Ilomedin

Ilomedin is an antiaggregant. This is the concentrate needed to make the infusion solution.

[1]

Indications of the ilomedine

It is shown for elimination of such violations:

• Buerger's disease, which appeared against the background of a critical degree of ischemia in the limb region, if there are no indications for revascularization;
• severe degree of endarteritis of the obliterating form (in particular, if there is a possibility of amputation, and besides, if it is not possible to perform angioplasty or to operate the vessels);
• Raynaud's syndrome in severe form (leading to disability), which can not be treated with the help of other drugs.

Release form

It is produced in ampoules (No. 5) with a volume of 1 ml.

[2], [3], [4], [5],

Pharmacodynamics

Iloprost is an artificial analogue of prostacyclin. Its pharmacological properties:

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

[6], [7], [8]

Pharmacokinetics

The equilibrium level within the plasma drug reaches 10-20 minutes from the beginning of the infusion. This indicator is linear depending on the speed of the infusion (if it is 3 ng / kg / min, then the concentration level of the substance will be approximately 135 ± 24 pg / ml). Upon completion of the infusion, the plasma index of the active component of the drug rapidly decreases (due to the increased intensity of its metabolism process).

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

The drug can not 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%), resulting in a very small amount of free iloprost. Along with this, the likelihood of exposure to iloprost on the processes of bioconversion of other drugs is extremely low (due to the ways of its metabolism and low absolute dosage).

The metabolism of the substance is carried out with the help of the b-oxidation process in the side carboxyl chain. Excretion of the unchanged component does not occur. The main product of decomposition is tetranor-iloprost, which falls into the urine (conjugated, as well as free form) under the guise of 4 diastereoisomers. This metabolite has no pharmacological activity (this has been shown by testing in animals). In vitro tests show that with inhalation or with / in the introduction, the metabolism of the substance inside the lungs is very similar.

In people with healthy renal and hepatic activity, the excretion of iloprost after the infusion procedure often occurs in 2 phases with half-lives of 3-5 or 3-5 minutes, respectively, and 15-30 minutes. At the same time, the total clearance of the component is about 20 ml / kg / minute, which demonstrates the presence of extrahepatic metabolic pathway of the substance.

With the participation of volunteers, testing was carried out to identify the mass fraction of the decay products (here, 3H-iloprost was used). After the infusion, the total radioactivity index was 81%, while in the stool with urine, respectively, 12% and 68% were detected. The decay products are excreted in the urine, and also from the plasma in a 2-phase way. In this case, the half-life in the 1-st phase is equal to about 2 hours, and in the second - about 5 hours. Of urine, the half-life lasts 2, and also 18 hours, respectively.

With reduced renal activity (terminal phase of kidney failure). Studies in people with this disorder, who also underwent periodic dialysis, show that after intravenous medications the clearance rate is much lower (on average 5 ± 2 ml / minute / kg) than the similar level in people with kidney failure, not who underwent periodic dialysis procedures (with an average of 18 ± 2 ml / minute / kg).

With decreased hepatic activity. Since most of the active substance of the drug passes the metabolism inside the liver, changes in its work affect the plasma values of drugs. Test results with the participation of 8 people with cirrhosis showed that the average level of clearance of the substance was 10 ml / minute / kg.

[9]

Dosing and administration

Use of drugs is allowed only in conditions of constant monitoring of the patient (in a hospital or an outpatient institution that has the necessary equipment).

Women need to exclude the possibility of pregnancy before starting a therapeutic course.

Diluted medicine should be administered in the form of infusion for 6 hours (the way of administration - through the catheter inside the central vein or without it inside the peripheral vein) every day. The rate of infusion is determined by the individual sensitivity of the patient and is approximately 0.5-2 ng / kg / minute.

Infusion solution must be prepared every day to ensure sterility of the drug. The solvent and the substance contained in the ampoule must be thoroughly mixed.

It is required to detect heart rate indicators, and also the level of blood pressure before the start of the course, and then after each increase in the rate of infusion.

During the first 2-3 days, the drug is tolerated (therapy begins with the administration of drugs at a rate of 0.5 ng / kg / minute for half an hour). Further, the dosage gradually increases approximately every half hour by 0.5 ng / kg / minute until a rate of 2 ng / kg / minute is reached. A more accurate speed is selected, taking into account the weight of the person with the maximum tolerated dosage within 0.5-2 ng / kg / minute.

If a patient develops such negative reactions as lowering blood pressure, headaches or nausea, it is required to lower the rate of administration to a level that will be well tolerated by the patient. If severe side effects have occurred, you need to cancel the infusion. Later treatment is resumed (often the infusion lasts for 1 month) with the use of a dosage that has come to the person in the first 2-3 days, when choosing the speed of infusion.

[15], [16]

Use of the ilomedine during pregnancy

The medicine is forbidden to be prescribed to pregnant and lactating women. There is no information on the use of drugs during pregnancy.

According to preclinical testing, it was found that the drug has a toxic effect on the fetus of the rat, although, at the same time, it does not affect fetal development in monkeys with rabbits.

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

There is no information on the passage of the substance into the breast milk, but at the same time, as it passes in small amounts into rat milk, it is not recommended to use the medicine in breastfeeding.

Contraindications

Among the contraindications of drugs:

• painful conditions during which, due to the influence of the drug on platelets, the risk of bleeding increases (for example, an active stage of an ulcer, a hemorrhage inside the skull, or trauma);
• severe form of ischemic heart disease or unstable type of angina pectoris;
• the myocardial infarction transferred in the last half a year;
• acute or chronic stage of heart failure in stagnant form (grade 2-4 according to NYHA classification);
• suspected development in mild stagnant phenomena;
• intolerance to iloprost or other elements of the drug.

Today only a few cases of using drugs in adolescents and children are allowed.

[10], [11]

Side effects of the ilomedine

Often as a result of the use of drugs during the period of clinical testing, such side effects were observed: vomiting, hot flashes, hyperhidrosis, and nausea and headaches. Basically, they arose at the initial stage of therapy in the titration process to select the optimal dosage for each patient. But these manifestations usually soon pass, after lowering the dosage.

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

Another category of undesirable manifestations is associated with local reactions at the site of infusion. For example, there may be pain and redness at the procedure site. Also, due to the expansion of the vessels of the skin, erythema (in the form of a strip) occasionally appeared on the infusion site.

Among the side effects that were detected during clinical testing and post-marketing observations in patients treated with Ilomedin:

• lymph and hematopoiesis system: thrombocytopenia developed occasionally;
• organs of the immune system: rarely - reactions of intolerance;
• metabolic disorders: appetite often worsens;
• mental disorders: often there is confusion or a feeling of apathy, occasionally develop depression, anxiety, and hallucinations;
• organs of the National Assembly: often there are headaches, often there are vertigo / dizziness, a sense of pulsation / paresthesia / hyperesthesia; in rare cases - migraines, tremors, seizures and loss of consciousness;
• visual organs: occasionally there is irritation or pain inside the eyes, and in addition, visual acuity deteriorates;
• balance and auditory organs: single - vestibular disorders;
• organs of the cardiac system: brady, tachy-or angina often develop, heart failure / arrhythmia, and myocardial infarction are less common;
• cardiovascular system: often there are hot flashes, the blood pressure index often increases or the blood pressure decreases; rarely there are cerebrovascular pathologies, PE, cerebrospinal ischemia, and also DVT;
• diseases of the chest and mediastinum, respiratory disorders: dyspnea often develops, pulmonary edema or asthma develops rarely, cough occurs in single cases;
• organs of the digestive tract: often there is nausea with vomiting, often also there are abdominal pains or discomfort, and in addition diarrhea, in rare cases - dyspeptic phenomena, hemorrhagic form of diarrhea, bleeding from the anus, constipation, tenesmus and eructation; single proctitis;
• digestive system: rarely jaundice develops;
• subcutaneous fat and skin: often increases sweating, rarely itching;
• connective tissues, skeleton and musculature: joints or muscles often develop, and in addition pain in the jaw and tricusa; rarely increases muscle tone, there are muscle cramps, and in addition to tetany;
• urinary system and kidneys: rarely - kidney pain, painful spasms inside the urine, urinalysis shows a change in indicators, pathology of the urinary tract and dysuria;
• general disorders and local reactions: fever often develops, fever occurs, fever raises, pains occur, fatigue, chills, thirst, malaise, and also asthenia; Also at the site of infusion, phlebitis, erythema, or pain can develop.

The medicine can cause angina pectoris, especially in individuals with ischemic heart disease. Increased the possibility of bleeding in people who are treated with heparin, antiaggregants or coumarin anticoagulants.

[12], [13], [14]

Overdose

As a result of overdose, hypotensive signs may appear, but in addition to the tides of blood to the skin of the face, headaches, vomiting, diarrhea and nausea. The level of blood pressure may increase, the pain in the back or legs may develop, and in addition tachycardia or bradycardia.

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

[17], [18], [19]

Interactions with other drugs

Iloprost is able to increase the antihypertensive properties of blockers of the channels of Ca, β-adrenoblockers, as well as vasodilating drugs with ACE inhibitors. In a situation where the level of blood pressure has decreased very significantly, you can correct this violation by lowering the dose of Ilomedin.

Since the drug slows platelet aggregation, combined use with anticoagulants (for example, coumarin derivatives or heparin), and in addition other antiplatelet agents (among such NSAIDs, aspirin, PDE inhibitors or nitro-containing drugs that dilate blood vessels: for example, Molsidomine) is capable of increasing probability of bleeding. When such a reaction appears, it is necessary to cancel the infusion.

With premedication with aspirin (300 mg tablets) taken daily for 8 days, no effects on the pharmacokinetics of Ilomedin were found.

During the testing on animals, it was found that the drug can lower the equilibrium plasma level of plasminogen (tissue activator).

Data from clinical trials demonstrate that drug infusions do not affect the pharmacokinetics of digoxin (with repeated internal use of the latter), and in addition to the properties of plasminogen administered simultaneously with Ilomedin.

The vasodilating properties of iloprost increase with preliminary glucocorticoids (animal testing), but at the same time, changes in the level of antiaggregation are not observed. To clarify the clinical significance of the above-described information has not yet been possible.

Although clinical tests on this issue have not been carried out, according to in vitro tests that examined the retarding properties of iloprost against the enzyme activity of the hemoprotein P450 system, it was found that this component can not slow down the metabolism of drugs that are metabolized by these enzymes.

[20], [21], [22]

Storage conditions

The medicine is recommended to be stored in a place where there is no access for young children. Temperature - no more than 30 ° С.

[23]

Shelf life

Ilomedin is allowed to be used within 5 years from the moment of its manufacture.

[24]