Vessel due f

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VESSELDUE F (VESSELDUEF)

Composition:

Active substance: sulodexide;

1 capsule contains 250 LP (lipoprotein lipase units) of sulodexide;

Excipients: sodium lauryl sarcosinate, colloidal anhydrous silicon dioxide, triacetin, gelatin, glycerin, sodium ethylparahydroxybenzoate (E 215), sodium propylparahydroxybenzoate (E 217), titanium dioxide (E 171), iron oxide red (E 172).

Pharmaceutical form. Soft capsules.

Main physicochemical properties: brick-red colored capsules containing a homogeneous greyish-white suspension.

Pharmacotherapeutic group. Antithrombotic agents. Sulodexide. ATC code B01A B11.

Pharmacological Properties

Pharmacodynamics

Vessel Due F is a sulodexide preparation, a natural mixture of glycosaminoglycans extracted from the intestinal mucosa of pigs. Sulodexide consists of a heparin-like fraction with a molecular weight of approximately 8000 Da (80%) and dermatan sulfate (20%).

Sulodexide possesses antithrombotic, anticoagulant, profibrinolytic, and angioprotective properties.

The anticoagulant effect of sulodexide is due to its affinity for heparin cofactor II, which inhibits thrombin.

The antithrombotic effect of sulodexide is mediated through inhibition of factor Xa activity, stimulation of synthesis and secretion of prostacyclin (PGI2), and reduction of plasma fibrinogen levels.

The profibrinolytic effect is attributed to increased tissue plasminogen activator activity and decreased activity of its inhibitor.

The angioprotective effect is associated with restoration of the structural and functional integrity of endothelial cells and normalization of the density of the negative charge in vascular basement membranes.

In addition, sulodexide normalizes the rheological properties of blood by reducing triglyceride levels (due to activation of lipoprotein lipase—the enzyme responsible for triglyceride hydrolysis).

The efficacy of the drug in diabetic nephropathy is attributed to sulodexide's ability to reduce basement membrane thickness and extracellular matrix production by inhibiting mesangial cell proliferation.

Pharmacokinetics

Sulodexide is absorbed in the small intestine. Approximately 90% of the administered dose accumulates in the vascular endothelium, where its concentrations are 20–30 times higher than in tissues of other organs. Sulodexide is primarily metabolized in the liver and mainly excreted by the kidneys. In contrast to unfractionated and low-molecular-weight heparins, desulfation—which would lead to reduced antithrombotic activity and significantly accelerated elimination—does not occur with sulodexide. Distribution studies have shown that sulodexide is eliminated by the kidneys with a half-life of approximately 4 hours.

Clinical characteristics.

Indications.

• Angiopathies with increased risk of thrombosis, including thrombosis following acute myocardial infarction;
• cerebrovascular diseases: stroke (acute ischemic stroke and early rehabilitation period after stroke);
• dyscirculatory encephalopathy caused by atherosclerosis, diabetes mellitus, arterial hypertension, and vascular dementia;
• occlusive diseases of peripheral arteries of both atherosclerotic and diabetic origin;
• phlebopathies and deep vein thrombosis;
• microangiopathies (nephropathy, retinopathy, neuropathy) and macroangiopathies (diabetic foot syndrome, encephalopathy, cardiopathy) associated with diabetes mellitus;
• thrombophilia, antiphospholipid syndrome;
• heparin-induced thrombocytopenia.

Contraindications.

• Hypersensitivity to the active substance, heparin and heparin-like substances, or to any other components of the drug;
• hemorrhagic diathesis and diseases associated with impaired blood coagulation.

Interaction with other medicinal products and other forms of interaction.

Since sulodexide is a heparin-like molecule, when used concomitantly it may enhance the anticoagulant effect of heparin and oral anticoagulants. No other clinically significant interactions of the drug with medicinal products have been identified.

Special precautions for use

During the course of treatment with the medicinal product, coagulation parameters should be monitored periodically (coagulogram assessment). Laboratory parameters such as activated partial thromboplastin time, bleeding time/clotting time, and antithrombin III levels should be determined at the beginning and after completion of therapy. During treatment, activated partial thromboplastin time increases approximately 1.5-fold.

Vessel Due F capsules contain sodium ethylparahydroxybenzoate and sodium propylparahydroxybenzoate, which may cause allergic reactions (possibly delayed-type).

Use during pregnancy or breast-feeding

Since there is no experience with the use of the medicinal product during the first trimester of pregnancy, administration to women during this period should be avoided, except when, in the opinion of the physician, the expected benefit of treatment for the mother outweighs the potential risk to the fetus.

There is limited experience with the use of sulodexide during the second and third trimesters of pregnancy for the treatment of vascular complications caused by type I and type II diabetes and late toxemia. In such cases, sulodexide was administered intramuscularly at a daily dose of 600 IU for 10 days, followed by oral administration of the medicinal product at a dose of 1 capsule twice daily (500 IU/day) for 15–30 days. In cases of toxemia, this treatment regimen may also be combined with conventional treatment methods.

During the second and third trimesters of pregnancy, the medicinal product should be used with caution under strict medical supervision.

It is currently unknown whether sulodexide or its metabolites are excreted in human breast milk. Therefore, as a precautionary measure, the medicinal product is not recommended for use in women during lactation.

Animal studies have not shown any direct or indirect harmful effects of sulodexide on male or female fertility.

Effect on the ability to drive and use machines

Generally, the medicinal product has no or negligible influence on the ability to drive a vehicle or operate machinery. However, if loss of consciousness occurs during treatment, patients should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage

General Instructions

The commonly used treatment regimens involve parenteral administration of the drug followed by oral intake of capsules; in some cases, treatment with sulodexide may be initiated directly with oral capsules. The treatment regimen and dosage may be adjusted at the physician's discretion based on clinical evaluation and laboratory test results.

Capsules are generally recommended to be taken between meals. If the daily dose is divided into multiple administrations, a 12-hour interval between doses should be maintained.

A full treatment course should generally be repeated at least twice a year.

Angiopathies with Increased Thrombosis Risk, including Post-Myocardial Infarction Thrombosis

During the first month, intramuscular injections of 600 LO sulodexide (contents of 1 ampoule) are administered daily. This is followed by continuation of treatment with oral administration of 1–2 capsules twice daily (500–1000 LO/day). Optimal results are achieved when treatment is initiated within the first 10 days after an acute myocardial infarction episode.

Cerebrovascular Disorders: Stroke (Acute Ischemic Stroke and Early Post-Stroke Rehabilitation Period)

Treatment is initiated with daily intramuscular administration of 600 LO sulodexide or by intravenous bolus or infusion, for which the contents of 1 ampoule are diluted in 150–200 mL of physiological saline. Infusion duration ranges from 60 minutes (rate of 25–50 drops/minute) to 120 minutes (rate of 35–65 drops/minute). The recommended treatment duration is 15–20 days. This should then be followed by continuation of therapy with oral capsules, 1 capsule twice daily (500 LO/day), for 30–40 days.

Disirculatory Encephalopathy due to Atherosclerosis, Diabetes Mellitus, or Arterial Hypertension, and Vascular Dementia

It is recommended to take 1–2 capsules twice daily (500–1000 LO/day) orally for 3–6 months. The treatment course may also begin with intramuscular administration of 600 LO sulodexide daily for 10–30 days.

Occlusive Peripheral Artery Diseases of Both Atherosclerotic and Diabetic Origin

Treatment begins with daily intramuscular administration of 600 LO sulodexide for 20–30 days. This is followed by continuation of therapy with oral administration of 1–2 capsules twice daily (500–1000 LO/day) for 2–3 months.

Phlebopathies and Deep Vein Thrombosis

Oral administration of sulodexide capsules at a dose of 500–1000 LO/day (2 or 4 capsules) is usually prescribed for 2–6 months. The treatment course may also begin with daily intramuscular administration of 600 LO sulodexide for 10–30 days.

Microangiopathies (Nephropathy, Retinopathy, Neuropathy) and Macroangiopathies (Diabetic Foot Syndrome, Encephalopathy, Cardiopathy) Associated with Diabetes Mellitus

Treatment of patients with micro- and macroangiopathies is recommended in two stages. Initially, 600 LO sulodexide is administered intramuscularly daily for 15 days, followed by continuation of treatment with 1–2 capsules twice daily (500–1000 LO/day). Since short-term treatment may result in partial loss of therapeutic effect, it is recommended to extend the duration of the second treatment stage to at least 4 months.

Thrombophilia, Antiphospholipid Syndrome

The standard treatment regimen involves oral administration of 500–1000 LO sulodexide daily (2 or 4 capsules) for 6–12 months. Sulodexide capsules are typically prescribed after treatment with low-molecular-weight heparin in combination with acetylsalicylic acid, without the need to modify the dosage regimen of the latter.

Heparin-Induced Thrombocytopenia

In cases of heparin-induced thrombocytopenia, administration of heparin or low-molecular-weight heparin should be replaced with sulodexide infusions. For this purpose, the contents of 1 ampoule (600 LO sulodexide) are diluted in 20 mL of 0.9% sodium chloride solution and administered as a slow infusion over 5 minutes (rate of 80 drops/minute). Subsequently, 600 LO sulodexide is diluted in 100 mL of 0.9% sodium chloride solution and administered as 60-minute infusions (rate of 35 drops/minute) every 12 hours, as long as anticoagulant therapy is required.

Children

There is limited experience with the use of sulodexide in the treatment of diabetic nephropathy and glomerulonephritis in adolescents aged 13–17 years. In such cases, 600 LO sulodexide was administered intramuscularly daily for 15 days, followed by oral administration of 1–2 capsules twice daily (500–1000 LO/day) for 2 weeks.

Data on the efficacy and safety of sulodexide in children under 12 years of age are lacking.

Overdose

Overdose of the drug may lead to hemorrhagic symptoms such as hemorrhagic diathesis or bleeding. In case of bleeding, 1% protamine sulfate solution should be administered. In general, in cases of overdose, the drug should be discontinued and appropriate symptomatic therapy initiated.

Adverse Reactions.

Adverse reactions identified in clinical trials and associated with the use of sulodexide are classified according to system organ classes and frequency. The following terminology is used to define the frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000).

Nervous system disorders

Uncommon: headache.

Rare: loss of consciousness.

Ear and labyrinth disorders

Common: dizziness.

Gastrointestinal disorders

Common: upper abdominal pain, diarrhoea, nausea.

Uncommon: abdominal discomfort, dyspepsia, flatulence, vomiting.

Rare: gastric haemorrhage.

Skin and subcutaneous tissue disorders

Common: skin rash.

Uncommon: eczema, erythema, urticaria.

General disorders and administration site conditions

Rare: peripheral oedema.

Additional adverse reactions have been reported during post-marketing use of sulodexide. The frequency of these reactions cannot be estimated reliably based on available data.

Blood and lymphatic system disorders: anaemia.

Metabolism and nutrition disorders: disturbances in plasma protein metabolism.

Gastrointestinal disorders: gastrointestinal disorders, melena.

Skin and subcutaneous tissue disorders: angioneurotic oedema, ecchymosis.

Reproductive system and breast disorders: genital oedema, genital erythema, polymenorrhoea.

Shelf life. 5 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 30 °C.

Keep out of the reach and sight of children.

Packaging.

25 capsules in a blister; 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Alfasigma S.p.A./Alfasigma S.p.A.,

Catalent Italy S.p.A./Catalent Italy S.p.A.

Manufacturer's address and location of activity.

Via Enrico Fermi 1, 65020 Alanno (Pescara), Italy.

Via Nettunense km 20, 100, 04011 – Aprilia (Latina), Italy.