Comprehensive Monograph on Diosmin (DB08995)

1.0 Executive Summary

Diosmin is a naturally derived flavonoid glycoside, classified therapeutically as a venoactive and vasoprotective agent, commonly referred to as a phlebotonic. Its primary clinical applications are in the management of chronic venous insufficiency (CVI) and both acute and chronic hemorrhoidal disease. Sourced primarily through the semi-synthetic modification of hesperidin from citrus peels, diosmin has a long history of use, particularly in Europe, where it is regulated as a prescription or over-the-counter medicinal product.

The pharmacological activity of diosmin is multifaceted, targeting the key pathophysiological elements of venous disease. Its mechanism of action includes enhancing venous tone by prolonging the vasoconstrictive effects of noradrenaline, reducing capillary hyperpermeability and increasing capillary resistance, and improving lymphatic drainage. Beyond these hemodynamic effects, diosmin exerts significant anti-inflammatory and antioxidant activities. It modulates critical inflammatory pathways, reducing the synthesis of prostaglandins and the expression of endothelial adhesion molecules, and has been shown in clinical studies to decrease plasma levels of key pro-inflammatory cytokines and pro-angiogenic factors.

A critical aspect of its pharmacology is its pharmacokinetic profile. Diosmin functions as a prodrug; in its native glycoside form, it is poorly absorbed. Following oral administration, it requires hydrolysis by intestinal microflora to release its active aglycone, diosmetin, which is then absorbed into the systemic circulation. This conversion is the rate-limiting step for its bioavailability, a challenge that has led to the development of advanced formulations such as micronized purified flavonoid fraction (MPFF).

Clinically, diosmin has demonstrated robust efficacy in alleviating the symptoms of CVI, including pain, leg heaviness, and edema. It is also highly effective in the management of hemorrhoidal disease, providing rapid relief from acute symptoms and aiding in post-surgical recovery. Notably, recent high-quality comparative efficacy studies have concluded that pure, non-micronized diosmin at a dose of 600 mg daily is clinically non-inferior to the more common and higher-dosed MPFF formulations (typically 1000 mg daily), challenging existing treatment guidelines.

Diosmin exhibits a favorable safety profile, with adverse events being generally mild and transient, most commonly involving the gastrointestinal tract. However, its potential for clinically significant drug interactions, particularly with anticoagulants and substrates of cytochrome P450 enzymes, necessitates careful clinical oversight. This pharmacological potency is in stark contrast with its regulatory status in the United States, where it is marketed as a dietary supplement. This global regulatory dichotomy—a rigorously controlled medicine in Europe versus a less-regulated supplement in the US—creates a significant gap in patient safety standards and clinical guidance, representing a central theme in the modern understanding of this agent.

2.0 Chemical Identity and Physicochemical Characteristics

2.1 Nomenclature, Synonyms, and Key Identifiers

The unambiguous identification of a pharmaceutical substance is fundamental to scientific communication and clinical practice. The compound is universally recognized by the generic name Diosmin.[1] It is assigned the Chemical Abstracts Service (CAS) Registry Number 520-27-4, which serves as a unique identifier for this specific chemical substance.[2] In pharmacological databases, it is cataloged under the DrugBank Accession Number DB08995.[1]

Reflecting its complex chemical structure and historical characterization, diosmin is known by numerous synonyms and systematic names. These include chemical descriptors such as 3',5,7-trihydroxy-4'-methoxyflavone 7-rhamnoglucoside and diosmetin 7-O-rutinoside, which detail its flavonoid backbone and attached sugar moiety.[1] Other common synonyms found in literature and commerce include Barosmin, Diosmina, Diosmine, and Diosminum.[1]

A comprehensive list of identifiers from various international databases is essential for cross-referencing and data integration. These are summarized in the table below.

2.2 Molecular Structure and Stereochemistry

Diosmin is a complex glycoside with the molecular formula C28​H32​O15​.[2] Its structure is composed of two main parts: an aglycone (the non-sugar portion) called diosmetin and a disaccharide (a two-unit sugar) called rutinose.

The aglycone, diosmetin (3',5,7-trihydroxy-4'-methoxyflavone), is a flavone, which is a class of flavonoids characterized by a specific three-ring structure (C6-C3-C6). This core structure consists of two benzene rings (A and B) linked by a three-carbon chain that forms a heterocyclic pyran ring (C). In diosmetin, the B-ring is substituted with a hydroxyl group at the 3' position and a methoxy group at the 4' position.

The defining feature of diosmin is the attachment of the disaccharide rutinose to the diosmetin backbone. This linkage occurs via a glycosidic bond at the hydroxyl group on position 7 of the A-ring. Rutinose itself is composed of two monosaccharides: rhamnose and glucose. Specifically, the structure is a 6-O-(alpha-L-rhamnopyranosyl)-beta-D-glucopyranosyl moiety.[2] The full, systematic IUPAC name for this intricate structure is 5-Hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-oxymethyl]oxan-2-yl]oxychromen-4-one.[5]

This glycosidic structure is of paramount pharmacological importance. The presence of the bulky, hydrophilic rutinose moiety renders the parent diosmin molecule poorly soluble and largely unabsorbable through the intestinal wall. This structural feature dictates that diosmin must function as a prodrug, requiring enzymatic cleavage in the gut to release the pharmacologically active and more readily absorbed aglycone, diosmetin.[6]

2.3 Chemical and Therapeutic Classification

Diosmin's classification reflects both its chemical nature and its clinical function.

Chemical Classification: Chemically, diosmin is a naturally occurring flavonoid, a large class of polyphenolic plant compounds.[2] More specifically, it is a flavone glycoside, meaning it is a flavone (diosmetin) attached to a sugar (rutinose).[2] Within the LIPID MAPS classification system, it falls under Polyketides [PK] -> Flavonoids [PK12] -> Flavones and Flavonols [PK1211].[2]

Therapeutic Classification: Therapeutically, diosmin belongs to a class of agents known as "venoactive drugs" or "phlebotonics".[1] This is a functional classification for substances that improve the health and function of veins.[11] Under the Anatomical Therapeutic Chemical (ATC) Classification System, diosmin is assigned the code C05CA03. This places it within the hierarchy of:

• C: Cardiovascular System
• C05: Vasoprotectives
• C05C: Capillary Stabilizing Agents
• C05CA: Bioflavonoids [5]

This ATC classification precisely defines its primary therapeutic role as an agent that protects blood vessels and stabilizes capillaries.

2.4 Physical and Chemical Properties

Diosmin presents as a greyish-yellow or light-yellow, crystalline powder.[3] Its physicochemical properties are central to its formulation, pharmacokinetics, and mechanism of action. The extremely low aqueous solubility is a defining characteristic that presents a significant challenge for oral bioavailability and has driven the development of formulation technologies like micronization to improve its dissolution and subsequent absorption.[7] The table below summarizes its key properties.

A notable point of ambiguity arises from the common use of the term "diosmin" in both clinical and commercial contexts. While chemically it refers to the pure compound, in a vast portion of the clinical literature and on product labels, "diosmin" is used as a shorthand for Micronized Purified Flavonoid Fraction (MPFF).[13] MPFF is a specific, widely studied formulation that typically contains 90% diosmin and 10% other flavonoids expressed as hesperidin.[1] Prominent commercial products such as Daflon and Detralex are, in fact, MPFF formulations.[5] This creates a potential for significant confusion. A clinician or researcher reviewing a study on "diosmin" might be examining data derived from an MPFF product without realizing the distinction. This is not merely a semantic issue; it has direct implications for dosage (e.g., a 600 mg dose of pure diosmin versus a 1000 mg dose of MPFF, which contains 900 mg of diosmin) and raises questions about the potential synergistic or additive roles of the other flavonoids, like hesperidin, present in MPFF. Therefore, for the remainder of this report, a clear distinction will be made between "pure diosmin" and "MPFF" to ensure clarity and precision in the analysis of pharmacological and clinical data.

Table 1: Key Identifiers and Physicochemical Properties of Diosmin

Property	Value	Source(s)
Identifiers
DrugBank ID	DB08995	1
CAS Number	520-27-4	1
PubChem CID	5281613	2
UNII	7QM776WJ5N	2
ATC Code	C05CA03	5
Molecular Properties
Molecular Formula	C28​H32​O15​	2
Molecular Weight (Average)	608.5 g/mol	1
Monoisotopic Mass	608.17412031 Da	2
Physical Properties
Appearance	Greyish-yellow or light-yellow powder	3
Melting Point	277-278 °C	1
Boiling Point (Experimental)	926.8 ± 65.0 °C	1
Water Solubility	0.019 ± 0.005 mg/L	1
Computed Properties
LogP (Experimental)	2.05	1
pKa (Dissociation Constant)	6.10 ± 0.40	1
Topological Polar Surface Area	234 Ų	1
Hydrogen Bond Donors	8	1
Hydrogen Bond Acceptors	15	1

3.0 Pharmacology and Molecular Mechanisms

The therapeutic efficacy of diosmin in vascular disorders stems from a complex and multifaceted mechanism of action that addresses the primary pathophysiological components of venous disease: altered hemodynamics, microcirculatory dysfunction, and chronic inflammation.

3.1 Primary Venoactive and Vasoprotective Mechanisms

Diosmin's primary classification as a venoactive drug is based on its direct effects on the structure and function of blood vessels, particularly veins and capillaries.[1] Its actions can be categorized into three core areas:

1. Enhancement of Venous Tone: Diosmin increases venous tone and elasticity, which is a crucial action for counteracting the venous dilation and stasis characteristic of CVI.[1] This effect is achieved, at least in part, by prolonging the vasoconstrictive action of noradrenaline on the venous wall.[1] By inhibiting the enzymatic breakdown of noradrenaline or sensitizing adrenergic receptors, diosmin helps veins contract more effectively, which reduces venous capacitance and distensibility, thereby improving venous return to the heart.[10]
2. Improvement of Microcirculation: At the level of the microvasculature, diosmin acts as a potent capillary-stabilizing agent.[12] It decreases capillary hyperpermeability and fragility, which are key factors leading to the leakage of fluid, proteins, and red blood cells into the interstitial space—the process that causes edema and skin changes like pigmentation.[8] By strengthening the capillary wall and reducing its leakiness, diosmin helps maintain the integrity of the microcirculatory barrier.[10]
3. Support of Lymphatic Drainage: Edema in CVI is exacerbated by an overwhelmed lymphatic system. Diosmin actively supports lymphatic function by increasing the frequency and intensity of lymphatic contractions.[1] This enhanced lymphatic pumping action facilitates the clearance of excess interstitial fluid, proteins, and inflammatory cells, contributing significantly to the reduction of edema.[2]

Together, these three hemodynamic actions provide a comprehensive approach to managing the primary symptoms of CVI, directly addressing venous hypertension, capillary leakage, and edema formation.

3.2 Modulation of Inflammatory and Angiogenic Pathways

The traditional view of CVI as a purely mechanical or hemodynamic disorder has evolved. It is now recognized as a condition sustained by chronic, low-grade inflammation within the venous wall and surrounding tissues.[8] Diosmin's efficacy is increasingly attributed to its ability to modulate these underlying inflammatory processes, positioning it not just as a symptomatic treatment but as an agent that targets the molecular drivers of disease progression.

Diosmin exerts significant anti-inflammatory effects through several pathways. It inhibits the synthesis of key inflammatory mediators, including prostaglandins and thromboxane A2, which are involved in pain signaling and platelet aggregation.[10] A crucial aspect of venous inflammation is the interaction between leukocytes (white blood cells) and the endothelial lining of the veins. Diosmin has been shown to inhibit this inflammatory cascade by reducing the expression of endothelial adhesion molecules (such as ICAM-1 and VCAM-1), which in turn limits the adhesion and migration of leukocytes from the bloodstream into the perivascular tissue.[10] This action reduces the local inflammatory response, mitigating tissue damage and edema.

Clinical studies have provided direct evidence of these effects in humans. Therapy with diosmin has been shown to significantly decrease the systemic plasma levels of key pro-inflammatory cytokines, including Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-6 (IL-6).[8] Furthermore, diosmin modulates the balance of factors that control the formation of new blood vessels (angiogenesis). In the advanced stages of CVI, pathological angiogenesis contributes to skin lesions. Diosmin has been found to reduce levels of pro-angiogenic factors like Vascular Endothelial Growth Factor (VEGF-A and VEGF-C) and Fibroblast Growth Factor 2 (FGF2), while simultaneously increasing levels of the endogenous anti-angiogenic factor, angiostatin.[8] This rebalancing of angiogenic signals may help normalize the microvascular environment and promote the healing of venous ulcers. The aglycone of diosmin, diosmetin, has been shown to exert its anti-inflammatory effects by modulating the nuclear factor-κB (NF-κB) signaling pathway, a master regulator of the inflammatory response.[18] By intervening in these fundamental processes, diosmin appears to modify the natural history of the disease, preventing the progression from simple edema to more severe complications like lipodermatosclerosis and ulceration.

3.3 Antioxidant Activity and Molecular Targets

Complementing its anti-inflammatory actions, diosmin possesses inherent antioxidant properties.[2] As a flavonoid, it can directly scavenge unstable and damaging molecules known as oxygen-free radicals.[1] Oxidative stress is a key contributor to endothelial dysfunction and inflammation in vascular diseases. By neutralizing these radicals, diosmin helps protect the vascular endothelium from damage, preserving its normal function and reducing a key trigger for the inflammatory cascade.

Despite a deep understanding of its downstream pharmacological effects, the precise upstream molecular target of diosmin or its active metabolite, diosmetin, has not been definitively established.[1] Some evidence suggests that diosmin may act as an agonist for the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor involved in regulating cellular responses to environmental stimuli. However, the clinical relevance of this interaction to its vascular functions remains unknown and requires further investigation.[1] The lack of a single, defined receptor target suggests that its broad spectrum of activity may result from interactions with multiple cellular pathways, a characteristic common to many flavonoid compounds.

4.0 Clinical Pharmacokinetics and Bioavailability

The clinical utility and dosing of diosmin are fundamentally governed by its pharmacokinetic profile, which is characterized by its nature as a prodrug, its reliance on the gut microbiome for activation, and the significant impact of formulation on its bioavailability.

4.1 Absorption, Metabolism to Diosmetin, and First-Pass Effects

Diosmin in its native glycoside form is a large, hydrophilic molecule that is poorly absorbed from the gastrointestinal tract.[7] Following oral administration, the parent diosmin compound is not detected in systemic circulation.[6] Instead, it must first undergo a critical activation step in the gut. Enzymes produced by the intestinal microflora, such as α-glucosidase and β-glucosidase, hydrolyze the glycosidic bond, cleaving off the rutinose sugar moiety to release the aglycone, diosmetin.[7] It is this less hydrophilic, smaller molecule, diosmetin, that is subsequently absorbed through the intestinal wall and enters the bloodstream.[6]

This complete reliance on bacterial enzymes for activation establishes diosmin as a prodrug and makes the gut microbiome an essential, albeit often unacknowledged, cofactor in its therapy. The composition, health, and metabolic activity of an individual's gut microbiota could theoretically be a major source of inter-individual variability in the clinical response to diosmin. Factors known to alter the microbiome, such as diet, concurrent antibiotic use, or gastrointestinal diseases, may significantly impact the efficiency of diosmin-to-diosmetin conversion, thereby affecting the amount of active drug absorbed. This represents a significant unexamined variable in most clinical trials and a promising avenue for future research to potentially personalize diosmin therapy.

4.2 Systemic Distribution and Tissue Affinity

Once absorbed, the active metabolite diosmetin distributes widely throughout the body. Pharmacokinetic studies have revealed a large apparent volume of distribution (Vd​) of approximately 62.1 liters.[1] A large

Vd​ indicates that the compound does not remain confined to the bloodstream but distributes extensively into peripheral tissues. This finding is highly relevant to its mechanism of action, as it supports the hypothesis that diosmetin exerts its therapeutic effects by binding directly to target tissues, most notably the vascular walls of veins and capillaries.[6] In the bloodstream, diosmetin is known to bind to serum albumin.[1]

4.3 Metabolic Fate and Excretion Pathways

After entering systemic circulation, diosmetin is subject to further metabolism. It is enzymatically esterified, primarily to its 3-O-glucuronide and subsequently to 3,7-O-diglucuronide conjugates.[7] The metabolic pattern is similar to that of other flavonoids, with further degradation leading to the formation of various phenolic acids, such as m-hydroxy-phenylpropionic acid, which are detectable in the urine.[1]

The primary route of elimination for diosmin and its metabolites is fecal excretion.[19] Pharmacokinetic data confirm a near-total absence of unchanged diosmin or diosmetin in the urine. Only the minor, further-metabolized phenolic acid byproducts are eliminated renally, mainly as glucuronic acid conjugates.[1] This excretion profile is consistent with a compound that is either poorly absorbed initially or undergoes significant enterohepatic circulation, where metabolites are excreted in the bile and re-enter the intestine.

4.4 Pharmacokinetic Parameters and Half-Life

The active metabolite, diosmetin, exhibits a long plasma elimination half-life, with studies reporting values ranging from 26 to 43 hours.[1] This prolonged half-life is a significant therapeutic advantage, as it allows for sustained plasma concentrations and supports convenient once or twice-daily dosing regimens. The time to reach maximum plasma concentration (

Tmax​) and the maximum plasma concentration (Cmax​) of diosmetin are highly variable across studies, reflecting the complex and variable nature of its absorption process.[1] The table below summarizes key pharmacokinetic parameters reported for diosmetin.

Table 2: Summary of Pharmacokinetic Parameters for Diosmetin (Active Metabolite) after Oral Diosmin Administration

Parameter	Value / Range (Mean ± SD)	Formulation / Study Context	Source(s)
Maximum Plasma Concentration (Cmax​)	417 ± 94.1 ng/dL (approx. 41.7 ng/mL)	Single oral dose (10 mg/kg) in 5 adults	1
	50.3 ± 22.6 ng/mL	Single 500 mg dose of µSmin® Plus (enhanced bioavailability formulation)	7
	2.4 ± 1.9 ng/mL	Single 500 mg dose of unformulated micronized diosmin	7
Time to Max. Concentration (Tmax​)	1 hour	Single oral dose (10 mg/kg) in 5 adults	6
	2.2 ± 2.9 hours	Single 500 mg dose of µSmin® Plus	7
Elimination Half-life (t1/2​)	26 to 43 hours	General range reported across studies	1
	31.5 hours (final elimination)	Single oral dose (10 mg/kg) in 5 adults	6
Volume of Distribution (Vd​)	62.1 ± 7.9 L	Single oral dose (10 mg/kg) in 5 adults	1
Area Under the Curve (AUC)	298.4 ± 163.7 ng·mL⁻¹·h	Single 500 mg dose of µSmin® Plus (AUC₀₋ₜ)	7
	31.9 ± 100.4 ng·mL⁻¹·h	Single 500 mg dose of unformulated micronized diosmin (AUC₀₋ₜ)	7

4.5 The Role of Formulation: Micronization and Bioavailability Enhancement

Given the inherent challenges of poor solubility and microbiome-dependent absorption, the pharmaceutical formulation of diosmin is a critical determinant of its clinical performance. The most common formulation strategy employed to improve its bioavailability is micronization, a process that reduces the particle size of the drug substance.[7] By increasing the surface area-to-volume ratio, micronization enhances the rate of dissolution in the gastrointestinal fluid, which can lead to improved absorption.[14]

However, studies have shown that micronization alone only marginally improves the plasma concentrations of diosmetin.[7] This has spurred the development of more advanced formulations. One such example is µSmin® Plus, a flavonoid complex that combines micronized diosmin with a buffering agent (calcium carbonate).[7] A comparative bioavailability study in healthy volunteers demonstrated that this enhanced formulation increased the relative oral bioavailability of diosmetin by 9.4-fold compared to standard, unformulated micronized diosmin.[7] This dramatic improvement highlights that optimizing the gastrointestinal environment for enzymatic conversion and absorption can be more impactful than simply reducing particle size. While this enhanced bioavailability is pharmacokinetically significant, its translation into superior clinical efficacy remains a subject of debate, as will be explored in the following section.

5.0 Evidence-Based Clinical Applications and Efficacy

The clinical utility of diosmin is well-established for a specific set of vascular disorders, supported by a substantial body of evidence from randomized controlled trials, systematic reviews, and meta-analyses.

5.1 Management of Chronic Venous Insufficiency (CVI)

The primary and most robustly supported indication for diosmin is the symptomatic management of CVI.[1] CVI encompasses a spectrum of conditions, including varicose veins, leg edema, stasis dermatitis, and venous ulcers, all stemming from venous hypertension.[5]

Numerous clinical trials, including large-scale, post-marketing Phase 4 studies, have consistently demonstrated the efficacy of diosmin in this population.[20] When compared to placebo or standard care, diosmin-containing preparations consistently demonstrate a 30-60% superiority in improving key patient-reported outcomes.[14] These include significant reductions in symptoms such as leg pain, a sensation of heaviness, swelling (edema), and nocturnal cramps.[13] Beyond symptom relief, treatment with diosmin has been shown to improve objective measures, such as reducing ankle circumference, and to enhance patients' overall quality of life.[13]

A comprehensive 2021 Cochrane review and meta-analysis of phlebotonics for venous insufficiency provides quantitative support for these findings. The analysis, which included multiple studies on diosmin, confirmed that these agents produce a statistically significant reduction in edema and ankle circumference. Furthermore, the meta-analysis showed a benefit for phlebotonics in reducing symptoms such as pain, cramps, heaviness, and swelling.[21] This high-level evidence solidifies diosmin's role as a cornerstone of pharmacotherapy for symptomatic CVI.

5.2 Treatment of Acute and Chronic Hemorrhoidal Disease

The second major, well-supported indication for diosmin is the treatment of hemorrhoidal disease, which is pathologically related to CVI as it involves venous dilation and inflammation in the anorectal region.[1] Diosmin, particularly in MPFF formulations, is considered a first-choice bioflavonoid for managing an acute hemorrhoidal crisis, characterized by pain, swelling, and bleeding.[22]

Clinical studies have demonstrated remarkable efficacy and speed of action. One study reported that during an acute attack, diosmin therapy led to a 79% reduction in pain and a 67% reduction in bleeding within the first week of treatment, with these figures improving to 98% and 86%, respectively, by the second week.[22] The efficacy extends to preventing the recurrence of hemorrhoidal attacks in patients with chronic disease.[23] Furthermore, diosmin has been shown to be a valuable adjunct in the post-surgical setting. A systematic review of clinical trials concluded that administration of 500 mg diosmin tablets can lead to a significant reduction in pain following a hemorrhoidectomy.[24] The collective evidence, supported by a Cochrane review that found flavonoids to be beneficial for hemorrhoids, establishes diosmin as a highly effective and versatile agent for managing the full spectrum of hemorrhoidal disease.[26]

5.3 Role in Lymphedema and Other Vascular Conditions

Based on its established mechanism of improving lymphatic drainage, diosmin is also indicated as an accessory treatment for lymphedema, a condition of chronic swelling due to impaired lymphatic system function.[10] However, the clinical evidence in this area is less conclusive and somewhat conflicting. While the pharmacological rationale is strong, and some sources support its use, the clinical trial data are mixed. For instance, some research suggests that a diosmin-hesperidin combination may not be effective in reducing arm lymphedema that occurs following surgery for breast cancer.[23] A clinical trial specifically investigating the prophylactic use of MPFF after axillary dissection for breast cancer found the treatment to be ineffective in preventing the onset of lymphedema.[28]

Diosmin has also been explored for other vascular-related conditions, such as varicocele (enlargement of veins within the scrotum), minor bleeding, and rosacea, but the evidence for these uses is currently limited and preliminary.[13] Therefore, while its role in CVI and hemorrhoids is clear, its utility in lymphedema and other conditions requires further, more robust clinical investigation to be definitively established.

5.4 Comparative Efficacy Analysis: Diosmin vs. MPFF and Other Phlebotonics

A critical area of recent investigation has been the comparative efficacy of different diosmin formulations, which has significant implications for clinical practice and treatment guidelines. The most widely studied and prescribed form of diosmin is MPFF, which contains 90% diosmin and 10% hesperidin. However, several high-quality, randomized, double-blind clinical trials have directly compared pure, non-micronized diosmin (typically dosed at 600 mg once daily) against MPFF (typically dosed at 1000 mg daily).[29]

The consistent and striking conclusion from this body of comparative evidence is that there is no statistically significant difference in the clinical efficacy of the two formulations for improving the global symptoms of CVI.[29] These studies, conducted over periods ranging from one to six months, found that both pure diosmin and MPFF produced a comparable and significant reduction in symptoms like pain, swelling, and leg heaviness.[29] One study even noted a trend suggesting that pure diosmin was more effective at reducing night cramps.[29] The overarching conclusion drawn from this literature review is that increasing the daily dose of diosmin beyond 600 mg, enhancing its bioavailability via micronization, or adding hesperidin does not appear to confer any additional clinical benefit for the relief of venous symptoms.[29]

This finding creates a notable disconnect with current international clinical guidelines for the management of CVI. These guidelines often assign a stronger recommendation grade to MPFF (e.g., Grade 1B, indicating a strong recommendation based on moderate-quality evidence) than to pure or hemisynthetic diosmin (e.g., Grade 2C, a weak recommendation based on low-quality evidence).[29] This discrepancy may be due to a form of "evidence inertia." MPFF, as the original branded product (Daflon/Detralex), has been on the market for decades and has accumulated a much larger volume of placebo-controlled studies. In contrast, the direct head-to-head comparative trials with pure diosmin are more recent. Guideline committees may be influenced by the historical weight and volume of the MPFF evidence base. However, for the purpose of clinical decision-making between two active treatments, direct comparative evidence is the most relevant. The current data strongly suggest that the different guideline ratings may no longer be justified and are ripe for re-evaluation, positioning 600 mg of pure diosmin as a clinically equivalent, rational, and potentially more cost-effective therapeutic option.

When compared to other venoactive agents, a study found a horse chestnut-based formulation to be non-inferior to a diosmin-hesperidin combination in managing CVI, with the added benefit of being easier to swallow, which could improve long-term adherence.[32]

6.0 Dosing Regimens, Administration, and Commercial Formulations

The administration of diosmin is tailored to the specific indication, with distinct dosing strategies for chronic management versus acute conditions. The market is dominated by combination products, primarily MPFF.

6.1 Established Dosage for Key Indications

The recommended dosage for diosmin-containing products varies significantly between the management of chronic venous insufficiency and acute hemorrhoidal disease.

• For Chronic Venous Insufficiency (CVI): The standard dosage for MPFF formulations (e.g., Daflon 500mg) is 1000 mg per day, typically administered as one 500 mg tablet twice daily, taken at midday and in the evening with meals.[10] Some newer formulations allow for a single 1000 mg dose per day. For pure, non-micronized diosmin, the established effective dose is 600 mg taken once daily.[29] The duration of treatment for CVI is typically long-term, often for a period of 3 to 6 months or longer, to manage the chronic nature of the symptoms.[13]
• For Acute Hemorrhoidal Disease: The treatment of an acute hemorrhoidal attack requires a high-dose loading regimen to rapidly achieve therapeutic concentrations and control the intense inflammatory symptoms. The standard regimen for MPFF is 3000 mg per day for the first four days (e.g., six 500 mg tablets per day, often divided into two or three doses), followed by a reduced dose of 2000 mg per day for the subsequent three days (e.g., four 500 mg tablets per day).[10] This short, high-dose course is intended for acute management only. If symptoms persist beyond 15 days, a proctological examination is recommended.[36]

The differing dosing strategies underscore the need for clear patient instruction to ensure correct use, particularly for the complex loading dose required for hemorrhoids.

Table 3: Summary of Dosing Regimens for Primary Indications

Indication	Formulation	Recommended Dosage	Duration	Source(s)
Chronic Venous Insufficiency (CVI)	MPFF (e.g., Daflon 500mg)	1000 mg per day, administered as one 500 mg tablet twice daily with meals.	3–6 months or as directed by a physician.	10
	Pure Diosmin (non-micronized)	600 mg per day, administered as a single dose.	Long-term, as directed by a physician.	29
Acute Hemorrhoidal Disease	MPFF (e.g., Daflon 500mg)	Loading Dose: 3000 mg per day (e.g., 6 tablets) for the first 4 days, followed by 2000 mg per day (e.g., 4 tablets) for the next 3 days.	7-day course. Medical review needed if symptoms persist beyond 15 days.	10

6.2 Analysis of Common Combination Products (e.g., Daflon, Detralex)

While pure diosmin is available, the vast majority of the global market and the clinical evidence base is centered on combination products, specifically Micronized Purified Flavonoid Fraction (MPFF).[1] These formulations are standardized to contain 90% micronized diosmin and 10% other flavonoids, which are expressed as hesperidin.[13]

• Daflon®: Manufactured by Laboratoires Servier, Daflon is one of the most recognized international brand names for MPFF. The standard tablet, Daflon 500mg, contains 450 mg of diosmin and 50 mg of hesperidin.[15] It is the subject of a large number of clinical trials for both CVI and hemorrhoids.
• Detralex®: This is another brand name for the same MPFF formulation from Servier, used in various international markets, particularly in Eastern Europe.[5] Pharmacologically and clinically, it is interchangeable with Daflon.
• Zeflavon®: A product marketed in Europe by Zentiva, Zeflavon 500mg also contains the standard MPFF composition of 450 mg diosmin and 50 mg hesperidin.[41] It has undergone formal regulatory assessment by European health authorities.

The market dominance of these 90/10 combination products has historically reinforced the clinical perception that the combination of diosmin and hesperidin is integral to the therapeutic effect. However, as discussed in Section 5.4, this perception is directly challenged by high-quality comparative trials showing the non-inferiority of pure diosmin, suggesting that the hesperidin component may not contribute significantly to the clinical outcomes for CVI symptoms.

7.0 Comprehensive Safety and Interaction Profile

Diosmin is characterized by a favorable safety profile, which has contributed to its widespread use and its availability as an over-the-counter product in many countries. However, it is a pharmacologically active substance with a distinct profile of adverse events and the potential for clinically significant drug interactions.

7.1 Adverse Event Profile and Tolerability

Across numerous clinical trials and decades of post-marketing surveillance, diosmin has been shown to be generally well-tolerated.[1] When adverse events occur, they are typically mild, transient, and do not necessitate discontinuation of therapy.[42]

• Common Adverse Effects: The most frequently reported side effects are gastrointestinal in nature. These include abdominal pain, dyspepsia (indigestion), nausea, vomiting, and diarrhea.[5] Taking the medication with meals can often mitigate this gastric discomfort.[34]
• Less Common Adverse Effects: Other reported adverse events include autonomic or neurological symptoms such as headache, dizziness, and general malaise.[13] Dermatological reactions like skin rash, pruritus (itching), and urticaria (hives) have also been observed.[13]
• Rare Adverse Effects: Severe adverse reactions are rare. There have been reports of cardiovascular effects such as tachycardia (irregular heartbeat) and documented cases of hemolytic anemia.[5] Exceptionally rare cases of angioedema (rapid swelling of the face, lips, and throat) have been reported, which constitutes a medical emergency.[37]
• Overdose: To date, no cases of diosmin overdose have been formally reported. An overdose is unlikely to be life-threatening but would be expected to result in an exacerbation of the common gastrointestinal side effects.[1]

7.2 Contraindications, Warnings, and Precautions

While no absolute contraindications have been officially established for diosmin, several important precautions and warnings must be observed.[46]

• Hypersensitivity: The drug should not be used in individuals with a known allergy to diosmin, hesperidin, or any other component of the formulation.[47]
• Bleeding Disorders: This is a critical precaution. Due to its potential effects on platelet aggregation, diosmin may worsen pre-existing bleeding disorders. It should be avoided or used with extreme caution and under medical supervision in these patients.[13]
• Pregnancy and Lactation: Although one study involving 50 pregnant women showed no apparent harm, comprehensive safety data are lacking.[49] Therefore, as a precautionary measure, the use of diosmin is generally not recommended during pregnancy or breastfeeding unless directed by a physician.[5]
• Pediatric Use: The safety and efficacy of diosmin have not been established in children, and its use in this population is not recommended.[5]
• Duration of Use: For self-treatment, particularly in the US where it is a supplement, use should not exceed 3 months without consulting a healthcare provider.[13]

7.3 Clinically Significant Drug and Herbal Interactions

Diosmin's classification as a "natural" supplement in some regions belies its significant pharmacological activity and potential for drug-drug interactions. This discrepancy creates a potential safety paradox, where patients and even some clinicians may underestimate its interaction risks. A patient taking a prescription anticoagulant, for example, might not think to report the use of an "herbal" supplement for leg veins, creating a dangerous communication gap. This risk is highlighted by a published case report of a patient on long-term warfarin and diosmin who presented with a spontaneous intraventricular hemorrhage, a severe brain bleed.[50] Clinicians must therefore treat diosmin with the same diligence regarding interaction screening as any prescription medication.

• Anticoagulants and Antiplatelet Agents: This is the most critical interaction. Diosmin can inhibit platelet aggregation. When co-administered with anticoagulants (e.g., warfarin) or antiplatelet drugs (e.g., clopidogrel, aspirin), it can potentiate their effects and significantly increase the risk of bruising and bleeding.[23]
• Cytochrome P450 (CYP) Enzyme Inhibition: Diosmin has been shown to inhibit several key drug-metabolizing enzymes in the liver. It is classified by the FDA as a weak inhibitor of CYP2C9 and has also been shown to inhibit CYP3A4 and CYP2E1.[23] This inhibition can decrease the metabolic clearance of other drugs that are substrates for these enzymes, leading to increased plasma concentrations and a higher risk of toxicity.
• P-glycoprotein (P-gp) Substrates: Diosmin may also inhibit P-glycoprotein, an efflux pump that removes drugs from cells. This can increase the absorption and bioavailability of P-gp substrate drugs, potentially increasing their effects and side effects.[23]
• Herbal Supplements: Concomitant use with other herbal supplements that possess blood-thinning properties (e.g., garlic, ginkgo, ginseng, ginger, turmeric) may have an additive effect and increase bleeding risk.[13]

Table 4: Clinically Significant Drug Interactions and Management Recommendations

Interacting Drug/Class	Mechanism of Interaction	Potential Clinical Outcome	Recommended Management	Source(s)
Anticoagulants (e.g., Warfarin)	Inhibition of platelet aggregation; potential additive anticoagulant effect.	Increased risk of serious bleeding, including spontaneous hemorrhage.	Use with extreme caution or avoid. If co-administration is necessary, monitor closely for signs of bleeding (bruising, hematuria). For warfarin, monitor INR frequently. Educate patient on bleeding risks.	46
Antiplatelet Drugs (e.g., Aspirin, Clopidogrel)	Inhibition of platelet aggregation.	Increased risk of bruising and bleeding.	Use with caution. Monitor for signs of bleeding. Consider alternative treatments if bleeding risk is significant.	23
CYP2C9 Substrates (e.g., Diclofenac, Ibuprofen, Celecoxib)	Weak inhibition of CYP2C9 metabolism.	Increased plasma concentrations and potential toxicity of the substrate drug.	Monitor for increased effects or adverse reactions of the substrate drug. Dose adjustment of the substrate may be necessary.	1
CYP3A4 Substrates (e.g., Carbamazepine, certain statins)	Inhibition of CYP3A4 metabolism.	Increased plasma concentrations and potential toxicity of the substrate drug (e.g., carbamazepine).	Use with caution. Monitor for signs of substrate drug toxicity. Consider therapeutic drug monitoring for drugs like carbamazepine. Dose adjustment may be required.	23
CYP2E1 Substrates (e.g., Chlorzoxazone, Acetaminophen)	Inhibition of CYP2E1 metabolism.	Increased plasma concentrations and potential toxicity of the substrate drug (e.g., chlorzoxazone).	Monitor for increased effects (e.g., sedation with chlorzoxazone) or toxicity (e.g., hepatotoxicity with acetaminophen, though clinical significance is less clear).	23
P-gp Substrates (e.g., Fexofenadine, Afatinib)	Inhibition of P-glycoprotein efflux pump.	Increased absorption and bioavailability of the substrate drug, leading to higher serum concentrations.	Monitor for increased side effects of the P-gp substrate. Dose reduction of the substrate may be needed.	1

8.0 Global Regulatory Landscape and Manufacturing

The way diosmin is regulated, manufactured, and made available to patients varies dramatically across the globe, with a significant divergence between the regulatory frameworks in Europe and the United States. This difference has profound implications for quality control, the generation of clinical evidence, and patient safety.

8.1 Regulatory Status in the United States (FDA) and Europe (EMA)

The regulatory handling of diosmin represents a tale of two continents.

• Europe: In many European countries, diosmin is regulated as a medicinal product, available either by prescription or over-the-counter (OTC).[5] For example, in Poland, it transitioned from a prescription-only drug to also being available OTC.[53] As a medicinal product, it is subject to the rigorous standards of the European Medicines Agency (EMA) and national health authorities. This requires manufacturers to provide extensive data on quality, safety, and efficacy to obtain marketing authorization. Products like Zeflavon have a publicly available Public Assessment Report detailing the scientific review that led to its approval.[41] This framework ensures that products meet pharmacopoeial standards for purity and content, and it mandates pharmacovigilance and the provision of a detailed Summary of Product Characteristics (SmPC) for healthcare professionals.
• United States: In stark contrast, diosmin is not approved by the Food and Drug Administration (FDA) as a prescription drug.[5] Instead, it is primarily regulated and sold as a dietary supplement.[5] Under the Dietary Supplement Health and Education Act (DSHEA), supplements are regulated more like food than drugs. Manufacturers are not required to prove safety or efficacy to the FDA before marketing their products. While the FDA acknowledged diosmin as a New Dietary Ingredient in 2000 [55], it also concluded in 2001 that there was inadequate evidence on which to base an expectation of safety, a position that has not been formally revised.[5] A specific formulation, diosmiplex, is available as a "medical food" for CVI.[5] Diosmin does hold an FDA Orphan Drug Designation for the treatment of systemic sclerosis, a rare disease, but it has not been approved for this indication.[56]

This regulatory divergence is the root of the "safety paradox." In Europe, a patient receives a standardized pharmaceutical product with a detailed information leaflet on dosing, side effects, and crucial drug interactions. In the US, a consumer can purchase a supplement with far less stringent quality control and without mandatory warnings about its potent pharmacological activities, such as its interaction with anticoagulants. This difference in regulatory oversight directly impacts the quality and consistency of the product the patient receives and the safety information they are provided.

8.2 Manufacturing Process: Synthesis from Hesperidin and Quality Standards

Diosmin is a naturally occurring flavonoid, but for commercial production, it is not typically isolated directly from plant sources in large quantities. The industrial manufacturing process is a semi-synthetic one that starts with another, more abundant flavonoid: hesperidin.[1] Hesperidin is readily extracted from the rinds of citrus fruits, especially oranges.[13]

The chemical conversion of hesperidin to diosmin involves the creation of a double bond between carbons 2 and 3 of the central pyran ring, as this is the key structural difference between the two molecules.[57] The process generally involves several steps:

1. Acylation: The hydroxyl groups on the hesperidin molecule are protected, often by acetylation using acetic anhydride.[57]
2. Halogenation/Oxidation: The protected hesperidin is then treated with a halogen (iodine or bromine) and an oxidant. This introduces the double bond through a halogenation-dehydrohalogenation mechanism.[57]
3. Deacylation: The protecting groups are removed to yield crude diosmin, which is then purified.[57]

Modern, patented manufacturing processes have focused on improving the efficiency and safety of this synthesis, particularly by developing methods that avoid the use of potentially toxic organic solvents like pyridine.[57]

The quality of the final Active Pharmaceutical Ingredient (API) is critical. In Europe, diosmin intended for medicinal products must comply with the standards set forth in the European Pharmacopoeia (Ph. Eur.).[41] These monographs define the required purity, set limits for specific impurities (such as process-related by-products), and outline the analytical methods for testing.[60] For dietary supplements in the US, while manufacturers are expected to follow Good Manufacturing Practices (GMPs), the specific purity and impurity standards are not as rigorously defined or enforced as they are under the European pharmaceutical framework.

9.0 Synthesis and Expert Analysis

Diosmin stands as a well-established and pharmacologically potent agent for the management of common vascular disorders. A comprehensive analysis of its chemistry, pharmacology, clinical efficacy, and regulatory status reveals a mature therapeutic agent whose modern understanding is shaped by several key considerations, including a nuanced mechanism of action, a critical debate on formulation, and a striking global regulatory dichotomy with significant safety implications.

Clinical Positioning:

The evidence base strongly supports the position of diosmin as a first-line or major adjunctive pharmacotherapy for the symptomatic management of Chronic Venous Insufficiency and both acute and chronic hemorrhoidal disease. Its multifaceted mechanism of action—enhancing venous tone, stabilizing capillaries, improving lymphatic flow, and potently suppressing the underlying inflammatory and angiogenic processes—provides a robust rationale for its efficacy. For CVI, it reliably improves key symptoms and quality of life. For hemorrhoids, it offers rapid relief in acute crises and valuable support in post-surgical care. Its role in other conditions, such as lymphedema, remains more speculative and requires further high-quality clinical evidence to be clearly defined.

The Formulation and Dosing Debate:

A central theme emerging from the most recent clinical evidence is the debate surrounding formulation and dosage. For decades, the market has been dominated by Micronized Purified Flavonoid Fraction (MPFF), a combination product containing 90% diosmin and 10% hesperidin, typically dosed at 1000 mg/day for CVI. However, direct, high-quality comparative efficacy trials have consistently concluded that 600 mg/day of pure, non-micronized diosmin is clinically non-inferior to 1000 mg/day of MPFF. This suggests that neither the addition of hesperidin nor the process of micronization provides a substantial, clinically detectable advantage for symptom relief in CVI, despite the pharmacokinetic benefits of the latter. This evidence challenges the higher recommendation grades given to MPFF in some international guidelines and suggests that pure diosmin at a lower daily dose is an equally valuable and potentially more cost-effective therapeutic option. A re-evaluation of these guidelines in light of this direct comparative evidence is warranted.

The Safety-Regulatory Nexus:

Perhaps the most critical issue for the practicing clinician is the profound impact of the global regulatory divide on patient safety. In Europe, diosmin is a medicine, subject to strict quality controls and accompanied by detailed, evidence-based information on its pharmacological properties, including its potential for serious drug interactions. In the United States, it is a dietary supplement, a classification that can foster a false sense of security and lead to a lack of appreciation for its potent pharmacological activity. The risk of interactions with anticoagulants and its role as an inhibitor of major drug-metabolizing enzymes are not theoretical; they are documented realities that demand the same level of clinical vigilance as any prescription medication. It is imperative that healthcare providers, particularly in jurisdictions where diosmin is sold as a supplement, actively screen for its use and educate patients about these risks to prevent potentially severe adverse events.

Future Research Directions:

Despite its long history of use, several key knowledge gaps remain, presenting opportunities for future research:

1. Molecular Target Elucidation: The precise upstream molecular target(s) of diosmin and its active metabolite, diosmetin, remain unconfirmed. Identifying these targets would provide a more complete understanding of its mechanism of action.
2. Role of the Gut Microbiome: Given that the activation of diosmin is entirely dependent on enzymes from the intestinal microflora, research is needed to investigate how the composition of the microbiome affects its pharmacokinetic variability and, ultimately, its clinical efficacy. This could pave the way for personalized therapy.
3. Disease-Modifying Potential: While diosmin's effects on inflammatory and angiogenic markers suggest it may alter the course of CVI, long-term, large-scale clinical trials are needed to definitively determine if it has true disease-modifying effects, such as preventing the progression from simple varicose veins to venous ulcers.
4. Clarification of Efficacy in Lymphedema: The current evidence for diosmin in lymphedema is conflicting. Well-designed, adequately powered, randomized controlled trials are necessary to clarify its efficacy, or lack thereof, in this challenging condition.

In conclusion, diosmin is a valuable therapeutic tool in the phlebologist's armamentarium. Its future is likely to be shaped by a deeper understanding of its molecular pharmacology, a re-evaluation of optimal formulation and dosing based on comparative evidence, and, critically, a greater global harmonization of regulatory standards to ensure its safe and effective use for all patients.

Works cited

1. Diosmin: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 9, 2025, https://go.drugbank.com/drugs/DB08995
2. Diosmin | C28H32O15 | CID 5281613 - PubChem, accessed September 9, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/5281613
3. Diosmin | CAS 520-27-4 | SCBT - Santa Cruz Biotechnology, accessed September 9, 2025, https://www.scbt.com/p/diosmin-520-27-4
4. Diosmin | C28H32O15 - ChemSpider, accessed September 9, 2025, https://www.chemspider.com/Chemical-Structure.4444932.html
5. Diosmin - Wikipedia, accessed September 9, 2025, https://en.wikipedia.org/wiki/Diosmin
6. Untitled - Regulations.gov, accessed September 9, 2025, https://downloads.regulations.gov/FDA-2005-S-0518-0116/attachment_63.pdf
7. Comparative Bioavailability of Two Diosmin Formulations after Oral ..., accessed September 9, 2025, https://www.mdpi.com/1420-3049/23/9/2174
8. Effect of Diosmin Administration in Patients with Chronic Venous ..., accessed September 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6767141/
9. en.wikipedia.org, accessed September 9, 2025, https://en.wikipedia.org/wiki/Diosmin#:~:text=Diosmin%20is%20included%20among%20a,chronic%20venous%20insufficiency%20or%20hemorrhoids.
10. What is Diosmin used for? - Patsnap Synapse, accessed September 9, 2025, https://synapse.patsnap.com/article/what-is-diosmin-used-for
11. Classification of Venoactive Drugs | Download Table - ResearchGate, accessed September 9, 2025, https://www.researchgate.net/figure/Classification-of-Venoactive-Drugs_tbl1_26670488
12. diosmin - ATCDDD - ATC/DDD Index, accessed September 9, 2025, https://atcddd.fhi.no/atc_ddd_index/?code=C05CA03
13. Diosmin: Benefits, Dosage, Side Effects, and More - Healthline, accessed September 9, 2025, https://www.healthline.com/nutrition/diosmin
14. What is the role of Daflon (Diosmin) in the treatment of chronic ..., accessed September 9, 2025, https://www.droracle.ai/articles/11926/role-of-daflon-in-venous-insufficiency
15. Daflon - Wikipedia, accessed September 9, 2025, https://en.wikipedia.org/wiki/Daflon
16. Detralex: uses & side-effects - PatientsLikeMe, accessed September 9, 2025, https://www.patientslikeme.com/treatment/detralex
17. Benefits of Diosmin and Hesperidin in venous insufficiency and ..., accessed September 9, 2025, https://www.physmedi.com/benefits-of-diosmin-and-hesperidin-in-venous-insufficiency-and-lymphedema/
18. Anti-Inflammatory Properties of the Citrus Flavonoid Diosmetin: An Updated Review of Experimental Models - MDPI, accessed September 9, 2025, https://www.mdpi.com/1420-3049/29/7/1521
19. DAFLON 500 mg, film-coated tablets, accessed September 9, 2025, https://myservier-me.com/wp-content/uploads/2022/09/SmPC_Daflon-500_Version-01.2019.pdf
20. Diosmin Completed Phase 4 Trials for Venous Insufficiency Treatment | DrugBank Online, accessed September 9, 2025, https://go.drugbank.com/drugs/DB08995/clinical_trials?conditions=DBCOND0029376&phase=4&purpose=treatment&status=completed
21. Phlebotonics for venous insufficiency - Martinez-Zapata, MJ - 2020 ..., accessed September 9, 2025, https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003229.pub4/references
22. (PDF) [Activity of purified diosmin in the treatment of hemorrhoids], accessed September 9, 2025, https://www.researchgate.net/publication/12186960_Activity_of_purified_diosmin_in_the_treatment_of_hemorrhoids
23. DIOSMIN: Overview, Uses, Side Effects, Precautions, Interactions ..., accessed September 9, 2025, https://www.webmd.com/vitamins/ai/ingredientmono-1030/diosmin
24. (PDF) Efficacy of Diosmin on Post- Hemorrhoidectomy Pain: A ..., accessed September 9, 2025, https://www.researchgate.net/publication/375120495_Efficacy_of_Diosmin_on_Post-_Hemorrhoidectomy_Pain_A_Systematic_Review_of_Clinical_Trials
25. Efficacy of Diosmin on Post-Hemorrhoidectomy Pain: A Systematic Review of Clinical Trials, accessed September 9, 2025, https://ejst.samipubco.com/article_169931.html
26. Common sense of diosmin administration in combined treatment of hemorrhoids, accessed September 9, 2025, https://www.researchgate.net/publication/327567923_Common_sense_of_diosmin_administration_in_combined_treatment_of_hemorrhoids
27. www.webmd.com, accessed September 9, 2025, https://www.webmd.com/vitamins/ai/ingredientmono-1030/diosmin#:~:text=Some%20research%20shows%20that%20taking,following%20surgery%20for%20breast%20cancer.
28. The efficacy of micronized flavonoid fraction (450 mg diosmin plus ..., accessed September 9, 2025, http://cmj.cumhuriyet.edu.tr/en/download/article-file/47820
29. Full article: Is There a Difference in the Clinical Efficacy of Diosmin ..., accessed September 9, 2025, https://www.tandfonline.com/doi/full/10.2147/VHRM.S324112
30. Is There a Difference in the Clinical Efficacy of Diosmin and Micronized Purified Flavonoid Fraction for the Treatment of Chronic Venous Disorders? Review of Available Evidence - ResearchGate, accessed September 9, 2025, https://www.researchgate.net/publication/354648407_Is_There_a_Difference_in_the_Clinical_Efficacy_of_Diosmin_and_Micronized_Purified_Flavonoid_Fraction_for_the_Treatment_of_Chronic_Venous_Disorders_Review_of_Available_Evidence
31. Is There a Difference in the Clinical Efficacy of Diosmin and Micronized Purified Flavonoid Fraction for the Treatment of Chronic Venous Disorders? Review of Available Evidence - PMC, accessed September 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8455100/
32. Comparative Efficacy and Safety of a Horse Chestnut Formulation vs ..., accessed September 9, 2025, https://www.scirp.org/journal/paperinformation?paperid=143525
33. Daflon 500mg: Uses, Dosage, and Side Effects - Vinmec, accessed September 9, 2025, https://www.vinmec.com/eng/blog/daflon-500mg-uses-dosage-and-side-effects-note-en
34. Drug Generic Name - Drug Information - Ministry of Health, accessed September 9, 2025, https://www.moh.gov.bh/HealthInfo/DrugDetail/91?lang=en
35. What is the recommended dosage of diosmin for treating ..., accessed September 9, 2025, https://www.droracle.ai/articles/171787/dosage-of-diosmin-for-hemorrhoids
36. 1 1. WHAT DAFLON 500 mg IS AND WHAT IT IS USED FOR 2. BEFORE YOU TAKE DAFLON 500 mg - Rwanda FDA, accessed September 9, 2025, https://rwandafda.gov.rw/wp-content/uploads/2024/01/DAFLON-500-mg-Film-coated-tablet-Micronised-purified-flavonoid-fraction-500mg-PIL.pdf
37. DIOSMIN HESPERIDIN - FDA Verification Portal, accessed September 9, 2025, https://verification.fda.gov.ph/files/DRP-12333_PI_01.pdf
38. diosmin hesperidin - diosmed - FDA Verification Portal, accessed September 9, 2025, https://verification.fda.gov.ph/files/DRP-8635_PIL_01.pdf
39. Medical product detail | ŠÚKL, accessed September 9, 2025, https://www.sukl.sk/hlavna-stranka-1/english-version/special-pages/medical-product-detail?page_id=842&lie_id=31176
40. Efficacy of a 6-month treatment with Detralex* in patients with venous edema (Efficacy of Detralex* in, accessed September 9, 2025, https://clinicaltrials.servier.com/wp-content/uploads/IC4-05682-099_abstract.pdf
41. Annex 1 Table of content of the PAR for MRP- and DCP- products, accessed September 9, 2025, https://ogyei.gov.hu/kiseroirat/ph/PAR-Zeflavon.pdf
42. SAFETY, EFFICACY & METABOLISM - diosmin, accessed September 9, 2025, http://www.diosmine.com/study/id/4.html
43. What are the side effects of Diosmin? - Patsnap Synapse, accessed September 9, 2025, https://synapse.patsnap.com/article/what-are-the-side-effects-of-diosmin
44. The Uses, Side Effects and Precautions of Diosmin - Yashoda Hospitals, accessed September 9, 2025, https://www.yashodahospitals.com/medicine-faqs/diosmin/
45. Diosmin Uses, Benefits & Dosage - Drugs.com, accessed September 9, 2025, https://www.drugs.com/npp/diosmin.html
46. What are the interactions and contraindications of Diosmin?, accessed September 9, 2025, https://droracle.ai/articles/230495/what-are-the-interactions-and-contraindications-of-diosmin
47. Diosmin and Hesperidin: Indications, Side Effects, Warnings - Drugs.com, accessed September 9, 2025, https://www.drugs.com/cdi/diosmin-and-hesperidin.html
48. Diosmin: Uses, Side Effects and Medicines | Apollo Pharmacy, accessed September 9, 2025, https://www.apollopharmacy.in/salt/Diosmin
49. Citrus bioflavonoids as dietary supplements | EBSCO Research ..., accessed September 9, 2025, https://www.ebsco.com/research-starters/nutrition-and-dietetics/citrus-bioflavonoids-dietary-supplements
50. Spontaneous intraventricular hemorrhage associated with prolonged diosmin therapy, accessed September 9, 2025, https://pubmed.ncbi.nlm.nih.gov/21400007/
51. For Healthcare Professionals | FDA's Examples of Drugs that Interact ..., accessed September 9, 2025, https://www.fda.gov/drugs/drug-interactions-labeling/healthcare-professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems
52. FDA-Approved Diosmin API Manufacturers & Suppliers, accessed September 9, 2025, https://pharmaoffer.com/api-excipient-supplier/phlebotonics/diosmin/fda
53. Safety of treatment and dietary supplementation with diosmin in ..., accessed September 9, 2025, https://www.czytelniamedyczna.pl/5596,safety-of-treatment-and-dietary-supplementation-with-diosmin-in-daily-doses-up-t.html
54. Safety of treatment and dietary Supplementation with dioSmin in daily doSeS up to 2000 mg a day - Semantic Scholar, accessed September 9, 2025, https://pdfs.semanticscholar.org/0b64/6ac6e2dcfd578101ad2c753b198859be25c4.pdf
55. Submitted 75-Day Premarket Notifications for New Dietary Ingredients - FDA, accessed September 9, 2025, https://www.fda.gov/media/160660/download
56. Search Orphan Drug Designations and Approvals - accessdata.fda ..., accessed September 9, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=582417
57. EP3053930A1 - Process for the preparation of diosmin - Google ..., accessed September 9, 2025, https://patents.google.com/patent/EP3053930A1/en
58. DIOSMIN MANUFACTURING, accessed September 9, 2025, http://www.diosmine.com/pro_detail/id/3.html
59. Top European Diosmin API GMP Manufacturers (2025) - Pharmaoffer.com, accessed September 9, 2025, https://pharmaoffer.com/api-excipient-supplier/phlebotonics/diosmin/europe
60. Comparative Assessment of Quality Requirements for Medicinal ..., accessed September 9, 2025, https://www.vedomostincesmp.ru/jour/article/view/420?locale=en_US