Dioflan

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

Composition:

Active substances: diosmin, hesperidin;

One tablet contains purified micronized flavonoid fraction – 500 mg, which includes diosmin – 450 mg, hesperidin* – 50 mg;

* – the term "hesperidin" refers to a mixture of flavonoids: isorhoifolin, hesperidin, linarin, diosmetin;

Excipients: microcrystalline cellulose; sodium starch glycolate (type A); hypromellose; talc; sodium lauryl sulfate; magnesium stearate; coating mixture "Opaglos 2 Orange" No. 97A23967 containing: sodium carboxymethylcellulose, maltodextrin, dextrose monohydrate, purified stearic acid, talc, yellow iron oxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), Yellow West FCF (E 110).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, pale pink in color, oval-shaped, biconvex surface, with a score line on one side of the tablet and the inscription "KMP" on the other side. The core is beige when broken.

Pharmacotherapeutic group. Capillary stabilizing agents. Bioflavonoids. Diosmin, combinations. ATC code C05CA53.

Pharmacological Properties

Pharmacodynamics.

Pharmacology.

Dioflan® exerts venotonic and angioprotective effects, reduces venous distensibility and venous stasis, improves microcirculation, decreases capillary permeability and increases their resistance, as well as enhances lymphatic drainage by increasing lymphatic outflow.

Preclinical Pharmacology.

Experimental studies in animals using the "ischemia/reperfusion" model demonstrated that administration of micronized purified flavonoid fraction is more effective in reducing vascular wall permeability and plasma extravasation compared to plain diosmin. This effect is attributed to the protective action on microcirculation provided by flavonoids such as hesperidin, diosmetin, linarin, and isorhoifolin, which are components of the fraction and are expressed in terms of hesperidin. The reduction in vascular wall permeability and plasma extravasation observed with the micronized purified flavonoid fraction was more pronounced than that observed with plain diosmin or with each individual flavonoid component administered separately.

Clinical Pharmacology.

The pharmacological properties described above have been confirmed in double-blind, placebo-controlled studies using methods capable of assessing the drug's effect on venous hemodynamics.

Dose–Response Relationship.

A statistically significant dose-dependent effect of the drug was established according to the following venous plethysmographic parameters: venous volume, venous distensibility, and venous drainage time. The optimal dose–response relationship was achieved with administration of 2 tablets.

Venotonic Activity.

Dioflan® increases venous tone: venous occlusion plethysmography demonstrated a reduction in venous drainage time.

Microcirculatory Activity.

Double-blind, placebo-controlled studies demonstrated a statistically significant difference between the drug and placebo. In patients with symptoms of capillary fragility, treatment increased capillary resistance, as determined by angio-stereometry.

The drug also reduces leukocyte–endothelium interaction and leukocyte adhesion in postcapillary venules. This reduces the damaging effects of inflammatory mediators on venous walls and venous valve leaflets.

In Clinical Practice.

Double-blind, placebo-controlled studies have demonstrated the therapeutic efficacy of the drug in phlebology for the treatment of functional and organic chronic venous insufficiency of the lower limbs, as well as in proctology for the treatment of hemorrhoids.

Pharmacokinetics.

Elimination of the active substance occurs primarily via feces. On average, 14% of the administered dose is excreted in urine.

The elimination half-life is 11 hours.

The drug is actively metabolized, as confirmed by the presence of various phenolic acids in urine.

Clinical characteristics.

Indications.

Symptomatic treatment of venous and lymphatic insufficiency (leg heaviness, pain, nocturnal cramps, edema, 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.

Studies on interaction have not been conducted. Data on cases of interaction are lacking.

Special precautions for use

The use of this medicinal product in acute haemorrhoids does not replace specific treatment and does not preclude the treatment 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 reviewed.

In disorders of venous circulation, treatment is more effective when combined with adherence to the following lifestyle recommendations:

• avoid prolonged exposure to sunlight, prolonged standing, and excess body weight;
• walk regularly and, in some cases, wear special compression stockings to improve circulation.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of micronized purified flavonoid fraction in pregnant women are lacking or limited in quantity.

Animal studies have not demonstrated reproductive toxicity.

As a precautionary measure, it is advisable to avoid using the drug during pregnancy.

Breastfeeding

It is unknown whether the active substance or its metabolites are excreted in human milk.

Risk to the newborn/infant cannot be excluded.

The decision on whether to discontinue breastfeeding or to discontinue/abstain from therapy with this medicinal product should be made by considering the benefits of breastfeeding for the child and the benefits of therapy for the mother.

Fertility

Reproductive toxicity studies in animals showed no effect on fertility.

Ability to affect reaction speed when driving or operating machinery

Studies on the influence of the flavonoid fraction on the ability to drive or operate machinery have not been conducted. However, based on the overall safety profile of the flavonoid fraction, Daflon® has no effect or a negligible effect on this ability. Nevertheless, caution should be exercised if adverse reactions occur (see section "Undesirable effects").

Dosage and Administration

For oral use.

For use in adults.

Venous and lymphatic insufficiency

The recommended dose is 2 tablets daily: 1 tablet during the day and 1 tablet in the evening, taken with meals. After one week of treatment, the dose may be adjusted to 2 tablets once daily taken with food.

Haemorrhoidal disease

Treatment of acute haemorrhoidal attacks: 6 tablets daily for 4 days, followed by 4 tablets daily for the next 3 days. Administer with meals. The daily dose should be divided into 2–3 doses. Maintenance therapy: 2 tablets daily.

The duration of therapy should be determined by the physician depending on the indication and course of the disease.

Children
There are no data regarding the use of this medicinal product in children.

Overdose

Symptoms
There is limited information on cases of overdose with this medicinal product. The most commonly reported adverse reactions in cases of overdose were gastrointestinal reactions (such as diarrhea, nausea, abdominal pain) and skin reactions (such as pruritus, rash).

Treatment
Treatment of overdose should be symptomatic.

Side effects.

During clinical trials, administration of micronized purified flavonoid fraction was associated with adverse effects of moderate intensity, primarily affecting the gastrointestinal tract (diarrhea, dyspepsia, nausea, vomiting).

The adverse reactions listed below have been reported with the following frequency: 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).

Neurological disorders:

rare: dizziness, headache, malaise.

Gastrointestinal disorders:

common: diarrhea, dyspepsia, nausea, vomiting;

uncommon: colitis;

frequency not known*: abdominal pain.

Skin and subcutaneous tissue disorders:

rare: rash, pruritus, urticaria;

frequency not known*: isolated facial, lip, or eyelid swelling. In exceptional cases – Quincke's edema (angioedema).

The presence of Sunset Yellow FCF (E 110) in the formulation may cause allergic reactions.

* Post-marketing surveillance data.

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

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

10 tablets per blister, 3 or 6 blisters per carton.

Availability. Over-the-counter (without prescription).

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and place of business.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.