Format, Content and Dissemination of the Product Monograph A Discussion Document in Support of Consultation Workshop September 11, 12 and 13, 2000

Date: 2000-09-11

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Contact: Policy Bureau Enquiries

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Table of Contents

1. INTRODUCTION
2. BACKGROUND
3. FORMAT AND CONTENT OF THE PM
4. ISSUES RELATED TO FORMAT AND CONTENT
5. CONSULTATIONS TO DATE ON FORMAT AND CONTENT
6. CONSIDERATIONS ON FORMAT AND CONTENT
7. DISSEMINATION OF THE PM
8. ISSUES RELATED TO PM DISSEMINATION
9. CONSULTATIONS ON PM DISSEMINATION
10. NEXT STEPS

APPENDIX A: DEVELOPMENT OF PRODUCT MONOGRAPH PROTOTYPE

APPENDIX B: SELECTED PATIENT INFORMATION MATERIALS

APPENDIX C: LETTER TO STAKEHOLDERS

APPENDIX D: LIST OF RESPONDENTS

APPENDIX E: SUMMARY OF RESPONSES

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I INTRODUCTION

This document provides background information on the issues surrounding the finalization of the new format and content of the Product Monograph (PM) as well the objectives, principles and considerations related to the dissemination/public availability of Product Monographs that are to be the focus of discussion at the multi-stakeholder consultation workshop in Ottawa on September 11, 12, 13, 2000.

II BACKGROUND

The Product Monograph

The Review of the Canadian Drug Approval System, Gagnon 1992, reported that most health professionals find the current PM document difficult to use. This was again confirmed by the results of a TPP questionnaire (February, 1998) which was sent to eighty-six health professionals (physicians, dentists, pharmacists and nurses). Health professionals, patients and the general public require accurate, objective and complete information on drugs approved for use in Canada, to ensure safe and effective use. The PM contains useful scientific information, but the information is not always easily retrievable, does not meet the needs of users, has no standard format and is not easily available to the general public.

The PM is developed by the drug manufacturer according to guidelines developed by the TPP which provide direction on the content and format of the PM. A draft PM is submitted as part of New Drug, Supplemental New Drug, Abbreviated New Drug and Supplemental Abbreviated New Drug Submissions prior to the issuance of a Notice of Compliance (NOC), as well as for Notifiable Changes for which a No Objection Letter is issued. Traditionally the PM has been considered to be the property of drug manufacturers which currently do not consistently disseminate them broadly.

The PM is a factual, scientific document on a drug that, devoid of promotional material, describes the properties, claims, indications, and conditions of use of the drug product and that contains other information that may be required for optimal, safe and effective use of the drug. It is currently used by the sponsor to inform physicians, pharmacists, dentists, nurses, and other health care professionals and, where appropriate, the general public, of the rational use of the drug. Health Canada established PMs 29 years ago as part of the drug regulatory process. Since 1976, PMs have evolved through the development and periodic revision of guidelines for format and content.

The PM serves as a standard against which all professional literature, promotional material, or advertising distributed by the sponsor about the drug can be compared. Without limiting its generality for use as a standard, the PM serves the following purposes:

• It contains all the representations to be made in respect of the new drug as required by paragraph C.08.002(2)(k) and C.08.003(1)(h) of the Food and Drug Regulations;
• It fulfills the requirements for adequate directions for use for new drugs included in a number of Sections having to do with labeling in Parts C, D and G of the Food and Drug Regulations;
• It identifies the information that is to be provided on request when a package insert is not included with a new drug product and a member of the health profession requests information relevant to clinical use;
• It identifies the information, restricted to Section (1) of the PM, that must be provided to the consumer respecting the use of that product;
• It establishes the limitations/parameters for all advertising, representations, and promotional or information material distributed or otherwise sponsored by the sponsor.
• It is used to assess the expectedness of adverse drug reactions (ADR), thereby determining whether ADRs are required to be reported as expedited reports.

III FORMAT AND CONTENT OF THE PM

PM Guidelines

The existing PM Guidelines, "Therapeutic Products Programme Guidelines: Product Monographs", were made available in 1989 and revised in 1990. These can be found at:

www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/guidmain.html#new

Since that time, several related initiatives have been implemented. These include the implementation of the recommendations from the 1992 Gagnon report which focused on changes to enhance the role of the PM to help in safe and effective drug use; the incorporation of new policies with respect to pediatric information and information on drug use in women; integration with Product Licensing; the requirement to incorporate international nomenclature (e.g., MedDRA); and finally, alignment with the new design for the PM proposed in 1998, which was tested via a survey of health professionals. They emphasized ease of information retrieval and clinical relevance.

An October 1994 document "Guidelines for Product Monographs and Package Inserts For Schedule C Drugs" is also available and will be used in the development of any new, compiled Guidelines.

Format and Content of Product Information in the United States

Drug product information is regulated in the United States by specific labeling requirements in the Federal Food, Drug and Cosmetic Act. Information required for professional labeling is similar to the requirements in Canada for PMs, although the US labeling regulations do not include an "information for the consumer" section. In the late 1970s, the US Food and Drug Administration proposed a rule requiring prescription drug manufacturers to produce FDA-approved written material, known as patient package inserts (PPIs), for about 375 prescription medicines. This rule was withdrawn in the early 1980s with assurances from the private sector that appropriate product information would be given to consumers voluntarily.

Private-sector initiatives proved inadequate, however, so the FDA tackled the issue again in 1995 with a new proposed rule: "Prescription Drug Product Labeling: Medication Guide Requirements." The rule evolved into a mandated private-sector initiative to develop and distribute patient-oriented written information leaflets for all prescription drugs, and complete with target dates for the distribution of these leaflets. The private-sector initiative, facilitated by the FDA, is guided by a stakeholder consensus document titled "Action Plan for the Provision of Useful Prescription Drug Information."

The Action Plan reiterated much of what was in the FDA "Medication Guide" proposal. That is, it accepted the proposed criteria by which written information would be judged to determine whether it was useful: the material should be useful, timely, up-to-date, scientifically accurate, unbiased in content and tone, sufficiently specific and comprehensive, and presented in an understandable and legible format that is readily comprehensible to consumers. It also accepted the proposed goals that by the year 2000, written information would be distributed to 75 percent of individuals receiving new prescriptions and, by the year 2006, to 95 percent of individuals receiving new prescriptions.

The action plan also called for the development of a mechanism to periodically assess the quality of written information for patients. As a result, the FDA entered into a contract with the National Association of Boards of Pharmacy (NABP) in 1998 that called for the selection of several state boards of pharmacy who would arrange for collecting, from a sample of pharmacies in their state, medication information materials given with new prescriptions for three commonly prescribed drugs chosen by the FDA. The medication information materials were collected by participating state boards last year, and the final report from the evaluation of these materials is now available.

The NABP studied 300 community pharmacies in eight US states and found that 87 percent of new prescriptions were dispensed with written information and that more than 75 percent of the information sheets received high ratings for quality criteria such as the drug and its benefits, adverse reactions, an unbiased tone and content, legibility, comprehensibility, scientific accuracy and inclusion of a disclaimer. Improvement was needed in directions, contraindications, precautions, storage, general information, details about the publisher and date of publication.

Existing Canadian Format and Content of the PM

The current PM must contain the following information in the order presented: title page, action and clinical pharmacology, indications and clinical use, contraindications, warnings, precautions, adverse reactions, symptoms and treatment of overdose, dosage and administration, pharmaceutical information, availability of dosage forms, information for the consumer, microbiology, pharmacology, toxicology and references or selected bibliography. According to the current PM Guidelines (section 2.12), the information for the consumer section is included in the PM "when deemed necessary". It is left up to the sponsor to determine the content of this section, except in the case of required patient package inserts (PPIs) for six drug groups. These drug groups are: isotretinoin, methotrexate, ticlopidine, nonsteroidal anti-inflammatory drugs, oral contraceptives, and drugs delivered with the assistance of a device.

IV ISSUES RELATED TO FORMAT AND CONTENT

New Format for the Product Monograph

A new draft PM format, developed in 1998, consists of three sections:

Section I - Information for the Health Care Professional

Section II - Scientific Information

Section III - Information for the Patient

As part of an assessment of this draft PM in 1998 a template was developed for section III. However, specific input was not solicited at that time: only Sections I and II have benefitted from extensive stakeholder input (see Appendix A).

Section I and II Templates

Although prior consultations have taken place on the proposed format and content of Sections I and II of the PM, there remain two areas within these sections which require additional input. Identifying these two areas of the PM in particular does not, however, preclude comments and discussion on other components of Sections I and II.

The two areas in question are: the Adverse Reactions component (Section I); and the Clinical Trials component (Section II).

Revising the PM Guidelines

Following the consultation workshop, the guidelines will be revised to be very specific. It is proposed that they could be in the form of a template with appendices added for specific information (e.g. antibiotic sensitivities).

The guidelines would be reorganized to be consistent with the new PM format. In terms of content, the current guidelines provide a good starting point so that an enrichment approach is preferred to a new development approach, for most of the sections. Much of the work in reorganizing the guidelines involves moving information from one section to another to reflect the new format. In some cases, information will have to be presented in tabular or summary form, and the guidelines will have to explain how to do that. In addition, the following additions or revisions to the content and format of the PM must be addressed:

1. Definition and Format and Content sections: These should be revised to take into account the addition of the section on clinical trials and the reorganization of the other sections into a new overall format for the PM.
2. Summary Pharmaceutical Information section: This section at the beginning of the PM summarizes information about dosage form and strength, storage and stability, special handling instructions and availability of dosage forms. In the current PM, this information was found under separate headings. Here, it should be reorganized into a concise table, with explanatory text as required, for easy reference. Some consideration should be given to how the information will be organized in this section, including the format and content of the summary table.
3. Contraindications section:In the current PM, information about contraindications is presented in a descriptive paragraph. Consideration should be given as to how it will be organized in bullet form.
4. Adverse Reactions section:This section should be revised to take into account international initiatives to standardize the presentation of ADR information.
5. Drug Interactions and Laboratory Tests sections: These sections have been taken from the Precautions section in the current PM. They were set out as sections of their own to give the subjects more emphasis. It has been proposed that the information in these sections be presented in table form. Consideration should be given as to how to organize the information.
6. Clinical trials:This section has been added to include clinical trial data (safety and efficacy). Data in support of new indications could be added to this section. In addition, important clinical data could be added in a systematic way to reflect current clinical practice. It is proposed that a working group made up of individuals with expertise in this area be established to develop guidelines for this section.
7. Information for the Patient section: As templates have been developed for Section I and Section II of the PM, a template for section III - Information for the Patient, is required. Guidelines will need to be developed to support the template for this section.

Guidelines for Section III - Information for the Patient

To assist in the workshop discussion on Section III, a resource document has been prepared which sets out: principles of patient information and a draft template. This resource binder containing samples of patient information materials, guidelines and other literature relating to patient information will be available for use at the consultation workshop (see Appendix B for a selection of material from this binder).

As Section III - Information for the Patient will become an integral part of all PMs, and potentially assume the role of PPIs, the current structure of PPIs should be taken into consideration in the development of the template and the guidelines for this section.

As discussed earlier, the US Department of Health and Human Services has accepted an "Action Plan for the Provision of Useful Prescription Drug Information." The Action Plan sets out specific guidelines for content and format of useful prescription drug information that will be useful in guiding the development of a Canadian patient information template.

Also of interest are the 1992 Directive of the European Economic Union that sets out specific requirements for patient information leaflets distributed with new prescriptions in member countries, and the EEUs readability guideline for package leaflets.

In Australia, the Therapeutic Goods Administration (TGA) has required since 1993 that all new prescription products be dispensed with consumer product information (CPIs). The TGA placed the onus on sponsors to supply CPIs and, to assist CPI writers, the Communication Research Institute of Australia has developed usability guidelines.

V CONSULTATIONS TO DATE ON FORMAT AND CONTENT

A TPP questionnaire (February, 1998) was sent to eighty-six health professionals (physicians, dentists, pharmacists and nurses) and included questions relating to the usefulness, availability, format and presentation of the existing PM (see Appendix A for a review of that work).

The proposed format for the PM, along with copies of the original PM for Imitrex and the revised Imitrex PM, was sent to twenty-six of TPP's main stakeholders for comment in July, 1998 (see Appendix C). Seven of the stakeholders responded with comments (see Appendix D). The general consensus indicated support for revising the format of the PM.

VI CONSIDERATIONS ON FORMAT AND CONTENT

The current regulatory framework and environment have given rise to the following issues that should be kept in mind during the consultation workshop. This section serves to highlight, but not analyse the key issues.

Stakeholder Comments

These considerations reflect comments provided by stakeholders on the project as a whole. An account of all the stakeholder comments submitted are themed and summarised in Appendix E.

• Concern that the TPP is undertaking an initiative which some stakeholders consider not to be a priority for the Programme at this time.
• Concern that this initiative will place an extra burden on industry.
• Need to harmonize with other agencies/organisations that either regulate and/or use the information contained in the PM, eg., ICH, PAAB, CPhA.
• Address specific content issues at the same time as proceeding with the format changes.
• Information for the patient should be the responsibility of the manufacturer.
• Confirm which sections of the PM will be available under Access to Information (ATI)
• Address the copyright and ownership implications for both brand name and generic manufacturers.

PM does not meet needs of Health Care Professionals

The Review of the Canadian Drug Approval System, Gagnon 1992, reported that most health professionals find the document difficult to use. This was again confirmed by the results of the aforementioned TPP questionnaire (February, 1998).

Feedback On the New Draft Format of the PM

A new format was developed and tested as part of the 1998 survey. Some of the comments made specifically on the new format were:

• Format quite attractive, easy to locate topics, easy to hone in on required/requested information. New format seems to conform more to clinical practices - the information I want first is at the front. Like the separation of information and science - easier to 'skim'
• Prefer the revised monograph. Well done. Generally easier to read. Easier to find what you want.
• I recently had to prepare a monograph for a product on short notice and decided to use the new format. It actually made my job much easier - information logically fell into the appropriate sections and users of the finished monographs found it very readable. Looks like you are on the right track. Good work!
• Timely revision. Easier to consider "evidence based medicine" with a standard format that is easy to read.

In general, pharmacists appeared to be more critical of the document. This may be due to the fact that they have more access to multiple drug information sources and tend to compare PM information to other monograph style information found in a number of other resources.

VII DISSEMINATION OF THE PM

Consumers/patients are becoming increasingly concerned about the lack of an unbiased Canadian source of information about the risks and benefits of drugs that are approved for use in Canada. They are obtaining information about drugs from a variety of sources that are not always accurate in the Canadian context. Sources are the Internet, which includes largely U.S. sites, and patient information handed out by pharmacists, most of which is generated in the U.S. only some of which is "Canadianized". Even though some drug manufacturers may post some information about the risks and benefits of their particular products on their websites, such information is not always easy to access and may be incomplete. Consumers/patients are looking to the TPP to facilitate access to comprehensive, accurate, impartial Canadian information.

The TPP supports the objective of disseminating PMs broadly making PMs publicly available in Canada. However, the TPP is interested in obtaining input from stakeholders on what mechanism(s) should be considered in achieving this objective. TPP would like to hear ideas about the roles to be played by various parties and the potential impact on those parties.

Current PM Dissemination Activities in Canada

The PM is currently considered a proprietary document and is distributed at the discretion of the product sponsor. As a result of an initiative of the Canadian Society of Hospital Pharmacists, the PM for new drug products is disseminated to drug information centres across Canada. Health professionals can also obtain the PM for a specific product by calling the medical information department of the individual companies. Consumers generally do not have that option. They can obtain the PM from Health Canada only through Access-to-Information procedures.

The main source of PM information is the Compendium of Pharmaceuticals and Specialties (CPS). Most health professionals and some consumers are familiar with the prescribing information section (sections 2.1 to 2.9 of the PM Guidelines) extracted from the PM that is reproduced in the CPS and in accompanying drug advertisements in professional journals. The CPS editorial staff have also included the patient information section of the PM, for those products that have such a section, in a separate section at the front of the CPS. The information is printed in large type and lends itself well to photocopying for distribution to patients. The CPS is distributed free of charge to all physicians in Canada as a result of industry sponsorship. It is sold in bookstores to consumers and is available in both hard copy and electronically. Information from the PM can also be found in health journals and must accompany product advertisements that appear in those journals, according to medical advertising standards.

Patient package inserts (PPIs) are given to patients at the time the drug product is dispensed. As stated previously, PPIs are mandatory for only six different drugs or drug groups. These products represent roughly 10% of the prescription drugs being offered for sale in Canada.

There are other sources of patient drug information available. Their link to the PM is not defined. Examples of these sources of patient drug information are summarized in the table below:

Canadian Drug Information Sources

Type	Source	Example
Sponsor	GlaxoWellcome	Canadian patient package insert (e.g., Imitrex Information for the Consumer)
Sponsor	Whitehall-Robbins	Canadian sponsor-produced patient package insert as required by Health Canada (e.g., Advil Patient Package Insert)
Health association	The Arthritis Society	A disease-oriented patient information site (e.g., Disease-Modifying Anti-Rheumatic Drugs).
Health association	Canadian Pharmacists Association Compendium of Pharmaceuticals and Specialties	Canadian sponsor-produced a) prescribing information extracted from the official PM (e.g., Imitrex Monograph); and b) patient Information (e.g., Imitrex, Information for the Patient) in special section of CPS ( large print)
Health association	Epilepsy Canada	A disease-oriented patient information (e.g., Anticonvulsant Medications)
Third party	Community AIDS Treatment Information  Exchange (Catie)	Patient drug information (e.g. delavirdine)
Third party	PharmaPlus DrugMart Shoppers Drug Mart	Patient information produced by First DataBank, Inc. (e.g. Imitrex patient information sheet)
Third party	Rinfocan	Prescription drug information written by a hospital-based pharmacist in British Columbia (e.g., enalapril patient information).
Third party	The Virtual Drugstore	Patient drug information from the New Drug Database, written by Canadian pharmacist Marie Berry (e.g., Zolmitriptan Patient Information).
Third party	Various independent Canadian drug stores	Canadian drug information for consumers from an unidentified database (e.g., Imitrex Patient Information)
Third party	Canada Drug Guide Project	Consumer-friendly health information sponsored by the Canadian Health Transition Fund (e.g., Heartburn patient information)

US Drug Information Sources

Type	Source	Example
Sponsor	Roche USA	Accutane prescribing information from US sponsor's web site (Accutane, complete product information).
Sponsor	Pfizer U.S. Pharmaceuticals	Information for US consumers produced by Pfizer U.S. Pharmaceuticals (e.g., Viagra Patient Information)
Health association	US National Diabetes Information Clearinghouse	Consumer information (e.g., Medicines for People with Diabetes)
Health association	American Medical Association Migraine Information Center	Disease-oriented information produced by The Journal of the American Medical Association (e.g., Overview of Drugs to Treat a Moderate to Severe Migraine Attack).
Third party	USP DI and Micromedex, Inc.	USP DI Advice for the Patient produced by the US-based Micromedex Inc. (e.g., Clarithromycin Patient Information)
Third party	MedicineNet	Consumer drug information written by US physicians (e.g., Imitrex Patient Information)
Third party	Multum Information Services	Patient drug information. (e.g., Celecoxib Patient Information).
Third party	RxList	Patient Information produced in the US by RxList, the Internet Drug Index, a HealthCentral.com Network Site (e.g., Sumatriptan Patient Information)
Third party	Stay Healthy	Drug information for the consumer from the First DataBank database (e.g., Imitrex Patient Information)
Third party	The PDR Family Guide to Prescription Drugs	Patient information taken from the US-based Physicians Desk Reference
Third party	Mayo Clinic	Drug information supplied by Micromedex Inc. and taken from the USP DI's Advice for the Patient volume (e.g., Sumatriptan Information for the Patient)
Third party	DrugInfoNet	US Patient Package Inserts supplied by Merck $\& Co. and made available on the Internet by DrugInfoNet (e.g., Zocor Patient Information)

International drug information sources

Type	Source	Example
Sponsor	GlaxoWellcome Australia	Consumer Medicine Information Consumer medicine information produced by sponsor (e.g., Imigran Patient Information)
Sponsor	GlaxoWellcome (NZ)Ltd.	Patient Information data sheets (e.g., Imigran Public Product Information).
Health association	New Zealand Rheumatology Association	Consumer drug information (e.g., Methotrexate Patient Information)
Third party	eMC	Electronic versions of Data Sheets and Summaries of Product Characteristics (SPCs) in the United Kingdom for medicines.(e.g., Pariet and Lustral Patient Information)

PM Dissemination Activities in the United States

The onus for disseminating product information in the United States rests with product sponsors. Most sponsors extract "prescribing information" from the official monograph and make this information widely available in printed form and on their web site. Prescribing information derived from the PM is also available in the Physicians Desk Reference. The US Pharmacopeia Drug Information publication provides product information that expands beyond the PM and attempts to include Canadian products.

As discussed earlier, the production and distribution of useful prescription drug information has been a subject of much discussion since 1995 when the Food and Drug Administration made a proposal that would regulate the content of patient information pamphlets and would set targets for distribution. The voluntary "Action Plan for the Provision of Useful Prescription Drug Information" has resulted in more than 85% of new prescriptions being dispensed with "useful" written prescription information.

VIII ISSUES RELATED TO PM DISSEMINATION

Public Interest in Broad Dissemination of the PM As outlined above, health professionals and consumers are becoming increasingly concerned about the lack of an unbiased Canadian source of information about the risks and benefits of drugs that are approved for use in Canada.

Consumers are increasingly becoming partners with health care practitioners in making treatment choices and both health professionals and consumers are seeking objective information about prescription drugs. Health professionals and consumers are looking to the Therapeutic Products TPP to facilitate the access to comprehensive, accurate Canadian information.

Public dissemination of the re-formatted PM would:

• assist in achieving safe and appropriate prescribing on the part of the health professional and informed participation in the therapeutic plan on the part of the patient.
• provide health professionals with access to the PM of all drug products, not just those products whose sponsors financially participate in the CPS.
• provide health professionals with detailed scientific and clinical trial information about specific patient groups, thus allowing them to better determine if a specific patient being treated is likely to respond to the drug therapy, compared with the study group.
• ensure a standardized format to make information retrieval easier and the presentation more consistent. Health professionals and consumers will know what to expect and where to find it.
• meet the demand for comprehensive information for the consumer. Although the technical information may not be understood by all consumers, it would potentially stimulate and encourage further discussion of the information with a health professional.
• serve as a guide for direct-to-consumer advertising (that is, information in direct-to-consumer advertisements would have to be consistent with patient information section of the PM; the advertisement could refer the consumer to the PM for additional information.)
• provide the basis for the package insert for all drugs. Currently, there are only select products requiring a package insert (e.g. oral contraceptives).
• promote transparency of the TPP-sponsor information partnership. Health professionals and the public would have the same information as the government and the sponsor.

If the PM are not publicly disseminated, health professionals would continue to rely on the CPS and on other tertiary sources for information about safe and appropriate prescribing and use of prescription medicines. Consumers would have to rely on whatever information they obtain or can find depending on their individual ability to seek out information. Some would continue to make Access-to-Information requests. Since the content of patient information is currently largely unregulated, there is great variability in content and in comprehensiveness of information given to consumers.

Principles in Relation to Information Dissemination, including PMs

In 1996, the TPP initiated a regulatory review process to address the issue of direct to consumer advertising (DTCA). A multi-stakeholder consultation workshop was held in June 1996, with representatives from the provinces, health practitioners, academe, the pharmaceutical industry, private insurers, consumer advocacy groups, professional associations and the media. Workshop participants were asked to provide advice and opinions on the objectives for DTCA. Their comments were compiled into a set of guiding principles. These principles, listed below, go beyond advertising and also apply to the provision of information on therapeutic products.

Ensuring Consumer Safety: information should be evidence-based and balanced with respect to risks and benefits.

For each drug, the PM clearly sets out indications, clinical uses, dosage, adverse reactions, contraindications, warnings and precautions, special handling instructions and other information for health professionals to ensure that the medication is appropriately prescribed. The proposed patient information section would distill the important patient-useful information from the health professional section and present it in an understandable and practical format.

Assisting Consumers in Making Informed Choices: information should include a discussion of the disease to be treated, and alternate drug and non-drug therapies.

The patient information section of the PM would explain in clear and understandable language what the medication is used for, how to use it, and reasons why it may not be used. It would also inform the consumer about precautions and about possible adverse reactions.

Respecting Health Care Practitioners: information should support and enhance the consumer - practitioner relationship.

The patient information section of the PM would be consistent with the section for health professionals, ensuring uniformity of the information communicated to the patient by physicians, pharmacists and other health professionals. The patient information section would also contain a statement encouraging discussion with a health professional about the prescription medication.

Addressing Health Care Costs: information policies should strive to optimize drug therapy and should not result in increased health care costs.

The proposed reformatted PM would clearly state for both the health professional and the patient what the medication is used for, who should not use it, how to use it, and what precautions and possible side effects a health practitioner and patient should be aware of. This would ensure that the medication is used appropriately and with full knowledge of what to expect, thereby eliminating waste resulting from unused medication. The information in the PM would also allow the patient to participate in the selection of a lower-cost medication based on a knowledge of indications and clinical uses.

Ensuring Accountability: information policies should be assessed by measuring their impact in terms of improved health outcomes.

The patient information section of the PM would present information about what to expect when taking the medication, allowing the patient to understand both the positive health outcomes to expect and the possible negative health outcomes. Important therapeutic endpoints would be described such as target blood glucose levels for anti-diabetic medications or onset of relief with analgesic medications.

Acknowledging the Canadian Environment: information policies may consider international practices, but they must be "made in Canada".

The PM reflects both Canadian and international clinical evidence in support of those indications that are approved in Canada. The medical and pharmaceutical terminology in the PM is consistent with Canadian nomenclature. Units of measure, such as drug serum levels or strength of the medication, are consistent with Canadian metric standards.

IX CONSULTATIONS ON PM DISSEMINATION

The consultation workshop will be the first opportunity for the TPP to consult stakeholders on the issues surrounding the public dissemination of PMs.

X NEXT STEPS

Format and Content of the PM

The revisions of the format for the PM and subsequent changes to the PM guidelines are seen as a high priority for TPP. Following the consultation workshop and once the format for Section III has been agreed, staff from each Bureau in the TPP, except for the Medical Devices Bureau, will participate in the planned core and sub-working groups that will revise the guidelines.

The core group will manage the process and provide overall guidance, while the working groups will provide expertise for the various sections of the PM. Each working group will conduct a thorough review and/or development of new sections (e.g., clinical trials, patient information) of their assigned section(s) of the PM guidelines.

Where necessary, the advice and assistance of specific clinicians, scientists, etc, external to TPP will be sought. Each working group will present their recommended changes to the core group. All sections will then be brought together and reviewed for consistency by the core group. As this will have a significant impact on internal reviewers, ongoing consultation with these individuals will be important to collect all the necessary feedback and concerns.

All sections of the revised PM guidelines will be translated, printed and distributed as a package for consultation with stakeholders.

Dissemination of the PM

Facilitating the public availability of the revised PM is also a high priority for the TPP. It will be important to have the reformatted PMs into the hands of health care professionals, patients and consumers in a timely fashion. There are several issues to address with respect to public dissemination:

What to disseminate? There are a number of possible options including:

• The PM in its entirety
• Specific sections of the PM

Who to disseminate? There are a number of possible options including:

• Dissemination by the sponsor
• Dissemination by the TPP
• Dissemination by a Third Party

When to disseminate? There are a number of possible options including:

• when the NOC is granted
• when the product is launched (i.e. at time of marketing)
• when new products are approved or older products revised

How to disseminate? There are a number of possible options including:

• individual paper copy of the PM
• publications, such as CPS
• through the intermediary of a health professional, for e.g. pharmacist, physician
• Internet

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Comments, and/or questions of clarification in respect of this document can be submitted prior to the consultation workshop. Where possible, these inquiries will be addressed prior to the workshop however, there may be instances when the matter may most appropriately be dealt with as a part of the workshop proceedings.

Please direct your inquiries to:

Marion Law
Chair, Product Monograph Working Group
TPP, Health Canada

phone: (613) 946-0372
fax: (613) 941-5841
e-mail: marion_law@hc-sc.gc.ca

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APPENDIX A: DEVELOPMENT OF PRODUCT MONOGRAPH PROTOTYPE

PURPOSE

As part of a larger Information Dissemination initiative, the Therapeutic Products Programme (TPP) identified a requirement to revise the Product Monograph (PM) to better meet the information needs of health professionals, including physicians, pharmacists, nurses and other practitioners and where appropriate, the consumer. The aim being to create a more logically organized, user-friendly document, with an emphasis on ease-of-use.

The study that was undertaken was limited to the format and flow of the monograph. The purpose of the study was to develop a new PM template and ascertain, with a small group of users, the acceptability of the suggested changes. The TPP will then subject the new format to a much broader consultation.

It was recognized that while the PM concept applies to a variety of products within the TPP, including radiopharmaceuticals, medical devices, contrast media, etc., the purpose of this study was to focus on drug products. Further work will be required in the other product areas regarding monograph format.

APPROACH

The study built on previous efforts by the TPP to revise the PM and to update the guidelines. All available background and historical information on PM format were first reviewed. A prototype monograph was then prepared and together with a questionnaire, was distributed to a predetermined number of health care professionals.

The Information Dissemination Steering Group (Steering Group) of the TPP provided guidance and support to Carruthers-Czyzewski and Associates (Consultants) during this project. A four-month time frame was provided in which to complete the study.

Information Gathering

The Steering Group directed the consultants to build on previous work done on the PM. The background information used in the development of the prototype included:

• Product Monograph Guidelines, 1989;
• A study on the usefulness of the Product Monograph, Robert Ferrier, 1990;
• Drug and class monograph, 1991. A TPP working group chaired by
  Dr. Sam Licata;
• M-12: Information Dissemination, Panacea Consulting Inc,
  August 4, 1994;
• An Independent Review of Australian Product Information,
  Wendy Bloom and Associates, April 1997
• European Monograph, Summary of Product Characteristics
• Product Monographs from Britain, Australia and the United States.

To acquire as much information as possible and to enhance understanding of the background information and its relevance for the project, interviews were conducted with key individuals who could provide in-depth knowledge on the evolution of the PM and experience with user needs. Preparation of a Prototype Monograph The Consultants proceeded to develop a prototype PM that, while taking into consideration the regulatory requirements of the PM, provided an enhanced information tool for health care users. The prototype was developed in consultation with the Steering Group.

In the proposed new format, the information in the PM has been divided into three sections:

• Section I contains the information required for the safe and appropriate prescribing, dispensing and administering of the medication;
• Section II contains more in-depth and complete scientific/research information such as toxicology and data from animal studies and human clinical trials. It complements and extends the information contained in Section I.
• Section III contains information for the patient.

The proposed new format was first applied to three different PMs. The Steering Group then selected one drug for the analysis. Imitrex® was chosen because it is well presented based on the current guidelines and the product is familiar to a broad group of users. Permission was obtained from the sponsor of Imitrex® to use its PM within the context of the study.

Questionnaire

To determine if the modifications made to the PM format met the information needs of the user, the prototype, together with a questionnaire were distributed to a target group of health professionals.

Wherever possible, questions were given a weighted value in order to quantitatively assess support for the proposed modification. The questionnaire asked whether the proposed change resulted in a "more useful format with information easier to find" and the following scale was used: 1 = not useful, not easy to find; 2 = useful, easy to read; and 3 = very useful, very easy to read.

The target group consisted of 86 health care professionals, including physicians, pharmacists, nurses and dentists. The group included a cross section of practice types (e.g., general practice, specialist, academia, research, etc) and representation from all regions of Canada. It was not possible to include all medical specialties as a result of the small sample size. Each user received a package consisting of the questionnaire (English or French), the revised Imitrex® PM and the original Imitrex® PM (to assist in evaluating the proposed format changes). After the due date, all non-responders were followed-up with a telephone call.

Analysis

Table 1 provides a description of the users who completed the questionnaire. Of the professional groups, pharmacists had the highest response rate at 73.3% while the other groups came in, at or near 50%. There was not much variance amongst the practice types within the professional groups (e.g., general practice and specialist for physicians), with the exception of drug information pharmacists and other pharmacists (100%). One would expect these groups to be more familiar with the PM, which may explain their perfect response rate.

Table 1 Characteristics of the Respondents

Practice type	Distributed	Response Number	Response Rate	Total
Physician General Practice Specialty	431825	20812	44.4% 48%	46.5%
Pharmacist Community Hospital Academia Drug Information Other	30143436	2292236	64.3% 66.6% 50% 100% 100%	73.3%
Nurse	9	5		55.5%
Dentist	4	2		50%
Total				59.3%

The high response rate indicates that health care professionals were willing to take time out of their busy schedules to complete the questionnaire, which in itself is interpreted as an endorsement for the PM review process. In fact, one pediatrician took the time and initiative to organize a group of 10 physicians (including the following practice types: pediatrics, internal medicine, emergency medicine, medical toxicology, clinical pharmacology and general practice) and obtain their feedback in preparing his response.

The overall response to the proposed changes was overwhelmingly supportive. In general, however, pharmacists appeared to be more critical of the document. This may be due to the fact that they have more access to multiple drug information sources and tend to compare PM information to other monograph style information found in a number of other resources.

Analysis of the questionnaire included a judgement as to whether level of usage of the Compendium of Pharmaceuticals and Specialties (CPS) accounted for differences in acceptance of the proposed changes. More than half of the respondents use the CPS on a daily basis (58%), while most respondents use the CPS at least once per week (91.3%). Daily use of the CPS is higher for general practitioner physicians (62.5%) compared to specialist physicians (42%). Of the pharmacists, 82% refer to the CPS on a daily basis.

The responses of those who did not use the CPS daily did not differ significantly from the responses of those who did use the CPS regularly. In some cases, the comments from the respondents refer to the information content of the PM, rather than the format.

Format Changes

A PM template has been developed taking into account all of the proposed format changes. For each of the proposed changes, the results of the questionnaire as well as the suggested changes are provided.

Proposed Format

SECTION	CONTENTS
I: Information for the health care professional	Dosage Form Summary Table Indications And Clinical Uses Action Contraindications Warnings And Precautions Adverse Reactions Drug Interactions & Effects On Laboratory Tests Dosage And Administration Storage And Stability Special Handling Instructions Symptoms & Treatment Of Overdose Availability Of Dosage Forms
II Scientific information	Pharmacology Clinical Trials Pharmaceutical Information Toxicology
III Information for the patient	To be determined

Section I: Format Changes and Respondent Suggestions

1. Dosage form and strength

In the revised PM, a summary table of dosage form, strength and nonmedicinal ingredients is placed at the very beginning of the PM. In the original monograph, this information is found at the end of the prescribing information in two different sections, Availability of Dosage Forms (dosage form and strength) and Pharmaceutical Information (nonmedicinal ingredients). Health care professionals often require this information at time of prescribing/dispensing and it is difficult to locate at the end of the PM.

Suggested Change:
Provide a summary table of dosage form, strength and nonmedicinal ingredients at the beginning of the PM.

2. Indications and clinical uses

In the revised PM "Indications and Clinical Uses" is presented as the first subsection. In the original PM it followed "Action and Clinical Pharmacology".

Suggested Change:
Place "Indications and Clinical Uses" at the beginning of Section I.

3. Contraindications

In the revised PM, the information is presented in bullet form. In the original PM, contraindications are listed in a descriptive paragraph. Putting the information in bullet format makes it easier to locate required information.

Suggested Change:
Present "Contraindications" in bullet format.

4. Warnings and Precautions

In the revised PM, "Warnings and Precautions" is presented as one subsection. In the original PM, "Warnings" and "Precautions" are separate subsections.

The Consultants were of the opinion that most users could not differentiate information presented in these two subsections. In addition, in their review of various monographs, they found that some information is presented in both "Warnings" and "Precautions" with slightly different wording, and that unless the user read all sections, some important information could be missed.

Suggested Change:
Combine "Warnings" and "Precautions" into one subsection and present the information by importance and by organ system.

5. Adverse reactions

No changes were brought to this subsection in the revised PM.

The Consultants suggested that the adverse effects from clinical trials be located in Section II, with a summary of the most common and severe reactions (incorporating post-approval surveillance data) appearing in Section I. There was some concern about the heading (Adverse Effects) appearing twice in the monograph; however, it proposed to lend itself to regular updating as per the Product Licensing Framework. The Steering Group identified other priorities, such as international standards, that influence to a great extent the ability to bring any changes to this section. Nevertheless, questions 5a to 5f attempted to determine users' need for information on adverse reactions and explored the possibility of making certain modifications.

Suggested Change:
The TPP will need to take leadership in the area of Adverse Effects: there is not a consensus amongst the target users; international standards may limit the ability to modify the format and content of this information; and the Product Licencing Framework will determine the availability of information.

6. Symptoms and Treatment of Overdose

In the revised PM, this section was unchanged but the questionnaire explored the possibility of moving it to Section II. In the original PM, this subsection includes symptoms of overdose and proposed treatment. For many drugs, where information specific to the drug is not available (i.e. no experience with an overdose situation), the treatment proposed is empiric and usually based on the drug class as a guide.

The Consultants were of the opinion that users (particularly CPS users) no longer relied on the PM as a source of information on poison treatment. Rather, they suggested a greater reliance on poison control centers. This assumption was tested in the questionnaire. The results show that the PM and Poison Control Centres are equally important sources of information on symptoms and treatment of overdose for all users. This result may have been influenced by the Other group, which although they considered the information important, it is not likely they would be consulted for this type of information.

Suggested Change:
Keep "Symptoms and Treatment of Overdose" in Section I.

7. Drug Interactions and Effects on Laboratory Tests

In the revised PM, this is a new subsection. In the original PM, Drug Interactions are included in the "Precautions" subsection.

The Consultants were of the opinion that this is important clinical information that needed to be highlighted.

Suggested Change:
Create a subsection for "Drug Interactions and Effects on Laboratory Tests".

8. Dosage and Administration

In the revised PM, this information was put into two subsections, "Dosage" and "Administration". In the original PM, this information is presented as one subsection "Dosage and Administration".

The Consultants felt that this change would make it easier to quickly locate of information, depending on the specific, for e.g. physician might focus on dosage whereas the nurse could focus immediately on administration issues.

Suggested Change:
Maintain "Dosage and Administration" as one subsection and organize the information by dosage form.

9. Special Handling Instructions

This is proposed as a new subsection to provide instructions for handling drugs such as toxic substances. While it did not apply for revised PM, the questionnaire explored the possibility of creating a new subsection.

Suggested Change:
Create a new subsection for "Special Handling Instructions".

Section II: Format Changes and Respondent Suggestions

1. Pharmacology

In the revised PM, the "Pharmacology" subsection, including mechanism of action, was placed in Section II. In the original PM, a brief description of the mechanism of action and clinical pharmacology appears as the first subsection of the monograph and is part of the prescribing information extracted in the CPS monograph. The Consultants felt this information is often acquired from other sources before the drug is prescribed and therefore not required in Section I.

Suggested Change:
Move "Clinical Pharmacology" from "Action and Clinical Pharmacology" to Section II. Retain the "Action" subsection in Section I for anti-infectives and certain other drugs. The types of drugs for which this will apply will be determined in the guideline review.

2. Clinical Trials

In the revised PM, a new subsection is created for clinical trial data (safety and efficacy). In the original PM, there is no clinical trials heading, and the placement of information is not consistent. Within the Product Licence Framework, data in support of new indications could be added to this section of the PM; in addition, important clinical data could be added in a systematic way to reflect current practice. The Consultants were of the opinion that this information is relevant and propose it be included in Section II.

Suggested Change: Create a new subsection for "Clinical Trials".

3. Toxicology

In the revised PM, this section was unchanged but the questionnaire explored the possibility of making certain modifications. The Consultants felt that, although this information is of most interest to researchers, it is important to provide this information and that perhaps a table format would capture most of the important details for reproducibility of results and might be preferred.

Suggested Change:
Further consultation is required in order to best define the format.

Section III: Format Changes and Respondent Suggestions

1. Information for the patient

The entire "Information for the Patient" section from the original monograph was reorganized and reformatted to emphasize the relevant and important elements of patient education. This was based in part on an FDA document Draft Action Plan for the Provision of Useful Prescription Medicine Information, Nov 20, 1996.

The proposed format could serve as a starting point; currently there is no standard format. The quality of the presentation of this information in the monographs varies from poor to excellent. Implementing this format would bring all monographs to an equal level.

Suggested Change:
Include the new format for the "Information for the patient" in the prototype PM as the first step in standardizing the information. Further consultation is required with user groups involved with patient education to obtain input regarding objectives, format, language, type of information, responsibility, etc.

Other Considerations

1. Electronic availability

In the questionnaire, the feasibility of acquiring PM information electronically was explored with users.

All physicians said they would access information electronically at least occasionally, if not often. Pharmacists seemed to be less interested in this manner of accessing the PM; this is likely because of limited workplace access to on-line technologies at this time.

The feasibility of disseminating the "Information for the Patient" section if it was available electronically was also explored. Over half of the respondents (45.8% occasionally and 39.6% often) would. The main concern for some was that at this point in time, their workplace was not set up to do this activity.

2. Other comments

There were a number of unsolicited comments. Overall, respondents were overwhelmingly supportive of the changes. None of the unsolicited comments suggested that the PM was not a useful document.

APPENDIX B: SELECTED PATIENT INFORMATION MATERIALS

Purpose and principles of a patient information section of the Product Monograph

As part of the revision process for the Product Monograph, the role of the patient information section must be reviewed and redefined. There are at least two possible roles for the patient information section:

1. To empower the patient by making useful information about drug products available in simple, easy-to-understand language.
2. To serve as a guideline for the information content of direct-to-consumer advertising.

Key considerations in development of a patient information template include:

1. Type of information:

• What information from the other sections of the Product Monograph should be made available to patients in the patient information section?

2. Language and format: Consideration should be given to the language and format such that the information is readily understandable and easy to find. Key points to consider include:

• A design that presents information in a readable and legible format
• Language use that is consistent with a Grade 6 to Grade 8 reading level.
• The use of illustration, pictograms or icons that made the information more understandable, particularly to individuals with low literacy levels.
• The use of both English and French, and, in some instances, other common languages in Canada.
• A consistent use of standardized phrases for heading so that consumers will become familiar with the layout and find information easily.

3. Length of document: The length of the document should reflect a balance between the need for comprehensive useful information about a drug and the need to be concise.

4. Link to Product Monograph: Consideration should be given to identifying clear links back to the Product Monograph to ensure that the same information is disseminated to both health professionals and consumers. Moreover, clear links to the Product Monograph would lend greater credibility and authority to the document.

Information for the patient: a proposed template

1. What is the medication?

Identification of the product, including:

• The brand name and common name
• A full statement of the active ingredients and excipients
• The pharmaceutical form and the contents by weight, by volume or by number of doses.
• The pharmacotherapeutic group
• The name of the product sponsor.

2. Is there anything I should be warned about before taking this medication?

Warnings: A prominently displayed statement that is consistent with or derived from any "black box" warnings that are relevant to the consumer.

3. What is this medication used for?

Indications: A section that identifies a medicine's indication for use, including pediatric indications, if any.
Unapproved indications: Indications for which a health professional may prescribe the medicine but which have not been approved in Canada.

4. How does this medication work?

Clinical pharmacology: An overview of how the medication works and what the patient can expect as a result of taking it.

5. How quickly will the treatment start to work?

Statements about expected effects of therapy, including:

• How long before the medicine will take effect (how long before patient will feel better or before symptoms will improve)?
• Should the patient continue to take the medicine when they feel better or symptoms disappear?

6. Who should not take this medication?

Contraindications: Information on the circumstances under which the medicine should not be used for its labeled indication.

7. What should I be aware of before taking this medication?

Precautions: A statement or statements of precautions the consumer should take to ensure proper use of the medication, including:

• Activities to avoid
• Risks to the mother and the fetus or infant if taken during pregnancy
• Risks to the pediatric or senior populations
• Additional precautions for safe and effective use of medication

8. Are there drugs or foods that might interact with this medication?

Drug and other interactions: A statement listing the possible interactions with other drugs, alcohol, tobacco and food.

9. What unwanted effects might occur when I take this medication and what should I do about it?

Adverse reactions: A statement of the symptoms that indicate possible adverse reactions from the use of the medicine and a course of action for each side effect (i.e. see your doctor only if severe, or in all cases.)

10. Will this medication become less effective with time, or might I develop dependence?

Tolerance or dependence potential: A statement of the risks, if any, to the patient of developing a tolerance to or dependence on the drug product.

11. How should I take this medication?

Proper use: Information on the proper use of the medicine, including the following:

• The dosage, the method and, if necessary, the route of administration
• The frequency of administration
• The duration of treatment
• Importance of following dosing instructions
• Special administration instructions
• What to do in the case of an overdose
• What to do in the case of withdrawal effects

12. What happens if I miss a dose?

Missed dose: Information on what to do it a dose of the medication is missed.

13. How do I store the medication?

Storage instructions: Information on how to store the medication

14. How do I know if the medication is still good?

Information about the expiry of a medicine, including

• How to find the expiry date of the medicine
• How to recognize signs of deterioration of the medicine

15. What else should I know about this medication?

General information, including statements:

• encouraging discussion with a health professional
  
• saying that medication is for use by patient only · disclosing the name of publisher of the information
• disclosing the date of publication or most recent revision or review for adequacy and accuracy of content

16. Where can I get more information about this medication?

A disclaimer stating the following:

• Information is a summary only and doesn't contain all information about drug
• Health professional has more information that addresses both the medicine and the patient's specific health needs.
• Health professional can provide and answer questions about information in the professional labeling.

Other options:

• A summary section containing the medicine's approved indications, critical aspects of proper use, significant warnings, precautions, contraindications, serious adverse reactions, and potential safety hazards.
• A 1-800 number to provide information to patients with impaired vision, marginal or no literacy, or whose first language is not English.

DRUG INFORMATION TOO COMPLEX, CONFUSING FOR CONSUMERS

COLUMBUS, Ohio -- The information in prescription drug leaflets and consumer-oriented magazine advertisements is too complex for most people, a recent study suggests.

In experiments at Ohio State University, scientists found that people who reviewed complex drug information leaflets were significantly more confused, doubtful and overwhelmed than people who read simple or intermediate-level materials.

"These results suggest that people can get overloaded with prescription drug information," said Jon Schommer, one of the authors of the study and an assistant professor of pharmaceutical administration at Ohio State.

"When you get overloaded, you can actually make poorer decisions than if you had an adequate amount of information. If you read a drug leaflet that's burdening you with information and you begin to feel confused, you might become indecisive, misinterpret what the information is saying and take the medication in the wrong way."

These results are especially pertinent given the increasing amount of technical drug information available to consumers, Schommer said.

"There's an information explosion," he said. "There are drug CD-ROMs. People are buying the Physician's Desk Reference like crazy. Direct-to-consumer ads for prescription drugs are showing up more and more in general interest publications. The question is whether the average consumer of prescriptions can handle the complexity of this information without detrimental consequences."

Schommer conducted the study with former graduate student Sarah L. Labor and Dev S. Pathak, Merrell Dow professor of pharmacy and marketing at Ohio State. He will present the group's findings November 8 in San Diego at the annual meeting of the American Association of Pharmaceutical Scientists.

For their study, Schommer and his colleagues designed five experimental drug leaflets about an allergy medication. The leaflets contained two to 12 topics. The simplest were written at a sixth-grade level and the most complex were written in the language of a medical professional.

The researchers distributed these leaflets randomly to 94 patients at the Ohio State University Medical Center clinic and asked these patients to read the leaflet and complete a short questionnaire. In the questionnaire, the patients indicated whether the number and complexity of topics in the leaflet was "too much," "too little" or "about right." In addition, they indicated how the information made them feel about their drug-taking decisions, how it made them feel emotionally and whether it was useful and practical.

The results:

Patients who read the two-topic, professional-level leaflet were the most confused, doubtful and overwhelmed about their drug-taking decisions. In contrast, patients who read the 12-topic, sixth-grade-level leaflet reported the lowest levels of confusion and doubt. "Patients want drug information that covers many topics, but they want it provided in simple language," Schommer said.

Although they were more confused, patients who read the more complex leaflets were not any more frustrated and angry than patients who read simpler leaflets. In addition, patients who read the more complex leaflets were no more likely to regard them as useless or unhelpful than other patients.

"This suggests that people can stop themselves short of emotional responses to varying amounts of information," Schommer said. "It also suggests people might think any kind of information is better than no information at all."

Overall, these results indicate that prescription drug information leaflets and magazine advertisements should be reevaluated, Schommer said. The number of topics covered in these materials is fine for most patients, he said. But the complexity is not.

"The technical information might be helping with liability concerns, but it might actually be hurting from a patient care standpoint," he said. "It might be having detrimental consequences in terms of drug-taking errors that result from patient confusion."

Schommer will test that idea in upcoming research. In the meantime, however, he suggests that pharmaceutical companies design information leaflets and drug ads that include both technical information and a summary of that information written at an eight-grade level. That way, both liability issues and patient understanding can be served.

"Is that burdensome for pharmaceutical companies, which already have many requirements to follow? We don't know. We're raising the question," he said.

Contact: Jon Schommer, (614) 292-3011
Written by Kelly Kershner, (614) 292-8308

LEAFLETS WITH NSAIDs DON'T WARN USERS CLEARLY: A UK SURVEY, February 1999

Andrew Herxheimer
Emeritus Fellow, UK Cochrane Centre
Address for correspondence:
9 Park Crescent, London N3 2NL
e-mail: Andrew_Herxheimer@compuserve.com

ABSTRACT

Objective
To examine how far Patient Information Leaflets (PIL) for non-steroidal anti-inflammatory drugs (NSAIDs) explain their safe use and warn about gastrointestinal side effects.

Design
Survey of PIL for 29 major NSAID preparations listed in the BNF.

Outcome measures
Does the PIL explain that:

[1] the NSAID relieves symptoms but does not influence the course of the disease?
[2] the use of high doses or of the strongest drugs to obtain complete relief increases the risk of serious adverse effects?
[3] if any 'stomach' symptom occurs, the patient should stop taking the medicine or at least reduce the dose, and seek advice?

Results
[1] only 4 of the 29 PIL clearly explained that the NSAID only relieves symptoms.
[2] None of the PIL discouraged efforts by the patient to obtain complete relief with the drug.
[3] 13 of the 29 PIL did not mention stopping the medicine if stomach symptoms occurred; ten advised stopping only if serious symptoms occurred (ie bleeding or severe stomach pain); six advised stopping, and seeking advice if any stomach symptom occurred.

Conclusion
The information in PIL should be more complete, clearer, and consistent for all NSAIDs. This requires urgent efforts by the Medicines Control Agency and the manufacturers.

INTRODUCTION

The commonest serious adverse effect of non-steroidal anti-inflammatory drugs (NSAIDs) is upper gastrointestinal bleeding, which lands thousands of mostly older people in hospital each year. The risk varies up to 20-fold with the type and dose of NSAID. How can we minimise it and help patients to do so?

Del Favero concluded in a recent review: "The main way to reduce risks from NSAIDs should .. be to limit their use rather than attempt to lower the relative risk further by co-prescription of other agents." ¹ We must explain to patients that the risk is much higher with NSAIDs than with most common medicines. They should understand three points:

[1] An NSAID is for symptomatic relief and does not influence the course of the disease, ² so that it should be used only when arthritic pain or inflammation is troublesome. Some patients with severe rheumatoid arthritis however need an NSAID all the time to be able to get up, get dressed, etc. These are a minority among NSAID users.

[2] To accept partial relief is better than to aim for complete relief by using high doses or the drugs that carry a relatively high risk of damaging the gut.²,³ Complete relief can also encourage over activity which may cause more wear on joints. Other measures - eg support, warmth, rest, paracetamol - instead of or in addition to the NSAID can help to ease pain.

[3] Stomach discomfort or pain, indigestion, or heartburn is a signal to stop taking the drug if possible, and if it is not possible then to use an H2-blocker, a proton pump inhibitor, or misoprostol together with it. In a recent small study 36% of patients taking an NSAID who had bled had noticed epigastric pain beforehand, as against 15% of takers who had not bled, a significant difference.⁴ Though dyspepsia is in general a poor guide to peptic ulceration, this has not been shown for ulcers or erosions related to NSAID use. Patients who cannot stop taking the NSAID should promptly ask their doctor for advice.

Few prescribers or pharmacists now emphasize and explain these points. If patient information leaflets [PIL] accompanying NSAIDs were to do so clearly and consistently, then doctors, pharmacists, nurses and others would be asked about them and able to back them up routinely. The points are not clear in the current leaflets because the regulations and guidelines for PIL do not require their inclusion. The texts drafted by individual manufacturers tend to be accepted by the Medicines Control Agency [MCA] if they are in accord with the Summary of Product Characteristics [SPC] or Data Sheet. Additional information may however be included in a PIL at the MCA's discretion if it is considered helpful to users and does not promote the product. Until now the MCA has done little to improve the consistency of SPCs or data sheets and PIL within therapeutic categories. This article examines how far current leaflets for NSAIDs express the three important messages for patients. A preliminary unpublished survey made early in 1997 was briefly referred to in a BMJ editorial.

AIM AND METHODS

The aim was to survey patient information leaflets for the main NSAID tablet and capsule products listed by brand names in the British National Formulary (No 35, March 1998), including all those marketed by major companies. For drugs marketed under many brands (eg ibuprofen, indomethacin, mefenamic acid) at least the leading brand was examined (see Table). All 11 PIL for NSAIDs reprinted in the 1998-99 ABPI Compendium of Patient Information Leaflets6 were looked at there. If the compendium did not include the leaflet, the manufacturer was asked for a copy. The cut-off date was 31 October 1998. Each PIL was examined for the presence of the three points listed above. The placing of the points within the PIL, and any emphasis, were noted.

RESULTS

The texts of 29 PIL were examined (see Table).

[1] The PIL for Feldene capsules and tablets states under the heading "What is your medicine for?" that the product "is used to relieve some symptoms caused by rheumatoid arthritis, osteoarthritis and ankylosing spondylitis (rheumatism of the spine) such as swelling, stiffness and joint pain. It does not cure arthritis and will help you only as long as you continue to take it." None of the other PIL was as explicit as the second sentence. Two leaflets (for Lodine and Ponstan) mention symptom relief. Many others use a phrase like "help to relieve pain and joint inflammation" without making it clear that the effect is temporary.

[2] The second basic message, that patients should accept alleviation rather than try to achieve complete relief of symptoms, was found in none of the leaflets. Many PIL encourage regular dosing, or imply that the dosage prescribed by the doctor should be followed exactly. None said explicitly that a patient should take the medicine only for a symptom that is troublesome or expected to be so, and not otherwise.

[3] The third, to stop taking the medicine if a gastrointestinal symptom occurs, is expressed in some form in 16 of the 29 leaflets (see Table). But in 10 of these 16 the warning applies only if the patient vomits blood or passes it in the stool, or has severe stomach pain. The six others tell the patient to stop if any 'stomach' symptom occurs, and nausea, vomiting, heartburn, indigestion are commonly mentioned. The warning to stop comes under the standard heading "After taking [your medicine]". It is clearest and strongest in the PIL for Voltarol - in bold type and prominently placed. It is also in bold for Preservex and Rheumox. In the leaflets for Indocid and Ponstan the warning is given but without emphasis, in the case of Indocid in a place where it is easy to miss.

The other 13 leaflets do not mention stopping and the message is a variation on "if [the symptoms] are severe or get worse" or "if they cause you distress" to "tell your doctor" or "contact your doctor or pharmacist for advice". For obviously serious events many but not all leaflets use the word "immediately" or "urgently", others say "as soon as possible".

Of other points that were noted incidentally, one was startling: the leaflet for Fenopron, prepared in 1996, states "Anti-inflammatory medicines help to reduce swelling and bone damage if you have arthritis" (my italics). This will surprise most rheumatologists.

DISCUSSION

This survey has found great inconsistencies in the information and warnings given in the leaflets, and serious deficiencies in the content of most of them. It is striking how greatly the leaflets differ. It appears that most have been prepared by people quite distant from patients and clinical practice and without any coordination by the ABPI. This is supported by a 1996 survey of 43 ABPI member companies: 26 of them reported that they did not consult patients, users of products or consumer panels when drafting patient information, but 17 did so at least sometimes.⁷

Neither the regulatory authorities nor the industry appear to be trying to achieve consistency, although it is plainly necessary to help patients (many of whom take different NSAIDs at different times) and the pharmacists and prescribers who advise them. They should note that two years ago an important initiative to develop consistency was taken in Australia, with the agreement of the national regulatory authority, the Therapeutic Goods Administration. Pharmaceutical companies marketing NSAIDs there, encouraged by the multidisciplinary PHARM (Pharmaceutical Health and Rational Use of Medicines) committee have jointly produced "Core Consumer Medicine Information" (CMI) for the various dosage forms of NSAIDs. ⁸ The statements in this core document are optional, but "CMI writers are encouraged to use [them] and follow the [Australian] Usability Guidelines wherever possible". Many are doing so. The Core CMI is comprehensive and clear: it is a major advance that should be emulated and developed elsewhere. It also offers a practical method for systematically updating and improving the information.

Consistency is however a separate point from content, and the Australian CMI only partly covers the three points examined in this survey. The concept of symptom relief [1 above] (as opposed to either maintenance treatment or "cure") is only rather vaguely understood by most people, and is not often clearly explained to patients. It should be, and with it the point that the decision whether a symptom needs relief belongs to the person who has the symptom, no one else.

The idea that the benefit/risk relationship changes with the dose of most drugs [2] has never been explicitly put across to the public, though it is implied in the routine warning "do not exceed the stated dose". More important, most doctors and pharmacists still seem to doubt that patients are capable of changing the dose of prescribed medicines on their own initiative - if they have the requisite knowledge.

The differing interpretations of moderate gastrointestinal symptoms [3] either as warning of potentially serious harm, or as possibly acceptable but perhaps worth discussing with the doctor, may stem from consideration of different sorts of patients and inappropriately lumping them together. Severely disabled patients with rheumatoid arthritis who depend on an NSAID for normal living and mobility may find it impossible to stop, and be willing to accept both unwanted effects and risk as a small price to pay. On the other hand almost all patients with osteoarthritis can stop, and will be wise to do so or at least to reduce their dosage. More of them are also older and run a higher risk of bleeding or perforation than younger NSAID users. The information in PIL should cater for both types of patient, and enable each user to understand which message applies to her or him.

It is worth noting that several leaflets carry the 'Crystal Mark' of the Plain English Campaign. This is commendable, but it relates to the form and not the content of the messages.

CONCLUSION

The content and form of patient information leaflets is plainly a regulatory matter. The implementation of the European Directives concerning them has improved both by specifying the points that leaflets must include, and by imposing a standard arrangement, but it seems to have led the MCA and industry to believe that they have done and are doing enough. The example of the NSAIDs shows that much greater effort is needed to improve and standardize the information that patients are offered about their medicines. Australian manufacturers of NSAIDs have shown that it can be done; they include subsidiaries of well known multinational companies. Of course this applies not only to NSAIDs: other major classes of drugs urgently need to be examined in analogous ways.

Acknowledgment: I thank all the manufacturers for their cooperation in sending me copies of their PILs.

References

1.Del Favero A. Anti-inflammatory and antipyretic analgesics and drugs used in gout. In Aronson JK, van Boxtel CJ. Eds. Side Effects of Drugs Annual 20. Amsterdam: Elsevier, 1998: 96-97.

2.British National Formulary No 36 (September 1998): 426, 428 box 2.

3.Biscarini L. Anti-inflammatory analgesics and drugs used in gout. In Dukes MNG. ed. Meyler's Side Effects of Drugs, 13th ed. Amsterdam: Elsevier, 1996: 207.

4. Wynne HA, Long A. Patient awareness of the adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs). Br J Clin Pharmacol 1996; 42: 253-256.

5. Herxheimer A. Many NSAID users who bleed don't know when to stop. BMJ 1998; 316: 492.

6. ABPI (Association of the British Pharmaceutical Industry). ABPI Compendium of Patient Information Leaflets 1998-99. London: Datapharm Publications, 1998.

7. Anonymous. The drug information gap. Health Which? 1996: 167-70. (October)

8. Australia. Core CMI for NSAIDs. Sydney: Australian Pharmaceutical Manufacturers Association, March 1997 (7 pages).

Table - What the leaflets say:

A. whether the medicine is for symptom relief

B. what the patient should do if s/he has 'stomach' symptoms -
1 = stop taking the medicine and tell the doctor
2 = stop taking the medicine, but only in case of stomach bleeding or severe stomach pain, otherwise just tell the doctor
[2*= (also) stop if stomach discomfort or heartburn occurs for the first time]
3 = stopping is not mentioned in relation to 'stomach' symptoms

Generic name	Brand	Date	A. Symptom Relief	B. 'Stomach' warnings
1 ibuprofen	Brufen 400 nc	11/97	Not clear	1
2 ibuprofen	Fenbid nc	7/98	No	3
3 aceclofenac	Preservex	1/97	Not clear	1
4 acemetacin	Emflex nc	?	No	3
5 azapropazone	Rheumox nc	2/95	No	2
6 diclofenac	Voltarol	6/96	No	1
7 "	Diclomax	1/97	No	3
8 "	Volsaid nc	11/95	No	3
9 " +misoprostol	Arthrotec nc	2/97	No	2
10 diflunisal	Dolobid	3/96	Not clear	3
11 etodolac	Lodine nc	12/96	Yes	2
12 fenbufen	Lederfen	7/96	Yes	3
13 fenoprofen	Fenopron nc	10/96	No	3
14 flurbiprofen	Froben nc	8/97	Not clear	2
15 indomethacin	Indocid	6/96	No	1
16 ketoprofen	Orudis	10/96	Not clear	2
17 "	Oruvail	11/96	Not clear	2
18 "	Ketocid nc	3/98	Not clear	2*
19 mefenamic acid	Ponstan nc	7/96	Yes	1
20 meloxicam	Mobic	12/95	No	3
21 nabumetone	Relifex	12/96	Not clear	3
22 naproxen	Naprosyn nc	9/97	No	2
23 "	Nycopren nc	3/96	Not clear	3
24 " +misoprostol	Napratec** nc	10/91	No	3
25 phenylbutazone	Butacote nc	4/98	No	1
26 piroxicam	Feldene nc	9/97	Yes	3
27 sulindac	Clinoril	12/96	No	3
28 tenoxicam	Mobiflex nc	1/97	Not clear	2
29 tiaprofenic acid	Surgam	10/96	No	2

nc= not in 1998-98 ABPI Compendium of PILs
**A new leaflet for Napratec awaits MCA approval

---

APPENDIX C: LETTER TO STAKEHOLDERS

Therapeutic Products TPP
Tunney's Pasture
A.L. # 0702A
OTTAWA (Ontario)
K1A 0L2

July 10, 1998

98-017656

To: Industry and Health Care Associations

This is further to the letter of February 20, 1998, which informed your association of the Therapeutic Products Programme's (TPP) initiative to revise the format and presentation of Drug Product Monographs (PM).

As indicated in the previous letter, a copy of the Imitrex PM, revised to reflect the new presenta- tion and format was sent, with a questionnaire, to 86 users, comprising physicians, pharmacists, dentists and nurses. I am pleased to report a 59% response rate to this questionnaire. All of the responses indicated a high degree of satisfaction with the proposed new presentation. This level of response and support for the proposed changes indicates to us, the importance of this initiative to revise the PM to better meet the needs of users.

The purpose of this letter is to invite you to comment on the revised presentation and format of the prototype and the proposal to adopt this prototype as the standard PM template for all new drugs in Canada.

I am providing you with a copy of the report of the project on PMs. This will provide information on the proposed new PM format, the approach taken with this project and results of the survey.

I would appreciate receiving comments by August 31, 1998.

It is our intention that on receipt of comments concerning the format and presentation of the prototype PM, the PM template will be finalised by October 30, 1998, and this will be followed by the development of new PM guidelines to be completed early in 1999.

Should you wish any further information about this initiative, please contact Beth Pieterson at (613) 957-4786.

Original signed by

Dann M. Michols
Director General

APPENDIX D: LIST OF RESPONDENTS

ASSOCIATIONS	INDUSTRY	OTHER
Canadian Drug Manufacturers Association (CDMA)	Hoffmann La Roche (2 responses)	Pharmaceutical Advertising Advisory Board (PAAB)
Canadian Society of Hospital Pharmacists
Nonprescription Drug Manufacturers Association of Canada (NDMAC)
Pharmaceutical Manufacturers Association of Canada (PMAC)

APPENDIX E: SUMMARY OF RESPONSES

• General agreement with proposed format and presentation
  (Sections I and II).

All six respondents acknowledge the need to revise the format and presentation of the PM and are of the opinion that the proposed changes to the PM are acceptable and appropriate. These changes will make the PM a more a useful document which will improve access to information about drugs. Two respondents further indicated that there is a need for more specific guidelines to be in place and the provision of a template would be useful.

One respondent indicated that there is a need to standardise the drug information that is available and the new format is a good starting point. This respondent was of the opinion that consumers would be the group most likely to seek online access to information and that it is important to pursue this method of delivering product information.

• Concern that the TPP is undertaking an initiative which some stakeholders consider not to be a priority for the Programme at this time.

Although there was general agreement that the PM needs to be revised, two respondents questioned whether this is a TPP priority at this time. They consider that it may not be the best time to undertake this initiative when reviewer resources appear to be very thin. These respondents consider that a better use of resources would be to help expedite the availability of new drugs in the marketplace.

• Concern that this initiative will place an extra burden on industry.

Two respondents expressed concern about the impact of implementing this initiative. Their membership have extensive product lines and it is their opinion that reformatting the PM could impose a significant burden. There is a concern from one respondent that, if this proposed template is adopted, it will result in newer approved products adopting the revised format, while older products (even within the same class or category) still retain the current format. This will create confusion for the end users until all PMs have been converted.

One other respondent indicated the importance of defining the provisions and time lines for updating existing PMs, along with any proposed fees that may also be imposed. All of the respondents indicated that this initiative will necessitate an extra workload for industry and it demands careful consideration of time and cost involved.

• Need to harmonize with other agencies/ organisations that regulate and/or use the information contained in the Product Monograph, eg., ICH, PAAB, CPhA.

One respondent pointed out the importance of linking this project with other related initiatives to ensure harmonization in the move towards addressing the provision of product information and labelling. The goal of this activity should be directed toward global uniformity. Input from all interested parties should be considered when developing the new revised PM, paying attention to harmonisation with other countries and the ICH process.

Two respondents reminded the TPP to consider that most health professionals consult the Compendium of Pharmaceutical Specialities (CPS) and not the PM. Therefore, it is their opinion that it is important to have a single, uniform format for all drug PMs. If the format of the PM is altered and the CPS does not follow suit, then the purpose of revising the format is defeated. This could lead to the CPS choosing to publish only Section 1, (Prescribing Information), thus eliminating information such as clinical pharmacology, which is of major importance to health professionals. These respondents want the TPP to carefully address this issue and to determine whether the CPS or the PM is used as the commonest source document by health professionals. In either instance, familiarity with the source document format becomes of major importance.

The respondents indicated that this consideration provides more support for efforts to be made to adopt a harmonized global labelling format for prescribing information, rather than developing another Canadian only requirement. Another benefit to this would be the simplifying and harmonizing of the review of labelling material with that of other countries.

One other respondent pointed out that the PAAB (Pharmaceutical Advertising Advisory Board) code for advertising parallels the current PM guidelines, particularly with respect to prescribing information. As these guidelines provide the source of information used for advertising drugs to health care professionals, this respondent reminded the TPP to consider the impact any changes to the guidelines may have on advertising. This respondent also added that this initiative may be an opportunity for the TPP to consider what information should be available as advertising and if this should be revised or expanded. It was also noted that the mechanisms used to make this information available may also impact on advertising policy.

• Address specific content issues at the same time a proceeding with the revised format.

One respondent suggested that the proposal should be refined to include other value-added changes to the PM. This should consider not only format changes but appropriate content issues too and these changes should be done simultaneously. Another respondent is of the opinion that key items which need to be addressed at this time, along with the revised format and presentation are, Adverse Events, Toxicology, and Information for the Patient. Two respondents indicate that the TPP Report states that " the PM is a factual, scientific document.....devoid of promotional material." These respondents want assurance that comparative claims are not considered "promotional" or inappropriate for a PM. The respondents recognise that this is a content issue and not a format issue, but consider this to be an appropriate time to address the issue as the PM guidelines undergo revision. The respondents are also of the opinion that it is necessary for the PM guidelines to be consistent with the comparative advertising guidelines currently being developed within the Programme. The two respondents who raise this issue want to have comparative claims permitted in the PM.

Two respondents expressed concern that the inclusion of pharmacoeconomic data in the PM, would be beyond the scope and mandate of the TPP.

One respondent indicated that it may be difficult to determine what clinical trial information should be included in the PM. Clinical trial data will presumably be required to support the information in Section I, therefore it may be useful to cite references for the data provided in this section.

It is recognised that Section I of the prototype PM constitutes the prescribing information. Two respondents want clarification that portions of Section II can be included in a package insert at the discretion of the drug manufacturer. One respondent wants to know if generic drugs approved without bioequivalence data will be requires to state this in Section II of the PM.

• Information for the patient should be the responsibility of the manufacturer

Two respondents requested clarification that the section for information for the patient will not be mandated for all products, but will be decided on a product-by-product basis, probably during the review process. Currently, it is understood that any information for the patient will be supplied by the manufacturer in the form of a package insert and that this requirement applies only to some products. One respondent went further to suggest that it may be inappropriate to include information for the patient in a document which is typically only provided to health professionals. This respondent indicated that perhaps patient information should be provided in a separate document.

Both these respondents agreed that it would be beneficial to the patient if the TPP establishes a general guideline for information to be provided to the patient, but the format and design, (with the exception of non steroidal anti-inflammatory drugs (NSAIDs)), should remain flexible and be left to the discretion and judgement of the drug manufacturer.

One respondent indicated that a specific "Information for the Patient" section could have implications for nonprescription drugs, particularly prescription to nonprescription switches that have inserts. It is their view that industry should take the lead in defining the format.

Two respondents wanted assurance that Section III (Information for the Patient) would apply to generic manufacturers also.

• Confirm which sections of the PM will be available under Access to Information (ATI).

Two respondents requested clarification that requests for the PM through ATI will encompass all three proposed sections of the PM.

· Address copyright and ownership implications for the brand name and generic manufacturers

One respondent indicated that if the Information to the Patient section is copyrighted by brand, the generic sponsor cannot provide the same information and this has implications for approval of the PM if this information is to be considered mandatory.

Another respondent indicated that there is a need to have assurance from the TPP that Section III (Information to the Patient) also applies to generic manufacturers.

COMMENTS SPECIFIC TO THE PROPOSED FORMAT

SECTION I

Information for the Health Professional

General Comments

• Two respondents requested the inclusion of a table of contents, with one of the respondents further suggesting that the table of contents should follow the cover page to facilitate information retrieval.
  
• One respondent suggested that the guidelines should define whether tables or narrative are acceptable. This should be standardised and not left to the manufacturers' or reviewers' preference.
  
• One respondent indicated that, in the proposed PM, nonmedicinal ingredients (NMIs) are listed three times. It is suggested that these be stated only once, preferably at the beginning of the document.
  
• Two respondents proposed that if a subsection is not applicable, it is not omitted but rather a statement to that fact is included (e.g. Special Handling in prototype Imitrex PM)
  
• One respondent recommended that an "Actions" subsection, as well as clinical results from efficacy studies, be incorporated for all drugs in Section I. The reason given that if this is listed only in Section II, it may not be published in the CPS and health professionals may not have ready access to this important information.

a) Dosage form and strength

One respondent suggested removing the list of NMIs from the dosage form summary table since many drugs have numerous NMIs the inclusion of which, upfront, would be cumbersome. This group felt a table of contents could guide the user to the location of NMI information in the PM.

One respondent suggested removing the quantity, ie., number of ampoules per box from this subsection as this information may change periodically and is available from other sources (price list or wholesaler). This respondent proposed the following wording "For packaging configurations, see published price list".

One respondent indicated that consideration should be given to removing this subsection altogether and instead provide complete information in the chart, at the beginning of the PM.

b) Indications and clinical uses

One respondent was of the opinion that it is preferable to have the order of content revised to show "Indications and Clinical Uses" first, followed by "Dosage and Administration", then "Contraindications", etc.

The same respondent noted that under the "Indications and Clinical Uses" subsection, there is provision for what the drug is not indicated for. They point out that this information is provided elsewhere in the monograph or is not present due to the fact that there is no supporting data available from the sponsor. It is this group's opinion that this requirement does not belong in the indications subsection because users could misinterpret this to mean that there is no scientific information available on other uses. This could be a disservice to practitioners in situations where a sponsor has chosen not to pursue clearance for minor off label indications, but where, in fact, there may very well be excellent literature representation of such additional uses.

c) Contraindications

One respondent suggested deleting any introductory statement in this subsection and using bullet points only, for ease of view.

d) Warnings and Precautions

Two respondents supported the proposal to combine the warnings and precautions subsections, but cautioned that the aspect of liability must be considered, especially if the aim is to harmonize with other countries. It was also pointed out that nonprescription drug labelling requirements have traditionally separated warnings and precautions on the labelling. If the requirements of the new PM format influence nonprescription drug labelling, further consultation will be required.

Another respondent agreed that combining warnings and precautions was a useful idea and proposed that presentation order should be based only on importance. Precautionary statements linked to warning statements should be presented together such that the precautionary statement immediately follows the warning statement. General precautions and catch-all statements would appear at the end of the subsection.

e) Adverse Events

One respondent felt a list of adverse drug reactions (ADR) would limit the reporting of adverse events considered to be "unexpected" and limit the usefulness of the TPP database for establishing a safety profile for marketed drugs.

Another respondent indicated a preference for the Adverse Drug Reaction subsection in Section 1 to include Clinical and Post-marketing experience for easier reference by health professionals.

One respondent disagreed that adverse effects from clinical trials be located in Section II. This respondent was of the opinion that adverse effects from clinical trials and post market spontaneous reports should be described in one subsection and suggested that adverse effects of higher incidence be presented in tabular format. Those of lower incidence would be listed in narrative form.

f) Symptoms and Treatment of Overdose

Two respondents recommended that this subsection be moved to immediately follow the Dosage and Administration subsection (before Storage and Stability and Special Handling Instructions) since it is more relevant to the dosing and administration of the drug.

g) Drug Interactions and Effects on Laboratory Tests

One respondent preferred that Drug Interactions should remain under Precautions.

Another respondent suggest that this section be moved to follow Warnings and Precautions and before the Adverse event listing. The reason given that as with Warnings and Precautions these issues are usually considered prior to prescribing as opposed to adverse events which occur after prescribing.

Three respondents indicated that tabular presentation for this subsection should be encouraged.

Two respondents indicated the need for confirmation that the information in the subsection "Effects on Laboratory Tests" signifies laboratory test values and not drug interference with the outcome of biochemical/ diagnostic tests. If this is the case, this respondent recommended that Drug Interactions be separated from Effects on Laboratory tests with the former appearing after Warnings and Precautions. The discussion of Effects on Laboratory Tests should remain under adverse effects.

h) Dosage and Administration

One respondent indicated that the location of this section appeared to be appropriate, however, it is recommended that it should not be organised by dosage form. This would be repetitive for a product with multiple indications. This group recommended organization by indication, then dosage form within each indication section.

i) Special Handling Instructions

Two respondents were of the opinion that the subsection on Special Handling Instructions is too removed from the Dosage and Administration subsection and could be overlooked. Retaining this information where it is currently found, is more appropriate from a safety point of view.

SECTION II

Scientific Information

General Comments

• One respondent suggested an alternative name for this section could be - Detailed Scientific Information
• The same respondent recommended the order of presentation to be: Pharmacology, Clinical trials, Pharmaceutical Information and Toxicology.

j) Clinical Pharmacology

One respondent offered the opinion that moving clinical pharmacology from " Clinical Pharmacology and Actions " to a subsection for Pharmacology in Section II, and retaining an Actions subsection in Section I for only certain drugs (eg., anti-infective) is not in keeping with the stated goal of ease of use and retrievability.

Another respondent also felt that an "Actions" subsection should be maintained for all drugs in Section I. If this subsection is in Section II, and the CPS chose not to publish Section II, this information will not be available to health professionals. Another respondent recommended that an "Action" subsection as well as clinical results from efficacy studies should be incorporated for all drugs into Section I.

k) Clinical Trials

Two respondents indicated support for the inclusion of a subsection for clinical trials. It is their opinion that this is long overdue. Both groups indicate the importance of having this reviewed consistently throughout the TPP and consider the guidelines can assist in the interpretation of requirements for this subsection.

l) Toxicology

Two respondents consider that clinicians are generally not interested in toxicology and pharmacists rarely refer to it. These groups point out that Canada is the only country where this is required on labelling. Consideration should be given to removing this subsection. Alternatively consideration should be given to using a format similar to the one used in the US Package Insert.

Another respondent felt it would be useful to have a summary of the pharmacology and pharmacokinetics of the drug in Section I. This group felt that this would help the health professional interpret some of the drug interactions.

Two respondents indicated that the use of tables to present toxicology and pharmacology data should be encouraged even although several other respondents preferred narrative format.

SECTION III

Information for the Patient

General Comments

One respondent questioned the appropriateness of including a section for "Information for the Patient" in the PM as this document is typically provided only to health professionals and then usually only on request. This respondent suggested that information for the patient should be provided as a separate document, such as a package insert.

The same respondent did not support the inclusion of the "checklist" in the this section. It is their opinion that this information is typically provided to the patient by either their doctor (verbally or with a product sample) or by the pharmacist (verbally or from their drug chain computer system). In the former case, the doctor has presumably already taken into consideration the information affecting the choice of the product for the patient. In the latter, the physician has already prescribed, and the pharmacist has presumably already filled the prescription. This group believe the information should be provided as a narrative for the patients' information.

The same respondent is of the opinion that the heading "Lifestyle Considerations" is not strong enough for the important information in that subsection, such as not driving due to drowsiness.

One respondent questioned the appropriateness of the Side Effects table and the "management" of adverse reactions; it could be dangerous for a patient to discontinue or keep taking the medication without consulting their physician. It would be safer to inform patients that if they experience certain adverse reactions, they should consult their physician immediately.