Alvolon 500 MG FILM-COATED TABLET

1. NAME OF THE MEDICINAL PRODUCT products have been reported. Diosmin (Alvolon) 500 mg film-coated tablet 4.6 Fertility, and lactation Pregnancy 2. QUALITATIVE AND QUANTITATIVE Animal studies do not indicate direct or COMPOSITION indirect harmful effects with respect to pregnancy, embryonic or foetal development Each film-coated tablet contains 500 mg (see section 5.3). diosmin. The available clinical experience in pregnant Excipients with known effect: women is too limited to exclude a risk, and Each tablet contains 4.626 mg lactose administration of diosmin is therefore not monohydrate. recommended during pregnancy. For the full list of excipients, see section 6.1. Breastfeeding It is not known whether diosmin is excreted into human milk. Therefore, in the absence 3. PHARMACEUTICAL FORM of further information, this medicinal product should not be administered during Film-coated tablet. breastfeeding. Salmon-coloured, oblong, biconvex coated 4.7 Effects on ability to drive and use tablets. machines Diosmin has no or negligible influence on the 4. CLINICAL pARTICULARS ability to drive and use machines.

4.1 Therapeutic indications 4.8 Undesirable effects Diosmin (Alvolon) is indicated in adults as Gastrointestinal adverse reactions were a short-term treatment of symptoms of the most common reported adverse drug established chronic venous insufficiency (CVI). reactions. They include nausea, dyspepsia, vomiting and diarrhoea. 4.2 Posology and method of administration The most serious ADR associated with the use of diosmin was angioedema. Posology The recommended adult daily dose is two Reporting of suspected adverse reactions tablets, taken twice a day: one tablet at noon Reporting suspected adverse reactions after and one tablet in the evening, with food. authorisation of the medicinal product is important. It allows continued monitoring The maximum duration of treatment is 2 to 3 of the benefit/risk balance of the medicinal months. product. Healthcare professionals are asked to report any suspected adverse reactions Method of administration via the national reporting system listed in For oral use. Appendix V. 4.3 Contraindications The following headings are used to rank the ADRs by frequency: common (≥ 1/100 to Hypersensitivity to the active substance, other < 1/10), rare (≥ 1/10,000 to < 1/1,000). flavonoids or to any of the excipients listed in Within each frequency grouping, ADRs are section 6.1. presented in order of decreasing seriousness.

4.4 Special warnings and precautions for MedDRA SOC Frequency Undesirable use effect See section 4.6. Nervous Rare Headache, system malaise, vertigo Warnings about the excipients disorders Common Insomnia, This medicinal product contains lactose dizziness, monohydrate. Patients with rare hereditary tiredness, problems of galactose intolerance, the Lapp anxiety, cramps, lactase deficiency or glucose-galactose drowsiness malabsorption should not take this medicine. Cardiac Common Palpitations, disorders hypotension The efficacy and safety of the preparation Gastrointestinal Common Nausea, have not been studied in the following vomiting, groups/conditions, which has to be taken into diarrhea, account when the preparation is used: dyspepsia - children and adolescents (under 18 years). - hepatic and/or renal impairment. Uncommon Colitis Skin and tissue Rare Rash, pruritus, 4.5 Interaction with other medicinal disorders urticaria products and other forms of subcutaneous interaction Not known Angioedema, of the No pharmacokinetic and pharmacodynamic face, lips and interaction studies have been performed with eyelids diosmin and other medicinal products or with diosmin and food. 4.9 Overdose In the extensive post-marketing experience, no interactions of diosmin and other medicinal No cases of overdose have been reported. 5. PHARMACOLOGICAL PROPERTIES Biotransformation is extensively metabolized to 5.1 Pharmacodynamic properties phenolic acids or to its glucuronide derivatives of aglycone that are eliminated in urine. Pharmacotherapeutic group: , bioflavonoids, ATC code: C05CA03 The major metabolite found in urine is m-hydroxyphenylpropionic which is mainly Mechanism of action eliminated in its conjugated form. Metabolites found in small quantities include phenolic acids Activity on veins corresponding to 1-hydroxy-4 methoxybenzoic This medicinal product reduces the acid, 3-metoxi-4-hidroxiphenil benzoicacetic acid predisposition of veins to vasodilate and and 3,4-dihydroxybenzoic acid. reduces venous stasis. Elimination Activity on microcirculation Elimination in humans is relatively fast. In This product reduces capillary permeability and studies with 14C radiolabelled diosmin, 34% of increases capillary resistance. the dose is found in urine and faeces after 24 hours and approximately 86% of the dose were Pharmacodynamic effects found in urine and faeces after 48 hours. Pharmacological activity of this medicinal product in humans has been substantiated Linearity/non-linearity by controlled, double-blind clinical studies and Diosmin pharmacokinetics is linear. also by objective and quantitative methods in investigating the influence of the active 5.3 Preclinical safety data substance on venous haemodynamics. There was no evidence of teratogenic effects in Effects on venous tone animal studies. This medicinal product enhances venous tone and therefore, reduces the capacitance, distensibility and stasis of blood: venous 6. PHARMACEUTICAL PARTICULARS occlusal mercurial plethysmography indicates reduction of emptying time of veins. 6.1 List of excipients The final effect is a reduction in venous hypertension in patients with venous Tablet core insufficiency. Microcrystalline cellulose (E460) Gelatin Effects on lymphatic system Sodium starch glycolate Diosmin stimulates the lymphatic activity, Talc improving drainage of the interstitial space and Magnesium stearate increasing lymphatic flow. The administration Purified water of 1 g a day for 28 days is capable of reducing lymphatic capillary diameter and intralymphatic Film-coating pressure, improving the number of functioning Lactose monohydrate lymphatic capillaries, in patients with severe Hypromellose (E464) chronic venous insufficiency, without ulcers. Macrogol 4000 Titanium dioxide (E171) Anti-inflammatory effects Iron oxide, yellow (E172) Diosmin reduces various inflammation indexes Iron oxide, red (E172) in peripheral microvascularisation. In vitro and in animal studies, diosmin reduces the 6.2 Incompatibilities release of different inflammation prostaglandin mediators E2 and F2α (PGE2 and PGF2α) Not applicable. and thromboxane A2 (TxA2). Consequently, it inhibits the adhesion of leukocytes to the 6.3 Shelf life vascular wall and reduces capillary permeability and resistance, thus favouring venous return. Please see outer packaging for the shelf-life data. Effects on microcirculation Controlled, double-blind clinical studies 6.4 Special precautions for storage demonstrate statistically significant difference between diosmin and placebo. In patients with Store at temperatures not exceeding 30 °C. capillary fragility, diosmin treatment increases This medicinal product does not require any capillary resistance and reduced the clinical special storage conditions. manifestations. 6.5 Nature and contents of container A decrease in capillary permeability was also observed after administration of 1 g of PVC-PVDC/aluminium blister packs of 30 film- daily diosmin for 6 weeks, with respect to coated tablet. placebo, using technetium-labelled albumin, or plethysmography. 6.6 Special precautions for disposal Clinical efficacy and safety No special requirements. Controlled, double-blind clinical studies demonstrate therapeutic activity of the Manufactured by: Laboratorios Cinfa, S.A. – product in adults as a short-term treatment Olaz-Chipi, 10 Poligono Industrial Areta of symptoms of established chronic venous 31620 Huarte-Pamplona (Navarra), Spain insufficiency (CVI) adjuvant to conventional for: Alvogen Asia Pacific Holdings Limited – treatment of CVI. 2F, Jonsim Place, No.228 Queen’s Road East, Wanchai, Hongkong 5.2 Pharmacokinetic properties Imported and Distributed by: Absorption Metro Drug, Inc. – Mañalac Avenue, Following oral administration, diosmin is rapidly Bagumbayan, Taguig City, Philippines hydrolyzed in the intestine by intestinal flora and absorbed as its aglicone derivative, diosmetin. Date of Revision of Package Insert Oral bioavailability is approximately 57.9%. (05/2016) Distribution Diosmetin has a volume of distribution of 62.1 1 indicating a broad distribution into tissues.

ARTDB004756P