CircuVein by Flora

POSSIBLY EFFECTIVE

• Chronic venous insufficiency (CVI). Oral diosmin, as part of a micronized purified flavonoid fraction, seems to be beneficial for reducing symptoms of CVI. It is unclear if oral diosmin alone is beneficial. Details: Most clinical research shows that taking 2-3 tablets daily of a specific combination product (Daflon 500, Les Laboratoires Servier) containing micronized purified flavonoid fraction (MPFF), providing diosmin 450 mg and other flavonoids, such as hesperidin, 50 mg per tablet, for 2-6 months modestly improves symptoms of chronic venous diseases such as varicose veins and CVI, including leg pain, heaviness, swelling, and cramps, when compared with baseline or placebo (50892,54755,54799,98597,98609). Additionally, a large clinical study in patients with CVI shows that results are similar when a chewable form of this product taken 1000 mg daily (Daflon 1000, Les Laboratoires Servier) is compared with 500 mg tablets taken twice daily (112796). An observational study in adults with advanced CVI suggests that taking MPFF 1000 mg, consisting of 90% micronized diosmin and 10% other flavonoids, daily for 6 months in addition to conservative treatment, mainly compression therapy, is associated with improved symptoms (e.g., varicose veins, venous edema, pain) and reduced subcutaneous adipose tissue thickness when compared to baseline (112795). The validity of these findings is limited by a lack of a comparator group. In patients with mild to moderate pelvic venous disorder due to valvular incompetence, two preliminary clinical trials show that this same combination product is beneficial for reducing pain and other symptoms (105287,108150). In one study, taking 1000 mg daily for 2 months modestly improves quality of life and reduces most symptoms, including pain, tenderness, edema, heaviness, and discomfort, when compared with placebo (108150). Other preliminary clinical research shows that dosing based on severity as either 1000 mg daily for 2 months or 1000 mg twice daily for one month and then 1000 mg once daily for an additional month, reduces pelvic pain by a moderate and large amount, respectively, when compared to baseline. The average time to pain relief was 13.7 or 3.1 days, respectively, for each dosing group. Pelvic venous congestion was reduced more in the higher dose group as calculated following transvaginal and transabdominal duplex ultrasound scanning (DUS) and single-photon emission computed tomography (SPECT) of the pelvic veins (105287). Micronized diosmin in combination with other flavonoids has also been compared with non-micronized diosmin alone. Although taking non-micronized diosmin 900 mg daily modestly improved clinical symptoms when compared with baseline in early research, taking 1000 mg of micronized purified flavonoid fraction daily for 2 months was more effective (54935,54950). However, more recent preliminary clinical research in a well-defined patient population with pre-CVI symptoms shows that taking one tablet of a specific non-micronized diosmin (Flebodia, Laboratoire Innotech International) 600 mg daily for 6 months is as effective for reducing leg pain, fatigue, swelling, or tension as taking 1000 mg daily of micronized purified flavonoid fraction providing diosmin plus other flavonoids (Daflon, Laboratórios Servier do Brasil Ltda.) (105293). Also, in a mixed population with pre-CVI and CVI, clinical research shows that taking a specific diosmin (as µsmin Plus, Giellepi S.p.A.) 450 mg once daily for 8 weeks reduces edema by approximately 4% when compared with placebo. Additionally, 98% of patients taking this diosmin product experienced symptom relief, compared with only 29% of those taking placebo (105294). The discrepancy in these findings may be related to the different products used or the severity of disease in the included patient populations.
• Hemorrhoids. Oral diosmin, as part of a micronized purified flavonoid fraction or in combination with other compounds, seems to be beneficial for hemorrhoids. Details: A meta-analysis of the available research, as well as individual clinical trials, show that taking three tablets of a specific combination product (Daflon 500, Les Laboratoires Servier), containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet, twice daily for 4-5 days followed by two tablets of this same product twice daily for up to 3 months, improves signs and symptoms of internal hemorrhoids. The combination appears to stop acute bleeding in up to 92% of patients after 4 days of treatment. It may also reduce symptoms such as anal discomfort, pain, discharge, and local lesions within 2 days of treatment. The combination also seems to reduce the duration and intensity of hemorrhoidal flare-ups (4861,4900,8077,54970,105282) and improve recovery after hemorrhoidopexy or hemorrhoidectomy (54793,105284). Maintenance treatment with one tablet of this product twice daily for 2-3 months following acute treatment for hemorrhoids decreases the relapse rate and improves symptoms, including pain, itching, tenesmus, mucous discharge, redness, swelling, and bleeding (4861,54954). Diosmin has also been evaluated in combination with hesperidin and troxerutin. Clinical research in adults with acute hemorrhoidal crisis shows that taking a combination product (Triade H, Omikron Italia Srl) providing these ingredients in tapered doses over 43 days reduces progressive pain in approximately 88% of patients, bleeding in 64% of patients, and anal itching in 56% of patients. These changes are significant when compared with placebo (93885). This product was given as one sachet of powdered diosmin 300 mg, troxerutin 300 mg, hesperidin 300 mg, and vitamin C 12 mg mixed in water orally three times daily for 3 days, then two sachets daily for 2 days, then one sachet daily for seven days, followed by one tablet containing diosmin 300 mg, troxerutin 300 mg, and hesperidin 100 mg daily for one month. Diosmin has also been evaluated in combination with bulk laxatives. Diosmin 600 mg three times daily for 4 days, then 300 mg twice daily for 10 more days in conjunction with psyllium 11 grams daily, seems to modestly improve symptoms after 4 days of treatment (4898). However, this combination does not seem to be as effective as the use of micronized purified flavonoid fraction.
• Venous leg ulcers. Oral diosmin, as part of a micronized purified flavonoid fraction, seems to be beneficial for venous leg ulcers. Details: Clinical research in adults with venous leg ulcers up to 10 cm in size shows that taking two tablets daily of a specific combination product (Daflon 500, Les Laboratoires Servier), containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet for 2 months in conjunction with compression dressing more than doubles the number of patients with complete healing of ulcers when compared with placebo. Also, the time to healing was reduced. However, in one study there was no effect on the ulcer surface area, symptoms, or healing of ulcers greater than 10 cm in size (10229,54972,54984).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Back pain. It is unclear if oral diosmin is beneficial for back pain. Details: Preliminary clinical research in patients with radicular low back pain shows that taking diosmin (Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd) moderately improves subjective pain scores after 8 weeks and reduces the use of rescue analgesics after 24 months similarly to intravenous dexamethasone every 3 days with monthly administration of mannitol. Diosmin was administered at doses of 900 mg orally three times daily for 2 weeks, then 900 mg twice daily for 2 weeks, then 450 mg twice daily for one month (95043).
• Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS). It is unclear if oral diosmin, as part of a micronized purified flavonoid fraction, is beneficial for CPPS. Details: Preliminary clinical research shows that taking one tablet daily of a specific combination product containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet (Daflon) for 8 weeks in combination with standard treatment involving antibiotics and anti-inflammatory drugs improves overall symptoms of CPPS at 6 months similarly to taking alfuzosin, an alpha-blocker, along with standard treatment for 12 weeks. However, there was no benefit when the diosmin product was used alone, without standard treatment. At 12 months, symptoms were modestly more improved in those taking alfuzosin (105297).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral diosmin, as part of a micronized purified flavonoid fraction, is beneficial for patients undergoing CABG surgery. Details: In patients about to undergo CABG for impaired left ventricular function, clinical research shows that a specific combination product containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet (Daflon 500, Les Laboratoires Servier), taken as 3000 mg daily for 4 days, followed by 1000 mg daily for 3 days preoperatively, does not reduce the postoperative length of stay in the intensive care unit or hospital, inotropic medication requirements, or left ventricular ejection fraction when compared with placebo. However, levels of troponin I and lactate were lower, and patient status based on the New York Heart Association (NYHA) classification was modestly improved (105285).
• Diabetes. It is unclear if oral diosmin, as part of a micronized purified flavonoid fraction or in combination with other compounds, is beneficial for diabetes. Details: Preliminary clinical research in females with type 2 diabetes shows that taking one tablet of a specific combination product containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet (Daflon 500, Les Laboratoires Servier) twice daily for 45 days modestly decreases glycated hemoglobin (HbA1c) and serum glucose when compared to baseline (54977). However, a prospective observational study in patients with type 1 or type 2 diabetes has found that taking a specific product (Flebotrofine, AMNOL Chimica Biologica) containing diosmin for 3 months is not associated with improvements in HbA1c, cholesterol, or triglyceride levels when compared with baseline. Other ingredients in this product included L-arginine, troxerutin, hesperidin, black currant extract, and gotu kola extract (108151). The validity of these findings is limited by the lack of a comparator group.
• Diabetic neuropathy. It is unclear if oral diosmin is beneficial for diabetic neuropathy. Details: A small clinical study in adults with type 2 diabetes, peripheral neuropathy, and metabolic syndrome on oral antidiabetic therapy shows that taking diosmin 1 gram daily (Dioven, Amryia Pharmaceutical Co.) for 12 weeks, with or without hesperidin 1 gram daily, improves diabetic neuropathy as measured by the Michigan Neuropathy Screening Instrument (MNSI) when compared with standard care alone. In addition, the improvements in measures of diabetic neuropathy were greater when diosmin and hesperidin are taken together compared with either supplement alone, suggesting a synergistic effect (112797). However, the validity of this study is limited by inadequate blinding.
• Lymphedema. It is unclear if oral diosmin, as part of a micronized purified flavonoid fraction or in combination with other compounds, is beneficial for lymphedema. Details: Clinical research shows that taking two tablets of a specific combination product (Daflon 500, Les Laboratoires Servier) containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet daily for 6 months may improve drainage of lymph from the arms after breast cancer surgery, but does not reduce arm swelling or other clinical signs of lymphedema, when compared with placebo (10227). A small clinical study in patients with severe breast cancer-related lymphedema shows that taking a specific combination product (Linfaden, OMEGA PHARMA Srl) containing diosmin 200 mg, coumarin 30.6 mg, and arbutin 3.7 mg twice daily for 2 weeks and then once daily for 4 weeks, in addition to complex congestive therapy (CDT), reduces upper limb excess volume by 521 mL, compared with a 256 mL reduction in the CDT-only group (101646). It is unclear if the effects are due to diosmin, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral diosmin is beneficial for metabolic syndrome. Details: A small clinical study in adults with metabolic syndrome, type 2 diabetes, and peripheral neuropathy on oral antidiabetic therapy shows that taking diosmin 1 gram daily (Dioven, Amryia Pharmaceutical Co.) for 12 weeks, with or without hesperidin 1 gram daily, reduces body mass index, fasting blood glucose, triglycerides, and low-density lipoprotein cholesterol but does not change systolic blood pressure, diastolic blood pressure, or high-density lipoprotein cholesterol when compared with standard care alone. These effects are enhanced when diosmin is taken in combination with hesperidin compared with either supplement taken alone or control (112797). However, the validity of this study is limited by inadequate blinding.
• Minor bleeding. It is unclear if oral diosmin, as part of a micronized purified flavonoid fraction, is beneficial for minor bleeding. Details: Preliminary clinical research in patients with idiopathic epistaxis shows that taking a specific combination product containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg (Daflon, Servier) daily for 1-3 months modestly reduces emergency room visits and need for cauterization due to failure of light nasal packing when compared with no treatment (101644). The validity of this study is limited by the lack of blinding.
• Ovarian hyperstimulation syndrome. It is unclear if oral diosmin is beneficial for reducing the occurrence of ovarian hyperstimulation syndrome. Details: Observational research in patients at high risk of ovarian hyperstimulation syndrome (OHSS) following a previous cancellation of embryo transfer has found that taking diosmin 1000 mg twice daily for 10 days after oocyte retrieval is associated with a 6.2% incidence of moderate to severe OHSS, compared to 13.4% in the patients that had not received diosmin. Also, there were no cases of severe OHSS (105295). This study is limited by its retrospective, observational design.
• Varicose veins. It is unclear if oral diosmin, as part of a micronized purified flavonoid fraction, is beneficial for varicose veins. Details: In patients with mild varicose veins such as spider veins or reticular veins, some observational research has evaluated the use of a specific combination product (Detralex; Servier France) containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet, taken as one tablet twice daily for 6 weeks, starting 2 weeks before sclerotherapy. This research has found that taking this product is associated with decreased leg heaviness, pain, swelling sensation, night cramps, and itching after sclerotherapy when compared with patients not using this treatment. It is also associated with a reduction in pain and swelling sensation from before sclerotherapy when compared with those not using this treatment. Additionally, the use of this product is associated with a slight reduction in hyperpigmentation following sclerotherapy, although there were no benefits on other sclerotherapy-related adverse effects, including phlebitis and necrosis (105283). In patients with varicose veins of greater severity, observational research has found that taking this same product 1000 mg daily for 30 days, starting on the day of mechanochemical ablation with mini-phlebectomy or foam sclerotherapy, is associated with a modest reduction in the severity of varicose veins, such as swelling, heaviness, and itching, after 30 days, but not after 7 or 14 days, when compared with no treatment (105286). For more information on the use of diosmin for chronic venous insufficiency (CVI), which can occur concomitantly with varicose veins, refer to the CVI discussion.
• Venous thromboembolism (VTE). It is unclear if oral diosmin is beneficial for prevention of VTE. Details: In patients experiencing their first femoropopliteal deep vein thrombosis (DVT), preliminary clinical research shows that taking diosmin 600 mg daily for 12 months, in addition to rivaroxaban and elastic compression stockings, reduces the frequency of post-thrombotic syndrome to 9%, compared to 49% in those not taking diosmin. There were also fewer patients with chronic venous disease or DVT recurrence at 12 months (105296). More evidence is needed to rate diosmin for these uses.

(Read more about DIOSMIN)

POSSIBLY INEFFECTIVE

• Hypercholesterolemia. Oral hesperidin does not seem to reduce cholesterol levels. Details: Clinical studies and a meta-analysis of the available clinical research show that taking hesperidin 400-800 mg daily for 4-12 weeks does not affect total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels when compared with placebo in healthy and obese individuals with or without mild hypercholesterolemia (94539,102315). However, some preliminary clinical research shows that taking glucosyl hesperidin, a soluble hesperidin derivative, 500 mg daily for 24 weeks modestly lowers serum levels of triglycerides and LDL cholesterol when compared with baseline in patients with both hypercholesterolemia and hypertriglyceridemia, but not in those without hypertriglyceridemia (54800). The validity of this finding is limited by the lack of a comparator group.
• Obesity. Oral hesperidin does not seem to be beneficial for weight loss. Details: A meta-analysis of two clinical trials shows that taking hesperidin for 6-12 weeks does not affect body weight or body mass index (BMI) when compared with placebo, although it may modestly improve waist circumference (105280,105281). The studies included in this analysis were short-term and were not designed to evaluate weight as a primary endpoint. Other clinical research conducted in Japan shows that taking glucosyl hesperidin, a soluble hesperidin derivative, 470 mg orally daily for 12 weeks does not reduce body weight, total fat area, or subcutaneous fat area when compared to baseline in modestly overweight patients (94544). Hesperidin has also been evaluated in combination with green tea extract. One clinical study in overweight individuals shows that taking a combination of glucosyl hesperidin 178 mg and green tea extract, providing epigallocatechin gallate (EGCG) 146 mg, daily for 12 weeks modestly attenuates an increase in weight and BMI when compared with placebo. Sub-group analyses suggest that the greatest effects occurred in individuals less than 50 years of age (108152). It is unclear if these effects are due to hesperidin, green tea extract, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. It is unclear if oral hesperidin is beneficial for improving athletic performance. Details: Small clinical studies in healthy male cyclists show that taking a specific form of hesperidin (Cardiose, HealthTech BioActives) has some benefit on athletic performance. One study shows that taking this form of hesperidin 500 mg once, five hours prior to exercise, improves average power, maximum speed, and total energy when compared with placebo. However, it does not improve peak power, time to peak power, or total oxygen consumption (102312). Taking this form of hesperidin 500 mg daily for 8 weeks modestly improves the highest average power output that can be maintained for one hour and the maximal power during an incremental test when compared with placebo. However, there was no effect on the aerobic or anaerobic ventilatory thresholds, oxygen use, or the times to peak power or maximum speed when compared with placebo (105277).
• Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS). Although there is interest in using oral hesperidin for CP/CPPS, there is insufficient reliable information about the clinical effects of hesperidin for this condition. There is research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin. See Diosmin for more information.
• Chronic venous insufficiency (CVI). Oral hesperidin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a specific combination product containing hesperidin methyl chalcone 150 mg, butcher's broom root extract 150 mg, and ascorbic acid 100 mg (Cyclo 3 Fort) usually for 1-3 months may decrease pain, heaviness, cramps, and paresthesia in patients with CVI (37483). There is also research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin, for CVI. See Diosmin for more information.
• Cognitive function. Although there is interest in using oral hesperidin for improving cognitive function, there is insufficient reliable information about the clinical effects of hesperidin for this condition.
• Coronary artery bypass graft (CABG) surgery. Although there is interest in using oral hesperidin for patients undergoing CABG surgery, there is insufficient reliable information about the clinical effects of hesperidin for this purpose. There is research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin. See Diosmin for more information.
• Coronavirus disease 2019 (COVID-2019). It is unclear if oral hesperidin is beneficial for COVID-19. Details: A large clinical study in unvaccinated outpatients with symptomatic COVID-19 shows that taking hesperidin 1000 mg at bedtime for 14 days after symptom onset does not reduce the proportion of subjects with the most common symptoms (e.g., fever, cough, shortness of breath, and anosmia), number of symptoms after 14 days, or duration of individual symptoms when compared with placebo (112800). However, the study was limited by significant attrition.
• Diabetes. It is unclear if oral hesperidin is beneficial for diabetes. Details: Clinical research in adults with diabetes shows that taking hesperidin (Swanson Health Products) 500 mg once daily for 6 weeks reduces systolic blood pressure and the mean arterial blood pressure by about 3% and 2.5%, respectively, when compared with placebo. Although this improvement is statistically significant, it is unlikely to be considered clinically significant. Also, hesperidin does not modify levels of fasting blood glucose or measures of insulin resistance (98697,105292). A prospective observational study in patients with type 1 or type 2 diabetes has found that taking a specific product (Flebotrofine, AMNOL Chimica Biologica) containing hesperidin for 3 months is not associated with improvements in HbA1c, cholesterol, or triglyceride levels when compared with baseline. Other ingredients in this product included L-arginine, troxerutin, diosmin, black currant extract, and gotu kola extract (108151). There is also research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin, for diabetes. See Diosmin for more information.
• Diabetic neuropathy. It is unclear if oral hesperidin is beneficial for diabetic neuropathy. Details: A small clinical study in adults with type 2 diabetes, peripheral neuropathy, and metabolic syndrome on oral antidiabetic therapy shows that taking hesperidin 1 gram daily improves diabetic neuropathy as measured by the Michigan Neuropathy Screening Instrument (MNSI) and a physical exam performed by a neurologist when compared with antidiabetic therapy alone. The improvements in measures of diabetic neuropathy were greater when hesperidin was taken with diosmin 1 gram daily compared with either supplement alone or antidiabetic therapy alone, suggesting a synergistic effect (112797).
• Diabetic retinopathy. Although there is interest in using oral hesperidin for diabetic retinopathy, there is insufficient reliable information about the clinical effects of hesperidin for this condition.
• Exercise-induced muscle soreness. It is unclear if oral hesperidin is beneficial for preventing muscle soreness due to exercise. Details: A very small clinical study in sedentary young adults shows that taking hesperidin methyl chalcone 500 mg daily for 3 days prior to intense exercise improves physical performance and postural balance and relieves impaired strength and muscle soreness upon palpation but does not relieve muscle soreness during active movement when compared with placebo (112801).
• Hemorrhoids. Oral hesperidin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with acute hemorrhoidal crisis shows that taking a specific supplement (Triade H, Omikron Italia Srl) containing hesperidin, diosmin, and troxerutin daily for 43 days results in significantly less pain, bleeding, anal itching, and medication use when compared with placebo (93885). This product was given as one sachet of powdered diosmin 300 mg, troxerutin 300 mg, hesperidin 300 mg, and vitamin C 12 mg mixed in water orally three times daily for 3 days, then two sachets daily for 2 days, then one sachet daily for seven days, followed by one tablet containing hesperidin 100 mg, diosmin 300 mg, and troxerutin 300 mg daily for one month (93885). There is also research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin, for hemorrhoids. See Diosmin for more information.
• Hypertension. It is unclear if oral hesperidin is beneficial for hypertension. Details: Preliminary clinical research in overweight males with or without hypertension shows that taking hesperidin 136 mg or drinking 250 mL of orange juice containing hesperidin 136 mg twice daily for 4 weeks lowers diastolic, but not systolic, blood pressure by around 5 mmHg when compared with placebo (94543). However, a meta-analysis of the available clinical research shows that taking hesperidin supplements 400-800 mg daily for 4-12 weeks does not reduce systolic or diastolic blood pressure when compared with placebo in healthy and obese individuals with or without hypertension (102315). Due to the mixed populations evaluated in this research, the effect of hesperidin in patients with diagnosed hypertension is unclear.
• Hypertriglyceridemia. It is unclear if oral hesperidin is beneficial for hypertriglyceridemia. Details: Preliminary clinical research in patients with hypercholesterolemia shows that taking glucosyl hesperidin, a soluble hesperidin derivative, 500 mg daily for 6 weeks modestly lowers triglyceride levels when compared with baseline in patients who also have hypertriglyceridemia, but not in those without hypertriglyceridemia. However, glucosyl hesperidin did not lower cholesterol levels; a lower dose of 100 mg daily had no effect on either outcome (105290). Clinical research in a similar population shows that taking glucosyl hesperidin 500 mg daily for 24 weeks reduces triglyceride levels by up to 34% from baseline and modestly reduces levels of low-density lipoprotein cholesterol (54800). The validity of the findings in these studies is limited by the lack of a comparator group.
• Lymphedema. Oral hesperidin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in females with lymphedema due to breast cancer surgery shows that taking three capsules of a specific combination product (Cyclo 3 Fort), which contains hesperidin methyl chalcone 150 mg, butcher's broom root extract 150 mg, and ascorbic acid 100 mg per capsule, three times daily orally for 90 days reduces swelling in the upper arm and forearm and improves mobility and heaviness when compared with placebo (37494). There is also research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin, for lymphedema. See Diosmin for more information.
• Metabolic syndrome. It is unclear if oral hesperidin is beneficial for metabolic syndrome. Details: A small clinical study in adults with metabolic syndrome shows that taking hesperidin (Shaanxi Yuantai Biological Technology Co., Ltd) 500 mg twice daily for 12 weeks increases the number of patients who no longer have defined metabolic syndrome by almost two-fold when compared with placebo. There were also modest reductions in fasting blood glucose, triglycerides, and systolic blood pressure, as well as the total number of patients with abdominal obesity, elevated blood pressure, and elevated fasting blood sugar. However, there were no differences in levels of high-density lipoprotein (HDL) cholesterol, diastolic blood pressure, or waist circumference (105288). In another preliminary clinical study using the same product, there were modest reductions in systolic blood pressure and triglyceride levels when compared with no treatment. However, there were no effects on other measures of metabolic syndrome or the overall number of patients with defined metabolic syndrome. This study also shows that when hesperidin is taken in combination with flaxseed 15 grams twice daily, serum concentrations of triglycerides and glucose, as well as systolic blood pressure, were modestly improved when compared with control. The prevalence of individuals with defined metabolic syndrome at the end of treatment was reduced by approximately 77%, which was significant when compared with the control group (105276). Another small clinical study in adults with metabolic syndrome, type 2 diabetes, and peripheral neuropathy on oral antidiabetic therapy shows that taking hesperidin 1 gram daily reduces body mass index, fasting blood glucose, triglycerides, and low-density lipoprotein cholesterol but not systolic blood pressure, diastolic blood pressure, or HDL cholesterol when compared with control. These effects are enhanced when hesperidin is combined with diosmin 1 gram daily (112797).
• Minor bleeding. Although there is interest in using oral hesperidin for minor bleeding, there is insufficient reliable information about the clinical effects of hesperidin for this purpose. There is research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin. See Diosmin for more information.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral hesperidin is beneficial for NAFLD; the available evidence is conflicting. Details: A small clinical trial in adults with NAFLD shows that taking hesperidin 1 gram daily for 12 weeks along with lifestyle modification improves hepatic steatosis as measured by transient elastography when compared with placebo and lifestyle modification. Taking hesperidin also modestly improves total cholesterol, triglyceride, alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) levels. However, there were no effects on liver fibrosis or levels of aspartate aminotransferase (AST), fasting blood glucose, insulin, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol (102313). Other preliminary clinical research using the same treatment protocol shows that although there were modest reductions in ALT, there was no effect on liver steatosis, liver fibrosis, or other metabolic measures. When used in combination with flaxseed 30 grams daily, levels of fasting blood glucose and a measure of insulin resistance were modestly improved (105275). These studies may have been too small to detect differences in most endpoints.
• Rheumatoid arthritis (RA). It is unclear if oral hesperidin is beneficial for RA. Details: A small clinical study shows that drinking a 100 mL beverage containing alpha-glucosyl hesperidin 3 grams daily orally for 12 weeks might improve symptoms of RA when compared with placebo (54850).
• Varicose veins. Although there is interest in using oral hesperidin for varicose veins, there is insufficient reliable information about the clinical effects of hesperidin for this condition. There is research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin, for this purpose. See Diosmin for more information.
• Venous leg ulcers. Although there is interest in using oral hesperidin for venous leg ulcers, there is insufficient reliable information about the clinical effects of hesperidin for this condition. There is research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin, for this purpose. See Diosmin for more information. More evidence is needed to rate hesperidin for these uses.

(Read more about HESPERIDIN)

LIKELY SAFE ...when used orally in amounts found in foods.

POSSIBLY SAFE ...when supplements are used orally and appropriately, short-term. Diosmin seems to be safe when used alone or in combination with other flavonoids in doses of up to 1350 mg daily for up to 6 months (4861,4898,10227,10229,93885,105283,105286,105287,105293,105294)(105296,108150).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods.

PREGNANCY AND LACTATION: POSSIBLY SAFE
when used orally in doses of up to 900 mg daily for 30 days in combination with other flavonoids, such as hesperidin. Some evidence suggests that taking this combination may be associated with placental insufficiency when used during the third trimester of pregnancy; however, the combination does not seem to induce fetal abnormalities, retard fetal growth, increase the risk of intrauterine death, or affect birth weight. Also, when breastfeeding, this combination does not seem to affect infant growth or feeding (54970).

(Read more about DIOSMIN)

LIKELY SAFE ...when used orally in amounts found in foods.

POSSIBLY SAFE ...when supplements are used orally and appropriately, short-term. Doses of up to 3 grams daily have been used with apparent safety for up to 3 months (37494,54850,94544,105275,105276).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods.

PREGNANCY AND LACTATION: POSSIBLY SAFE
when used orally in doses of up to 100 mg daily for 30 days in combination with diosmin. Some evidence suggests that taking this combination may be associated with placental insufficiency when used during the third trimester of pregnancy; however, the combination does not seem to induce fetal abnormalities, retard fetal growth, increase the risk of intrauterine death, or affect birth weight. Also, when breastfeeding, this combination does not seem to affect infant growth or feeding (54970).

(Read more about HESPERIDIN)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, diosmin may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details A case of spontaneous intraventricular hemorrhage has been reported for a 77-year-old female after 6 weeks of warfarin therapy, despite an international normalized ratio (INR) of only 1.8. The patient had also been taking aspirin and diosmin for several years. Experts speculate that chronic intake of diosmin predisposed the patient to spontaneous intraventricular hemorrhage by inducing chronic microcirculatory hypertension and inhibiting platelet aggregation. The presence of aspirin was also thought to play a role in this event (93886).

CARBAMAZEPINE (Tegretol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, diosmin might reduce the effects of carbamazepine and increase the risk for convulsions.  Details A pharmacokinetic study in humans shows that taking diosmin (Venex) 500 mg daily for 10 days prior to oral administration of carbamazepine 200 mg increases blood levels of carbamazepine by approximately 58% and decreases carbamazepine clearance by 42%. It also decreases the formation of carbamazepine's active metabolite. It is speculated that diosmin reduces the metabolism of carbamazepine by inhibiting cytochrome P450 3A4 (CYP3A4) (95041).

CHLORZOXAZONE (Parafon Forte, Paraflex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, diosmin might increase the levels and clinical effects of chlorzoxazone.  Details A pharmacokinetic study in humans shows that taking diosmin (Venex 500) 500 mg daily for 9 days prior to oral administration of chlorzoxazone 250 mg increases blood levels of chlorzoxazone by 53% and decreases chlorzoxazone clearance by 40%. It is speculated that diosmin reduces the metabolism of chlorzoxazone by inhibiting cytochrome P450 2E1 (CYP2E1) (93889).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, diosmin might inhibit the metabolism of CYP2C9 substrates.  Details Diclofenac is metabolized by CYP2C9 enzymes. Clinical and laboratory research shows that diosmin inhibits the metabolism of diclofenac (93888,98596). A pharmacokinetic study in humans shows that taking diosmin (Venex 500) 500 mg daily for 9 days prior to oral administration of diclofenac 100 mg increases blood levels of diclofenac and decreases diclofenac clearance (93888).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, diosmin might inhibit the metabolism of CYP2E1 substrates.  Details Chlorzoxazone is metabolized by CYP2E1 enzymes. A pharmacokinetic study in humans shows that taking diosmin (Venex 500) 500 mg daily for 9 days prior to oral administration of chlorzoxazone (Paraflex 250) 250 mg increases blood levels of chlorzoxazone by 34% and decreases chlorzoxazone clearance by 40%. It is speculated that diosmin reduces the metabolism of chlorzoxazone by inhibiting CYP2E1 (93889).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, diosmin might inhibit the metabolism of CYP3A4 substrates.  Details Laboratory research is conflicting with respect to the effects of diosmin on CYP3A4. Some research suggests that diosmin does not affect CYP3A4 activity (95040). However, other research suggests that diosmin alters the metabolism of carbamazepine, a CYP3A4 substrate. Laboratory and animal research show that oral administration of diosmin for 7 days prior to oral administration of carbamazepine increases plasma concentrations of carbamazepine, decreases the clearance of carbamazepine, and decreases the formation of carbamazepine's active metabolite (95039). Additionally, pharmacokinetic research in healthy male subjects shows that taking diosmin (Venex) 500 mg daily for 10 days prior to oral administration of carbamazepine 200 mg increases blood levels of carbamazepine by approximately 58% and decreases carbamazepine clearance by 42% (95041). It is speculated that diosmin reduces the metabolism of carbamazepine by inhibiting CYP3A4 (95039,95041). Diosmetin, a metabolite of diosmin, may also inhibit CYP3A4 (95041).

DICLOFENAC (Voltaren, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, diosmin might increase the levels and clinical effects of diclofenac.  Details Clinical and laboratory research shows that diosmin inhibits the metabolism of diclofenac (93888,98596). A pharmacokinetic study in humans shows that taking diosmin (Venex 500) 500 mg daily for 9 days prior to oral administration of diclofenac 100 mg increases blood levels of diclofenac and decreases diclofenac clearance. It is speculated that diosmin reduces the metabolism of diclofenac by inhibiting cytochrome P450 2C9 (CYP2C9) (93888).

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, diosmin might increase the levels and clinical effects of fexofenadine.  Details A pharmacokinetic study in humans shows that taking diosmin (Venex) 500 mg daily for 10 days prior to oral administration of fexofenadine 120 mg increases blood levels of fexofenadine by approximately 49% and decreases the apparent oral clearance of fexofenadine by 41%. The time taken to reach maximum plasma concentration, the half-life, and the apparent renal clearance of fexofenadine are not affected. For this reason, it is speculated that diosmin alters the pharmacokinetics of fexofenadine via inhibition of P-glycoprotein in the intestine, but not in the kidney or liver (95042).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, diosmin might increase levels of drugs that are substrates of P-glycoprotein (P-gp).  Details Preliminary laboratory research suggests that diosmin inhibits P-gp (93890). Additionally, pharmacokinetic research in healthy male subjects shows that taking diosmin (Venex) 500 mg daily for 10 days prior to oral administration of fexofenadine 120 mg increases blood levels of fexofenadine, a P-gp substrate, by approximately 49% and decreases the apparent oral clearance of fexofenadine by 41%. The time taken to reach maximum plasma concentration, the half-life, and the apparent renal clearance of fexofenadine are not affected. For this reason, it is speculated that diosmin inhibits P-gp in the intestine, but not in the kidney or liver (95042).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hesperidin may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Animal research suggests that hesperetin, a bioflavonoid aglycone derivative of hesperidin, may have antiplatelet activity (54822).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking hesperidin with antihypertensive drugs might increase the risk of hypotension.  Details Some clinical and animal research shows that hesperidin can decrease blood pressure (54851,94543,98697,105278). However, other clinical research shows that hesperidin does not affect blood pressure (102315).

CELIPROLOL (Celicard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hesperidin may decrease the levels and clinical effects of celiprolol.  Details Animal research shows that concomitant use of hesperidin may reduce the plasma area under the curve of celiprolol by up to 75% (91760). This effect has not been reported in humans.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use with CNS depressants may cause additive sedative effects.  Details Animal studies show that hesperidin has sedative effects, due to opioid receptor activity (54841) and can increase sedation when used with diazepam (54789). This effect has not been reported in humans.

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hesperidin may increase the levels and clinical effects of diltiazem.  Details Animal research suggests that hesperidin may enhance the bioavailability of diltiazem, increasing the plasma area under the curve of diltiazem by up to 65.3% (91761). This effect has not been reported in humans.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, hesperidin might inhibit P-glycoprotein-mediated drug efflux and potentially increase levels of drugs that are substrates of P-glycoprotein.  Details In vitro research shows that hesperidin can inhibit P-glycoprotein efflux (54908). This effect has not been reported in humans.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hesperidin might increase the levels and clinical effects of verapamil.  Details Animal research suggests that hesperidin may enhance the bioavailability of verapamil, increasing the plasma area under the curve of verapamil by 96.8% (91762). This effect has not been reported in humans

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General ...Orally, diosmin is generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, dizziness, gastritis, nausea, skin inflammation, and skin redness.
Serious Adverse Effects (Rare):
Orally: Cardiac arrhythmias and hemolytic anemia.

Cardiovascular ...Orally, diosmin can cause cardiac arrhythmias (93887,105293).

Dermatologic ...Orally, diosmin can cause skin redness, hives, itchiness, and inflammation (93887).

Gastrointestinal ...Orally, diosmin can cause gastrointestinal side effects, including abdominal pain, diarrhea, nausea, flatulence, and gastritis (4861,4898,4900,10229,54935,54970,93887,105287,105293,105296)(112796). In one case, exacerbation of chronic colopathy was reported after taking a specific diosmin-containing product (Daflon 500, Les Laboratoires Servier) (10229).

Hematologic ...Orally, diosmin can cause hemolytic anemia (93887).

Musculoskeletal ...Orally, one case report of muscle pain was thought to be related to diosmin use (93887).

Neurologic/CNS ...Orally, diosmin can cause headache, low energy, and dizziness in some patients (4861,4898,4900,10229,93887,105293,112796).

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General ...Orally, hesperidin is generally well tolerated.

Dermatologic ...A case of recurrent allergic dermatitis was reported in a 70-year-old female with no known allergies who applied topical hesperidin methyl chalchone (94538).

Immunologic ...A case of recurrent allergic dermatitis was reported in a 70-year-old female with no known allergies who applied topical hesperidin methyl chalchone (94538).

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