Ilopera (Solution) Instructions for Use

Marketing Authorization Holder

Gen İlaç Ve Sağlık Ürünleri San. Ve Tic., A.Ş. (Turkey)

ATC Code

B01AC11 (Iloprost)

Active Substance

Iloprost (Rec.INN registered by WHO)

Dosage Form

Ilopera

Solution for inhalation 10 mcg/ml

Dosage Form, Packaging, and Composition

Solution for inhalation

2 ml – ampoules (30 pcs.) – cardboard packs – By prescription

Clinical-Pharmacological Group

Antiplatelet agent. Synthetic analogue of prostacyclin

Pharmacotherapeutic Group

Antithrombotic agents; antiplatelet agents, other than heparin

Pharmacological Action

Iloprost is an 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 administered by inhalation, direct vasodilation of the pulmonary arterial bed is observed, followed by significant improvement in parameters such as pulmonary arterial 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, steady-state concentration (C_ss) is reached within 10-15 minutes (the time to reach it is linearly dependent on the infusion rate). The maximum concentration (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). Two hours after stopping the infusion, the concentration of the active substance is less than 10% of C_ss.

Distribution

Plasma protein binding with albumin is 60%. Metabolic clearance is 20±5 ml/kg/min. The terminal distribution half-life (T_1/2) is 1/2 hour.

Metabolism

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

Excretion

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

Intravenous infusion: obliterating thromboangiitis (in late stages with critical limb ischemia when revascularization is not indicated); obliterating endarteritis (severe forms, especially in cases with 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).

Inhalation: treatment of moderate and severe stages of pulmonary hypertension in cases of idiopathic (primary) pulmonary arterial hypertension, familial pulmonary arterial hypertension; in cases of pulmonary arterial hypertension associated with connective tissue disease or the use of drugs or toxins; in cases of pulmonary hypertension due to chronic thrombosis and/or embolism of the pulmonary artery when surgical treatment is not possible.

ICD codes

Dosage Regimen

Intravenous infusion, administered daily as a 6-hour infusion into a peripheral vein or a catheter placed in a central vein. The infusion rate (dose) depends on individual tolerance and ranges from 0.5 to 2 ng/kg/min.

During the first 2-3 days, 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 starts with an infusion 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 delivery system used.

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

If side effects such as headache, nausea, or decreased blood pressure occur, the infusion rate should be reduced to the maximum tolerated level. If severe side effects develop, the infusion must be interrupted. Treatment is usually resumed after 4 weeks at doses that the patient tolerated well during 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.

For inhalation use 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 cases of impaired liver or kidney function, dose adjustment 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, syncope, prolonged loss of consciousness, blurred vision, eye irritation and pain; rare – vestibular disorders; frequency unknown – confusion.

Cardiovascular system disorders: frequent – decreased blood pressure, bradycardia, flushing and sensation 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 alteration, tenesmus, constipation, belching, dysphagia, diarrhea, melena, rectal bleeding, jaundice.

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

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

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

Other: very frequent – sweating; frequent – localized 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 of 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 cases of impaired liver function, dose adjustment is required.

Use in Renal Impairment

In cases of impaired renal function, dose adjustment is required.

Special Precautions

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

Pregnancy should be excluded in women before starting treatment.

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 comes into contact with any area of the skin, it should be immediately washed off with plenty of water or 0.9% sodium chloride solution.

Surgical intervention should not be delayed in patients requiring emergency leg amputation (e.g., in 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 considered.

Accidental injection of the 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 as a weakening of the effect on platelets, and the possibility of a “rebound syndrome”, manifested as an increased tendency for platelet aggregation upon completion of the therapy course (reports of clinical complications associated with these phenomena are lacking).

Drug Interactions

It may enhance 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 vasodilatory effect of iloprost without changing the nature of the antiplatelet action (clinical effect not identified).

Heparin, indirect anticoagulants (coumarin derivatives) may theoretically 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 25°C (77°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.