Micronised Purified Flavonoid Fraction
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Micronised purified flavonoid fraction (MPFF) [Daflon® 500mg1], an oral phlebotropic drug consisting of 90% micronised diosmin and 10% flavonoids expressed as hesperidin, improves venous tone and lymphatic drainage, and reduces capillary hyperpermeability by protecting the microcirculation from inflammatory processes. The absorption of diosmin is improved by its micronisation to particles with a diameter <2μm.
Compared with placebo, MPFF 500mg twice daily significantly decreased ankle or calf circumference, and improved many symptoms of chronic venous insufficiency (CVI) and plethysmographic parameters in two randomised, double-blind, 2-month studies. Improvement in symptoms was parallelled by an improvement in health-related quality of life in a nonblind, 6-month trial.
Significantly more venous leg ulcers ≤10cm in diameter completely healed with MPFF 500mg twice daily plus standard management (compression and local treatment) for 2–6 months than with standard management alone or with placebo in a nonblind and a double-blind trial. The addition of MPFF to standard management was cost effective in a retrospective pharmacoeconomic analysis of the 6-month trial.
Compared with placebo, the duration and/or intensity of individual symptoms of grade 1 or 2 acute internal haemorrhoids improved significantly with 3 tablets of MPFF 500mg twice daily for 4 days then 2 tablets of MPFF 500mg twice daily for 3 days. Two tablets of MPFF 500mg daily for 60 or 83 days reduced the frequency, duration and/or severity of acute haemorrhoidal symptoms and improved the overall signs and symptoms of chronic (recurrent) haemorrhoids compared with placebo. Compared with a control group, MPFF significantly reduced the risk of secondary bleeding after elective haemorrhoidectomy.
In clinical trials, MPFF had a tolerability profile similar to that of placebo; the most frequently reported adverse events were gastrointestinal and autonomic in nature.
In conclusion, MPFF is a well established and well tolerated treatment option in patients with CVI, venous ulcers, or acute or chronic internal haemorrhoids. MPFF is indicated as a first-line treatment of oedema and the symptoms of CVI in patients in any stage of the disease. In more advanced disease stages, MPFF may be used in conjunction with sclerotherapy, surgery and/or compression therapy, or as an alternative treatment when surgery is not indicated or is unfeasible. The healing of venous ulcers ≤10 cm in diameter is accelerated by the addition of MPFF to standard venous ulcer management. MPFF may reduce the frequency, duration and/or intensity of symptoms of grade 1 or 2 acute internal haemorrhoids, and also the severity of the signs and symptoms of chronic haemorrhoids.
MPFF, an oral phlebotropic and vascular protective agent consisting of 90% micronised diosmin and 10% flavonoids expressed as hesperidin, increases venous tone, improves lymphatic drainage and reduces capillary hyperpermeability. By reducing the expression of some endothelial adhesion molecules, MPFF inhibits the activation, migration and adhesion of leukocytes, which leads to a reduction in the release of inflammatory mediators and thereby a reduction in capillary hyperpermeability.
Two tablets of MPFF 500mg daily reduced venous distensibility and capacitance, and improved venous tone in patients with various types of venous insufficiency.
Several indices of inflammation in the microcirculation are reduced by MPFF. Plasma levels of some markers of endothelial activation (intercellular adhesion molecule-1 and vascular cell adhesion molecule) and surface expression of some leukocyte adhesion molecules (monocyte or neutrophil CD62L) were significantly reduced from baseline with 2 tablets of MPFF 500mg daily for 60 days in patients with CVI. Capillary hyperpermeability decreased with 2 or 3 tablets of MPFF 500mg daily resulting in a decrease in oedema in patients in two trials.
Daily administration of 1–4 tablets of MPFF 500mg for 1–3 months had beneficial effects on venous oximetry measurements (e.g. increases from baseline in oxygen pressure, oxygen saturation or pH, and decreases from baseline in carbon dioxide pressure) in patients with mild to moderate CVI in two studies. In patients with CVI, 2 tablets of MPFF 500mg daily for 4 weeks increased red blood cell velocity in capillaries; however, relative capillary packed cell volume also increased.
In patients with severe CVI, 2 tablets of MPFF 500mg daily for 28 days decreased intralymphatic pressure and the diameter of lymphatic capillaries and increased the number of functional lymphatic capillaries compared with baseline.
Most information on the pharmacokinetics of oral MPFF relates to the diosmin portion of the drug. Diosmin is rapidly transformed in the intestine by intestinal flora and absorbed as its aglycone, diosmetin; the unchanged form of diosmin does not appear to be absorbed. Approximately half of an oral 500mg dose of radiolabelled MPFF was absorbed within 48 hours of administration in healthy volunteers. Micronisation of diosmin increased oral absorption compared with nonmicronised diosmin (57.9 vs 32.7% of a radiolabelled dose was absorbed 0–168 hours postdose). Diosmetin has a rapid distribution period followed by a slower elimination period. Animal studies have demonstrated that radiolabelled diosmetin and/or its metabolites are widely distributed throughout the body.
Diosmetin is rapidly and extensively degraded to phenolic acids or their glycine conjugate derivatives, which are eliminated in the urine; unmetabolised diosmin and diosmetin are not excreted in the urine. The predominant metabolite, 3-hydroxy-phenylpropionic acid, is mainly eliminated in its conjugated form. Unidentified metabolites may be responsible for the pharmacological activity of diosmin.
Approximately half of a radiolabelled dose of diosmin was eliminated in the faeces as unchanged diosmin and diosmetin. Elimination of micronised diosmin is relatively rapid (≈34% of the dose excreted in the urine and faeces over the first 24 hours and ≈86% over the first 48 hours). There are no known drug interactions with MPFF.
In Patients with Chronic Venous Insufficiency: Compared with placebo, MPFF 500mg twice daily for 2 months significantly decreased ankle and calf circumferences from baseline in two double-blind trials in 36 and 150 patients; improvements were also seen in the symptoms of CVI (e.g. functional discomfort, nocturnal cramps and sensations of leg heaviness, swelling or heat) and plethysmographic parameters (e.g. venous capacitance, distensibility and emptying time).
The efficacy of 2 tablets of MPFF 500mg daily was maintained in the long-term nonblind treatment (6–12 months) of patients with symptoms of CVI. Patients with or without venous reflux in the large (n = 4527) 6-month Reflux Assessment and Quality of Life Improvement with Micronised Flavonoids study showed a significant improvement in CEAP (Clinical signs, Etiology, Anatomical distribution, and Pathophysiological dysfunction) classification. Moreover, both groups of patients also showed a significant improvement in their health-related quality of life, as measured by the Chronic Venous Insufficiency Questionnaire global index scores.
In double-blind, 2-month trials in patients with CVI, 2 tablets of MPFF 500mg daily was more effective than the same nominal dosage of nonmicronised diosmin in improving most of the subjective symptoms and objective parameters of CVI; MPFF 500mg improved the signs and symptoms of CVI regardless of the daily administration schedule (2 tablets in either the morning or the evening, or 1 tablet twice daily).
Effects on Venous Ulcer Healing: MPFF 500mg twice daily plus standard management (compression and local therapy) for 2–6 months was more effective than standard management alone or with placebo in the complete healing of venous leg ulcers ≤10cm in diameter in a nonblind and a double-blind trial. Venous leg ulcers with a diameter ≤10cm were completely healed in 32 or 46.5% of patients receiving 2 tablets of MPFF 500mg daily for 2 or 6 months compared with 13% of patients receiving placebo for 2 months or 27.5% of patients in the control group in the 6-month trial. Ulcers >10cm in diameter did not completely heal in either the active-treatment or placebo group during the 2-month trial. Compared with the control group in the longer trial, MPFF reduced mean ulcer area (80 vs 65%) and discomfort related to ulcer (64.8 vs 38.3% of patients); this trial did not include ulcers >10cm in diameter.
In a retrospective pharmacoeconomic analysis of the 6-month trial, 2 tablets of MPFF 500mg daily was cost-effective in the treatment of venous ulcers compared with the control group receiving standard venous ulcer treatment. Based on the cost per healed ulcer over 6 months, the cost-effectiveness ratio in the MPFF group was 1026 euros (EUR) compared with EUR1872 in the control group (year of costing 1998).
In Patients with Haemorrhoids: In two randomised, double-blind, placebocontrolled trials, MPFF 500mg (3 tablets twice daily for 4 days then 2 tablets twice daily for 3 days) significantly reduced the duration and/or intensity of symptoms of acute internal haemorrhoids (e.g. bleeding, pain, and anal discharge) compared with placebo. After the first few days of treatment, systemic and topical anaesthetics were used less by patients receiving MPFF than patients receiving placebo.
In two double-blind trials, treatment with MPFF 500mg twice daily for 60 or 83 days reduced the frequency, duration and/or severity of acute haemorrhoidal symptoms in patients with chronic symptoms of haemorrhoids compared with placebo. Relapses of bleeding were prevented in 18 or 36% more patients receiving MPFF than those receiving placebo; MPFF also effectively treated the symptoms and signs of chronic haemorrhoids.
In a randomised, nonblind trial, MPFF 500mg (3 tablets twice daily for 5 days, then 2 tablets twice daily for 3 weeks) plus fibre (ispaghula husk) resolved bleeding from nonprolapsed internal haemorrhoids as effectively as with rubber band ligation plus fibre and more rapidly than with fibre alone.
In a noncomparative trial in pregnant women, MPFF 500mg (6 tablets daily for 4 days, then 4 tablets for 3 days) reduced median symptom scores for bleeding, pain, rectal discomfort and rectal exudation from baseline. Maintenance treatment with MPFF 500mg twice daily in the antenatal and 30-day postnatal periods reduced the duration of relapses of symptoms of acute haemorrhoids compared with the patient’s history.
The proportion of patients with secondary postoperative bleeding after open pedicular haemorrhoidectomy was less in patients receiving MPFF 500mg (2 tablets three times daily for 3 days then 1 tablet three times daily for 4 days) than in the control group (0.9 vs 6.1%).
In clinical trials, MPFF was well tolerated with most reported events being mild and transitory. The adverse events most commonly associated with MPFF are gastrointestinal (e.g. abdominal pain, gastric discomfort, nausea, dyspepsia, vomiting and diarrhoea) or autonomic (e.g. insomnia, drowsiness, vertigo, headache and tiredness) in nature. Combined data from clinical trials in patients with CVI or haemorrhoids indicated that the incidence of adverse events was similar in 2850 patients receiving 2 tablets of MPFF 500mg daily and 225 patients receiving placebo (10 vs 13.9% of patients). Gastrointestinal and autonomic events were reported by 6.9 and 1.7% of patients receiving MPFF. Adverse events were the reason for discontinuation in the trials of 1.1 % of MPFF recipients compared with 3.2% of placebo recipients.
The incidence or nature of adverse events was not changed by long-term treatment (1 year) with 2 tablets of MPFF 500mg daily, dosages of MPFF 500mg of up to 6 tablets daily for 7 days, age ≥70 years or the presence of concomitant diseases (i.e. hypertension, atherosclerosis, diabetes mellitus, neurological/psychiatric disease or alcoholism). Two tablets of MPFF 500mg daily for 1 year did not modify blood pressure or laboratory parameters.
Dosage and Administration
MPFF is available as 500mg tablets and is administered orally. Prescribing information for MPFF may differ between the more than 100 countries (including 9 countries in the EU and 20 other European countries) that have approved its use. In general, MPFF is indicated for the treatment of organic or idiopathic CVI of the lower limbs with symptoms of heavy legs, pain or nocturnal cramps, acute haemorrhoidal attacks or chronic haemorrhoids. In CVI, the recommended dosage is 2 tablets daily (as a single dose in the morning or evening or 1 tablet twice daily); in acute haemorrhoidal attacks, 2 tablets three times daily for 4 days followed by 2 tablets twice daily for 3 days; and in chronic haemorrhoids, 2 tablets daily. MPFF does not interact with any drugs. Caution is recommended when administering MPFF to patients who are breast feeding.
KeywordsVaricose Vein Venous Ulcer Calf Circumference Rubber Band Ligation Chronic Venous Insufficiency
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