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The Official Publication of the American Herbal Products Association
copyright 2012 The American Herbal Products Association Excerpted from the January 2012 issue of the AHPA Report Articles may not be reproduced or reprinted without written Health Canada Allows for OTC Use
of 10 Naturally Sourced Ingredients
by Anne Wilkie, Senior Regulatory Strategy and Policy Advisor,
dicentra Inc.
What do oil of apiol, deanol, theobromine, Centella asiatica, dopa- Widespread confusion surrounded the legal interpretation and mine, gold, uracil, dimethyl sulfoxide, levocarnitine, and implementation of Schedule F of the Regulations. Did products L-tryptophan have in common? that naturally contained Schedule F ingredients automatically Until recently, they were classified as prescription drugs in Canada, become prescription products? At one point in time, shipments of meaning the only way consumers could access products containing blue-green algae were being turned back at the borders because of any of these ingredients was by virtue of a licensed health care prac- the presence of naturally occurring vitamin K. (Until 2005, all titioner writing a prescription for their use. However, with the recent forms and dosages of vitamin K were considered to be prescription passage of amendments to Schedule F of the Food and Drug drugs.) Following this logic, it could be argued that chocolate and Regulations, suppliers will now have the opportunity to bring these tea, natural sources of theobromine, should also be considered pre- ingredients to market as natural health products (dietary supple- scription drugs. The determination of whether gotu kola was a pre- ments). These amendments came into force Nov. 24, 2011.
scription drug by virtue of the presence of the “active principles of Centella asiatica” also flip-flopped back and forth, with shipments of When the Natural Health Products Regulations became law in the raw herb often being refused entry into Canada. 2004, all naturally sourced ingredients meeting the definition of a natural health product (e.g., vitamins, minerals, amino acids, and In addition, Canadian consumers were restricted in purchasing plant and animal extracts) came under the scope of these regula- L-tryptophan and carnitine, while these ingredients were freely tions. However, products containing ingredients listed on Schedule available over the counter in the United States. Industry had F of the Food and Drug Regulations were explicitly excluded from expected that the Natural Health Products Regulations would help the Natural Health Products Regulations. Natural health products, to level the playing field and increase the number of products avail- by definition, are only allowed to be sold for over-the-counter able to consumers in Canada. However, this discrepancy only rein- (OTC) uses—that is, for conditions amenable to self-care.
forced the viability of Internet and black-market sales. Sections C.01.041 to C.01.049 of the Food and Drug Regulations The qualifying language for L-tryptophan on Schedule F, “trypto- control the sale of medicinal ingredients listed on Schedule F— phan, when sold as a single ingredient,” served to add further confu- those that require a prescription for human and/or veterinary use. sion. This language was intended to differentiate between L-trytophan as an isolated, pure substance and L-tryptophan as one of many amino Industry Concerns
acid residues in a protein. However, it was often interpreted by indus-try to mean that L-tryptophan could be sold over the counter as long The previous classification of these ingredients has caused the natural as it was in combination with other ingredients. It further aggravated products industry much grief over the years, and with the imple- the industry that carnitine, routinely found in meat and dairy prod- mentation of the Natural Health Products Regulations in 2004, ucts, nuts, seeds, and a host of other foods, and allowed to be added stakeholders thought they would see an end to the confusion and a to foods such as infant formula, required a prescription for consumer move to change the Regulations. At that time, the Natural Health Products Directorate (NHPD) actually agreed to review the classifi-cation of carnitine and L-tryptophan, ingredients of primary impor-tance to the industry. Monographs were written for these ingredients Health Canada Review
by consultants at the request of NHPD, but the monographs sat on The industry lobbied extensively over the years for the revision of a shelf and changes were not forthcoming.
Schedule F. But it was not until 2008 that Health Canada initiated January 2012 • Page 1
its own review of naturally sourced medicinal ingredients listed on In discussions with Health Canada personnel, it became apparent Schedule F. As part of this undertaking, the department’s Drug that documentation explaining why many of these ingredients had Schedule Status Committee reviewed science assessments for 11 been placed on Schedule F either could not be located or did not naturally sourced ingredients to evaluate the merit of their remain- exist. Compliance with the Schedule F factors is lacking for many of ing on Schedule F based upon established criteria. The committee these ingredients. For example, for oil of apiol, deanol and its salts concluded that these 11 ingredients could be regulated in whole or and derivatives, and theobromine and its salts, the recent Health in part as natural health products under the Natural Health Products Canada science review confirmed that “none of the factors for listing Health Canada used the following factors to determine whether pre- The proposed regulatory amendments were put forward in three scription status of drugs is appropriate. Project 1577 reviewed the application of Schedule F factors to oil of a. Individualized instructions and/or direct practitioner supervi- apiol, deanol and its salts and derivatives, theobromine and its salts, sion, adjunctive therapy with scheduled drugs or routine and Centella asiatica extract and its active principles. The review of available science revealed that none of the criteria for Schedule F listing applied to any of these four ingredients, and it was therefore b. There is a narrow margin of safety between the therapeutic and recommended that they be removed completely from Schedule F. toxic doses, especially in populations such as geriatrics, children The Health Canada committee made the following comments to c. There are potential or known undesirable or severe side effects at 1. Oil of apiol: A wide margin of safety exists between the thera- peutic and toxic doses. The common presence of apiol oil in d. They are known by experimental data to induce toxicity in foods (essential oils of parsley seed, dill seed, fennel seed, animals but have not been in clinical use long enough to sassafras root bark, and other plant species) indicates a lack of establish the pattern or frequency of long-term toxic effects in toxicity at doses likely to be found in herbal medicines.
2. Centella asiatica extract and active principles thereof (derived e. They are used in treatment of a serious disease easily misdiag- from gotu kola): There is a wide margin of safety between therapeutic and toxic doses. These substances pose a low risk of g. They have contributed to, or are likely to contribute to, the 3. Deanol (and its salts and derivatives), also known as dimethyl- development of resistant strains of micro-organisms in humans; aminoethanol or DMAE, is a naturally sourced chemical found h. They possess a dependence or abuse potential that is likely to in salmon roe, shellfish, and fish oils. Available scientific literature indicates that deanol does not have a narrow margin of safety between therapeutic and toxic doses.
i. They possess a high level of risk relative to expected benefits; or 4. Theobromine (and its salts) is a naturally occurring chemical j. They have a therapeutic effect based on recently elucidated substance found in cocoa and chocolate. Toxicity from theobro- pharmacological concepts, the consequences of which have not mine is very rare and is only seen at very high doses in humans. It does not pose a high level of risk relative to expected benefits.
Exceptions will be considered for drugs, which: The “Regulations Amending the Food and Drug Regulations (1577 k. Are required to be readily available under emergency circum- — Schedule F)” can be viewed at the Canada Gazette stances where it is not practical to obtain a prescription (such Project 1651 reviewed the available evidence for dopamine and its salts, gold and its salts, and uracil and its salts, and the need to retain l. Are rarely used without a practitioner’s supervision, and prescription status via Schedule F. The committee concluded that where the need for free availability outweighs the need for nonprescription status should be allowed for all strengths, doses, protection under Schedule F, such as insulin and nitroglyc- dosage forms, and uses that do not meet the factors for listing on erin; or have potential to produce dangerous interactions Schedule F. The following recommendations and supporting state- with other drugs or food constituents but effective labelling 1. Dopamine and its salts: Prescription status will be retained for A list of factors for listing drugs on Schedule F is available at the dopamine and its salts when sold for administration by injec- tion. All other dosage forms and routes of administration at any January 2012 • Page 2
strength and for any use are exempt from prescription status. consultation. The review of lovastatin will now proceed Dopamine is inactive in the body when administered orally; separately as Project 1668. It was originally proposed that the however, allowing OTC use for oral administration will mitigate listing for lovastatin would be revised to retain prescription issues that arise with ingredients that might naturally contain status for all strengths and dosage forms except when lovastatin was sold in an oral dosage form that provides less than 1.0 mg 2. Gold and its salts: Prescription status will be retained for gold per dosage unit or per daily dose. Oral dosage forms contain- and its salts when sold for administration by injection; any other ing less than 1.0 mg of lovastatin would be exempt from dosage form or route of administration at any strength and or prescription status. The proposed exemption for less than 1.0 any use are exempt from prescription status. This revision to mg is only 10 percent of the lowest therapeutic dose of 10 mg Schedule F will avoid unintentionally subjecting products of lovastatin. This would allow red yeast rice products contain- containing trace amounts of gold to prescription requirements ing only trace amounts of lovastatin to be marketed as natural health products in Canada. Red yeast rice is derived from yeast grown on rice and is used as food in some Asian countries. It 3. Uracil and its salts: Prescription status will be retained for uracil contains several substances, including lovastatin, known to and its salts when sold for the treatment of cancer; all other uses at any strength, dosage form, or route of administration are exempt from prescription status. Uracil is found in all living organisms, so The “Regulations Amending the Food and Drug Regulations (1651 listing in Schedule F without qualifiers in inappropriate.
— Schedule F)” can be viewed at the Canada Gazette 4. Lovastatin was initially included in this proposal but was Project 1656 dealt with the science surrounding dimethyl sulfoxide, removed based upon information submitted during the initial levocarnitine and its salts and derivatives, and L-tryptophan, when Status Summary of Naturally Sourced Ingredients
MI = medical ingredient; NMI = non-medical ingredient United States
Australia
United Kingdom
Prescription only when sold for administration by Prescription only when sold for administration by Prescription only when sold for the treatment of cancer No approved drugs medicine (prescrip-tion, pharmacy, or general sale) Prescription status only when sold for veterinary use or when sold for the treatment of interstitial cystitis or scleroderma in humans Levocarnitine (and its salts and Prescription status only when sold for the treatment of primary or secondary levocarnitine deficiency Prescription status when sold (a) for human use in oral dosage form at a concentration of more than 220 mg per dosage unit or per daily dose, as a single ingredient (dietary supplement) or in combination with other ingredients; or (b) for human or veterinary use as a single ingredient intended for any route of administration other than oral January 2012 • Page 3
sold as a single ingredient, and the need to control their availability bring their classifications into line with major trading partners through prescription status. The following recommendations and such as the United States, Australia, and the United Kingdom (see table, page 3). Where classifications differ, it is important to 1. Dimethyl sulfoxide: Prescription status is to be retained for note that Canada has the authority to evoke additional controls veterinary use or when sold for the treatment of interstitial cystitis under the Natural Health Products Regulations. Although these or scleroderma in humans. All other human uses at any strength, ingredients are now allowed for OTC use in natural health prod- and in any dosage form are exempt from prescription status.
ucts under specific circumstances, the premarket review process for natural health products requires that the safety and efficacy of 2. Levocarnitine and its salts and derivatives: Prescription status all medicinal ingredients in each proposed formula must be dem- will be retained when it is sold for the treatment of primary or secondary levocarnitine deficiency; all other uses, strengths, onstrated to Health Canada’s standards with human clinical evi- dosage forms, and routes of administration are exempt from dence. Where potential safety concerns exist, they could be mitigated through the use of lower dosages, specified durations of use, target populations, and/or cautions, warnings, and con- 3. L-tryptophan: Prescription status will be retained for when it is traindications on the product label. Natural health products are sold (a) for human use in oral dosage form at a concentration of only issued a license by Health Canada once safety, efficacy, and more than 220 mg per dosage unit or per daily dose, as a single ingredient or in combination with other ingredients; or (b) for human or veterinary use as a single ingredient intended for any These amendments are a positive step forward in providing sup- route of administration other than oral.
pliers with new options for product formulation and increasing the availability of products to consumers. However, it remains to The “Regulations Amending the Food and Drug Regulations (1656 be seen how many will appear in product formulations in the — Schedule F)” can be viewed at the Canada Gazette .
In general, comments received from stakeholders during the initial is senior regulatory strategy and policy advisor for Toronto- consultations, although limited, were supportive of the proposed ., a leading scientific and regulatory affairs consulting amendments. The one exception was a lack of support from two firm with specialized expertise in the areas of natural health products, respondents for the revision to the listing for lovastatin. Lovastatin foods, beverages, cosmetics, and OTCs. For more information, contact is currently widely available in Canada as a prescription drug for the treatment of high cholesterol. However, work on this proposal is continuing, and a revised proposal is expected in the near future. For more than 10 years, dicentra has been helping clients resolve complex Stakeholders supported all other recommendations for the 10 other scientific issues, develop safe and effective market-leading products, and ingredients discussed above, and regulatory amendments to that facilitate timely regulatory global approvals. Dicentra has advised hun- effect came into force on Nov. 24, 2011.
dreds of companies, financial institutions, governments, associations, law firms, and individual investors on the regulatory and scientific aspects of product creation and maintenance. Dicentra has been directly Other Regulatory Jurisdictions
involved in the successful development of hundreds of leading products Most of the changes made to the status of the 10 ingredients in North America and throughout the world. January 2012 • Page 4

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