day course of 8 days prior to use Ilomedina, has no effect on the pharmacokinetics of iloprost. In animal studies, it was found that iloprost may decrease Csspreparatov tissue plasminogen activator (tPA) in plasma. Results of studies in humans show that infusion of iloprost not affect the pharmacokinetics of digoxin multiple oral doses in patients and if applied simultaneously with TPA preparations iloprost has no effect on its pharmacokinetics.
In animal experiments vasodilator action iloprost weakened if the experimental animals were pretreated with corticosteroids, but the inhibitory effect on platelet aggregation is not changed. The significance of these data for the clinic until set.
Although clinical studies have been conducted, studies in vitro, during which studied the inhibitory potential of iloprost in relation to the activity of the cytochrome P450 enzyme system, revealed that a significant inhibition of the metabolism of drugs by these enzymes as a result of exposure to iloprost is unlikely.
Pregnancy and lactation
Ilomedin should not be administered to women during pregnancy and lactation. Data on the use of iloprost in pregnant women are missing. According to preclinical studies, iloprost has a toxic effect on the fetus in rats, but not in rabbits and monkeys. Due to the fact that the potential risk of the therapeutic use of iloprost during pregnancy is unknown, in the treatment of iloprost women of childbearing age should use reliable contraception.
Currently, there are no data on the penetration of iloprost into breast milk in humans, however, since there is evidence that iloprost may be a small amount of penetrating into the milk of rats, it should not be administered to nursing mothers.
Symptoms: reduced blood pressure, as well as headache, blood flow to the face, nausea, vomiting and diarrhea. There may be an increase in blood pressure, bradycardia or tachycardia, pain in the legs or back.
Treatment: interruption of the infusion, further monitoring of patients and symptomatic therapy. Specific antidotes are not known.