Instructions Vasaprox-alpha powder for solution for infusion 20 mcg vial No. 10
Composition
active ingredient: alprostadil;
1 vial contains 20 mcg of alprostadil;
excipients: alfadex, lactose monohydrate, sodium citrate, hydrochloric acid (as a 0.1 M solution).
Dosage form
Powder for solution for infusion.
Main physicochemical properties: white or almost white powder, free from visual agglomerates.
Pharmacotherapeutic group
Cardiological drugs. Prostaglandins. ATC code C01E A01.
Pharmacological properties
Pharmacodynamics.
Alprostadil, the active ingredient of Vasaprox-Alfa, is a vasodilator. It increases blood flow by dilating arterioles and precapillary sphincters. The drug improves microcirculation and rheological properties of blood. After intravenous administration to healthy volunteers or patients, an increase in erythrocyte elasticity and inhibition of their aggregation ex vivo are observed. In humans and animals, alprostadil effectively inhibits platelet activation in vitro. This effect also extends to parameters of platelet shape change, aggregation, secretion of substances contained in granules, and the release of thromboxane, a substance that promotes aggregation. In animal experiments, the drug leads to a decrease in thrombus formation in vivo.
Therapeutic use of the drug in humans stimulates fibrinolysis and increases certain indicators of endogenous fibrinolysis (plasminogen, plasmin, tissue plasminogen activator activity).
Pharmacokinetics.
The complex consisting of alprostadil (PGE1) and Alfadex (alpha-cyclodextrin) dissociates into separate components during preparation of the infusion solution. Therefore, the pharmacokinetics of the two substances is independent of the presence of the complex in the lyophilisate.
After intravenous administration of alprostadil at a dose of 60 μg/2 hours, the maximum plasma concentration (Cmax) in healthy volunteers was 6 pg/ml higher than the maximum concentration in the placebo phase (2.4 pg/ml). The half-life during the alpha phase is approximately 0.2 minutes (estimated value) and during the beta phase is approximately 8 minutes. Thus, the equilibrium concentration is reached shortly after the start of the infusion. Data on the time to maximum concentration (Tmax) are not available due to the development of a plateau.
Alprostadil is metabolized mainly in the lungs: 80–90% during the first pass through the lungs. During this process, the primary metabolites are formed - 15-keto-PGE1, PGE0 (13,14-dihydro-PGE1) and 15-keto-PGE0, which undergo further degradation, in particular by beta-oxidation and omega-oxidation. The metabolites are excreted in the urine (88%) and feces (12%). Complete excretion occurs within 72 hours. Of the primary metabolites, only 15-keto-PGE0 can be detected in vitro using lung homogenates. After administration of 60 μg/2 h alprostadil to healthy volunteers, the maximum concentration of PGE0 in the blood plasma of healthy volunteers was 11.8 pg/ml higher than the maximum concentration in 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 reached after 119 minutes. The corresponding values for 15-keto-PGE0 are as follows: Cmax - 151 pg/ml (placebo - 8 μg/ml), t½α - approximately 2 minutes, t½ß - 20 minutes and Tmax - 106 minutes.
Alprostadil is 93% bound to macromolecular components of blood plasma. In animal experiments, it was found that the half-life of Alfadex is approximately 7 minutes, it is excreted in the urine unchanged.
Indication
Treatment of chronic peripheral arterial occlusive disease stages 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 chronic obliterating peripheral arterial disease stage IV.
Contraindication
Hypersensitivity to alprostadil or to other components of the drug;
the presence of the following heart function disorders:
decompensated heart failure class III and IV according to the New York Heart Association (NYHA) classification;
inadequate treatment of heart failure;
arrhythmias of various etiologies, including arrhythmias causing hemodynamic disturbances;
inadequate treatment of cardiac arrhythmia;
insufficiency and/or stenosis of the 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 disease, veno-occlusive pulmonary disease;
documented liver disease, including signs of acute liver failure (elevated transaminases or gamma-GT) or documented severe liver failure (including a history);
severe renal dysfunction (oligoanuria) (GFR ≤ 29 ml/min/1.73 m2);
damage to multiple organs (polytrauma);
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 to infusion therapy (e.g., congestive heart failure, pulmonary or cerebral edema, and hyperhydration);
pregnancy or breastfeeding;
childhood.
Interaction with other medicinal products and other types of interactions
When using the drug Vasaprox-Alfa, the effect of antihypertensive drugs, vasodilators, and antianginal drugs may be enhanced. When using these drugs simultaneously with alprostadil, careful monitoring of the cardiovascular system is necessary, including monitoring of blood pressure.
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 bleed. Given the weak inhibitory effect of alprostadil on platelet aggregation in vitro, the drug should be used with caution in patients who are simultaneously taking anticoagulants or platelet aggregation inhibitors.
Simultaneous use with cefamandole, cefoperazone, cefatetan reduces the effect of the drug Vasaprox-Alfa.
Application features
Patients receiving Vasaprox-Alfa should be closely monitored during each dose. This is especially true for patients with age-related heart failure and patients with ischemic heart disease, who should be monitored in a hospital during and for one day after discontinuation of the drug. Use with caution in mild to moderate hypotension.
To prevent symptoms of hyperhydration, infusion volumes should not exceed 50–100 ml per day (administered via an infusion device). The recommendations for the duration of infusion should also be followed (see section “Method of administration and dosage”). Frequent monitoring of the patient’s cardiovascular parameters (blood pressure and heart rate), fluid balance and, if necessary, body weight, central venous pressure and echocardiography are necessary. The patient can be discharged from the hospital only if stable cardiovascular parameters are established.
The same close monitoring (monitoring of fluid balance and renal function) is required in patients with peripheral edema or mild (GFR ≤ 89 mL/min/1.73 m2) and moderate (GFR ≤ 59 mL/min/1.73 m2) renal dysfunction.
The drug should be prescribed with caution to patients on hemodialysis (treatment should be carried out in the post-dialysis period) and patients with type 1 diabetes mellitus, especially with severe vascular damage.
The drug should be administered only by physicians who have experience in the treatment of peripheral arterial occlusive disease, are familiar with modern methods of continuous monitoring of cardiovascular parameters, and have the appropriate equipment for this purpose. Intravenous bolus administration of alprostadil should not be used.
In case of simultaneous use with antihypertensive drugs, vasodilators and antianginal drugs, careful monitoring of cardiovascular system parameters should be carried out (see section "Interaction with other medicinal products and other types of interactions").
Alprostadil should be used with caution in patients with a history of gastrointestinal diseases, including erosive gastritis, gastrointestinal bleeding and gastric and/or duodenal ulcers, or with a history of intracerebral hemorrhage or other diseases accompanied by bleeding (see section "Contraindications").
Caution is advised when treating patients receiving concomitant medications that may increase the risk of bleeding, such as anticoagulants or platelet aggregation inhibitors (see section 4.5). Such patients should be closely monitored for signs and symptoms of bleeding.
Use during pregnancy or breastfeeding
Do not use the drug in women of reproductive age, pregnant women and women who are breastfeeding. If necessary, use of the drug should be discontinued.
Women of reproductive age should use effective contraceptives to prevent pregnancy while using the drug.
Data from nonclinical fertility studies do not indicate an effect of the drug on fertility when used at clinical doses.
Ability to influence reaction speed when driving vehicles or other mechanisms
Alprostadil may cause a decrease in systolic blood pressure, so the drug may moderately affect the ability to drive and use machines, especially at the beginning of treatment, when increasing the dose, stopping the drug, and drinking alcohol. Patients should be informed of the need to exercise caution when driving and using machines.
Method of administration and doses
Vasaprox-Alfa is administered only intravenously or intraarterially, provided that the physician has experience in angiology, is familiar with modern methods of continuous monitoring of cardiovascular parameters, and has the appropriate equipment for this purpose. The drug should not be administered intravenously as a jet (bolus).
Stage III intravenous therapy
Intravenous administration is not recommended for the treatment of chronic obliterating peripheral arterial disease stage IV.
Based on available information, unless otherwise indicated, intravenous therapy should be administered according to the following schedule.
The contents of 2 vials (40 mcg of alprostadil) of the drug 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 2 times a day. Alternatively: 1 time a day intravenous infusion over 3 hours of 3 vials (60 mcg of alprostadil), the contents of which should be dissolved in 50–250 ml of 0.9% sodium chloride solution.
In patients with renal impairment (renal failure with creatinine values > 1.5 mg/dl), intravenous administration of the drug should be started with 1 vial 2 times a day (2 × 20 μg alprostadil), each infusion lasting 2 hours. Depending on the overall clinical picture, the dose can be increased to the above normal dose within 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 instructions").
Intraarterial therapy for stage III and IV
Based on available information, intra-arterial therapy should be administered according to the following regimen.
The contents of 1 vial (20 mcg of alprostadil) are dissolved in 50 ml of 0.9% sodium chloride solution. The volume of the resulting solution, corresponding to the contents of half a vial of the drug (25 ml of solution contain 10 mcg of alprostadil), is administered intraarterially over 60–120 minutes using an infusion device. If tolerated satisfactorily, the dose can be increased to 1 vial (20 mcg of alprostadil), especially in the presence of necrosis. Usually, 1 infusion is performed per day.
If intra-arterial infusion is performed through an indwelling catheter, a dose of 0.1–0.6 ng/kg body weight/min (corresponding to the contents of ¼–1½ vials of the drug) is recommended, depending on drug tolerance and disease severity; infusion using an infusion device lasts 12 hours.
Special populations
Elderly patients prone to heart failure and patients with coronary heart disease
Elderly patients prone to heart failure and patients with ischemic heart disease should be under constant medical supervision (see section "Special warnings and precautions for use").
Patients with peripheral edema
Patients with peripheral edema should be under constant medical supervision (see section "Special warnings and precautions for use").
Patients with renal failure
Patients with mild (GFR ≤ 89 ml/min/1.73 m2) and moderate (GFR ≤ 59 ml/min/1.73 m2) renal impairment should be under close medical supervision (e.g. fluid balance monitoring and laboratory monitoring of renal function) (see section 4.4).
Women of reproductive age
Women of reproductive age should use effective contraceptives while using the drug (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
Duration of administration
After a three-week course of treatment, the appropriateness of further use of the drug should be considered. If the patient does not have a therapeutic effect, treatment should be discontinued. The course of treatment should not exceed 4 weeks.
Input method
The solution must be prepared immediately before infusion. A solution prepared more than 12 hours ago should not be administered.
The contents of the vial are a dry white powder that forms a solid layer 3 mm thick. This layer may have small cracks and crumbs. If the vial is damaged, the dry substance usually becomes wet and sticky and loses a lot of volume. In this case, the drug cannot be used.
The dry substance dissolves immediately after adding 0.9% sodium chloride solution. After dissolution, the solution may initially become slightly cloudy due to the formation of air bubbles. After a short time, the bubbles disappear and the solution becomes clear.
The ready-to-use solution is stable for 24 hours at 20°C to 25°C. From a microbiological point of view, the ready-to-use infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 25°C.
Children.
Do not use on children.
Overdose
Symptoms. Overdose of the drug may lead to a decrease in blood pressure and tachycardia due to the vasodilating effect. Other possible symptoms: vasovagal syncope with pallor, increased sweating, nausea, vomiting, myocardial ischemia, heart failure. Possible local reactions: pain, swelling and redness of the infused limb, manifestations of hypersensitivity.
Treatment is symptomatic. There is no specific antidote. In case of overdose, the infusion should be reduced or stopped immediately. If blood pressure decreases, the patient should first be placed on his back with the lower extremities elevated. If symptoms persist, cardiovascular parameters should be checked/monitored. If necessary, drugs that stabilize blood circulation (e.g. sympathomimetics) can be used. In case of severe symptoms from the cardiovascular system (e.g. myocardial ischemia, heart failure), the 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 (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency unknown (cannot be estimated from the available data).
From the blood and lymphatic system: rarely - thrombocytopenia, leukopenia, leukocytosis, anemia.
From the nervous system: often - headache, paresthesia of the limb on which the manipulation was performed; infrequently - confusion; rarely - cerebral convulsions; frequency unknown - stroke.
From the cardiovascular system: infrequently - decreased blood pressure, tachycardia, angina pectoris; rarely - arrhythmia, heart failure with cases of acute pulmonary edema, which can lead to general heart failure; frequency unknown - myocardial infarction, hemorrhage.
From the respiratory system, thoracic organs and mediastinum: rarely - pulmonary edema; frequency unknown - dyspnea.
Gastrointestinal disorders: uncommon: gastrointestinal disorders, including diarrhea, nausea, vomiting, and increased intestinal motility (diarrhea, nausea, vomiting), which is a property of alprostadil; frequency unknown: gastrointestinal hemorrhage.
On the part of the hepatobiliary system: rarely - increased levels of liver enzymes.
Investigations: infrequently - increased liver function tests (transaminases), fever, changes in C-reactive protein, rapid normalization occurs after completion of treatment.
Skin and subcutaneous tissue disorders: often – redness, swelling, flushing.
General disorders and administration site conditions: very common - pain, erythema or swelling of the limb into which intra-arterial infusion was administered; common - similar symptoms with intravenous administration, additionally - redness of the veins at the infusion site; after intra-arterial administration - a feeling of warmth, a feeling of swelling, swelling at the injection site, paresthesia; uncommon - increased sweating, chills, fever; after intravenous administration - a feeling of warmth, a feeling of swelling, swelling at the injection site, paresthesia; frequency unknown - phlebitis at the injection site, thrombosis at the catheter insertion site, local bleeding.
On the part of the immune system: infrequently - allergic reactions (skin hypersensitivity reactions, including skin rash, swelling, joint discomfort, febrile reaction, increased sweating, chills); very rarely - anaphylactic or anaphylactoid reactions.
Musculoskeletal and connective tissue disorders: uncommon – joint symptoms, including pain; very rare – reversible hyperostosis of long bones after use of the drug for more than 4 weeks; frequency unknown – orthostatic hypotension, increased fatigue.
Adverse reaction reporting
Reporting of suspected adverse reactions after the approval of a medicinal product is important. This allows for 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.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C in the original packaging to protect from light.
Keep out of reach of children.
Packaging
Glass bottle, 5 bottles in a plastic package, 2 plastic packages in a cardboard box.
Vacation category
According to the recipe.
Producer
K.T. ROMPHARM COMPANY SRL/SC ROMPHARM COMPANY SRL
Location of the manufacturer and address of its place of business.
Eroilor St. No. 1A, Otopeni, 075100, Ilfov County, Romania – Romfarm 1 and Romfarm 2 buildings/
Str. Eroilor, nr.1A, buildings Rompharm 1 and Rompharm 2, Oraş Otopeni, Județul Ilfov, cod poștal 075100, Romania.
Applicant.
“SAF INVEST” Ltd.
Location of the applicant.
Bulgaria, Sofia 1618, Tsar Boris III Blvd., No. 168, 3rd floor, apt. 34/
Bulgaria, Sofia 1618, Tzar Boris III Blvd., No. 168, Floor 3, Suite 34.
