ARCHIVED — Regulations Amending the Food and Drug
Regulations (1584 — Schedule F)
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Vol. 143, No. 10 — May 13, 2009
SOR/2009-119 April 23, 2009
FOOD AND DRUGS ACT
P.C. 2009-585 April 23, 2009
Her 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 (1584 — Schedule F).
REGULATIONS AMENDING THE FOOD AND
DRUG REGULATIONS (1584 — SCHEDULE F)
1. The reference to
Naproxen and its salts
Naproxène et ses sels
in Part I of Schedule F to the Food and Drug Regulations (see footnote 1) is replaced by the following:
Naproxen and its salts, except when sold for oral use with a daily dosage of 440 mg
Naproxène et ses sels,sauf lorsque vendu pour administration par voie orale en dose quotidienne de 440 mg
COMING INTO FORCE
2. These Regulations come into force on the day on which they are registered.
(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 provides an exemption to allow nonprescription status for naproxen and its salts when sold for oral use with a daily dose of 440 mg.
Naproxen and its salts is currently in Schedule F to the Food and Drug Regulations without any qualifying phrases or exceptions and is therefore currently available by prescription only.
Schedule F is a list of medicinal ingredients, the sale of which is controlled under sections C.01.041 to C.01.049 of the Food and Drug Regulations. 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.
Drugs can only be sold in Canada once Health Canada has assessed them for safety, efficacy and quality as required by the Food and Drugs Act and the Food and Drug Regulations.
Description and rationale
Health Canada’s Drug Schedule Status Committee (Committee) recommends prescription status or exemption from prescription status for medicinal ingredients on the basis of an assessment of the medicinal ingredient against a set of established and publicly available factors. These factors include, but are not limited to, toxicity, pharmacological properties and therapeutic uses of the medicinal ingredients.
The Committee recommended that naproxen and its salts when sold for oral use with a daily dose of 440 mg be accorded nonprescription status because, when assessed against the factors for listing in Schedule F, none of the factors supported prescription status for oral use at that dose. All other strengths and dosage forms of naproxen and its salts will still require a prescription in order to be sold.
When a Schedule F listing is modified or deleted to afford a medicinal ingredient nonprescription status, a manufacturer can sell a nonprescription drug product that contains the medicinal ingredient only upon final approval of the regulatory amendment that modifies or deletes the wording of a medicinal ingredient listed in Schedule F and its publication in the Canada Gazette, Part II.
Naproxen and its salts is a nonsteroidal anti-inflammatory drug (NSAID) that is used to treat inflammation and pain. Naproxen and naproxen sodium, a naproxen salt, have been available as prescription drugs in Canada since 1975 and 1980, respectively.
Naproxen and its salts as a nonprescription drug will have indications for use that are amenable to self-diagnosis, self-treatment and self-monitoring. These indications for use include symptomatic treatment of headache, toothache, muscular ache, backache, pain or stiffness of arthritic conditions, menstrual pain, minor aches and pain associated with the common cold and pain due to minor surgery, dental extractions and muscle sprains as well as for fever reduction. The recommended nonprescription daily dose is 440 mg. The duration of use should not exceed five days of continuous treatment without consulting a practitioner.
Naproxen sodium was approved for nonprescription use in the United States in 1994 and, subsequently, in 33 other countries. Nonprescription status is currently under review in four additional countries, including Canada. Naproxen sodium has a wide margin of safety. Postmarketing experience has shown that a 440 mg daily dose is not associated with significant adverse effects. There are no dose-related or age-related adverse effects, no unidentified special populations at risk and no clinically significant drug or food interactions. In addition to its large safety margin, side effects associated with the use of a daily 440 mg dose are minor and transient in nature, with incidence and severity being equivalent to that observed in placebo-treated groups in clinical trials.
The availability of nonprescription naproxen and its salts when sold for oral use with a daily dose of 440 mg will provide a treatment option for pain and fever.
The expected benefits and costs of this regulatory amendment on public health care plans are listed below:
1. The availability of naproxen and its salts when sold for oral use with a daily dose of 440 mg as a nonprescription product will provide consumers with more convenient access to this treatment for pain and fever.
2. Product labels will be required to include directions for use and applicable cautionary statements. This will help to provide information to the public about the product’s safe and proper use.
3. The public will be required to pay directly for the product as products which do not require a prescription are not usually covered by drug insurance plans.
There is no anticipated cost for privately funded drug benefit plans since most do not cover the cost of nonprescription drugs.
There is no anticipated cost to provincial drug benefit plans since most do not cover the cost of nonprescription drugs.
Direct notice of this regulatory proposal was provided to external stakeholders, including provincial and territorial Ministries of Health, medical and pharmacy licensing bodies, and industry, consumer and professional associations on March 5, 2008 with a 75-day comment period. This initiative was published as a Notice of Intent in the Canada Gazette, Part I, on March 1, 2008. It was also posted on the Health Canada Web site and the Consulting With Canadians Web site. 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 22, 2005, is posted on the Health Canada Web site.
Comments were received from 13 respondents. Two respondents asked questions about the status of the product being switched and direct responses were provided to these two stakeholders. Comments received from the remaining respondents are addressed below.
Support the proposal
The applicant for this proposal submitted one comment of support. Five other respondents expressed support for the proposed amendment. Their comments included the following:
— provides Canadians with another safe and effective option to better manage their pain,
— presents a benefit to consumers seeking pain relief with a long-lasting effect (i.e., a single dose of naproxen at 220 mg can last up to 12 hours, whereas other analgesics must be dosed every six hours),
— the experience of other countries where this product is already available without a prescription has shown that it is a safe and effective medication at this dose,
— a literature review shows that naproxen sodium used in over the counter doses for a short period has an acceptable safety profile.
Oppose the proposal
Two respondents expressed opposition to the proposed amendment. One respondent did not provide any comment or rationale for opposing the proposal while the other respondent raised specific issues. These issues are summarized below with Health Canada’s responses:
1. Statements regarding the safety of naproxen sodium are inconsistent with Health Canada’s own Guidance document, Basic Product Monograph Information for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). These statements relate to naproxen’s margin of safety, age related adverse effects and effects on special populations.
The Health Canada guidance document, Basic Product Monograph Information for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), is intended for the preparation of product monographs (PMs) for prescription NSAID products and, while the format would be similar, the content provided in the guidance is not intended for use in preparing PMs for nonprescription NSAIDs. The warnings and precaution information described in the guidance are applicable only to prescription doses and indications for use as prescription products containing naproxen having a higher single (500 mg) and daily dose (1000 mg) than that proposed for nonprescription use (220 mg/tablet; maximum recommended daily dose 440 mg). Since the prescription dose of naproxen is more than twice the proposed maximum recommended dose for nonprescription use, the guidance’s warning and precaution information do not necessarily apply to nonprescription doses or indications for use. In addition, prescription products are frequently prescribed for daily use over a prolonged period of time. The labelling of the nonprescription products containing naproxen and its salts will include appropriate warnings and precautions for the recommended dosage (440 mg/day) and length of use (5 days).
2. The proposal contends that post-marketing experience has shown that 440 mg naproxen daily is not associated with significant adverse effects. However, in 2005, Health Canada’s Expert Advisory Panel (EAP) on the Safety of COX-2 Selective NSAIDs stated that adverse event reporting was not useful for assessing the cardiovascular risks of anti-inflammatory drugs. It is not scientifically justified to conclude that post-marketing data confirms the safety of naproxen taken daily at a dose of 440 mg. Systematic, long-term controlled trials would be required to support such a conclusion.
The EAP qualified its statement regarding adverse event reporting by stating that it was not useful for assessing the cardiovascular risks of anti-inflammatory drugs because of the relatively high frequency of underlying cardiovascular disease in the patient population taking these drugs. When NSAIDs are prescribed for their anti-inflammatory action they are generally administered for a prolonged period of time and at higher doses than that proposed for naproxen and its salts as a nonprescription drug. The labelling for the nonprescription product includes a warning to consult a physician or pharmacist before taking naproxen and its salts if the consumer has or has had high blood pressure or heart disease or heart failure.
The 2004 withdrawal of rofecoxib, a COX-2 NSAID due to an increased risk of myocardial infarction (MI), has led to closer scrutiny of the cardiovascular (CV) risks of all NSAIDs. The Global Drug Safety Assessment report for cardiovascular events found no increased risk of MI and cerebrovascular events associated with naproxen use. A meta-analysis involving 138 randomized controlled trials (RCTs) examined the CV risk from COX-2 NSAIDs vs. traditional NSAIDs (e.g. naproxen, ibuprofen) or placebo. Naproxen exposures in these trials were at higher doses (1000 mg/day) and for a longer duration (³4 weeks) than the proposed nonprescription dose (440 mg/day) and duration (5 days). There was no increased risk of vascular events among naproxen users.
Similar findings were reported in two recent, well conducted meta-analyses of randomized (Kearney et al 2006, BritishMedical Journal 332:1302-8) and epidemiological (i.e. non-randomized; McGettigan et al 2006, Journal of the American Medical Association 296:1633-44) studies that examined the CV risks associated with exposure to NSAIDs. One analysis examined the risk of acute myocardial infarction (AMI) associated with NSAID exposure and reported no increased risk of AMI associated with naproxen in randomized clinical studies (0.98; 95% CI 0.87-1.11). Similarly for epidemiological (non-randomized) studies, there was no increased risk of serious cardiovascular events (e.g., AMI, sudden cardiovascular death) associated with naproxen use (0.97; 95% CI 0.87-1.07). It is important to note that in the majority of these non-randomized studies, naproxen was administered at prescription doses; i.e., doses exceeding the recommended nonprescription maximum dose of 440 mg per day for 5 days.
3. The proposal contends that there are no significant drug interactions. However, the Health Canada guidance document Basic Product Monograph Information for Nonsteroidal Anti-Inflammatory Drugs, Section 184.108.40.206, states that some NSAIDs (e.g. ibuprofen) may interfere with the antiplatelet effects of low dose ASA. There is some evidence that use of NSAIDs with ASA can markedly attenuate the cardioprotective effects of ASA. There is evidence that naproxen may have the same effect of interfering with ASA.
Consumers should be aware of the potential interactions between ASA and naproxen and its salts, and the fact that naproxen and its salts, like ibuprofen, can block the antiplatelet effect of aspirin. To address this, the consumer information leaflet for naproxen and its salts includes a section on possible drug interactions and directs the consumer to consult with their doctor or pharmacist before taking naproxen if they are taking low dose ASA for doctor supervised daily preventative therapy.
4. While it may be argued that the relative risk of naproxen would be diminished if it were taken at a low dose and for short duration, there is no firm evidence that naproxen can be used safely by all patients at the proposed dose of 440 mg daily and the available scientific evidence indicates that there is indeed the potential for undesirable or severe effects at this therapeutic dose.
Nonprescription naproxen and its salts should not be taken by people with certain diseases or conditions. A list of these diseases and conditions is provided in the consumer information leaflet. The leaflet further includes a section of warnings and precautions directing the consumer to consult a doctor or pharmacist before taking naproxen if they have or have had any of the conditions or diseases listed.
The risk for severe side effects at the proposed nonprescription dose of naproxen and its salts is remote and similar to that of nonprescription ibuprofen. Evidence from clinical efficacy and safety trials, epidemiological studies, meta-analyses, consumer studies, Periodic Safety Update Reports (PSURs) and Global Drug Safety Assessment Reports support the safety of naproxen and its salts at the proposed Canadian nonprescription exposures (i.e. 440 mg/day for a maximum of 5 days).
5. Even though the labelling of nonprescription naproxen will include a maximum daily dose and duration of use, there is a very high likelihood that it would be taken at doses higher than recommended and for longer duration than recommended.
When used at higher than recommended doses or for longer than recommended, the risk of adverse effects increases in a similar manner to that of ibuprofen.
A consumer safety study reviewed as part of the safety data demonstrated that there were no safety differences between naproxen and its salts, ibuprofen and acetaminophen when taken according to label instructions. As with any new nonprescription drug introduced onto the market for the first time, it is essential that consumers are well aware of the health risks associated with its use.
Three respondents expressed concerns about the proposal without explicitly opposing it. Below is a summary of their comments with Health Canada’s responses:
6. The proposal to change the status of naproxen should be reviewed with caution by Health Canada. This is especially important given naproxen’s long half-life. A prudent approach by Health Canada has lead to a safe transition of prescription analgesic medicines to nonprescription status.
Health Canada’s proposal to allow nonprescription status for naproxen and its salts is based on the review of a substantial amount of information. Safety data included evidence from over 30 clinical efficacy and safety trials involving more than 10 000 subjects, three safety studies evaluating the gastrointestinal (GI) risk of naproxen in over 2 000 patients, numerous epidemiological studies, three well conducted meta-analyses, consumer studies, Periodic Safety Update Reports (PSURs) and three Global Drug Safety Assessment Reports. The longer duration of action is reflected in the labelling which specifies that the interval between doses should be only every 8 to 12 hours.
7. Is there a need for another nonprescription NSAID in the Canadian market place? The potential for overuse and abuse increases as more analgesic products are given non-prescription status. The use of ASA, ibuprofen and naproxen and its salts can cause adverse events by inadvertent concomitant use due to this misunderstanding of similar pharmacological properties.
The nonprescription availability of the proposed 440 mg daily dose of naproxen and its salts will provide another option for consumers who wish to treat their short term pain and fever. The main difference between naproxen and its salts and other currently available nonprescription analgesics is its half-life. It has a much longer duration of action (12 to 15 hours) compared to the other nonprescription analgesics, e.g. acetylsalicylic acid, ibuprofen and acetaminophen. The longer duration of action means that doses should be taken only every 8 to 12 hours.
The consumer information leaflet for naproxen and its salts directs the consumer to consult a pharmacist or doctor before taking naproxen if they are taking any other pain medications such as ibuprofen or acetaminophen.
8. Concern was expressed about advertising claims that could be made for naproxen.
Only drugs that have been authorized for sale in Canada by Health Canada may be advertised. Health Canada is the national regulatory authority for drug advertisements. The Department provides policies to effectively regulate marketed drugs, puts in place guidelines for the interpretation of the Regulations, and oversees regulated advertising activities. Health Canada sets the standards for drug advertising material that is not false, misleading or deceptive. To this effect, advertisements of authorized nonprescription drugs must comply with Section 3 and Section 9 of the Food and Drugs Act, which respectively read as follows:
- Section 3(1) of the Food and Drugs Act: “no person shall advertise any food, drug, cosmetic or device to the general public as a treatment, preventative or cure for any of the diseases, disorders or abnormal physical states referred to in Schedule A.”
- Section 9(1) of the Food and Drugs Act: “no person shall label, package, treat, process, sell or advertise any drug in manner that is false, misleading or deceptive or is likely to create an erroneous impression regarding its character, value, quantity, composition, merit or safety.”
Health Canada has issued the Consumer Advertising Guidelines for Marketed Health Products (the “Guidelines,” available on the Health Canada Web site) which apply to advertising of nonprescription drugs, including natural health products, and are intended to provide guidance regarding Health Canada’s interpretation of relevant provisions of the Food and Drugs Act and the Food and Drug Regulations. The Guidelines provide guidance regarding Health Canada’s interpretations of Section 9(1). The Guidelines note, in Section 1.1, that therapeutic claims must be consistent with the Terms of Market Authorization of the product. Therefore, in the case of non-prescription drugs, the claims made in advertising should not exceed the scope of either the Labelling Standards, Category IV Monographs, authorized labelling, or Product Monographs.
It should be noted that since an amendment to the Food and Drug Regulations became effective June 1st, 2008, consumer advertising of nonprescription drugs and natural health products are allowed to include preventative claims for Schedule A diseases. However, in order to include specific Schedule A preventative claims in advertising, manufacturers need to file an application for market authorization with Health Canada, and only the exact wording approved by Health Canada is to be used in advertising.
Advertising material for nonprescription drugs directed to consumers is reviewed and precleared by independent advertising preclearance agencies prior to release in order to help industry ensure compliance with the regulatory provisions of the Food and Drugs Act and the Food and Drugs Regulations, the Natural Health Products Regulations and the various Health Canada guidance documents and codes of advertising. Although this self-regulatory system is voluntary, various manufacturer associations such as NDMAC and Canada’s Research-Based Pharmaceutical Companies (Rx&D) support preclearance by independent advertising preclearance agencies. As well, Health Canada strongly encourages all sponsors to comply with the voluntary preclearance review prior to exposure to health care professionals and consumers.
9. The expert advisory panel (EAP) that reviewed the safety of COX-2 inhibitors in June 2005, made comments about ibuprofen as the only nonprescription NSAID available in Canada. The EAP suggested that nonprescription ibuprofen was being used at higher doses and for longer periods than indicated on the labelling. The EAP suggested that Health Canada should consider that ibuprofen only be sold after discussion with a pharmacist. Even though the product in this project is not ibuprofen, it belongs to the same therapeutic class and the proposed amendment would give it similar status. Although conditions of sale for drugs is a provincial matter, the comments in the expert advisory panel report concerning nonprescription ibuprofen and the information included in the NSAID monographs requires caution concerning the availability of naproxen as a nonprescription drug.
Conditions of sale for nonprescription drugs is a provincial responsibility. Provincial pharmacy regulatory authorities decide whether drugs that will be available without a prescription should be on Schedule II (behind the counter in a pharmacy and available from the pharmacist), on Schedule III (available in self-selection area of pharmacy) or Unscheduled (available from any retail outlet). Provincial scheduling decisions are coordinated nationally through the umbrella association, the National Association of Pharmacy Regulatory Authorities (NAPRA). In addition, please see the response to comment No. 5 above.
The Consumer Information Section (Part III) of the naproxen product monograph includes directions to consult a doctor or pharmacist before using if a person has or previously had any of a list of diseases or conditions, or if the person is taking any of a list of other medications or experiences side effects after taking naproxen and its salts.
10. The Health Canada guidance document Basic Product Monograph Information for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) outlines information that should be included in the product monograph regarding people with specific health risks related to using NSAIDs and also specific contraindications for NSAID use.
While the guidance document referenced is intended for use with prescription NSAID products, the product monograph for nonprescription naproxen and its salts does include specific contraindications for NSAID use and precautions and warnings related to specific health risks.
11. A team of Quebec researchers noted in the study, Rahme, E., Joseph, L. Gastrointestinal health care resource use and costs associated with nonsteroidal anti-inflammatory drugs versus acetaminophen; Arthritis & Rheumatism, Vol. 43, No. 4, April 2000, pp. 917-924, that for each dollar spent on treating the elderly with anti-inflammatories, $0.66 was spent on health care to treat gastrointestinal (GI) effects, probably caused by the anti-inflammatory products. The impact on health care budgets should therefore be considered in making this decision.
The study cited was a retrospective cohort study based on administration of prescription NSAIDs with a mean duration of therapy of 80.2 days. The study did not identify which NSAIDs were prescribed nor the doses that were prescribed.
The results from all of the studies related to nonprescription naproxen and its salts reviewed by Health Canada supported the GI safety of naproxen at the recommended nonprescription dose (220-440 mg/day) for short term duration (up to 5 days).
12. Given the controversy in recent years concerning nonsteroidal anti-inflammatory drugs (NSAIDs), especially related to cardiovascular problems, we should be careful about deregulating a new medication in this class. Even though naproxen is associated with less cardiovascular risk than the other NSAIDs, it has a higher risk of gastro-intestinal problems than ibuprofen. In Quebec, regulations require that all drug products removed from Schedule F be placed on the provincial Schedule II (behind the counter in a pharmacy and available from the pharmacist) until the provincial expert committee rules on its status.
As indicated in the response to comment No. 11, studies support the gastro-intestinal safety of naproxen at the recommended nonprescription dose and duration of treatment. Regarding conditions of sale and provincial scheduling of nonprescription drugs, please see the response to comment No. 9.
Implementation, enforcement and service standards
This amendment will be implemented by notifying the general public through publication in the Canada Gazette, Part II, and by notifying both internal and external stakeholders via email of this publication.
This amendment does not alter existing compliance mechanisms under the provisions of the Food and Drugs Act and the Food and Drug Regulations enforced by the Health Products and Food Branch Inspectorate.
Refer to Project No. 1584
Bureau of Policy, Science and International Programs
Therapeutic Products Directorate
1600 Scott Street, Tower B, 2nd Floor
Address Locator 3102C5
S.C. 2005, c. 42, s. 2
R.S., c. F-27
C.R.C., c. 870
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