Vol. 145, No. 25 — December 7, 2011

Registration

SOR/2011-275 November 24, 2011

FOOD AND DRUGS ACT

Regulations Amending the Food and Drug Regulations (1656 — Schedule F)

P.C. 2011-1353 November 24, 2011

His Excellency the Governor General in Council, on the recommendation of the Minister of Health, pursuant to subsection 30(1) (see footnote a) of the Food and Drugs Act (see footnote b), hereby makes the annexed Regulations Amending the Food and Drug Regulations (1656 — Schedule F).

REGULATIONS AMENDING THE FOOD AND DRUG REGULATIONS (1656 — SCHEDULE F)
AMENDMENTS

1. The reference to

Dimethyl sulfoxide
Diméthylsulfoxide

in Part Ⅰ of Schedule F to the Food and Drug Regulations (see footnote 1) is replaced by the following:

Dimethyl sulfoxide, for veterinary use or when sold for the treatment of interstitial cystitis or scleroderma in humans
Diméthylsulfoxide, s’il est vendu pour usage vétérinaire ou pour le traitement de la cystite interstitielle ou de la sclérodermie chez les humains

2. The reference to

Levocarnitine and its salts and derivatives
Lévocarnitine et ses sels et dérivés

in Part Ⅰ of Schedule F to the Regulations is replaced by the following:

Levocarnitine and its salts and derivatives, when sold for the treatment of primary or secondary levocarnitine deficiency
Lévocarnitine et ses sels et dérivés, s’ils sont vendus pour le traitement de la déficience primaire ou secondaire en lévocarnitine

3. The reference to

L-Tryptophan, when sold as a single ingredient
L-Tryptophane, s’il est vendu comme seul ingrédient

in Part Ⅰ of Schedule F to the Regulations is replaced by the following:

L-Tryptophan, 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 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.

L-Tryptophane, s’il est vendu, selon le cas :

  • a) pour usage humain sous forme posologique orale à une concentration de plus de 220 mg par unité posologique ou par dose quotidienne, comme ingrédient unique ou en combinaison avec d’autres ingrédients;
  • b) pour usage humain ou vétérinaire, comme ingrédient unique destiné à être administré par toute voie autre que la voie orale.

COMING INTO FORCE

4. These Regulations come into force on the day on which they are registered.

REGULATORY IMPACT
ANALYSIS STATEMENT

(This statement is not part of the Regulations.)

Issue and objectives

This amendment to Part Ⅰ of Schedule F to the Food and Drug Regulations revises the listings for three naturally sourced medicinal ingredients to retain prescription status for specific strengths, uses, routes of administration or dosages while providing exemptions to allow nonprescription status.

The three medicinal ingredients are dimethyl sulfoxide, levocarnitine and L-tryptophan. These three medicinal ingredients are currently in Schedule F to the Food and Drug Regulations without any qualifying phrases or exceptions, and are therefore currently available by prescription only.

Sections C.01.041 to C.01.049 of the Food and Drug Regulations control the sale of medicinal ingredients that are listed in Schedule F. Part Ⅰ of Schedule F lists ingredients that require a prescription for human use and for veterinary use. Part Ⅱ of Schedule F lists ingredients that require a prescription for human use, but do not require a prescription for veterinary use if so labelled or if in a form unsuitable for human use.

Since the coming into force of the Natural Health Products Regulations in 2004, all naturally sourced ingredients meeting the definition of a natural health product are governed by these regulations. However, products containing ingredients listed in Schedule F to the Food and Drug Regulations are explicitly excluded from the Natural Health Products Regulations.

Description and rationale

Health Canada undertook a review of the naturally sourced medicinal ingredients listed in Schedule F. As part of this undertaking, the Department’s Drug Schedule Status Committee (“the Committee”) reviewed science assessments for 11 naturally sourced medicinal ingredients and recommended that these medicinal ingredients could be regulated (in whole or in part) as nonprescription natural health products under the Natural Health Products Regulations. The Committee recommends prescription status or exemption from prescription status for medicinal ingredients on the basis of established and publicly available factors. These factors include, but are not limited to, toxicity, pharmacological properties and therapeutic uses of the ingredients. Three of these eleven medicinal ingredients are presented in this project.

These three naturally sourced medicinal ingredients were added to Schedule F prior to the Natural Health Products Regulations coming into force in 2004. Following the review of the naturally sourced medicinal ingredients in Schedule F, the Committee recommended that the listings in Schedule F to the Food and Drug Regulations for the following three naturally sourced medicinal ingredients be revised to allow nonprescription status for strengths, doses, dosage forms or uses that do not meet the factors for listing in Schedule F.

Manufacturers will be able to apply for market authorization for products containing the exempted strengths, uses, routes of administration or dosages of these medicinal ingredients as natural health products pursuant to the Natural Health Products Regulations once the regulatory amendment comes into force. There are no known market-authorized health products containing these medicinal ingredients whose status will be affected by this regulatory amendment.

Description of the medicinal ingredients:

Dimethyl sulfoxide — The current listing in Part Ⅰ for dimethyl sulfoxide (also referred to as DMSO) is revised to retain prescription status for dimethyl sulfoxide for veterinary use, or when sold for the treatment of interstitial cystitis or scleroderma in humans. All other human uses for dimethyl sulfoxide at any strength and in any dosage form are exempt from prescription status. Dimethyl sulfoxide is found in many natural sources such as broad beans, alfalfa and garlic.

Drugs containing dimethyl sulfoxide for human use are available in Canada with a prescription for treatment of interstitial cystitis (a urinary bladder condition) and scleroderma (abnormal growth of connective tissue that supports the skin). Several products are currently available as prescription drugs for veterinary use to treat conditions such as ear inflammation in dogs. These products would retain prescription status.

Dimethyl sulfoxide is sold as a prescription medicinal ingredient (without exemptions) in the United States (US), the United Kingdom (UK) and Australia. Revising the listing for DMSO on Schedule F results in the retention of prescription status when the ingredient is sold for specific indications that require diagnosis and treatment by a practitioner while at the same time allowing exemptions for nonprescription drug products containing DMSO that come from natural sources such as garlic and alfalfa that would not require practitioner intervention.

Levocarnitine — The current listing for levocarnitine (also called L-carnitine) is revised to retain prescription status for levocarnitine and its salts and derivatives when sold for the treatment of primary or secondary levocarnitine deficiency. Levocarnitine and its salts and derivatives for any other uses at any strength, dosage form or route of administration are exempt from prescription status. Levocarnitine occurs naturally in animal products and in small amounts in most plants.

Overall, levocarnitine functions in the body mainly in optimal fat utilization for energy production. Absorption of levocarnitine is high from dietary sources but if dietary intake is low then the body can maintain a balanced level by synthesizing or reducing elimination of levocarnitine. In most people, sufficient quantities of levocarnitine are obtained from the diet or synthesized in order to meet human requirements.

Primary levocarnitine deficiency is a genetically inherited condition related to the processing of levocarnitine in the body and can lead to muscle weakness and death from heart failure. Secondary levocarnitine deficiency syndromes are numerous, and include genetic defects of metabolism. Treatment of these conditions with levocarnitine requires the supervision of a practitioner and routine laboratory monitoring.

Similar to Canada, in the US, UK and Australia, levocarnitine is sold as a prescription medicinal ingredient with exemptions for nonprescription use.

L-tryptophan — The current listing for L-tryptophan when sold as a single ingredient is revised to provide prescription status for L-tryptophan 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 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.

L-tryptophan is one of the essential amino acids that cannot be synthesized in the human body and must be provided in the diet. L-tryptophan acts in the body in the formation of the vitamin niacin and the neurotransmitter serotonin.

L-tryptophan is available in Canada as a prescription drug for use in combination with antidepressant drugs to enhance the activity of the antidepressant. L-tryptophan is also sold in combination with other amino acids in kidney dialysis and intravenous nutrition solutions without a prescription. The amendment does not change the status of these products.

In the U.S., there are no approved single ingredient prescription drug products for sale containing l-tryptophan; however, the ingredient has limited approved use as a nutrient. In the UK, L-tryptophan is a prescription medicinal ingredient with exemptions for dietary supplementation and for external use. In Australia, L-tryptophan is available as a prescription medicinal ingredient in preparations labelled with a recommended daily dose of 100 mg or less.

The availability of these three naturally sourced medicinal ingredients as nonprescription products may provide consumers with potential access to licensed natural health products. Potential safety concerns for products containing these nonprescription medicinal ingredients would be considered during the premarket review process under the Natural Health Products Regulations.

Manufacturers may benefit by being provided an opportunity to apply for product licences for natural health products containing these ingredients. There is no immediate impact on manufacturers as there are currently no known market-authorized health products containing these medicinal ingredients on the market in Canada whose status will be affected by this regulatory amendment.

There is no change in costs to provincial or privately funded drug benefit plans for the authorized drugs containing these medicinal ingredients on the market in Canada. Should natural health products containing these medicinal ingredients receive market authorization from Health Canada, there would be no anticipated additional costs to provincial or privately funded drugs benefit plans since at this time most do not cover the cost of natural health products.

Consultation

Direct notice of this regulatory proposal was provided to external stakeholders including provincial and territorial departments of Health, medical and pharmacy licensing bodies, and industry, consumer and professional associations in a Notice of Intent sent out on December 29, 2009, and published in the Canada Gazette, Part Ⅰ, on December 26, 2009, with a 75-day comment period. It was also posted on the Health Canada and Consulting With Canadians Web sites. The process for this consultation with stakeholders is described in the Memorandum of Understanding (MOU) to streamline regulatory amendments to Schedule F. The MOU, signed by Health Canada, the Privy Council Office and the Department of International Trade on February 23, 2005, is posted on the Health Canada Web site.

Comments were received from nine respondents, who addressed the proposed listings for the medicinal ingredients individually as follows:

Dimethyl sulfoxide(DMSO)

Five respondents expressed support for the proposed amendment to the Schedule F listing for dimethyl sulfoxide. One respondent objected as follows:

Although DMSO would retain prescription status for all veterinary uses, DMSO could be sourced by animal owners without a prescription by purchasing the human-exempt compounds and could proceed to self-medicate their animals without veterinary oversight.

Health Canada response: This issue involves off-label use in animals of products authorized to be sold for use only in humans. It would not be appropriate for Health Canada to restrict consumer access to health products that can be used safely and effectively without prescription in humans because a consumer might use the products inappropriately for treating animals.

Levocarnitine

Eight respondents expressed support for the proposed amendment. No respondents objected to the proposed amendment to the Schedule F listing for levocarnitine. One of the eight respondents who expressed support for the proposed amendment also expressed an additional comment as follows:

The respondent indicated an intent to continue to work with government to ensure that naturopathic doctors have access to all the substances they require to treat patients safely and effectively.

Health Canada response: The determination of which categories of regulated health care practitioners have the right to prescribe medications, and which prescription medications are included within those rights, are matters of provincial/territorial jurisdiction, not federal jurisdiction, so this issue is outside of the purview of Health Canada.

L-tryptophan

Five respondents expressed support for the proposed amendment to the Schedule F listing for L-tryptophan. Three respondents raised two objections to the proposal as follows:

Comment #1

It is unclear why such restrictions have been placed limiting its use to no more than 220 mg per day in mono- and multi-ingredient products. There are no clear risks identified with the use of much higher dosages of L-tryptophan in oral supplements. Studies using doses of 1 g–3 g (Hartmann et al. 1977), 2 g (Demisch et al. 1987) and even up to 6 g (Steinberg et al. 1999) daily revealed no adverse reactions. A review performed by Schneider-Helmert et al. in 1986 on the usefulness of L-tryptophan for the treatment of insomnia revealed that doses ranging from 1 g to 15 g daily had an absence of side effects and lack the development of tolerance in long-term use.

Health Canada response to comment #1: The clinical studies cited for the use of L-tryptophan for insomnia and premenstrual symptoms and those studies included in the cited review article typically involved small numbers of patients (fewer than 50) and were designed to study efficacy, not safety. Health Canada does not dispute the effectiveness of L-tryptophan for certain sleep and mood disorders but these articles do not constitute adequate evidence that high doses of L-tryptophan can be used safely as nonprescription health products in the absence of health care practitioner monitoring. Three of the articles were published more than 20 years ago and since then a great deal has been learned about the potential risks to health from high-dose L-tryptophan.

To mitigate potential risks to the health of consumers, Health Canada is proposing the threshold dosage of 220 mg/day for nonprescription L-tryptophan health products based on a detailed review of safety information including adverse reaction reports and the rationales used by other nations’ regulators in setting dosage limitations for nonprescription L-tryptophan supplements.

Health Canada chose the same threshold dosage as the United Kingdom of 220 mg of L-tryptophan for single or multiple ingredient nonprescription health products since it is based on a reasonable, scientific risk mitigation approach. This dosage level is higher than either the United States or Australia allows. Higher doses of L-tryptophan remain readily available in Canada as prescription products where health care practitioners can provide the necessary oversight for their appropriate, effective and safe use.

Comment #2

The proposed revision actually makes the overall restriction on L-tryptophan even more restrictive. The current Schedule F restriction applies to the use of L-tryptophan as a single ingredient. The use of L-tryptophan currently does not have any restrictions when used in multi-ingredient products and it does not include any daily dose limitations. In the absence of a clear and demonstrated risk associated with a much higher daily dosage of L-tryptophan, we are not in agreement with restricting the ingredient to a daily dose of 220 mg. This will limit industry’s ability to make scientifically supported claims (e.g. sleep related claims) and will inhibit consumer choice and access to self care products. We strongly oppose the proposal as written and request that the dosage limit be removed based upon available safety and efficacy data.

Health Canada response to comment #2: There may be a misunderstanding of the wording of the current Schedule F listing, which is clarified by reviewing those L-tryptophan health products currently authorized for marketing in Canada. The current Schedule F listing of “L-Tryptophan when sold as a single ingredient” refers to L-tryptophan as an isolated pure substance, to distinguish it from the presence of L-tryptophan as one of many amino acid residues in a protein. This does not mean that the isolated L-tryptophan, as a pure substance, would not require a prescription if one or more other medicinal ingredients were to be included in the product. As an isolated pure substance, L-tryptophan at any dose and in combination with any other medicinal ingredient currently requires a prescription. Please note that there are currently 17 authorized prescription products containing L-tryptophan as a single ingredient, all of which have L-tryptophan as the sole medicinal ingredient. There are no authorized prescription, nonprescription pharmaceutical or natural health products containing L-tryptophan as a pure substance medicinal ingredient in combination with any other medicinal ingredient. Therefore the statement that “L-Tryptophan currently does not have any restrictions when used in multi-ingredient products and it does not include any daily dose limitations” is not correct. These products are not currently available legally to consumers. The intent of the proposed amendment is to clarify that misunderstanding, which has arisen previously, and improve access to safe, effective, high quality health products containing L-tryptophan.

Implementation, enforcement and service standards

These Regulations come into force on the day on which they are registered.

This amendment does not alter existing compliance mechanisms under the provisions of the Food and Drugs Act, the Food and Drug Regulations and the Natural Health Products Regulations enforced by the Health Products and Food Branch Inspectorate.

Contact

Refer to Project No. 1656
Bureau of Policy, Science and International Programs
Therapeutic Products Directorate
Health Canada
1600 Scott Street, Holland Cross, Tower B, 2nd Floor
Address Locator: 3102C5
Ottawa, Ontario
K1A 0K9
Telephone: 613-948-4623
Fax: 613-941-6458
Email: regaff-affreg@hc-sc.gc.ca

Footnote a
S.C. 2005, c. 42, s. 2

Footnote b
R.S., c. F-27

Footnote 1
C.R.C., c. 870