Vazostenon

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VASOSTENOON (VASOSTENOON)

Composition:

Active substance: alprostadil;

1 ampoule contains 20 mcg of alprostadil;

Excipient: anhydrous ethanol.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: colorless clear solution without mechanical impurities.

Pharmacotherapeutic group. Prostaglandins. ATC code C01EA01.

Pharmacological Properties

Pharmacodynamics

Alprostadil, the active substance of the drug Vazostenon, is a vasodilator. It enhances blood flow by dilating arterioles and precapillary sphincters. Alprostadil improves microcirculation and the rheological properties of blood. After intravenous administration in healthy volunteers and patients, increased erythrocyte elasticity and inhibition of their aggregation ex vivo have been observed.

Alprostadil effectively inhibits platelet activation in vitro. This effect extends to platelet shape, aggregation, secretion of substances contained in granules, and release of thromboxane—a substance promoting aggregation. The drug reduces the incidence of arterial thrombus formation.

In humans, alprostadil stimulates fibrinolysis and increases certain indicators of endogenous fibrinolysis (plasminogen, plasmin, tissue plasminogen activator activity).

Pharmacokinetics

After intravenous administration of alprostadil at a dose of 60 μg/2 hours, the maximum plasma concentration in healthy volunteers exceeded the maximum concentration during the placebo phase by 6 pg/mL (placebo: 2.4 pg/mL).

The elimination half-life during the alpha phase is approximately 0.2 minutes (calculated value), and during the beta phase, approximately 8 minutes. Thus, steady-state concentration is achieved shortly after the start of infusion. Data on Tmax are unavailable due to the development of a plateau.

Alprostadil is metabolized primarily in the lungs—approximately 80–90% during the first pass. The primary metabolites formed during the first pass—15-keto-PGE1, PGE0 (13,14-dihydro-PGE1), and 15-keto-PGE0 (13,14-dihydro-15-keto-PGE1)—undergo further degradation, including via beta-oxidation and omega-oxidation.

Metabolites are excreted in urine (88%) and feces (12%). Complete elimination occurs within 72 hours. Among the primary metabolites, only 15-keto-PGE0 can be detected in vitro using lung homogenates.

After administration of alprostadil at 60 μg/2 hours to healthy volunteers, PGE0 reached a maximum plasma concentration of 11.8 pg/mL (placebo: 1.7 pg/mL), with an elimination half-life of approximately 2 minutes during the alpha phase and approximately 33 minutes during the beta phase. Tmax was reached at 119 minutes. Corresponding values for

15-keto-PGE0 are: Cmax 151 pg/mL (placebo: 8 pg/mL), t½α approximately 2 minutes, t½ß 20 minutes, and Tmax 106 minutes.

Alprostadil is 93% bound to macromolecular components of blood plasma.

Clinical characteristics.

Indications.

Treatment of chronic occlusive diseases of peripheral arteries, stages III and IV, in adults when a vasodilatory procedure cannot be performed or when such a procedure has been unsuccessful.

Intravenous administration is not recommended for the treatment of stage IV chronic occlusive diseases of peripheral arteries.

Contraindications.

• Hypersensitivity to alprostadil or to any of the excipients;
• Cardiac function disorders:
  • decompensated heart failure class III and IV according to the New York Heart Association (NYHA) classification;
  • heart failure due to previous ineffective treatment;
  • arrhythmia of various etiologies, including arrhythmia causing hemodynamic disturbances;
  • cardiac arrhythmia due to previous ineffective treatment;
  • insufficiency and/or stenosis of aortic and/or mitral valves;
  • inadequately controlled coronary heart disease;
  • ischemic heart disease;
  • recent myocardial infarction (within the last 6 months);
• Suspected acute/chronic pulmonary edema based on clinical or radiological findings, history of pulmonary edema, or pulmonary infiltration;
• Severe chronic obstructive pulmonary diseases, veno-occlusive lung diseases;
• Liver diseases, particularly signs of acute liver failure (elevated levels of transaminases or gamma-glutamyl transferase) or severe liver insufficiency (including in medical history);
• Severe renal dysfunction (oligoanuria) (eGFR ≤ 29 mL/min/1.73 m²);
• Multiple injuries (polytrauma);
• Hemorrhagic disorders;
• Active or potential sites of bleeding, such as acute erosive gastritis, active gastric and/or duodenal ulcers;
• Intracerebral hemorrhage;
• Stroke within the last 6 months;
• Severe arterial hypotension;
• General contraindications for infusion therapy (e.g., congestive heart failure, pulmonary or cerebral edema, and hyperhydration);
• Pregnancy or breastfeeding;
• Pediatric age.

Interaction with other medicinal products and other forms of interaction.

The effect of antihypertensive drugs, vasodilators, and antianginal agents may be enhanced during treatment with this medicinal product. Careful monitoring of the cardiovascular system, including blood pressure monitoring, is required when these drugs are used concomitantly with alprostadil or other vasodilators.

Sympathomimetics, adrenaline, and noradrenaline reduce the vasodilatory effect of the drug. Concomitant use of the drug with antithrombotic agents (anticoagulants, platelet aggregation inhibitors, thrombolytic agents) may increase the tendency to bleeding. Given the weak inhibitory effect of alprostadil on platelet aggregation in vitro, caution should be exercised when administering to patients who are concurrently receiving anticoagulants.

Concomitant use with cefamandole, cefoperazone, or cefotetan reduces the effect of Vazostenon.

Special precautions for use.

Patients in risk groups should be treated with caution, with close monitoring during the administration of each dose.

Patients predisposed to heart failure due to age, as well as those with ischemic heart disease, should be hospitalized during treatment and for one day after discontinuation of therapy with the drug. The drug should be administered cautiously in patients with arterial hypotension.

To prevent hyperhydration, infusion volumes should not exceed 50–100 mL per day (administered via an infusion device). The recommended duration of infusion should also be followed (see section "Dosage and administration"). Monitoring of cardiovascular parameters (arterial pressure and heart rate), body weight, fluid balance, central venous pressure, and echocardiography are required. A patient may be discharged from hospital only after stable cardiovascular parameters have been established.

Similarly careful monitoring (fluid balance and renal function parameters) is required for patients with peripheral edema or mild (eGFR ≤ 89 mL/min/1.73 m²) and moderate (eGFR ≤ 59 mL/min/1.73 m²) renal dysfunction.

The drug should be used with caution in patients undergoing hemodialysis (treatment should be performed in the post-dialysis period), and in patients with type 1 diabetes, especially in cases with pronounced vascular involvement.

Vazostenon must be administered by a physician experienced in the treatment of peripheral arterial occlusive diseases, who is familiar with modern methods of continuous monitoring of cardiovascular parameters and has appropriate equipment for this purpose. Alprostadil must not be administered by intravenous bolus (rapid bolus) injection.

When used concomitantly with antihypertensive drugs, vasodilators, and antianginal agents, careful monitoring of cardiovascular parameters is required (see section "Interaction with other medicinal products and other forms of interaction").

Alprostadil should be used with caution in patients with a history of gastrointestinal disorders, including erosive gastritis, gastrointestinal bleeding, and gastric and/or duodenal ulcers, or in patients with a history of intracerebral hemorrhage or other bleeding episodes.

Caution is advised in patients taking concomitant medications that may increase the risk of bleeding, such as anticoagulants or platelet aggregation inhibitors. Such patients should be carefully monitored for signs and symptoms of bleeding.

This medicinal product contains 99.5 vol.% ethanol (alcohol), i.e., 786 mg per dose, equivalent to 15.9 mL of beer or 6.7 mL of wine per dose. It is harmful for patients suffering from alcoholism. Caution is advised when administering to patients with liver disease and patients with epilepsy.

Use during pregnancy or breastfeeding.

The drug must not be administered to women of childbearing potential or during pregnancy. If use of the drug is necessary during lactation, breastfeeding must be discontinued.

Women of childbearing potential must use effective contraceptive methods to prevent pregnancy during treatment with the drug.

Preclinical fertility studies do not indicate any effect of the drug on fertility when clinical doses are used.

Ability to affect reaction speed when driving or operating machinery.

Like all drugs acting on the cardiovascular system (which may cause a decrease in systolic blood pressure), the drug may negatively affect the ability to drive or operate machinery, especially at the beginning of treatment, when the dose is increased, when the drug is discontinued, or when alcohol is consumed, as it may cause a reduction in systolic arterial pressure. Patients should be informed of the need for caution when driving or operating machinery.

Administration and Dosage

Vazostanon is intended for intra-arterial or intravenous administration as a solution, provided that the physician has experience in angiology and is familiar with modern methods of continuous monitoring of cardiovascular parameters, and has appropriate equipment for this purpose. The drug should not be administered intravenously as a bolus (rapid injection).

An automatic syringe, infusion pump, and infusion catheter are recommended for drug administration.

Intravenous administration is not recommended for the treatment of stage IV chronic occlusive peripheral arterial disease.

Stage III Intravenous Therapy

Intravenous therapy should be administered according to the following scheme:

The contents of 2 ampoules (40 mcg of alprostadil) should be dissolved in 50–250 mL of 0.9% sodium chloride solution. The resulting solution should be administered intravenously over 2 hours. This dose should be administered twice daily. Alternatively: once daily intravenous infusion over 3 hours of 3 ampoules (60 mcg of alprostadil), the contents of which should be dissolved in 50–250 mL of 0.9% sodium chloride solution.

In patients with impaired renal function (renal insufficiency with creatinine values > 1.5 mg/dL), intravenous administration of the drug should be initiated with:

1 ampoule twice daily (2 × 20 mcg of alprostadil), each infusion lasting 2 hours. Depending on the overall clinical condition, the dose may be increased to the above-mentioned standard dose over 2–3 days.

Patients with renal insufficiency and patients at risk of cardiac dysfunction should have their infusion volume limited to 50–100 mL per day and must receive the drug via an infusion device (see section "Administration and Dosage").

Stage III and IV Intra-arterial Therapy

Intra-arterial therapy should be administered according to the following scheme:

The contents of 1 ampoule (20 mcg of alprostadil) should be dissolved in 50 mL of 0.9% sodium chloride solution.

The volume of the resulting solution corresponding to half an ampoule (25 mL of solution containing 10 mcg of alprostadil) should be administered intra-arterially over 60–120 minutes using an infusion device. If tolerated well, the dose may be increased to 1 full ampoule (20 mcg of alprostadil), especially in the presence of necrosis. Usually, one infusion per day is recommended.

If intra-arterial infusion is administered through an indwelling catheter, the recommended dose is 0.1–0.6 ng/kg body weight/minute (equivalent to ¼–1½ ampoules of the drug), depending on drug tolerance and disease severity. The infusion, administered via an infusion device, should last 12 hours.

Special Populations

Elderly patients, patients predisposed to heart failure, and patients with ischemic heart disease

Elderly patients, patients predisposed to heart failure, and patients with ischemic heart disease should be under continuous medical supervision (see section "Special Precautions").

Patients with peripheral edema

Patients with peripheral edema should be under continuous medical supervision (see section "Special Precautions").

Patients with renal impairment

Patients with mild (GFR ≤ 89 mL/min/1.73 m²) and moderate (GFR ≤ 59 mL/min/1.73 m²) renal impairment should be under continuous close medical supervision (e.g., fluid balance monitoring and laboratory monitoring of renal function) (see section "Special Precautions").

Women of reproductive age

Women of reproductive age should use effective contraception during treatment with this drug (see sections "Special Precautions" and "Use during Pregnancy or Breastfeeding").

Children

Not to be used in children.

Duration of Administration

After a three-week course of treatment, the need for further administration of the drug should be reassessed. If no therapeutic effect is observed in the patient, treatment should be discontinued. The total treatment duration should not exceed 4 weeks.

Method of Administration

Chemical and physical stability of the drug during use is maintained for 12 hours at temperatures up to 20°C, protected from light. From a microbiological standpoint, the drug should be used immediately. If not used immediately, the user is responsible for the storage duration and conditions.

Children

Not to be used in children.

Overdose

Symptoms. Overdose may lead to decreased arterial blood pressure and reflex tachycardia due to vasodilatory effects. Other possible symptoms include vasovagal syncope with pallor, increased sweating, nausea, vomiting, myocardial ischemia, and heart failure. Local reactions may also occur: pain, swelling, and redness at the limb where infusion is administered, and hypersensitivity reactions.

Treatment is symptomatic. There is no specific antidote. In case of overdose (severe pain, decreased arterial blood pressure), the dose should be reduced or infusion should be stopped immediately. In case of decreased arterial blood pressure, the patient should first be placed in a supine position with legs elevated. If symptoms persist, cardiovascular parameters should be monitored. If necessary, drugs that stabilize circulation (e.g., sympathomimetics) may be administered. In case of severe cardiovascular symptoms (e.g., myocardial ischemia, heart failure), infusion should be stopped immediately.

Adverse Reactions

Adverse reactions are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Central nervous system:
Common – headache, limb paraesthesia at the site of intervention;
Uncommon – confusion;
Rare – cerebral seizures;
Frequency not known – stroke.

Gastrointestinal disorders:
Uncommon – gastrointestinal disorders including diarrhea, nausea, vomiting, and increased intestinal peristalsis;
Frequency not known – gastrointestinal bleeding.

Cardiovascular system:
Uncommon – decreased blood pressure, tachycardia, angina pectoris;
Rare – arrhythmias, heart failure with episodes of acute pulmonary edema, which may lead to overall cardiac failure;
Frequency not known – myocardial infarction, hemorrhage.

Hepatobiliary disorders:
Rare – disturbances in liver enzyme levels.

Respiratory, thoracic and mediastinal disorders:
Rare – pulmonary edema;
Frequency not known – dyspnea.

Blood and lymphatic system disorders:
Rare – leukopenia, leukocytosis, thrombocytopenia, anemia.

Investigations:
Uncommon – increased liver function parameters (transaminases), increased body temperature, changes in CRP (C-reactive protein); these parameters rapidly normalize after completion of treatment.

Skin and subcutaneous tissue disorders:
Common – redness, swelling, flushing.

General disorders and administration site conditions:
Very common – pain, erythema, or swelling of the limb receiving intra-arterial infusion;
Common – sensation of warmth, sensation of swelling, swelling at the site of administration, paraesthesia; with intravenous administration – redness of veins at the infusion site; after intra-arterial administration – sensation of warmth, sensation of swelling, swelling at the site of administration, paraesthesia;
Uncommon – increased sweating, chills, fever; with intravenous administration – sensation of warmth, sensation of swelling, swelling at the site of administration, paraesthesia;
Frequency not known – phlebitis at the site of administration, catheter site thrombosis, local hemorrhage.

Immune system disorders:
Uncommon – allergic reactions (hypersensitivity skin reactions including skin rash, sensation of swelling, joint discomfort, febrile reaction, sweating, chills);
Very rare – anaphylactic or anaphylactoid reactions.

Musculoskeletal and connective tissue disorders:
Uncommon – joint symptoms including pain;
Very rare – reversible hyperostosis of long tubular bones after administration of the drug for more than 4 weeks.
Frequency not known – orthostatic hypotension, increased fatigue.

Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.
Store in the original packaging, protected from light, at 2 to 8 °C. Keep out of the reach of children.

Packaging.
1 ml in vials made of borosilicate glass.
Each vial contains 20 mcg of alprostadil.
Packaged in cardboard boxes containing 5, 10, or 20 vials with a special vial holder.

Prescription status. Prescription only.

Manufacturer/Marketing Authorization Holder. AS Kevelt, Estonia.

Address of manufacturer and/or marketing authorization holder.
Teaduspargi 3/1, 12618 Tallinn, Estonia.