A nattokinase product (BXD Nattokinase Q) was recalled by Health Canada on October 29, 2012 (Health Canada 2012), citing a Section 7(d) Notice Of Refusal due to the possibility of injury to the consumer at all doses¹. Two other Nattokinase products, AOR Nattokinase and AOR Nattokinase (Ultra) were recalled in 2006 (Health Canada 2007) as a result of a trade complaint in which the products were classified as a Type II Health Hazard due to a label indication².

What is nattokinase?

Nattokinase is a protease derived from the microorganism Bacillus natto^3,4 that is extracted from the traditional Japanese food “natto”, prepared from fermented soybean. Although nattokinase is commonly regarded as “safe”, there are not a significant number of large scale studies to support its purported use in the prevention of cardiovascular disease or its possible thrombolytic activity, which has been documented both in vitro and in vivo⁵.

What evidence is available for nattokinase?

In a study by Sumi et al. (1990) 3900 mg nattokinase was administered after meals in a study of 12 healthy Japanese men and women aged 21-55 years. Although, the sample size was small, the authors claimed that the intervention was safe as a result of the use of natto in food in Japan for over 1000 years³.Those familiar with the regulatory environment in Canada will be aware that the assumption of safety of a given extract of a food is not the same as the safety of the food from which the extract is derived.

A study by Cesarone et al. (2003) demonstrated the efficacy of a combination product including nattokinase and Pycnogenol® in reducing thrombotic events and edema associated with long flights in high risk subjects compared to placebo (P<0.05). Although the study did not result in any adverse effects, is not clear which component of the intervention was responsible for the efficacy, as the dose of nattokinase is not divulged in the article⁶.

Furthermore, a six month intervention conducted by Yang et al combined red yeast rice extract and nattokinase in the treatment of hyperlipidemic persons in a randomized, double-blind, placebo-controlled, parallel comparison study7. Nattokinase was supplied at a dose of 50 mg (1,750 Fibrinolysis Units) per day and no adverse events were reported.

A more recent open-label, self-controlled 2 month clinical trial was conducted on various subpopulations in 2009 by Hsia et al. All 45 subjects received 2 capsules per day (2000 fibrinolysis units per capsule) and showed decreased levels of fibrinogen (P = .003), factor VII (P <.001), and factor VIII (P<.001), whereas blood lipid levels remained unchanged. Importantly, there were no reported adverse events in any of the subjects⁴.

Challenges with licensing nattokinase in a natural health product

Based on the evidence, it appears that nattokinase is safe for periods of up to 6 months. However, the conditions of clinical trials, in which patients are monitored by a qualified investigator are not the same as self-treatment. The Hsia study above illustrates the problems inherent to nattokinase. Indeed it is likely to have some effect on blood clotting cascades; however, clotting and thrombosis risks are not the kinds of risk factors that are amenable to non physician-supervised or self-administered treatment. Canadian law prohibits the use of natural health products in the treatment of Thrombotic and Embolic disorders, as well as Haematologic Bleeding disorders, as these are outlined in Schedule A of the Food and Drugs Act⁸. Ironically, the efficacy of nattokinase in treating Schedule A conditions or physiological states is a hindrance to its inclusion in a natural health product application for consumer directed use.

dicentra prides itself on providing the industry with the most up-to-date information on the changing natural health product regulations landscape. We will be sure to update you if any products are licensed with nattokinase. We can be reached at 1-866-647-3279 or info@dicentra.com.

References:

1. Drug and Medical Device Recall Listings. October 2012 – December 2012. Available: http://www.hc-sc.gc.ca/dhp-mps/compli-conform/recall-retrait/_list/rec-ret_drugs-med_trade-marque_oct-dec_2012-eng.php. Accessed: November 12, 2012.
2. Drug Recall Listings. January 2007 – March 2007. Available: http://www.hc-sc.gc.ca/dhp-mps/compli-conform/recall-retrait/_list/rec-ret_drugs-med_trade-marque_jan-march_2007-eng.php. Accessed: November 12, 2012.
3. Sumi H, Hamada H, Nakanishi K, Hiratani H. Enhancement of the fibrinolytic activity in plasma by oral administration of nattokinase. Acta Haematol. 1990;84(3):139-43.
4. Hsia CH, Shen MC, Lin JS, Wen YK, Hwang KL, Cham TM, Yang NC. Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects. Nutr Res. 2009 Mar;29(3):190-6.
5. Chang YY, Liu JS, Lai SL, Wu HS, Lan MY. Cerebellar hemorrhage provoked by combined use of nattokinase and aspirin in a patient with cerebral microbleeds. Intern Med. 2008;47(5):467-9. Epub 2008 Mar 3.
6. Cesarone MR, Belcaro G, Nicolaides AN, Ricci A, Geroulakos G, Ippolito E, Brandolini R, Vinciguerra G, Dugall M, Griffin M, Ruffini I, Acerbi G, Corsi M, Riordan NH, Stuard S, Bavera P, Di Renzo A, Kenyon J, Errichi BM. Prevention of venous thrombosis in long-haul flights with Flite Tabs: the LONFLIT-FLITE randomized, controlled trial. Angiology. 2003 Sep-Oct;54(5):531-9.
7. Yang NC, Chou CW, Chen CY, Hwang KL, Yang YC. Combined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in human subjects with hyperlipidemia. Asia Pac J Clin Nutr. 2009;18(3):310-7.
8. Minister of Justice: Food and Drugs Act ( 2012). Available: http://laws-lois.justice.gc.ca/PDF/F-27.pdf. Accessed: November 21, 2012.