Vap 20

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VAP 20 (VAP 20)

Composition:

Active substance: alprostadil;

1 ampoule contains alprostadil 20 mcg;

Excipient: ethanol 788 mg.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical characteristics: clear, colorless liquid with a characteristic odour of ethanol.

Pharmacotherapeutic group.

Prostaglandins. ATC code C01EA01.

Pharmacological properties.

Pharmacodynamics.

Alprostadil, the active substance of VAP 20, is a vasodilator. It enhances blood flow by dilating arterioles and precapillary sphincters. The drug improves microcirculation and the rheological properties of blood. After intravenous administration, increased erythrocyte elasticity and inhibition of their aggregation ex vivo are observed. Alprostadil effectively inhibits platelet activation in vitro. This effect extends to parameters involving platelet shape change, aggregation, secretion of substances contained in granules, and release of thromboxane—a substance promoting aggregation. The drug reduces arterial thrombus formation in vivo in animal studies.

The use of the drug stimulates fibrinolysis and increases certain indicators of endogenous fibrinolysis (plasminogen, plasmin, tissue plasminogen activator activity).

Pharmacokinetics.

Alprostadil is a synthetic analogue of the natural prostaglandin E1 with a short elimination half-life (T1/2). 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 (2.4 pg/mL). The 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 reached shortly after the start of infusion.

Alprostadil is metabolized mainly in the lungs—approximately 80–90% during the first pass. The primary metabolites formed during the first pass are 15-keto-PGE1, PGE0 (13,14-dihydro-PGE1), and 15-keto-PGE0 (13,14-dihydro-15-keto-PGE1), which in turn 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 reaches a maximum plasma concentration of 11.8 pg/mL compared to the placebo phase (1.7 pg/mL), with a half-life of approximately 2 minutes during the alpha phase and approximately 33 minutes during the beta phase. Tmax is achieved 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.

Clinical characteristics.

Indications.

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

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

Contraindications.

• Hypersensitivity to alprostadil or to any of the excipients;
• patients with the following cardiac function disorders:
• decompensated heart failure class III and IV according to New York Heart Association (NYHA) classification;
• inadequate treatment of heart failure;
• arrhythmias of various etiologies, including arrhythmia causing hemodynamic disturbances;
• inadequate treatment of cardiac arrhythmia;
• 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);
• suspicion of 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;
• patients with documented liver disease, including patients with signs of acute liver failure (elevated transaminase or gamma-GT levels) or documented severe liver insufficiency (including in medical history);
• renal dysfunction (oligoanuria);
• bleeding tendency (acute erosive or hemorrhagic gastric and/or duodenal ulcer, polytrauma);
• 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, and hyperhydration);
• pregnancy or breastfeeding period;
• pediatric age.

Interaction with other medicinal products and other types of interactions.

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

Sympathomimetics, adrenaline, noradrenaline reduce the vasodilatory effect of the drug.

Concomitant use of the drug and 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 simultaneously taking anticoagulants.

Concomitant use with cefamandole, cefaperazone, cefotetan reduces the effect of alprostadil.

Special precautions for use

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

Patients predisposed to heart failure due to age and patients with ischemic heart disease should be hospitalized and monitored during treatment and for one day after discontinuation of the drug. The drug should also be prescribed with caution in cases of mild or moderate arterial hypotension.

To prevent symptoms of fluid overload, infusion volumes should not exceed 50–100 mL per day (administered via an infusion device). Recommendations regarding infusion duration should also be strictly followed. Monitoring of cardiovascular parameters (arterial pressure and heart rate), body weight, fluid balance, central venous pressure, echocardiography, blood biochemical parameters, and coagulation (in case of coagulation disorders or concomitant use of drugs affecting the coagulation system) is essential. Discharge from hospital is permissible only after stable cardiovascular parameters have been established.

The same careful monitoring (fluid balance and renal function parameters) is required for patients with peripheral edema or renal dysfunction (serum creatinine >1.5 mg/dL or glomerular filtration rate <90 mL/min).

The drug should be used with caution in patients undergoing hemodialysis (treatment should be performed in the post-dialysis period), in patients with type I diabetes mellitus, especially in the presence of pronounced vascular complications.

Alprostadil should be administered only by physicians experienced in treating 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 (rapid bolus) injection should not be used for alprostadil administration.

Phlebitis (proximal to the infusion site) is generally not a reason to discontinue treatment; inflammatory signs usually resolve within several hours after stopping the infusion or changing the infusion site. Specific treatment is not required in such cases. Central venous catheterization may reduce the frequency of this adverse reaction.

Careful monitoring of cardiovascular parameters is necessary when the drug is used concomitantly with antihypertensive agents, vasodilators, and antianginal drugs (see section "Interaction with other medicinal products and other forms of interaction").

The drug may be used only under strict medical supervision in the following conditions:

thrombocytosis (platelet count less than 4×10^6/mL), peripheral neuropathy, history of cholelithiasis, history of gastric ulcers or trophic ulcers; glaucoma, epilepsy.

Other medicinal products must not be added to the infusion solution. If other drugs are prescribed to the patient, they should be administered into another vein; if this is not possible, an alternative route of administration must be established.

The drug contains 788 mg of ethanol per 1 mL. This should be taken into account when prescribing the drug to patients with alcoholism and patients at increased risk (liver disease, epilepsy).

Use during pregnancy or breastfeeding

The drug is contraindicated in pregnant women. Breastfeeding should be discontinued if treatment with the drug is necessary.

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

Like all drugs acting on the cardiovascular system (which may cause a decrease in systolic blood pressure), this drug may negatively affect the ability to drive vehicles or operate machinery, especially at the beginning of treatment, during dose escalation, upon discontinuation of the drug, or when consuming alcohol, as it may cause a reduction in systolic arterial pressure. Patients should be advised to exercise caution when driving vehicles or operating machinery.

Administration and Dosage

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

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

Intravenous therapy for stage III.

Administer intravenous therapy according to the following regimen:

Dissolve the contents of 2 ampoules (40 mcg of alprostadil) in 50–250 mL of 0.9% sodium chloride solution. Infuse the resulting solution intravenously over 2 hours. Administer this dose twice daily. Alternatively: administer 1 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.

For patients with impaired renal function (renal insufficiency with creatinine levels > 1.5 mg/dL), intravenous treatment should be initiated with 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 above-mentioned standard dose over 2–3 days.

For 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.

Intra-arterial therapy for stages III and IV.

Administer intra-arterial therapy according to the following regimen:

Dissolve the contents of 1 ampoule (20 mcg of alprostadil) in 50 mL of 0.9% sodium chloride solution.

Infuse the volume corresponding to half the ampoule (25 mL of solution containing 10 mcg of alprostadil) 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 of alprostadil), especially in the presence of necrosis. Typically, 1 infusion per day is administered.

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

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

Children.

There are no available clinical data on the use of the drug in children. The drug is contraindicated in this patient population.

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 of the limb receiving the infusion, as well as hypersensitivity reactions.

Treatment is symptomatic. There is no specific antidote. In cases of overdose (severe pain, decreased arterial blood pressure), the infusion should be reduced or immediately discontinued. If hypotension occurs, 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, sympathomimetic agents may be administered.

Adverse reactions.

Adverse events 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).

From the nervous system: common – headache, limb paraesthesia at the site of intervention; rare – confusion, cerebral seizures; frequency not known – stroke, dizziness, psychosis.

From the gastrointestinal tract: uncommon – gastrointestinal disorders including diarrhea, nausea, vomiting, and increased intestinal peristalsis (diarrhea, nausea, vomiting), which are properties of alprostadil; frequency not known – anorexia, heartburn, stomach pain.

From the cardiovascular system: uncommon – decreased arterial pressure, tachycardia, angina pectoris; rare – arrhythmias, heart failure with episodes of acute pulmonary edema, which may lead to global heart failure; frequency not known – myocardial infarction, atrioventricular block.

From the hepatobiliary system: rare – alterations in liver enzyme levels.

From the respiratory system: rare – pulmonary edema; frequency not known – dyspnea.

From the blood system: rare – leukopenia, leukocytosis, thrombocytopenia, anemia.

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

From the skin and subcutaneous tissue: common – erythema, swelling, flushing.

General disorders and administration site reactions: common – sensation of warmth, sensation of swelling, edema at the injection site, paraesthesia, venous redness at the infusion site; uncommon – increased sweating, chills, fever; frequency not known – phlebitis at the injection site, thrombosis at the catheter site, local bleeding, malaise, skin and mucous membrane sensory disturbances.

From the immune system: uncommon – allergic reactions (hypersensitivity skin reactions including skin rash, sensation of swelling, joint discomfort, febrile reaction, sweating, chills); very rare – anaphylactic or anaphylactoid reactions; frequency not known – anaphylactic shock.

From the musculoskeletal system: uncommon – joint symptoms including pain; very rare – reversible hyperostosis of long tubular bones after administration of the drug for more than 4 weeks.

Other: frequency not known – orthostatic hypotension, increased fatigue, general weakness, renal failure, anuria, vasalgia.

Shelf life.

1 year.

Storage conditions.

Store at a temperature of 2 to 8 °C, in a place protected from light.

Keep out of reach of children.

Incompatibilities.

The medicinal product should not be mixed with other medicinal products in the same container, except as specified in the section "Instructions for use and dosage".

Packaging.

1 ml in ampoules made of brown neutral glass (type I Ph. Eur.) with a white ring.

5 or 10 ampoules in a cardboard pack with a special ampoule holder.

Prescription category.

Prescription only.

Manufacturer. Drem Pharma GmbH

(Manufacturer responsible for batch release).

Manufacturer's address and place of business. Hietsinger Hauptstrasse, 37/2, 1130 Vienna, Austria.