Summary Safety Review - Diosmin and Hesperidin - Assessing the Potential Increased Risk of Bleeding

• Health Canada’s review of the available information found a possible link between the use of either diosmin or diosmin in combination with hesperidin, and the increased risk of bleeding.

• Although there is a possible increased risk of bleeding with the use of either diosmin or diosmin in combination with hesperidin across the general population, evidence suggests that the severity of bleeding may be greater in individuals who are taking medications that affect blood clotting, such as anticoagulants (also known as blood thinners).

• Health Canada will update the related monographs^a,^b,^c to include a recommendation for consumers to consult a healthcare professional prior to taking the product if they are taking medications, including anticoagulants.

• Health Canada expects licence holders to update the risk information on product labels for all licensed diosmin-containing NHPs, as well as diosmin- and hesperidin-containing NHPs, to include a recommendation for consumers to consult a healthcare professional prior to taking the product if they are taking medications, including anticoagulants.

• Health Canada will also inform healthcare professionals about these updates through a Health Product InfoWatch communication.

Health Canada reviewed the potential increased risk of bleeding with the use of either diosmin or diosmin in combination with hesperidin. This safety review was triggered by a Canadian case of severe rectal bleeding in a patient who had been taking Hemovel, a diosmin-containing NHP, in combination with other medications (including an anticoagulant), for 2 days.

Bioflavonoids are a diverse group of phytochemicals (compounds produced by plants to provide colour, flavour and protection against pests or disease). Diosmin and hesperidin are bioflavonoids present in a number of plants, including citrus fruits (also known as citrus bioflavonoids). As medicinal ingredients, diosmin and hesperidin may be present in a variety of NHPs, including those for the relief of symptoms of hemorrhoids, varicose veins and chronic veinous insufficiency. In addition to diosmin and hesperidin, there are many compounds that are classified as citrus bioflavonoids. However, this safety review only focused on diosmin and hesperidin as Health Canada had not received reports of bleeding events concerning other citrus bioflavonoids.

• Diosmin and hesperidin are authorized in Canada for use in NHPs for their antioxidant effects (helps protect cells from harmful free radicals, which have been linked to certain health conditions), and for the relief of symptoms of venous insufficiency (failure of veins to adequately circulate blood), varicose veins (swollen veins that bulge under the surface of the skin) and hemorrhoids (swollen veins in the anus and lower rectum).

• Health Canada has authorized diosmin- and/or hesperidin-containing NHPs (either as a single ingredient product or in combination with other ingredients) for oral use under the Natural Health Products Regulations.

• In Canada, diosmin-containing NHPs, with or without hesperidin, are the primary available treatments tot help strengthen vein walls and improve circulation in people with chronic venous insufficiency.

• Health Canada reviewed the available information from searches of the Canada Vigilance database^d, the World Health Organization’s (WHO) adverse drug reaction database^e and the scientific literature.

• Health Canada reviewed 19 cases (4 Canadian and 15 international) of bleeding events in patients taking either diosmin or diosmin in combination with hesperidin, including 1 case from the published literature.¹ Of the 19 cases, 4 international cases were found to be possibly linked to the use of either diosmin or diosmin in combination with hesperidin, and the remaining 15 (4 Canadian and 11 international) were unassessable due to limited clinical information and the presence of confounders (other factors that may have contributed to the occurrence of bleeding), such as underlying medical conditions, and the use of prescription drugs and other NHPs. Two deaths (1 Canadian and 1 international) were reported among the unassessable cases.

• Health Canada also reviewed the scientific literature and real-world evidence, which suggested the presence of multiple factors that could increase the risk of bleeding when using either diosmin or diosmin in combination with hesperidin.

  • The scientific literature provided evidence that diosmin may interfere with how certain medications, including anticoagulants, function in the body, such as how they are cleared and/or eliminated from the body.^2-6 This could result in increased levels of anticoagulants in the blood, increasing their blood thinning effects and the risk of bleeding.² Some manufacturers of diosmin-containing health products and diosmin- and hesperidin-containing health products marketed in other countries, such as the United States and Australia, have voluntarily updated the risk information on the product labels for these products to include warnings about their use with anticoagulants or during medical procedures.

  • Studies have also shown that diosmin and hesperidin can themselves have blood-thinning effects.^7-9

• Health Canada’s review found a possible link between the use of either diosmin or diosmin in combination with hesperidin and the increased risk of bleeding.

• Although there is a possible increased risk of bleeding with the use of either diosmin or diosmin in combination with hesperidin across the general population, evidence suggests that the severity of bleeding may be greater in individuals who are taking medications that affect blood clotting, such as anticoagulants. Health Canada will update the related monographs to include a recommendation for consumers to consult a healthcare professional prior to taking the product if they are taking medications, including anticoagulants.

• Health Canada expects licence holders to update the risk information on product labels for all licensed diosmin-containing NHPs, as well as diosmin- and hesperidin-containing NHPs to include a recommendation for consumers to consult a healthcare professional prior to taking the product if they are taking medications, including anticoagulants.

• Information about NHPs licensed in Canada is available through the Licensed Natural Health Products Database.

• Health Canada will also inform healthcare professionals about these updates through a Health Product InfoWatch communication.

• Health Canada encourages consumers and healthcare professionals to report any side effects with the use of diosmin or hesperidin, or other health products, to the Canada Vigilance Program.

• Health Canada will continue to monitor safety information involving diosmin and hesperidin, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action should new health risks be identified.

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international information, as well as what is known about the use of diosmin and hesperidin both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

1. Kumar R.M., Van Gompel J.J., Bower R. et al. Spontaneous Intraventricular Hemorrhage Associated with Prolonged Diosmin Therapy. Neurocrit Care 14, 438–440 (2011). https://doi.org/10.1007/s12028-011-9524-9

2. Poór M, Boda G, Mohos V, Kuzma M, Bálint M, Hetényi C, Bencsik T. Pharmacokinetic interaction of diosmetin and silibinin with other drugs: Inhibition of CYP2C9-mediated biotransformation and displacement from serum albumin. Biomed Pharmacother. 2018 Jun;102:912-921. doi: 10.1016/j.biopha.2018.03.146. Accessible at: https://www.sciencedirect.com/science/article/pii/S0753332217370725?via%3Dihub

3. Bajraktari G, Weiss J. The aglycone diosmetin has the higher perpetrator drug-drug interaction potential compared to the parent flavone diosmin. Journal of Functional Foods. Volume 67. 2020. https://doi.org/10.1016/j.jff.2020.103842. Accessible at: https://www.sciencedirect.com/science/article/pii/S1756464620300669

4. Barreca D, Lagana G, Bruno G, Magazu S, Bellocco E. Diosmin binding to human serum albumin and its preventive action against degradation due to oxidative injuries. Biochimie. 95(11). July 2013. Abstract accessible at: https://www.researchgate.net/publication/252324636_Diosmin_binding_to_human_serum_albumin_and_its_preventive_action_against_degradation_due_to_oxidative_injuries

5. Kong W, Ling X, Chen Y, Wu X, Zhao Z, Wang W, Wang S, Lai G and Yu Z: Hesperetin reverses P‑glycoprotein‑mediated cisplatin resistance in DDP‑resistant human lung cancer cells via modulation of the nuclear factor‑κB signaling pathway. Int J Mol Med 45: 1213-1224, 2020. Accessible at: https://www.spandidos-publications.com/10.3892/ijmm.2020.4485

6. Michalczyk M., Humeniuk, E Kubik, J. et al. Enhancement of doxorubicin efficacy by diosmetin through DNA damage accumulation and P-glycoprotein inhibition in breast cancer cells. Sci Rep 15, 30814 (2025). https://doi.org/10.1038/s41598-025-16681-3 Accessible at: https://www.nature.com/articles/s41598-025-16681-3#citeas

7. Jin YR, Han XH, Zhang YH, Lee JJ, Lim Y, Chung JH, Yun YP. Antiplatelet activity of hesperetin, a bioflavonoid, is mainly mediated by inhibition of PLC-gamma2 phosphorylation and cyclooxygenase-1 activity. Atherosclerosis. 2007 Sep;194(1):144-52. doi: 10.1016/j.atherosclerosis.2006.10.011. Accessible at: https://www.sciencedirect.com/science/article/pii/S0021915006006149?via%3Dihub

8. Zaragozá C, Monserrat J, Mantecón C, Villaescusa L, Álvarez-Mon MA, Zaragozá F, Álvarez-Mon, M. Binding and antiplatelet activity of quercetin, rutin, diosmetin, and diosmin flavonoids. Biomedicine & Pharmacotherapy. Volume 141. 2021. https://doi.org/10.1016/j.biopha.2021.111867. Accessible at: https://www.sciencedirect.com/science/article/pii/S0753332221006491?via%3Dihub

9. Jomova K, Alomar SY, Valko R, Liska J, Nepovimova E, Kuca K, Valko M. Flavonoids and their role in oxidative stress, inflammation, and human diseases. Chemico-Biological Interactions. Volume 413. 2025. https://doi.org/10.1016/j.cbi.2025.111489 Accessible at: https://www.sciencedirect.com/science/article/pii/S000927972500119X

1. Monographs and product monographs are a written description of particular elements on an identified topic. In the case of NHPs, a monograph is specific to an individual ingredient or a combination of ingredients that are authorized for use in NHPs sold in Canada. In the case of drugs, product monographs are specific to a particular drug product authorized for sale in Canada.

2. Monographs for NHP ingredients can be accessed through the Compendium of monographs.

3. The medicinal ingredient hesperidin is represented in the monographs for citrus bioflavonoids and antioxidants. Diosmin is represented as a sub-ingredient in citrus bioflavonoids.

4. Canadian reports can be accessed through the Canada Vigilance Online Database.

5. World Health Organization’s adverse drug reaction database