Ilomedin

Ilomedin is an antiplatelet agent. It is a concentrate required for the preparation of an infusion solution.

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Indications Ilomedina

It is indicated for the elimination of such disorders:

• Buerger's disease, which appears against the background of a critical degree of ischemia in the limbs, if there are no indications for revascularization;
• severe degree of obliterating endarteritis (especially if there is a risk of amputation, and also if it is not possible to perform angioplasty or operate on the vessels);
• severe Raynaud's syndrome (leading to disability), which cannot be treated with other drugs.

Release form

Available in ampoules (No. 5) with a volume of 1 ml.

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Pharmacodynamics

Iloprost is a synthetic analogue of the substance prostacyclin. Its pharmacological properties:

• inhibition of adhesion processes, aggregation, and also the release of platelets;
• dilation of venules with arterioles;
• strengthening of capillary density, and at the same time strengthening of weakened vessel walls within the microcirculatory system (with permeability caused by such conductors as histamine or serotonin);
• activation of the process of internal fibrinolysis;
• anti-inflammatory properties (slowing down the adhesion of leukocytes in endothelial injuries, and in addition, leukocyte accumulation inside damaged tissues and weakening of tumor necrosis release factor).

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Pharmacokinetics

The drug reaches its equilibrium level in plasma 10-20 minutes after the start of the infusion. This indicator is linearly dependent on the infusion rate (if it is 3 ng/kg/minute, the concentration level of the substance will be approximately 135±24 pg/ml). Upon completion of the infusion, the plasma indicator of the active component of the drug quickly decreases (due to the increased intensity of its metabolism).

The plasma clearance rate is 20±5 ml/kg/minute. The plasma half-life (terminal phase) is 30 minutes. As a result, 2 hours after completion of the infusion, the drug level will be less than 10% of the equilibrium level.

The drug cannot interact with other drugs at the level of protein synthesis, since most of its active component is synthesized with plasma albumin (with protein, synthesis is 60%), as a result of which a very small amount of free iloprost remains. At the same time, the likelihood of iloprost affecting the biotransformation processes of other drugs is extremely low (due to its metabolic pathways and low absolute dosage).

The substance is metabolized by the β-oxidative process in the side carboxyl chain. No excretion of the unchanged component occurs. The main breakdown product is tetranor-iloprost, which enters the urine (conjugated and free form) in the form of 4 diastereoisomers. This metabolite has no pharmacological activity (this was shown by animal testing). In vitro test data show that when inhaled or intravenously administered, the metabolism of the substance inside the lungs is very similar.

In people with healthy renal and hepatic function, iloprost excretion after the infusion procedure often occurs in 2 phases with half-lives of 3-5 and 15-30 minutes, respectively. The overall clearance rate of the component is about 20 ml/kg/minute, which demonstrates the presence of an extrahepatic metabolic pathway for the substance.

Volunteers were tested to determine the mass fraction of decay products (using 3H-iloprost). After infusion, the total radioactivity was 81%, and 12% and 68% were found in feces and urine, respectively. Decay products are excreted in urine and plasma in a 2-phase manner. The half-life in phase 1 is about 2 hours, and in phase 2, about 5 hours. From urine, the half-life is 2 and 18 hours, respectively.

In cases of decreased renal function (end-stage renal failure). Studies in individuals with this disorder who also underwent periodic dialysis show that after intravenous infusions of the drug, the clearance rate is much lower (on average, 5±2 ml/minute/kg) than the same rate in individuals with renal failure who did not undergo periodic dialysis (with an average rate of 18±2 ml/minute/kg).

With decreased liver function. Since most of the active substance of the drug undergoes metabolism in the liver, changes in its functioning affect the plasma values of the drug. The results of tests involving 8 people with liver cirrhosis showed that the average clearance level of the substance was 10 ml/minute/kg.

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Dosing and administration

The use of drugs is permitted only under conditions of constant monitoring of the patient (in a hospital or outpatient facility that has the necessary equipment).

In women, the possibility of pregnancy must be excluded before starting a course of therapy.

The diluted drug should be administered as an infusion over 6 hours (administration method - through a catheter into the central vein or without it into the peripheral vein) every day. The infusion rate is determined by the individual sensitivity of the patient and is approximately 0.5-2 ng/kg/minute.

The infusion solution must be prepared daily to ensure the sterility of the medicine. The solvent and the substance contained in the ampoule must be thoroughly mixed.

It is necessary to determine the heart rate indicators, as well as the blood pressure level before starting the course, and then after each increase in the infusion rate.

During the first 2-3 days, the tolerance of the drug is determined (therapy begins with the introduction of the drug at a rate of 0.5 ng/kg/minute for half an hour). Then the dosage is gradually increased approximately every half hour by 0.5 ng/kg/minute until a rate of 2 ng/kg/minute is reached. A more precise rate is selected taking into account the person's weight with the maximum tolerated dosage within 0.5-2 ng/kg/minute.

If the patient develops adverse reactions such as decreased blood pressure, headaches or nausea, the rate of administration should be reduced to a level that is well tolerated by the patient. If severe side effects occur, the infusion should be stopped. Later, treatment is resumed (infusions are often administered for 1 month) using the dosage that was appropriate for the person in the first 2-3 days, when selecting the infusion rate.

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Use Ilomedina during pregnancy

The drug is prohibited for use in pregnant and lactating women. There is no information on the use of the drug during pregnancy.

Preclinical testing showed that the drug has a toxic effect on rat fetuses, although it does not affect fetal development in monkeys and rabbits.

Since there is no information about the possible risk of medicinal use of Ilomedin, women of childbearing age should use reliable contraception throughout the entire period of therapy with the drug.

There is no information about the passage of the substance into breast milk, but at the same time, because it passes into rat milk in small quantities, it is not recommended to use the drug during breastfeeding.

Contraindications

Among the contraindications of the drug:

• painful conditions during which, due to the effect of the drug on platelets, the likelihood of bleeding increases (for example, an active stage of an ulcer, intracranial hemorrhage, or trauma);
• severe form of coronary heart disease or unstable type of angina;
• myocardial infarction suffered within the last six months;
• acute or chronic stage of congestive heart failure (grades 2-4 according to the NYHA classification);
• suspicion of development of congestive phenomena in the lungs;
• intolerance to iloprost or other components of the drug.

Nowadays, only isolated cases of drug use in adolescents and children are permitted.

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Side effects Ilomedina

Frequently, the following side effects were observed as a result of using the drug during clinical trials: vomiting, hot flashes, hyperhidrosis, as well as nausea and headaches. They mainly occurred at the initial stage of therapy during titration to select the optimal dosage for each patient. But these manifestations usually soon disappear after the dosage is reduced.

The most severe adverse reactions to the use of drugs were cerebrovascular manifestations, pulmonary embolism, myocardial infarction, decreased blood pressure, heart failure. In addition, asthma, tachycardia, pulmonary edema, angina pectoris also developed, and in addition, convulsions or dyspnea occurred.

Another category of adverse events is related to local reactions at the site of infusion. For example, pain and redness may occur at the site of the procedure. Also, due to the dilation of blood vessels in the skin, erythema (in the form of a strip) occasionally appeared at the site of infusion.

Side effects that have been identified during clinical trials and post-marketing observations in individuals treated with Ilomedin include:

• lymph and hematopoietic system: thrombocytopenia occasionally developed;
• immune system organs: rarely – intolerance reactions;
• metabolic disorders: appetite often worsens;
• mental disorders: confusion or apathy often occurs, depression, anxiety, and hallucinations occasionally develop;
• organs of the nervous system: headaches often appear, vertigo/dizziness, a feeling of pulsation/paresthesia/hyperesthesia are often observed; in rare cases – migraines, tremors, seizures and loss of consciousness;
• visual organs: occasionally irritation or pain inside the eyes appears, and in addition, visual acuity deteriorates;
• balance and auditory organs: isolated – vestibular disorders;
• organs of the cardiac system: brady-, tachy- or angina pectoris often develops, less common is heart failure/arrhythmia, as well as myocardial infarction;
• vascular system: hot flashes often occur, blood pressure often increases or blood pressure decreases; cerebrovascular pathologies, pulmonary embolism, cerebral ischemia, and deep venous thrombosis rarely occur;
• diseases of the chest and mediastinum, respiratory disorders: dyspnea often appears, pulmonary edema or asthma rarely develops, in isolated cases a cough occurs;
• Gastrointestinal tract: nausea and vomiting often occur, abdominal pain or discomfort are also quite common, as well as diarrhea, in rare cases – dyspeptic symptoms, hemorrhagic diarrhea, bleeding from the anus, constipation, tenesmus and belching; isolated cases – proctitis;
• digestive system: jaundice rarely develops;
• subcutaneous tissue and skin: sweating often increases, itching rarely occurs;
• connective tissues, skeleton and muscles: pain in the joints or muscles often develops, as well as pain in the jaw and trismus; muscle tone rarely increases, muscle cramps occur, and in addition, tetany;
• urinary system and kidneys: rarely - kidney pain, painful spasms inside the urinary organs, urine analysis shows changes in indicators, pathologies of the urinary tract and dysuria;
• General disorders and local reactions: fever often develops, heat appears, temperature rises, pain occurs, fatigue, chills, thirst, malaise, and asthenia appear; phlebitis, erythema, or pain may also develop at the site of infusion.

The drug may cause angina, especially in people with coronary artery disease. The risk of bleeding increases in people who are treated with heparin, antiplatelet agents or coumarin anticoagulants.

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Overdose

Overdose may cause hypotensive symptoms, as well as flushing of the skin, headaches, vomiting, diarrhea and nausea. Blood pressure may increase, back or shin pain may develop, as well as tachycardia or bradycardia.

There are no specific antidotes. To eliminate symptoms, it is necessary to stop the infusion, monitor the patient's condition, and then treat the manifestations of overdose.

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Interactions with other drugs

Iloprost can increase the antihypertensive properties of Ca channel blockers, β-blockers, and also vasodilators with ACE inhibitors. In a situation where the blood pressure level has dropped very significantly, this disorder can be corrected by lowering the dose of Ilomedin.

Since the drug slows down platelet aggregation, combined use with anticoagulants (for example, coumarin derivatives or heparin), as well as other antiplatelet agents (including NSAIDs, aspirin, PDE inhibitors or nitro-containing drugs that dilate blood vessels: for example, Molsidomine) can increase the likelihood of bleeding. If such a reaction occurs, the infusion must be stopped.

Premedication with aspirin (300 mg tablets) taken daily for 8 days had no effect on the pharmacokinetics of Ilomedin.

Animal testing showed that the drug can reduce the steady-state plasma level of plasminogen (a tissue activator).

Clinical trial data demonstrate that drug infusions do not affect the pharmacokinetics of digoxin (with repeated internal use of the latter), nor do they affect the properties of plasminogen administered simultaneously with Ilomedin.

The vasodilatory properties of iloprost are increased by prior glucocorticoid administration (animal testing), but at the same time, no changes in the level of antiaggregation are observed. The clinical significance of the above information has not yet been determined.

Although clinical tests on this issue have not been carried out, in vitro tests examining the inhibitory properties of iloprost on the activity of enzymes of the hemoprotein P450 system have shown that this component cannot inhibit the metabolism of drugs that are metabolized by these enzymes.

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Storage conditions

It is recommended to store the medicine in a place where small children cannot reach it. Temperature – no more than 30°С.

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Shelf life

Ilomedin is permitted to be used for 5 years from the date of its manufacture.

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