Ilomedin^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Bayer, AG (Germany)

Manufactured By

Berlimed S.A. (Spain)

ATC Code

B01AC11 (Iloprost)

Active Substance

Iloprost

Dosage Forms

	Ilomedin®	Concentrate for solution for infusion 20 mcg/1 ml: amp. 1 ml 1, 5 or 20 pcs.
		Concentrate for solution for infusion 20 mcg/1 ml: amp. 2.5 ml 1, 5 or 20 pcs.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion clear, colorless or almost colorless.

Excipients: trometamol, ethanol 96%, sodium chloride, hydrochloric acid 1M, water for injections.

1 ml – ampoules of colorless glass with a capacity of 1 ml (1) – cardboard trays (1) – cardboard packs.
1 ml – ampoules of colorless glass with a capacity of 1 ml (5) – cardboard trays (1) – cardboard packs.
1 ml – ampoules of colorless glass with a capacity of 1 ml (5) – cardboard trays (4) – cardboard packs.

Concentrate for solution for infusion clear, colorless or almost colorless.

Excipients: trometamol, ethanol 96%, sodium chloride, hydrochloric acid 1M, water for injections.

2.5 ml – ampoules of colorless glass with a capacity of 3 ml (1) – cardboard trays (1) – cardboard packs.
2.5 ml – ampoules of colorless glass with a capacity of 3 ml (5) – cardboard trays (1) – cardboard packs.
2.5 ml – ampoules of colorless glass with a capacity of 3 ml (5) – cardboard trays (4) – cardboard packs.

Clinical-Pharmacological Group

Antiplatelet agent. Synthetic analogue of prostacyclin

Pharmacotherapeutic Group

Antiaggregant agent

Pharmacological Action

Antiplatelet agent, an analogue of prostacyclin. It inhibits platelet aggregation, platelet adhesion and the release reactions of soluble adhesion molecules; dilates arterioles and venules; increases capillary density and reduces increased vascular permeability caused by mediators such as serotonin or histamine at the level of the microcirculatory bed; stimulates endogenous fibrinolytic activity; exerts anti-inflammatory effects, such as inhibition of leukocyte adhesion after endothelial damage and leukocyte infiltration into damaged tissues, as well as reduction of TNFα release.

When used by inhalation, direct vasodilation of the pulmonary arterial bed is observed, followed by significant improvement in parameters such as pulmonary artery pressure, pulmonary vascular resistance, cardiac output, and mixed venous blood oxygen saturation. The effect on systemic vascular resistance and systemic blood pressure is minimal.

Pharmacokinetics

After IV infusion, C_ss is reached in 10-15 min (the time to reach it depends linearly on the infusion rate). C_max at an infusion rate of 3 ng/kg/min is 135±24 pg/ml. After the end of the infusion, the plasma concentration decreases rapidly (due to high metabolic intensity). 2 hours after stopping the infusion, the concentration of the active substance is less than 10% of C_ss.

Distribution

Binding to plasma albumin is 60%. Metabolic clearance is 20±5 ml/kg/min. T_1/2 in the terminal distribution phase is 1/2 hour.

Metabolism

It is metabolized mainly by beta-oxidation of the side carboxyl chain and the formation of the main pharmacologically inactive metabolite tetranoriloprost.

Excretion

It is excreted mainly by the kidneys (80% – in the form of tetranoriloprost and four of its conjugated forms – diastereoisomers), 20% – with bile. The elimination of metabolites from plasma and urine is biphasic: T_1/2 from plasma in the first phase is about 2 hours, in the second phase – about 5 hours, and for urine – 2 and 18 hours, respectively.

Pharmacokinetics in special clinical cases

Pharmacokinetic parameters do not depend on age and sex. In liver cirrhosis and renal failure requiring dialysis, clearance decreases by 2-4 times.

Indications

IV as infusions: obliterating thromboangiitis (in late stages with critical limb ischemia in cases where revascularization is not indicated); obliterating endarteritis (severe forms, especially in cases of risk of amputation and when vascular surgery or angioplasty is not possible); Raynaud’s syndrome (in late stages leading to disability, not responding to other drugs).

By inhalation: treatment of moderate and severe stages of pulmonary hypertension in case of idiopathic (primary) pulmonary arterial hypertension, familial pulmonary arterial hypertension; in case of pulmonary arterial hypertension due to connective tissue disease or the action of drugs or toxins; in case of pulmonary hypertension due to chronic thrombosis and/or pulmonary embolism when surgical treatment is not possible.

ICD codes

Dosage Regimen

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

During the first 2-3 days, the individual tolerance of the drug is determined under the control of heart rate and blood pressure (should be determined at the beginning of the infusion and after each dose increase): treatment is started at an administration rate of 0.5 ng/kg/min for 30 minutes, then the dose is gradually increased by 0.5 ng/kg/min every 30 minutes. The exact infusion rate is calculated based on body weight and the maximum tolerated dose, within the range of 0.5-2 ng/kg/min, taking into account the means used for administration.

The duration of treatment is up to 4 weeks. In patients with Raynaud’s syndrome, to achieve a short-term remission (several weeks), shorter courses of treatment – 3-5 days – are often sufficient.

If side effects such as headache, nausea, or decreased blood pressure occur, the infusion rate should be reduced to the maximum tolerated. If severe side effects develop, the infusion must be interrupted. Treatment is usually resumed after 4 weeks at doses that the patient tolerated well in the first 2-3 days of the previous course of treatment.

In renal failure requiring dialysis and in liver cirrhosis, the recommended dose should be reduced by half.

When used by inhalation in the appropriate dosage form, a single dose is 2.5-5 mcg. The frequency and duration of use are determined by the clinical situation. In case of impaired liver or kidney function, adjustment of the dosage regimen is required.

Adverse Reactions

Nervous system disorders frequent – dizziness, headache, paresthesia, hyperesthesia, tinnitus, anxiety, agitation, lethargy, apathy, drowsiness; infrequent – tremor, cerebrovascular disorders, depression, hallucinations, migraine, fainting, prolonged loss of consciousness, impaired visual clarity, eye irritation and pain; rare – vestibular disorders; frequency unknown – confusion.

Cardiovascular system disorders frequent – decreased blood pressure, bradycardia, skin flushing and feeling of heat; infrequent – arrhythmia (including extrasystole), myocardial ischemia, myocardial infarction, deep vein thrombosis, pulmonary embolism; frequency unknown – increased blood pressure, tachycardia; in isolated cases (in elderly patients with severe atherosclerosis) – pulmonary edema.

Respiratory system disorders infrequent – bronchial asthma; rare – cough; in isolated cases (in elderly patients with severe atherosclerosis) – heart failure.

Digestive system disorders very frequent – nausea, vomiting; frequent – anorexia, diarrhea, abdominal discomfort, abdominal pain; infrequent – dry mouth, taste change, tenesmus, constipation, belching, dysphagia, diarrhea, melena, rectal bleeding, jaundice.

Musculoskeletal system disorders frequent – pain in the masticatory muscles, trismus, myalgia, arthralgia, muscle weakness; infrequent – tetany, muscle twitching, hypertonia.

Urinary system disorders back pain, renal colic, change in urine cellular composition, dysuria.

Local reactions frequent – skin hyperemia, pain, phlebitis at the injection site.

Other very frequent – sweating; frequent – local pain, generalized pain, hyperthermia, skin itching, increased fatigue, thirst; frequency unknown – allergic reactions.

Contraindications

Pathological conditions with an increased risk of bleeding (including peptic ulcer of the stomach or duodenum in the acute phase, hemorrhagic stroke), severe coronary artery disease (unstable angina, myocardial infarction within the last 6 months); acute or chronic heart failure class II-IV, severe arrhythmias, pregnancy, lactation (breastfeeding), hypersensitivity to iloprost.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

In case of impaired liver function, adjustment of the dosage regimen is required.

Use in Renal Impairment

In case of impaired renal function, adjustment of the dosage regimen is required.

Special Precautions

Use only under conditions of careful monitoring in a hospital or outpatient facilities with appropriate capabilities.

Before starting treatment, pregnancy should be excluded in women.

Ingestion of the drug substance, or contact with mucous membranes and skin should be avoided (may lead to prolonged and painless erythema). If the drug substance gets on any area of the skin, it should be immediately washed with plenty of water or 0.9% sodium chloride solution.

Surgery should not be delayed in patients requiring emergency leg amputation (for example, with infected gas gangrene).

Patients should be strongly advised to quit smoking.

During therapy in patients with arterial hypotension, measures should be taken against further decrease in blood pressure.

Patients with severe heart disease should be under careful monitor observation.

After the end of the course of treatment, the possibility of orthostatic hypotension when the patient moves from a horizontal to a vertical position should be taken into account.

Accidental administration of undiluted solution into the tissues surrounding the vessel may lead to their damage.

Continuous infusions over several days are not recommended due to the possibility of developing tachyphylaxis, expressed in a weakening of the effect on platelets and the possibility of a “rebound syndrome”, manifested in an increased tendency to platelet aggregation upon completion of the course of therapy (reports of clinical complications associated with these phenomena are absent).

Drug Interactions

It enhances the hypotensive effect of beta-blockers, slow calcium channel blockers, vasodilators, ACE inhibitors (not confirmed in clinical studies on volunteers).

In experiments, corticosteroids enhance the vasodilating effect of iloprost without changing the nature of the antiplatelet effect (clinical effect has not been identified).

Heparin, indirect anticoagulants (coumarin derivatives), theoretically may increase the risk of bleeding (the drug infusion should be stopped).

The antiplatelet effect is enhanced by other inhibitors of platelet aggregation (acetylsalicylic acid and other NSAIDs, phosphodiesterase inhibitors, nitrates and molsidomine).

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.