Ilomedin concentrate 20 µg/ml 2.5 ml, 5 pcs.

Ilomedin is an anti-aggregative.

Pharmacodynamics

Iloprost is a synthetic analog of prostacyclin, inhibits platelet aggregation, adhesion and release reaction; dilates arterioles and venules; increases capillary density (restores impaired microcirculation by inducing vasodilation, inhibition of platelet activation, endothelial repair and protection, activation of endogenous fibrinolysis and correction of imbalance in cytokine system) and reduces increased vascular permeability due to mediators such as serotonin or histamine in microcirculation system; activates endogenous fibrinolysis; shows anti-inflammatory effect Inhibits leukocyte adhesion and migration after endothelial damage, as well as leukocyte accumulation in damaged tissue; reduces production of tumor necrosis factor (TNF-alpha;).

Pharmacokinetics

Distribution. C_ss in plasma is reached very rapidly, 10-20 min after the start of the v/v infusion. Its time to reach is linearly dependent on the infusion rate; at an infusion rate of 3 ng/kg/min, a concentration of approximately (135±24) pg/mL is reached. After the end of infusion, plasma concentration of iloprost decreases very rapidly (this is due to its very high metabolic rate). Metabolic clearance is approximately (20±5) ml/kg/min. T_1/2 from plasma during the terminal phase of distribution is about 0.5 h. Two hours after cessation of infusion, the drug content is less than 10% of C_ss. The binding to plasma albumin is 60%.

Metabolism and elimination. Iloprost is metabolized mainly by B-oxidation of the side carboxyl chain. The substance is not excreted from the body unchanged. The main metabolite, tetranoriloprost, is found in the urine in free form and in 4 conjugated forms of diastereoisomers. As experiments on animals have shown, tetranoriloprost is pharmacologically inactive. Results of in vitro studies indicate a similar nature of iloprost metabolism in the lungs after IV injection or inhalation.

Evacuation. 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 mean T_1/2 durations of 3-5 and 15-30 min, respectively. The total clearance of iloprost is approximately 20 ml/kg/min, indicating that the metabolism of iloprost occurs partially outside the liver.

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 from plasma and excretion with the urine are biphasic, with T_1/2 from plasma being about 2 h in the first phase and about 5 h in the second, and 2 and 18 h for urine, respectively.

Renal insufficiency. In a study using IV infusions of iloprost, it has been shown that patients with end-stage renal failure who receive intermittent dialysis treatment have significantly lower clearance (mean clearance = (5±2) ml/min/kg) than patients with renal failure who do not receive dialysis treatment (mean clearance = (18±2) ml/min/kg).

Liver dysfunction. Because iloprost is extensively metabolized 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. Mean clearance of iloprost was calculated to be 10 ml/min/kg.

Age and sex. The pharmacokinetics of iloprost are independent of patient age and sex.

Indications

Active ingredient

Composition

Active ingredient:

iloprost trometamol0.027 mg (corresponding to 0.02 mg (20 µg) of iloprost);

Associates:

Trometamol, 0.235 mg;

Ethanol 96%, 1.62 mg;

Sodium chloride, 9 mg;

1M hydrochloric acid solution – 0.76 mg;

water for injection – 990.758 mg

How to take, the dosage

Intravenously, by infusion (using an infusion machine or automated syringe).

Ilomedin should only be used when the patient is closely monitored and controlled in a hospital or outpatient setting with adequate technical facilities.

Pregnancy should be excluded before starting treatment in women.

The duration of treatment is 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 must be thoroughly mixed.

Dilution

The method of dilution must be strictly followed depending on the method of administration of the solution.

1. Using an infusion-machine (infusion pump)

The contents of the ampoule with 1 ml of concentrate for preparing solution for infusion are diluted with sterile 0.9% sodium chloride solution or 5% glucose (dextrose) solution for injection to 100 ml; the contents of the ampoule with 2.5 ml of concentrate for preparing solution for infusion – to 250 ml.

2.

The contents of the ampoule with 1 ml of concentrate for infusion solution preparation is diluted with sterile 0.9% sodium chloride solution or 5% glucose (dextrose) solution for injection to the volume of 10 ml; the contents of the ampoule with 2.5 ml of concentrate for infusion solution preparation – to the volume of 25 ml.

After dilution, Ilomedin is administered daily as a 6-hour infusion into the peripheral vein or a catheter placed in the central vein. The rate of administration (dose) depends on individual tolerance and is 0.5-2 ng/kg/min.

The BP and HR should be monitored at the start of infusions and each time the dose is increased.

In the first 2-3 days, individual tolerance of the drug is determined – treatment begins at an infusion rate of 0.5 ng/kg/min for 30 minutes. After that, the dose is increased in steps by 0.5 ng/kg/min approximately every 30 min. The exact infusion rate is calculated based on body weight at the maximum tolerated dose, ranging from 0.5 to 2 ng/kg/min (see infusion rate tables below when using an infusion machine or automatic syringe).

Depending on the frequency of adverse events such as headache, nausea, or decreased BP, the infusion rate should be reduced to the maximum tolerated rate. If severe adverse events develop, the infusion should be interrupted. Treatment is usually continued for 4 weeks, using doses that were well tolerated during the first 2-3 days of the previous course of treatment.

Interaction

Because of possible interactions, Ilomedin should not be mixed in the same solution with other medicinal products.

Iloprost increases the antihypertensive effect of β-adrenoblockers, BKK and all vasodilators and ACE inhibitors. If significant hypotension occurs, however, BP can be corrected by reducing the dose of iloprost.

Because iloprost suppresses platelet function, its use in combination with heparin or indirect anticoagulants (coumarin derivatives) or other platelet aggregation inhibitors (acetylsalicylic acid, NSAIDs, PDE inhibitors and nitrate vasodilators such as molcidomine) may increase the risk of bleeding. In such a case, Ilomsdin infusion should be discontinued.

The administration of acetylsalicylic acid at a dose of up to 300 mg/day for a course of 8 days preceding the use of Ilomedin had no effect on the pharmacokinetics of Iloprost. In an animal study, it was found that iloprost can cause a decrease in Css preparations of tissue plasminogen activator (TAP) in plasma. Results from human studies indicate that iloprost infusions do not affect the pharmacokinetics of multiple oral doses of digoxin in patients, and iloprost has no effect on its pharmacokinetics when used concomitantly with TAP drugs.

In animal experiments, the vasodilatory effect of iloprost was attenuated if experimental animals were previously treated with GCS, but the inhibitory effect on platelet aggregation was not altered. The clinical relevance of these data has not yet been established.

While no clinical studies have been performed, in vitro studies examining the inhibitory potential of iloprost against cytochrome P450 enzyme activity have indicated that significant suppression of drug metabolism by these enzymes through exposure to iloprost is unlikely.

Contraindications

With caution: patients with impaired cerebral circulation within the last 3 months (e.g., transient ischemic disorder, stroke). Such patients need a careful assessment of the benefit-risk ratio of treatment (see also Contraindications – risk of bleeding, e.g., intracranial bleeding). In renal failure requiring dialysis and in liver cirrhosis, the excretion of iloprost is reduced (see “Dosage and administration”). Measures should be taken against further reductions in BP (before initiating therapy with Ilomedin) in patients with baseline low BP; patients with severe heart disease should be closely monitored. The possibility of orthostatic hypotension when patients switch from horizontal to vertical position after the end of Ilomedin administration should be considered.

Side effects

Nervous system and sensory organs: often (more than 1%, but less than 10%) – dizziness, headache, paresthesia, hyperesthesia, tinnitus, anxiety, agitation, lethargy, apathy, somnolence; less often (more than 0.1%, but less than 1%) – tremor, cerebrovascular disorders, depression, hallucinations, migraine, fainting, prolonged loss of consciousness, visual disturbance, eye irritation and pain; rarely (more than 0.01%, but less than 0.1%) – vestibular disorders; frequency unknown – confusion.

Systems: often (more than 1%, but less than 10%) – decreased BP, bradycardia, blood rush to the skin and fever; less often (more than 0.1%, but less than 1%) – arrhythmia (including extrasystole), myocardial ischemia, myocardial infarction, deep vein thrombosis, pulmonary embolism; frequency unknown – BP increase, tachycardia; in single cases (in elderly patients with significant atherosclerosis) – pulmonary edema.

Respiratory system: less frequently (more than 0.1%, but less than 1%) – bronchial asthma; rarely (more than 0.01%, but less than 0.1%) – cough; in single cases (in elderly patients with significant atherosclerosis) – heart failure.

Gastrointestinal system: more frequently (more than 10%) – nausea, vomiting; frequently (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, change of taste, tenesms, constipation, belching, dysphagia, diarrhea, melena, rectal bleeding, jaundice.

Motor system disorders: frequently (more than 1% but less than 10%) – pain in masticatory muscles, trism, myalgia, arthralgia, muscle weakness; less frequently (more than 0.1% but less than 1%) – tetany, twitching of muscles, hypertonicity.

Urinary system: pain in the lower back, renal colic, changes in the cellular composition of the urine, dysuria.

Local reactions: often (more than 1%, but less than 10%) – skin hyperemia, pain, phlebitis at the injection site.

Others: more often (more than 10%) – sweating; often (more than 1% but less than 10%) – local pain, generalized pain, hyperthermia, skin itching, increased fatigue, thirst; frequency unknown – allergic reactions.

Overdose

Symptoms: decreased BP may occur, as well as headache, facial flushing, nausea, vomiting, and diarrhea. Increased BP, bradycardia or tachycardia, and pain in the shins or back may occur.

Treatment: interruption of the infusion, further patient monitoring and symptomatic therapy. Specific antidotes are not known.

Pregnancy use

Ilomedin should not be prescribed to women during pregnancy and lactation. There are no data on the use of iloprost in pregnant women. According to preclinical studies, iloprost has a toxic effect on the fetus in rats, but not in rabbits and monkeys. Because the potential risk of therapeutic use of iloprost in pregnancy is unknown, women of childbearing age should use reliable contraception when treated with iloprost.

There are currently no reports of iloprost penetrating into human breast milk, but because there are reports that iloprost may penetrate into milk in small amounts in rats, it should not be administered to nursing mothers.