Best Vein Support featuring DiosVein by Doctor's Best

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.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Asthma. It is unclear if dietary citrus fruits are beneficial in patients with asthma. Details: There is some evidence that consumption of vitamin C-rich citrus fruits, including sweet orange and others, might improve lung function in people with asthma. However, this is controversial. Some studies show that intake of citrus fruits 1-2 times per week produces significant benefit (6049,6055,6056), while other studies have not found this benefit (6057,6058).
• Common cold. It is unclear if drinking sweet orange juice prevents the common cold. Details: Preliminary clinical research in healthy individuals ages 17 to 25 years suggests that drinking sweet orange juice 180 mL daily for 72 days might decrease the risk of developing common cold-related symptoms (15328).
• Depression. It is unclear if drinking sweet orange juice or using sweet orange essential oil as aromatherapy is beneficial for depression. Details: Preliminary clinical research in adults with depression shows that drinking flavonoid-rich sweet orange juice 190 mL three times daily for 8 weeks modestly improves depression scores when compared to baseline, but not when compared with a low-flavonoid orange drink (110045). Sweet orange has also been studied as part of a combination aromatherapy. A very small clinical study in community-dwelling older adults shows that massage therapy to the upper body with sweet orange, lavender, and bergamot oils twice weekly for 8 weeks improves symptoms of depression in 65% of patients when compared with no intervention. Twice weekly inhalation of the same essential oils via nebulizer, without massage, also improves symptoms of depression in 55% of patients when compared with no intervention (98474).
• Hypercholesterolemia. It is unclear if drinking sweet orange juice improves blood lipid levels. Details: A very small clinical study in hypercholesterolemic patients shows that drinking large amounts of sweet orange juice (750 mL daily for four weeks) seems to increase high-density lipoprotein (HDL) cholesterol by 21% and reduce the ratio of low-density lipoprotein (LDL) to HDL cholesterol by 16% when compared to baseline. This effect was not seen with 250-500 mL of sweet orange juice. Because consumption of this large amount of juice daily provides approximately 20% of the daily energy requirement, this regimen may not be practical (3340).
• Insomnia. Sweet orange essential oil as aromatherapy has only been evaluated in combination with other essential oils; its effect when used alone is unclear. Details: Preliminary clinical research in adults undergoing hemodialysis shows that inhaling aromatherapy with sweet orange and lavender oil nightly before bed for one month improves overall sleep quality by 72% and fatigue by about 78% when compared with no treatment (98508).
• Kidney failure. It is unclear if sweet orange oil massage can improve fatigue or symptoms of restless leg syndrome (RLS) in adults receiving hemodialysis. Details: A small clinical study shows that receiving an 18-minute foot massage with sweet orange oil 1.5% for 3 weeks during hemodialysis sessions modestly improves sleep quality and symptoms of RLS when compared with routine care. However, it does not seem to be more effective than using lavender oil (109859).
• Kidney stones (nephrolithiasis). It is unclear if drinking sweet orange juice is beneficial for preventing kidney stones. Details: Consuming 400 mL of sweet orange juice three times a day, providing a total of 100 mEq of citrate daily, increases urinary pH and urinary citrate levels (15171). Theoretically, this might reduce kidney stone formation in patients with calcium nephrolithiasis. However, this outcome has not been evaluated in clinical research.
• Obesity. It is unclear if drinking sweet orange juice or taking oral sweet orange extract improves weight loss or other metabolic parameters in adults with overweight or obesity. Most studies suggest that any effects are unlikely to be considered clinically relevant. Details: Some preliminary clinical research in adults with overweight or obesity shows that taking a specific sweet orange extract (Morosil, Bionap S.R.L.) 400 mg orally once daily for six months reduces waist circumference, body weight, fat mass, and body mass index (BMI) by 2% to 5% when compared with placebo (110046). However, other preliminary clinical research in this population shows that drinking red sweet orange juice 750 mL daily for 8 weeks does not reduce body weight or BMI when compared with baseline (92309). A meta-analysis of clinical research in adults, most of whom were overweight or obese at baseline, shows that drinking 250-750 mL of various types of sweet orange juice daily for 2-12 weeks does not reduce body weight, BMI, waist circumference, or body fat percentage (BFP) when compared with control groups, which included either no supplementation, pomegranate juice, or exercise (107853). The validity of this meta-analysis is limited due to the population heterogeneity and variety of orange juice formulations and controls utilized. Some clinical studies have also evaluated sweet orange juice for improving cardiovascular risk factors in overweight and obese adults. Although some research has shown benefit, not all research agrees (110046,110047). A meta-analysis of randomized clinical trials in adults with overweight or obesity shows that drinking sweet orange juice 250-600 mL daily for 2-13 weeks modestly increases high-density lipoprotein cholesterol levels and decrease average systolic blood pressure by 1 mmHg when compared with control. However, drinking sweet orange juice does not affect other blood lipid levels, blood glucose levels, or markers of insulin resistance (110048). The validity of this study is limited by high heterogeneity and a small sample size. In addition, these improvements are unlikely to be considered clinically relevant. Sweet orange extract has also been studied in combination with other ingredients. Some clinical research in overweight adults shows that taking a specific combination product (Sinetrol, Fytexia) 450-700 mg twice daily containing sweet orange, blood orange, and grapefruit extracts for 12 weeks reduces body weight, BFP, and BMI when compared with placebo or baseline (95517,95518). It is unclear if these effects are due to sweet orange, other ingredients, or the combination.
• Pre-procedural anxiety. It is unclear if inhaling sweet orange essential oil as aromatherapy reduces anxiety before surgeries or invasive procedures. Details: A small, low-quality study suggests that inhaling the scent from 3 drops of sweet orange essential oil applied to a cotton ball for 5 minutes modesty reduces anxiety and pain scores in patients undergoing needle insertion for hemodialysis when compared with performing a breathing exercise for 3 minutes (105455).
• Prostate cancer. It is unclear if drinking sweet orange juice reduces prostate cancer risk. Details: Observational research has found that increasing dietary intake of sweet orange or sweet orange juice is not associated with a reduced risk of developing prostate cancer (15172).
• Stress. It is unclear if inhaling sweet orange essential oil as aromatherapy is beneficial for stress. Details: Preliminary clinical research shows that using up to 10 drops of sweet orange essential oil as aromatherapy helps prevent some anxiety and tension associated with stressful tasks when compared with control (90505). More evidence is needed to rate sweet orange for these uses.

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EFFECTIVE

• Hemorrhagic disease. Oral or intramuscular vitamin K1 is effective for preventing hemorrhagic disease in newborns. Details: Vitamin K1 (phytonadione) administered orally or intramuscularly can prevent classic hemorrhagic disease of newborns (15,85367,85484). A single intramuscular administration of vitamin K1 1 mg is considered to be the most effective method, while oral administration of three doses of vitamin K1 1-2 mg over 8 weeks is considered to be an acceptable alternative (85506). The effects of vitamin K on late hemorrhagic disease of newborns is less clear (85367,85484). In the Netherlands, an oral dose of 25 mcg daily for 3 months was used until 2011, when it was increased to 150 mcg daily. A reduction of late intracranial vitamin K deficiency bleeding in the general pediatric population, from 1.6 per 100,000 to 1.3 per 100,000, was associated with this dose increase (102351).
• Hypoprothrombinemia. Oral or parenteral vitamin K1 is effective for treating and preventing hypoprothrombinemia. Details: Vitamin K1 (phytonadione) 2.5-25 mg, used orally or parenterally, can prevent and treat hypoprothrombinemia caused by vitamin K deficiency or induced by salicylates, sulfonamides, quinine, quinidine, or broad-spectrum antibiotic therapy (15).
• Vitamin K-dependent clotting factors deficiency (VKCFD). Oral and intravenous vitamin K1 is the primary treatment for VKCFD. Details: Oral supplementation with vitamin K 10 mg two to three times weekly seems to prevent major hemorrhages and reduce mucocutaneous bleeding in individuals with VKCFD. Also, intravenous vitamin K may improve the prothrombin time-international normalized ratio (PT-INR) values in these patients. While vitamin K supplementation is the primary treatment method for VKCFD, the response to treatment varies significantly (85481).
• Warfarin anticoagulation. Oral and intravenous vitamin K1 reverse warfarin-related excessive anticoagulation. Evidence for the use of oral vitamin K1 in patients with an unstable INR is conflicting. Details: Taking vitamin K1 (phytonadione) orally or parenterally, but not subcutaneously, can counteract excessive warfarin anticoagulation and restore therapeutic international normalized ratio (INR) levels. Usually a single dose of 1-5 mg is used (85406,85425,85429). Vitamin K might also be effective for stabilizing warfarin anticoagulation in patients with low intake of vitamin K. Patients with a low dietary vitamin K intake are significantly more likely to have an unstable INR than those who ingest higher amounts of vitamin K (16803). It is thought that vitamin K-depleted patients become more sensitive when vitamin K is ingested, even in small quantities, resulting in erratic or unstable INR (16804). One small clinical study and one small retrospective chart review show that taking oral vitamin K1 (phytonadione) 100-150 mcg daily improves INR stability in patients taking warfarin who previously had an unstable INR (16805,16806). However, a larger clinical study found no significant differences in INR stability in patients taking vitamin K 100 mcg daily when compared with placebo (16807). Also, some research suggests that, although taking vitamin K 1250 mcg daily may reduce INR in patients with excessive warfarin anticoagulation more significantly than placebo, there may not be a significant difference in the risk of bleeding complications (23380). It is important to keep in mind that, if a patient is stabilized on warfarin therapy plus vitamin K supplementation, discontinuing vitamin K can significantly increase the INR within 2-3 weeks after discontinuation (17714). The most recent guidelines by the American College of Chest Physicians do not recommend routine use of vitamin K supplementation for patients on warfarin therapy with unstable INR (94926). However, the previous guidelines recommended vitamin K 100-200 mcg daily for these patients. Therefore, some providers still use vitamin K for this purpose (16808).

POSSIBLY EFFECTIVE

• Osteoporosis. Oral vitamin K might reduce the risk of fractures and bone loss in patients with osteoporosis. However, it may not be beneficial in patients at risk for developing osteoporosis. Details: Although observational and clinical research on dietary and supplemental vitamin K for osteoporosis has been conflicting (14364,85392,85445,102354), overall, vitamin K supplementation seems to slightly reduce fracture risk (102354). A meta-analysis combining data from 36 heterogeneous studies in osteoporotic or postmenopausal patients shows that taking different regimens of either vitamin K1 or vitamin K2 is associated with a small reduction in clinical fractures (from 3.1% to 2.2%), but not with changes in vertebral fractures or BMD when compared with control (102354). This analysis is limited by the high variability in study designs and a lack of subgroup analyses stratifying different patient populations and forms of vitamin K. An older meta-analysis of 19 clinical studies in osteoporotic or postmenopausal patients shows that taking vitamin K2 (menaquinone) 45 mg, primarily used in the MK-4 form, daily does not reduce the risk of fractures when compared with control, although there was a non-significant trend towards a reduction (91451). A sensitivity analysis that excluded the largest negative study of over 4000 postmenopausal Japanese females with mild osteoporosis (85456), showed that vitamin K2 45 mg daily reduces the risk of fractures by 53% and improves lumbar and vertebral BMD in patients with osteoporosis when compared with control (91451). This effect was not seen in patients without osteoporosis (91451). Vitamin K2 also does not seem to benefit patients with osteopenia. A recent clinical trial in postmenopausal patients with osteopenia shows that taking a larger dose of vitamin K2 (375 mcg, MK-7) with calcium 800 mg and vitamin D 1500 IU daily for 3 years does not seem to affect BMD, bone turnover, or bone microarchitecture when compared with placebo (105035). Vitamin K1 (phytonadione) has also been evaluated, with mixed findings. One clinical study in postmenopausal patients with osteopenia shows that taking vitamin K1 5 mg daily with calcium 1500 and vitamin D 800 IU for up to 4 years reduces clinical fractures, but does not reduce clinical fragility fractures or improve BMD, when compared with placebo and vitamin D with calcium (85453). In healthy, non-osteoporotic patients ages 60-80 years, one clinical study shows that taking vitamin K1 500 mcg daily with calcium 600 mg and vitamin D 400 IU for 3 years does not affect BMD, despite increased plasma vitamin K levels and reduced undercarboxylated osteocalcin concentrations, when compared with taking calcium and vitamin D alone (16404). The same null effect on BMD and a reduced undercarboxylated osteocalcin was shown in a small clinical study in patients with Crohn disease without osteoporosis, taking vitamin K1 1-2 mg in combination with vitamin D3 400 IU and calcium 500 mg daily for 12 months (91454).

POSSIBLY INEFFECTIVE

• Intraventricular hemorrhage. Oral vitamin K does not reduce the risk of periventricular hemorrhage in preterm infants. Details: A meta-analysis of results from clinical research shows that administering vitamin K to pregnant patients at risk for very preterm birth does not reduce the overall risk of periventricular hemorrhage in preterm infants, perinatal mortality, or the associated neurological injury by the age of 7 years when compared to control. A subgroup analysis shows that vitamin K might reduce the risk of severe periventricular hemorrhage by 42% in preterm infants. However, when trials with inadequate blinding were excluded, this result was not statistically significant (85469).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. It is unclear if oral vitamin K2 improves athletic performance. Details: A small clinical study shows that taking vitamin K2 (menaquinone) 320 mcg orally daily for 4 weeks followed by 160 mg daily for 4 weeks, increases maximal cardiac output by 12% when compared with placebo in trained athletes performing standardized cycle ergometer exercise tests (95937).
• Beta-thalassemia. Oral vitamin K2 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking the menaquinone-7 (MK-7) form of vitamin K2 50 mcg daily plus vitamin D3 (calcitriol) 5 mcg daily for 12 months modestly improves bone mineral density (BMD) at the lumbar spine when compared to baseline in children with beta-thalassemia aged 3-18 years (91456). It is not clear if this improvement can be attributed to vitamin K, vitamin D3, or the combination.
• Breast cancer. It is unclear if dietary intake of vitamin K2 reduces the risk of breast cancer. Details: Population research has found that higher dietary intake of vitamin K2 (menaquinone) or vitamin K1 (phytonadione) is not associated with a reduced risk of premenopausal or postmenopausal breast cancer (85474).
• Cancer. It is unclear if dietary intake of vitamin K reduces the risk of cancer or cancer-related mortality. Details: One large population study involving healthy German patients has found that consuming more than 42-46 mcg of vitamin K2 (menaquinone) daily is associated with a 27% reduced risk of cancer mortality, but not cancer incidence, when compared with consuming less than 23-26 mcg daily. Dietary intake of vitamin K1 (phytonadione) was not associated with the risk of cancer or cancer mortality (85474). Another population study involving Mediterranean patients at high risk for cardiovascular disease has found that consuming about 630 mcg of vitamin K1 daily is associated with a 46% lower risk of cancer mortality when compared with consuming about 171 mcg of vitamin K1 daily. However, higher dietary intake of vitamin K2, 87 mcg daily, was not associated with a lower risk of cancer mortality when compared to those with lower dietary intake (79 mcg daily) (91452). Reasons for these discrepancies may relate to the definitions for high and low intake, the use of different databases to calculate vitamin K intake, and the different populations studied.
• Cardiovascular disease (CVD). It is unclear if dietary or supplemental vitamin K reduces the risk of CVD events; the available research is conflicting. Details: Most population research, including a meta-analysis of 21 observational cohort studies, has found that dietary intake of vitamin K1 (phytonadione) or vitamin K2 (menaquinone) is not associated with reduced risk for most cardiovascular events, such as CVD mortality, nonfatal MI, or stroke, although there might be a slightly reduced risk for CHD (85414,85482,91452,102353,103922). However, some population studies have found benefit. Observational research in a Danish cohort aged 50-65 years with no history of atherosclerotic cardiovascular disease at baseline shows that those in the highest quintile of dietary vitamin K1 intake have a 21% lower risk of CVD-related hospitalization and complications, such as ischemic heart disease, ischemic stroke, or peripheral artery disease, over 17-22 years when compared with the lowest quintile of intake. This inverse association tapers off at intakes above 100 mcg daily. For vitamin K2 intake, the highest quintile has a 14% lower risk of hospitalization when compared with the lowest quintile, although the association is U-shaped, indicating an increased risk at high doses. The researchers theorize that this may be due to the fact that vitamin K2-rich foods include cheese, eggs, and butter (109910,109920). There is also interest in using vitamin K to slow aortic valve calcification (AVC) and coronary artery calcification (CAC), which are CVD risk factors. In healthy patients ages 60-80 years with pre-existing CAC, taking a multivitamin with vitamin K1 (phytonadione) 500 mcg orally daily for 3 years reduces CAC progression by 6% when compared with the multivitamin alone (85461). However, research in patients with AVC has found no benefit. One small clinical study in patients on hemodialysis shows that taking the menaquinone-7 form of vitamin K2, 200 mcg orally daily for 1 year, does not affect the rate of AVC progression when compared with placebo (102352). Also, clinical research in males with significant AVC shows that taking the menaquinone-7 form of vitamin K2 720 mcg and vitamin D 25 mcg orally daily for 2 years does not reduce the rate of AVC progression or the rate of cardiovascular events, heart valve surgery, or all-cause mortality when compared with placebo (109916).
• Cataracts. It is unclear if dietary vitamin K reduces the risk of cataracts in older adults. Details: A secondary analysis of results from clinical research has found that higher dietary vitamin K1 (phytonadione) intake over a mean 5.6 years' follow-up is associated with a lower risk of cataracts and a lower incidence of cataract surgery in older adults at high risk for cardiovascular disease. The hazard ratio for developing cataracts was 0.71 and the hazard ratio for cataract surgery was 0.75 for people in the highest tertile of dietary vitamin K1 intake when compared with the lowest tertile (95936).
• Cognitive impairment. It is unclear if dietary vitamin K alters the rate of decline in adults with cognitive impairment. Details: Clinical research in adults aged 55-75 years with overweight or obesity, metabolic syndrome, and cognitive impairment shows that the largest increases in dietary vitamin K intake over a 2-year period are linked to a slower rate of cognitive decline when compared with the lowest increases in intake. This is demonstrated by higher scores on the mini-mental state examination (MMSE) and verbal fluency tests, and a greater number of patients maintaining an MMSE score of at least 24 (109919).
• Colorectal cancer. It is unclear if dietary intake of vitamin K2 reduces the risk of colorectal cancer. Details: Population research has found that higher dietary intake of vitamin K2 (menaquinone) or vitamin K1 (phytonadione) is not associated with a reduced risk of colorectal cancer (85474).
• Cystic fibrosis. It is unclear if oral vitamin K improves coagulopathy in patients with cystic fibrosis. Details: Suboptimal vitamin K status is common in patients with cystic fibrosis, especially those with pancreatic insufficiency, due to problems with fat digestion (85359,85479). Preliminary clinical research in patients with cystic fibrosis shows that taking vitamin K 1-5 mg orally for one month might decrease osteocalcin levels when compared with baseline, which suggests a lower risk of bone fractures (103920). Also, a small clinical trial in adults and children with cystic fibrosis and pancreatic insufficiency shows that taking a supplement containing fat-soluble vitamins A, D, E, and K for an average of 8.6 months reduces the number of patients with abnormal levels of protein induced by vitamin K absence (PIVKA-II), a defective form of prothrombin (85374).
• Depression. It is unclear if dietary intake of vitamin K reduces depression. Details: Population research has found that a dietary intake of vitamin K greater than 232 mcg daily is associated with reduced odds of depressive symptoms when compared with intakes of less than 83 mcg daily in older adults who are not taking vitamin D supplements. For every 100 mcg increase in vitamin K intake per day, the study found an 18% reduction in odds of depressive symptoms. However, there was no association identified in individuals taking vitamin D (100181). The effect of vitamin K for the prevention or treatment of clinical depression has not been investigated.
• Diabetes. It is unclear if oral vitamin K1 improves glycemic control in patients with diabetes. Details: A small clinical study in patients with diabetes who are taking oral antidiabetes medications shows that taking vitamin K2 (MK-7) 180 mcg twice daily for 12 weeks seems to reduce glycated hemoglobin by 1.6%, compared with a slight increase in the placebo group (105034). This study is limited due to high dropout rate in the placebo group.
• EGFR inhibitor-induced acneiform rash. It is unclear if topical vitamin K is beneficial for the treatment or prevention of acneiform rash caused by EGFR inhibitors. Details: Preliminary clinical research in adults receiving treatment with cetuximab, an EGFR inhibitor, shows that applying vitamin K1 (phytonadione) 0.1% cream (Vigorskin, Merck Serono SpA) twice daily to the face and trunk for 12 weeks may modestly reduce the percentage of patients who develop a moderate to severe acneiform rash (91455). The validity of this finding is limited by the lack of a control group. In patients with an existing rash after receiving the EGFR inhibitors cetuximab and panitumumab, a small clinical study shows that applying vitamin K1 (phytonadione) 1% ointment twice daily for 8 weeks to half of the affected area does not reduce the number of acneiform eruptions when compared with using placebo ointment on the other half of the affected area (103919). Patients in this study were allowed to use concomitant antibiotics and moisturizing agents, which may have confounded the results.
• Kidney failure. It is unclear if oral vitamin K2 reduces the incidence or severity of muscle cramps in adults with kidney failure. Details: Preliminary clinical research in patients on maintenance hemodialysis for at least 3 months with treatment-resistant muscle cramps shows that taking the menaquinone form of vitamin K2 360 mcg orally daily for 8 weeks reduces the frequency, severity, and duration of muscle cramps when compared with placebo (109917).
• Kidney transplant. It is unclear if vitamin K is beneficial for reducing cardiovascular risk in kidney transplant recipients. Details: Preliminary clinical research in adults with a stable kidney transplant for at least 1 year shows that taking vitamin K (menadiol diphosphate) 5 mg orally three times weekly for 1 year does not reduce aortic stiffness or coronary artery calcification, which are markers of cardiovascular disease, when compared with placebo (109913). The effects of long-term supplementation are unclear.
• Liver cancer. Small clinical studies suggests that vitamin K2 reduces mortality and the risk for hepatocellular carcinoma recurrence. Details: Meta-analyses of 9-11 small clinical trials in patients with resectable hepatocellular carcinoma show that adding vitamin K2 45 mg daily for up to 3 years seems to reduce cancer recurrence by 9.5% and reduce the risk of mortality by 7% when compared with control. Meta-analyses of 3-4 small clinical trials in patients with non-resectable carcinoma show that taking vitamin K2 45 mg for up to 2 years seems to reduce cancer recurrence by 3% and reduce mortality by 16% when compared with control (105032). Most of the included studies were conducted in Japan, so it is unclear if these results are generalizable to other geographic locations.
• Liver disease. It is unclear if dietary intake of vitamin K reduces the risk of liver disease. Details: A small observational study in patients with chronic liver failure due to cholestatic liver disease has found that receiving intramuscular vitamin K1 10 mg daily for an average of 16 days is associated with a lower risk of death when compared with control (103926).
• Lung cancer. It is unclear if dietary intake of vitamin K reduces the risk of lung cancer. Details: Population research has found that consuming greater than 42-46 mcg of vitamin K2 (menaquinone) daily is associated with a 62% lower risk of lung cancer occurrence and a 59% lower risk of lung cancer mortality when compared to those who consume less than 23-26 mcg of vitamin K2 daily. Dietary intake of vitamin K1 (phytonadione) is not associated with a reduced risk of lung cancer or lung cancer mortality (85474).
• Multiple sclerosis (MS). It is unclear if topical vitamin K reduces cutaneous adverse effects of MS treatment. Details: In patients with relapsing-remitting MS, burning and pain can accompany subcutaneous interferon treatment. Preliminary clinical research shows that topical application of vitamin K cream (dose not specified) for 8 weeks reduces burning by approximately 8% and pain by 9% when compared with no prophylactic treatment. Redness of the skin is also reduced with vitamin K (91453).
• Overall mortality. It is unclear if dietary intake of vitamin K reduces overall mortality. Details: Observational research in healthy older adults has found that serum vitamin K levels 0.5 nmol/L or less, which corresponds to consuming about 50% of the recommended vitamin K adequate intake, is associated with a 19% higher risk of overall mortality when compared with higher serum levels of vitamin K (103922). In a Danish cohort of adults with a median age of 56 years at baseline, the comparative risk for all-cause mortality between the highest and lowest quintiles of K1 intake over a period of 17-23 years was 0.76. The risk for cardiovascular mortality was 0.72, and the risk of cancer-related mortality in smokers or former smokers, specifically, was 0.8. However, the correlation tapered off above a daily intake of 100 mcg (109911).
• Pancreatic cancer. It is unclear if dietary intake of vitamin K reduces the risk of pancreatic cancer. Details: Observational research in over 100,000 Americans aged 55-74 years at baseline has found no association between dietary vitamin K2 intake and pancreatic cancer incidence over an average follow-up of 9 years. However, the hazard ratio for development of pancreatic cancer was 0.57 for the highest quintile of dietary vitamin K1 intake when compared with the lowest quintile (109912).
• Polycystic ovary syndrome (PCOS). It is unclear if vitamin K improves PCOS symptoms. Details: Small clinical study in patients with PCOS show that taking vitamin K2 (menaquinone-7) 90 mcg daily for 8 weeks does not reduce fasting blood glucose, acne, hirsutism, or weight, although it improves depression and seems to reduce fasting insulin, when compared with placebo (105036,109918).
• Prostate cancer. It is unclear if dietary intake of vitamin K reduces the risk of prostate cancer. Details: Population research has found that higher dietary intake of vitamin K2 (menaquinone), but not vitamin K1 (phytonadione), is associated with a reduced risk of prostate cancer, particularly advanced prostate cancer (85443,85474).
• Rheumatoid arthritis (RA). It is unclear if oral vitamin K improves RA symptoms. Details: One small clinical study in patients with RA shows that adding the MK-7 form of vitamin K2 (menaquinone) 100 mcg daily to treatment with conventional antirheumatic agents for 3 months improves disease activity and inflammatory markers when compared with antirheumatic agents alone. When compared to the control group, vitamin K2 reduced disease activity scores by 41% (91449). However, another small clinical study in patients with mild to moderate RA shows that taking vitamin K1 (phytonadione) 10 mg daily for 8 weeks with conventional antirheumatic agents does not improve disease activity or inflammatory markers when compared with placebo (100182). These contrasting outcomes may be related to the type of vitamin K used, the duration of treatment, and the severity of the illness.
• Rosacea. Although there is interest in using topical vitamin K1 for rosacea, there is insufficient reliable information about the clinical effects of vitamin K for this condition.
• Stroke. It is unclear if dietary intake of vitamin K1 reduces the risk of stroke. Details: Population research has found that higher dietary intake of vitamin K1 is not associated with a reduced risk of stroke (85482).
• Wound healing. Although there is interest in using topical vitamin K1 for wound healing, there is insufficient reliable information about the clinical effects of vitamin K for this condition. More evidence is needed to rate vitamin K for these uses.

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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).

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LIKELY SAFE ...when sweet orange juice or fruit is used orally in amounts commonly found in foods (1310,3340,15171,92309).

POSSIBLY SAFE ...when the essential oil of sweet orange is inhaled as aromatherapy, short-term (35735,58060,90505,105455). There is insufficient reliable information available about the safety of sweet orange peel when used orally.

CHILDREN: LIKELY SAFE
when sweet orange juice or fruit is used orally in amounts commonly found in foods.

CHILDREN: POSSIBLY UNSAFE
when the sweet orange peel is used orally in excessive amounts. There have been reports of intestinal colic, convulsions, and death in children given large amounts of sweet orange peel (11).

PREGNANCY AND LACTATION: LIKELY SAFE
when sweet orange juice or fruit is used orally in amounts commonly found in foods (1310,3340).

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LIKELY SAFE ...when vitamin K1 (phytonadione) or vitamin K2 (menaquinone) is used orally and appropriately. Vitamin K1 up to 10 mg daily and vitamin K2 up to 45 mg daily have been safely used in clinical trials lasting up to 2 years. A tolerable upper intake level for vitamin K in adults has not been set (54,55,58,6799,7135,14364). ...when vitamin K1 (phytonadione) is used parenterally and appropriately. Vitamin K1 (phytonadione) in oral and injectable form is an FDA-approved drug (7135).

POSSIBLY SAFE ...when vitamin K1 (phytonadione) 0. 1% is used topically in a cream or ointment for up to 12 weeks (91455,103919).

CHILDREN: LIKELY SAFE
when vitamin K1 (phytonadione) is used orally or parenterally and appropriately. Vitamin K1 (phytonadione) in oral and injectable form is FDA approved for use in children. A tolerable upper intake level for vitamin K in children has not been set (7135).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the daily adequate intake level (AI). A tolerable upper intake level for vitamin K in pregnancy and lactation has not been set (7135).

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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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CELIPROLOL (Celicard) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Consuming sweet orange with celiprolol can decrease oral absorption of celiprolol.  Details A pharmacokinetic study in healthy volunteers shows that celiprolol levels, after a single dose of 100 mg, are decreased by up to 90% in people who drink sweet orange juice 200 mL three times daily. It's not known if lower consumption of sweet orange juice will have the same effect. Theoretically, this occurs due to short-term inhibition of organic anion transporting polypeptide (OATP) (12115,17603,17604). Recommend separating drug administration and consumption of sweet orange by at least 4 hours (17603,17604).

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Consuming sweet orange juice with fexofenadine can decrease oral absorption of fexofenadine.  Details Clinical research shows that coadministration of sweet orange juice 1200 mL decreases bioavailability of fexofenadine by about 72% (7046,17604). In an animal model, sweet orange juice decreased bioavailability of fexofenadine by 31% (17605). Fexofenadine manufacturer data indicates that concomitant administration of sweet orange juice and fexofenadine results in larger wheal and flare sizes in research models. This suggests that sweet orange reduces the clinical response to fexofenadine (17603). Theoretically, this occurs due to short-term inhibition of organic anion transporting polypeptide (OATP) (7046). Recommend separating drug administration and consumption of sweet orange by at least 4 hours (17603,17604).

IVERMECTIN (Stromectol, others) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Consuming sweet orange juice with ivermectin can decrease the oral absorption of ivermectin.  Details A pharmacokinetic study in healthy volunteers shows that taking ivermectin orally with sweet orange juice 750 mL over 4 hours reduces the bioavailability of ivermectin. This effect does not seem to be related to effects on P-glycoprotein. The effect on ivermectin is more pronounced in males compared to females (12154).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Consuming sweet orange juice can decrease oral absorption of OATP substrates. Separate administration by at least 4 hours.  Details Clinical research shows that consuming sweet orange juice inhibits OATP, which reduces bioavailability of oral drugs that are substrates of OATP (17603,17604). For example, sweet orange juice decreases bioavailability of fexofenadine, a substrate of OATP, by about 72% and of celiprolol, another OATP substrate, by up to 90% (7046,12115). Since sweet orange juice seems to affect OATP for a short time, recommend separating drug administration and consumption of sweet orange juice by at least 4 hours (17603,17604).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Sweet orange juice seems to modulate P-glycoprotein (P-gp), which might affect the blood levels of P-gp substrates.  Details Animal and in vitro research suggest that orange juice extract inhibits drug efflux by P-gp, increasing absorption and levels of P-gp substrates (12116,15327). In contrast, pharmacokinetic research in humans shows that drinking large amounts of sweet orange juice decreases absorption and levels of the P-gp substrate celiprolol. This suggests that orange juice actually induces drug efflux by P-gp or affects drug levels by another mechanism such as inhibiting the gut drug transporter called organic anion transporting polypeptide (OATP) (7046,12115). Until more is known, sweet orange juice should be used cautiously in people taking P-gp substrates.

PRAVASTATIN (Pravachol) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Consuming sweet orange juice with pravastatin can increase the absorption of pravastatin.  Details A small pharmacokinetic study in healthy volunteers shows that consuming sweet orange juice 800 mL over 3 hours, including before, during, and after taking pravastatin 10 mg, increases pravastatin levels by about 149%, without affecting pravastatin elimination. Theoretically this effect might be due to modulation of organic anion transporting polypeptides (OATPs) by sweet orange juice (14348). Sweet orange juice does not seem to affect simvastatin levels, but it is not known if sweet orange affects any of the other statins.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Calcium-fortified sweet orange juice might reduce quinolone absorption.  Details Calcium binds to quinolones in the gut. Theoretically, the calcium in certain fortified orange juices can also bind to quinolone antibiotics and reduce their absorption and levels (4412,10339,13714,21638,38570).

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WARFARIN (Coumadin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = C Vitamin K can antagonize and reverse the therapeutic effects of warfarin.  Details Vitamin K antagonizes the effects of warfarin (15,23380,25507,25508,85425,85429). Excessive vitamin K intake, either from supplements or from changes in the diet, can reduce the anticoagulant effect of warfarin (15).

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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, sweet orange juice or fruit seem to be well tolerated. Large amounts of sweet orange peel may be unsafe, especially for children. When inhaled, sweet orange essential oil seems to be generally well tolerated.

Gastrointestinal ...There have been reports of intestinal colic in children following ingestion of large amounts of sweet orange peel (11).

Neurologic/CNS ...There have been reports of convulsions in children following ingestion of large amounts of sweet orange peel (11).

(Read more about SWEET ORANGE)

General ...Orally, vitamin K is generally well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, nausea, and stomach upset.
Serious Adverse Effects (Rare):
Intravenously: There have been rare cases of anaphylaxis and hyperbilirubinemia (in infants).

Dermatologic ...Orally, intake of vitamin K2 (menaquinone) along with calcium and vitamin D3 can cause an increased incidence of skin and skin appendage lesions compared to taking calcium and vitamin D3 alone. However, the risk of this adverse event is low, with 0.5 incidences per 100 patient-years occurring for patients treated with vitamin K, calcium, and vitamin D3 and 0.1 incidences per 100 patient-years occurring for patients treated with calcium and vitamin D3 alone (85467).

Gastrointestinal ...Orally, vitamin K can cause mild to moderate gastrointestinal side effects (91450,91451). The most common effects include nausea, abdominal pain, and diarrhea (91450,91451).

Hepatic ...Orally, vitamin K3 (menadione) has been linked to hepatotoxicity. Vitamin K3 is no longer used therapeutically in North America because it has been linked to hepatic toxicity and jaundice in animal research (7135).

Other ...Intravenously, vitamin K can cause reactions that resemble hypersensitivity or anaphylaxis (85389). These reactions are rare. It is unclear whether the adverse effect is caused by the drug or a component of the solution. There have been very rare cases of hyperbilirubinemia, particularly in premature neonates, following large doses of vitamin K (15).

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