Flebaven® 1000

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Flebaven® 1000 (Flebaven® 1000)

Composition:

Active substance: diosmin;

One tablet contains 1000 mg of micronized diosmin;

Excipients: polyvinyl alcohol, sodium croscarmellose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: pale greenish or grayish-yellow to pale greenish or grayish-brown, marbled, slightly biconvex oval tablets.

Pharmacotherapeutic group.

Angioprotectors. Bioflavonoids. Capillary stabilizing agents. Diosmin.

ATC code C05CA03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Venotonic activity. Diosmin reduces venous distensibility and decreases venous stasis. Diosmin increases venous tone and consequently reduces venous capacity, venous distensibility, and blood pooling: venous occlusion mercury plethysmography indicates a shortened venous emptying time.

The final effect is a reduction in venous hypertension in patients with venous disorders.

Microcirculatory activity. Diosmin reduces capillary permeability and increases capillary resistance. It also exerts an anti-inflammatory effect by influencing prostaglandin synthesis. Controlled double-blind clinical trials have demonstrated a statistically significant difference between diosmin and placebo. In patients with capillary fragility, treatment with diosmin increases capillary resistance and reduces clinical manifestations. After administration of 1 g of diosmin daily, compared to placebo, a reduction in capillary permeability was also observed, as determined by the use of technetium-labeled albumin or plethysmography.

Pharmacodynamic effects. The pharmacological activity of diosmin in humans has been confirmed in controlled double-blind clinical trials, as well as by objective and quantitative methods assessing the effect of the active substance on venous hemodynamics.

Effect on the lymphatic system. Diosmin stimulates lymphatic activity, improving drainage of the interstitial space and increasing lymphatic flow. Daily administration of 1 g of diosmin reduces the diameter of lymphatic capillaries and intralymphatic pressure, improving the number of functioning lymphatic capillaries in patients with severe chronic venous insufficiency without ulcers.

Clinical efficacy and safety. Controlled double-blind clinical trials demonstrate the therapeutic activity of the drug in the treatment of signs and symptoms of established chronic venous disease and in the treatment of acute hemorrhoidal disease.

Pharmacokinetics.

Absorption. After oral administration, diosmin is rapidly hydrolyzed in the intestine by intestinal flora and absorbed in the form of its aglycone derivative—diosmetin. The oral bioavailability of micronized diosmin is approximately 60%.

Distribution. The volume of distribution of diosmetin is 62.1 L, indicating extensive tissue distribution.

Biological transformation. Diosmetin is intensively metabolized to phenolic acids or their glycine conjugated derivatives, which are excreted in urine. In humans, the predominant metabolite detected in urine is m-hydroxy-phenylpropionic acid, mainly excreted in conjugated form. Metabolites found in smaller amounts include phenolic acids corresponding to 3-hydroxy-4-methoxybenzoic acid and 3-methoxy-4-hydroxyphenylacetic acid.

Elimination. Elimination of micronized diosmin occurs relatively rapidly, as approximately 34% of the radiolabeled dose of 14C-diosmin is excreted in urine and feces within the first 24 hours and reaches approximately 86% within the first 48 hours. About half of the dose is excreted in feces as unchanged diosmin or diosmetin, whereas these two compounds are not excreted in urine.

The elimination half-life of diosmetin showed a mean value of 31.5 hours, ranging from 26 to 43 hours.

Clinical characteristics.

Indications.

Symptomatic treatment of chronic venous and lymphatic insufficiency (leg heaviness, pain, nocturnal cramps, leg swelling, trophic disorders including varicose ulcers).

Symptomatic treatment of hemorrhoids.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted. During the post-marketing period, no interactions between diosmin and other medicinal products have been reported.

Special precautions for use.

The use of the medicinal product Flebaven® 1000 in acute hemorrhoids does not replace specific treatment and does not interfere with the management of other proctological diseases. If symptoms do not rapidly resolve during a short course of treatment, a proctological examination should be performed and the therapy re-evaluated.

In venous circulation disorders, therapy combined with the following lifestyle recommendations is more effective:

• Avoid excessive sun exposure and prolonged standing still;
• Maintain a healthy body weight;
• Walk regularly and, in some cases, wear compression stockings to improve circulation.

Special attention should be paid if the patient's condition worsens during treatment. This may manifest as skin inflammation, phlebitis, subcutaneous induration, severe pain, skin ulcers, or atypical symptoms (e.g., sudden swelling of one or both legs).

Flebaven® 1000 is not effective in reducing lower limb edema caused by heart, liver, or kidney diseases.

Use during pregnancy or breastfeeding.

Pregnancy

Flebaven® 1000 should be used with caution in pregnant women. Consultation with a physician is recommended prior to use.

Studies have not revealed teratogenic effects of the drug; adverse effects have not been reported.

Breastfeeding

Due to lack of data on the passage of the medicinal product into breast milk, it should not be used during breastfeeding.

Fertility

Reproductive toxicity studies in animals showed no effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of diosmin on the ability to drive or operate machinery have not been conducted. However, according to the overall safety profile, diosmin has no effect or only a negligible effect on this ability. Patients should pay attention to any adverse effects listed in the section "Adverse reactions".

Method of administration and dosage.

For oral use.

Intended for adults. The tablets should be taken during meals.

Chronic venous-lymphatic insufficiency

The recommended dose is 1 tablet daily in the morning. Treatment duration should be at least 4–5 weeks.

Hemorrhoidal disease

Treatment of acute hemorrhoidal episodes: 3 tablets daily for 4 days, followed by 2 tablets daily for the next 3 days. The daily dose should be divided into 2–3 doses. Maintenance therapy: 1 tablet daily.

The duration of treatment is determined by the physician depending on the indication and course of the disease (see section "Special instructions").

Children.

Due to lack of data, the medicinal product Flebaven® 1000 should not be used in children.

Overdose.

Cases of overdose have not been reported.

Adverse reactions.

During clinical studies with the use of diosmin, transient adverse effects of moderate intensity were observed, mainly related to the gastrointestinal tract (diarrhea, dyspepsia, nausea, vomiting).

The adverse reactions listed below have been reported. The reactions are categorized 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 not known (cannot be estimated from the available data).

* Data from post-marketing surveillance.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging to protect from moisture.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister; 3 or 6 blisters per cardboard box.

Availability.

Over-the-counter (without prescription).

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of manufacturing site.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.