Vazaprostan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VASAPROSTAN® (VASAPROSTAN®)

Composition:

Active substance: alprostadil;

1 ampoule contains 20 mcg of alprostadil;

Excipients: alfadex, anhydrous lactose.

Pharmaceutical form. Powder for solution for infusion.

Main physico-chemical properties:

Content of the ampoule: white lyophilisate, settled at the bottom of the ampoule;

Ampoule: colorless, 5 ml "OPC" (one-point-cut) ampoule made of type I glass, with a blue dot above the score line on the neck and one red coded ring.

Pharmacotherapeutic group. Cardiological agents. Prostaglandins.

ATC code C01EA01.

Pharmacological properties.

Pharmacodynamics.

Alprostadil, the active substance of Vazaprostane®, is a vasodilator. It enhances blood flow by dilating arterioles and precapillary sphincters. The drug improves microcirculation and blood rheological properties. After intravenous administration to healthy volunteers or patients, increased erythrocyte deformability and inhibition of their aggregation ex vivo have been observed. In humans and animals, alprostadil effectively inhibits platelet activation in vitro. This effect extends to parameters involving changes in platelet shape, aggregation, secretion of granule-contained substances, and release of thromboxane—a substance promoting aggregation. In animal experiments, the drug reduces thrombus formation in vivo.

Therapeutic use of the drug in humans stimulates fibrinolysis and increases certain indices of endogenous fibrinolysis (plasminogen, plasmic activity, tissue plasminogen activator activity).

Pharmacokinetics.

The complex composed of alprostadil (PGE1) and alphadex (alpha-cyclodextrin) dissociates into individual components upon reconstitution of the infusion solution. Therefore, the pharmacokinetics of each substance is independent of the presence of the complex in the lyophilisate.

After intravenous administration of alprostadil at a dose of 60 mcg/2 hours, the maximum plasma concentration in healthy volunteers exceeded the maximum concentration during 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 mainly metabolized in the lungs: 80–90% during the first pass through the lungs. During this process, primary metabolites are formed—15-keto-PGE1, PGE0 (13,14-dihydro-PGE1), and 15-keto-PGE0—which 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 mcg/2 hours to healthy volunteers, the maximum plasma concentration of PGE0 exceeded the placebo-phase maximum by 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 is reached after 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 plasma. Animal experiments have shown that the elimination half-life of alphadex is approximately 7 minutes; it is excreted unchanged in urine.

Clinical characteristics.

Indications.

Treatment of chronic occlusive arterial diseases at stages III and IV in adult patients (according to Fontaine classification) who are not candidates for revascularization or in whom revascularization has been unsuccessful.

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

Contraindications.

• Hypersensitivity to alprostadil or to any of the excipients;
• Presence of the following cardiac function disorders:
• Decompensated heart failure class III and IV according to New York Heart Association (NYHA) classification;
• Inadequately treated heart failure;
• Arrhythmias of various etiologies, including arrhythmia causing hemodynamic disturbances;
• Inadequately treated cardiac arrhythmia;
• Aortic and/or mitral valve insufficiency and/or stenosis;
• 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 pulmonary diseases;
• Documented liver disease, particularly with signs of acute liver failure (elevated transaminases or gamma-GT levels) or documented severe liver insufficiency (including history);
• Severe renal dysfunction (oligoanuria) (eGFR ≤ 29 mL/min/1.73 m²);
• Multiple organ injury (polytrauma);
• Hemorrhagic diathesis;
• Active or potential source of bleeding, such as acute erosive gastritis, active gastric and/or duodenal ulcer;
• Intracerebral hemorrhage;
• History of stroke within the last 6 months;
• Severe arterial hypotension;
• General contraindications against infusion therapy (e.g., congestive heart failure, pulmonary or cerebral edema, or hyperhydration);
• Pregnancy or breastfeeding period;
• Pediatric age.

Interaction with other medicinal products and other forms of interaction.

Treatment with this medicinal product may enhance the effects of antihypertensive drugs, vasodilators, and antianginal agents. Careful monitoring of the cardiovascular system, including arterial pressure monitoring, is required when these drugs are used concomitantly with alprostadil.

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. Due to the weak in vitro inhibitory effect of alprostadil on platelet aggregation, caution should be exercised when administering to patients who are concurrently receiving anticoagulants or platelet aggregation inhibitors.

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

Special precautions for use.

Patients receiving Vazaprostane® should be carefully monitored during the administration of each dose. This is particularly important for patients predisposed to heart failure due to age, and for patients with ischemic heart disease, who should remain under inpatient supervision during treatment and for one day after discontinuation of the drug. The drug should be administered with caution in patients with mild or moderate arterial hypotension.

To prevent symptoms of hyperhydration, infusion volumes should not exceed 50–100 ml per day (administered via an infusion device). The recommended duration of infusion should also be strictly observed (see section "Dosage and administration"). Frequent monitoring of cardiovascular parameters (arterial pressure and heart rate), fluid balance, and, if necessary, body weight, central venous pressure, and echocardiography is required. Patients may be discharged from hospital only after stable cardiovascular parameters have been established.

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

Vazaprostane® should be used with caution in patients undergoing hemodialysis (treatment should be administered in the post-dialysis period), in patients with type 1 diabetes mellitus, especially in the presence of significant vascular involvement.

Vazaprostane® must be administered only by physicians experienced in the treatment of peripheral arterial occlusive diseases, who are familiar with modern methods of continuous monitoring of cardiovascular parameters and have appropriate equipment for this purpose. Intravenous bolus injection of alprostadil should not be used.

Careful monitoring of cardiovascular parameters is required when alprostadil is used concomitantly with antihypertensive drugs, vasodilators, and antianginal agents (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, gastric and/or duodenal ulcer, or intracerebral hemorrhage, or other conditions associated with bleeding (see section "Contraindications").

Caution is recommended when treating patients receiving concomitant therapy with medicinal products that may increase the risk of bleeding, such as anticoagulants or platelet aggregation inhibitors (see section "Interaction with other medicinal products and other forms of interaction"). Close observation for signs and symptoms of bleeding is required in such patients.

Use during pregnancy or breastfeeding.

Vazaprostane® should not be used in women of childbearing potential, pregnant women, or women who are breastfeeding. If treatment with the drug is necessary, breastfeeding should be discontinued.

Women of childbearing potential should 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 at clinically relevant doses.

Ability to affect reaction speed when driving or operating machinery.

Alprostadil may cause a decrease in systolic blood pressure; therefore, the drug may have a moderate effect on the ability to drive or operate machinery, particularly at the beginning of treatment, when the dose is increased, upon discontinuation of the drug, or when alcohol is consumed. Patients should be advised to exercise caution when driving or operating machinery.

Method of Administration and Dosage

Vazaprostane® must be administered only intravenously or intra-arterially by a physician experienced in angiology, who is familiar with modern methods of continuous monitoring of cardiovascular parameters and has appropriate equipment for such monitoring. The drug must not be administered intravenously as a bolus (i.e., by rapid push injection).

Intravenous Therapy for Stage III

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

Based on available data, unless otherwise prescribed, intravenous therapy should be performed according to the following regimen:

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 levels > 1.5 mg/dL), intravenous administration should be initiated at 1 ampoule twice daily (2 × 20 mcg alprostadil), each infusion lasting 2 hours. Depending on the overall clinical condition, the dose may be increased to the standard dose mentioned above over 2–3 days.

In patients with renal insufficiency and patients at risk of cardiac dysfunction, the infusion volume should be limited to 50–100 mL per day and must be administered using an infusion device (see section "Special Warnings and Precautions for Use").

Intra-arterial Therapy for Stages III and IV

Based on available data, intra-arterial therapy should be performed according to the following regimen:

The contents of 1 ampoule (20 mcg alprostadil) should be dissolved in 50 mL of 0.9% sodium chloride solution. The volume of the resulting solution corresponding to half the ampoule content (25 mL of solution containing 10 mcg alprostadil) should be administered intra-arterially over 60–120 minutes using an infusion device. If the drug is well tolerated, the dose may be increased to 1 full ampoule (20 mcg alprostadil), especially in the presence of necrosis. Typically, one infusion per day is administered.

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

Special Populations

Elderly Patients Predisposed to Heart Failure and Patients with Ischemic Heart Disease

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

Patients with Peripheral Edema

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

Patients with Renal Impairment

Patients with mild (eGFR ≤ 89 mL/min/1.73 m²) and moderate (eGFR ≤ 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 Warnings and Precautions for Use").

Women of Reproductive Age

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

Duration of Administration

After a three-week course of treatment, the need for continued therapy should be re-evaluated. If no therapeutic effect is observed in the patient, treatment should be discontinued. The treatment course should not exceed 4 weeks.

Method of Administration

The solution should be prepared immediately before infusion. A solution prepared more than 12 hours previously must not be used.

The ampoule does not require additional scoring: the break point is located beneath the blue dot.

The ampoule contains a dry, white powder forming a solid layer approximately 3 mm thick. Small cracks or crumbs may be present on this layer. If the ampoule is damaged, the dry substance usually becomes moist and sticky and significantly decreases in volume. In such cases, the drug must not be used.

The dry substance dissolves immediately after addition of 0.9% sodium chloride solution. After dissolution, the solution may initially appear slightly cloudy due to the formation of air bubbles. These bubbles disappear quickly, and the solution becomes clear.

Chemical and physical in-use stability is maintained for 24 hours at temperatures between 21 and 24°C. From a microbiological standpoint, the drug should be used immediately. If not used immediately, the responsibility for storage duration and conditions lies with the user. Generally, the drug should not be stored for more than 24 hours at 2–8°C, except when dilution is performed under controlled and validated aseptic conditions.

Children

The drug is not intended for use in children.

Overdose

Symptoms

Overdose may lead to arterial hypotension and 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 of the limb receiving the infusion, as well as hypersensitivity reactions.

Treatment

Symptomatic. There is no specific antidote. In case of overdose, the infusion rate should be reduced or immediately discontinued. In case of hypotension, the patient should first be placed in a supine position with legs elevated. If symptoms persist, cardiovascular parameters should be assessed and monitored. If necessary, circulatory-stabilizing medications (e.g., sympathomimetics) may be administered. In cases of severe cardiovascular symptoms (e.g., myocardial ischemia, heart failure), the infusion must be immediately discontinued.

Adverse Reactions

Adverse reactions are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

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

Nervous system disorders:
Common – headache, limb paraesthesia at the site of intervention; uncommon – confusion; rare – cerebral seizures; frequency not known – stroke.

Cardiovascular system disorders:
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, hemorrhages.

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

Gastrointestinal disorders:
Uncommon – gastrointestinal disorders including diarrhea, nausea, vomiting, and increased intestinal peristalsis (diarrhea, nausea, vomiting), which are properties of alprostadil; frequency not known – gastrointestinal hemorrhages.

Hepatobiliary disorders:
Rare – increased levels of liver enzymes.

Investigations:
Uncommon – increased liver function parameters (transaminases), increased body temperature, changes in CRP (C-reactive protein) levels; rapid normalization occurs after completion of treatment.

Skin and subcutaneous tissue disorders:
Common – erythema, edema, flushing.

General disorders and administration site conditions:
Very common – pain, erythema, or edema in the limb receiving intra-arterial infusion; common – similar symptoms with intravenous administration, additionally erythema of veins at the infusion site; after intra-arterial administration – sensation of warmth, sensation of swelling, edema at the injection site, paraesthesia; uncommon – increased sweating, chills, fever; after intravenous administration – sensation of warmth, sensation of swelling, edema at the injection site, paraesthesia; frequency not known – phlebitis at the injection site, catheter site thrombosis, local bleeding.

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 Adverse Reactions

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

Shelf Life.
4 years.

Storage Conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Incompatibilities.

Exposure to high temperatures, humidity, and light may cause cleavage of the OH group at the 11th position and lead to the formation of prostaglandin A1.

Packaging.

Powder in 5 ml vials. 10 vials per cardboard box.

Prescription Category.

Prescription only.

Manufacturer.

Aciex Pharmaceuticals GmbH, Germany.

Manufacturer's Address and Place of Business.

Alfred-Nobel-Str. 10, Monheim am Rhein, 40789, Germany.