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Guidance Document Acetaminophen Labelling Standard

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Contact: Natural and Non-prescription Health Products Directorate

September 15, 2015

Notice

Our file number: 15-108939 - 956

Draft Revised Guidance Document: Acetaminophen Labelling Standard Released for comment

A draft version of the Health Canada Revised Guidance Document - Acetaminophen Labelling Standard is now available for a 75-day comment period. The labelling standard has been revised based on the outcome of the 2014 acetaminophen review which recommended that the label include stronger alcohol consumption-related warnings and more safety information with regards to the product's content. A copy of the Summary Safety Review - Acetaminophen - Liver Injury is avaliable.

This draft labelling standard, once finalized, will replace the October 28, 2009 Acetaminophen Labelling StandardGuidance Document. The updated labelling standard includes a Product Facts Table that will provide safety information in an easy-to-read format and uses plain language, so that consumers can more easily identify products that contain acetaminophen, understand the risks of liver injury and use the products as directed. The table also includes alcohol-related directions and clearer identification of products that contain acetaminophen.

Once Health Canada has had an opportunity to review all the comments received, the revised final labelling standard and a clear implementation plan will be published.

Comments on the draft acetaminophen labelling standard should be submitted in the attached template by November 29, 2015 to the following address:

Natural and Non-prescription Health Products Directorate
Health Products and Food Branch
2936 Baseline Road
Qualicum Tower A
Postal Locator: 3303B
Ottawa, Ontario  K1A 0K9

Facsimile: 613-954-2877
E-Mail: NNHPD_Consultation_DPSNSO@hc-sc.gc.ca

Guidance Document Acetaminophen Labelling Standard

Published by authority of the Minister of Health

Date Adopted: 2015/07/17
Effective Date: XXXX/XX/XX

FOREWORD

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. They also provide assistance to staff on how Health Canada mandates and objectives should be implemented in a manner that is fair, consistent and effective.

Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. These alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this document, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidance documents.

TABLE OF CONTENTS

1. Introduction

This labelling standard describes the requirements necessary to receive marketing authorization (a Drug Identification Number (DIN)) for non-prescription oral analgesics containing acetaminophen as a single ingredient and in combination with caffeine and/or with codeine. Preparations containing codeine for paediatric use are not acceptable under this labelling standard.

2. Medicinal Ingredients

Table 1: Drug Medicinal Ingredients and Dosage
Medicinal ingredient preferred name Dosage Units (adult ≥12years)Footnote a Dosage Units (children <12 years) Footnote b Specific Regulatory Requirement
Acetaminophen 325 mg 80mg/mL or 160 mg/5mL
  • C.09.020 (1), (2) of the Food and Drug Regulations (FDR);
  • A liquid dosage form is to be either of the children's standard dosage units per mL for drops, or per teaspoon (5 mL) for other liquid formulations. C.09.022 (4), (5);
  • An accurate measuring device shall be provided and must be capable of accurately delivering 0.5 millilitres of the children's drops. C.09.022 (6)
500 mg   The label must state this is not a standard dosage unit.Footnote c
650 mg   The label must state this is not a standard dosage unit.Footnote c
Caffeine 15 or 65 mgFootnote d Not applicable Acetaminophen and caffeine are acceptable in combination products. C.09.021 (1) of the Food and Drug Regulations (FDR)
CodeineFootnote e 8 mg (solid)

20 mg/30 mL

(liquid)Footnote e

0 mg May be combined with adult dosage of acetaminophen + 15 mg caffeine per dosage unitFootnote f

3. PHARMACEUTICAL FORMS

3.1 Acceptable:

  • Immediate release solid oral dosage forms such as tablets, caplets, capsules, chewable tablets, effervescent tablets, granules or powder.
  • Oral liquid formulations such as solutions, suspensions, syrups, drops, elixir.

3.2  Unacceptable:

  • Modified dose release (e.g. liquid extended release, solid oral sustained release, bi-layer formulations or enteric coated products).
  • Products that require evaluation of animal sourced ingredients (e.g. animal tissue based gelatin capsules, where a valid European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability or equivalent is not provided).
  • Other dosage forms: e.g. chewable liquid filled capsule, powder dosage form intended for direct application to the mouth, thin strips, lollipops, popsicles/freezer pops, etc.

4. USES

To help prevent dosing errors, acetaminophen-containing products may not be concurrently labeled for:

  • both adults and children (>12 years) and children (<12 years); OR
  • both infants (<2 years) and children (>2 years).

4.1   Acceptable Indications

Pain reliever or fever reducer

Antipyretic:

  • Temporarily relieves fever.

Analgesic:

Temporarily relieves minor aches and pains due to:

  • headache / migraine
  • arthritis or rheumatism
  • pre-menstrual  / menstrual cramps
  • toothache
  • muscular sprains and strains
  • common cold and flu
  • immunization

4.2   Unacceptable Indications

The following indications for acetaminophen products are excluded and would require a review outside of the labelling standard. These include but are not limited to:

  • severe pain;
  • treatment of arthritis, rheumatism;
  • rheumatic fever;
  • migraine and associated symptoms (nausea, sensitivity to light and/or sound, etc.);
  • neuralgia;
  • pain relief adjuvant/enhancer;
  • mental alertness/prevents drowsiness/stimulant;
  • enhancement of motor/cognitive performance;
  • sleep aid;
  • sedation.

5. DOSAGE DIRECTIONS

5.1   Dosage for Adults and Children 12 years and older

Table 2: Dosages for Adults and Children 12 years and older
Dosage UnitFootnote g Single Dose Dose IntervalFootnote h MaximumFootnote i Daily Dose Maximum Daily Dosage Units
325 mg 1 or 2 x 325mg every 4 - 6 hours 4000 mg 12
500 mgFootnote j 1 or 2 x 500 mg every 4 - 6 hours 4000 mg 8
650 mg 1 x 650 mg every 4 - 6 hours 4000 mg 6

Dosage directions for adults and children 12 years and older must state:

  1. For all doses:
    • Take 1 (caplet/tablet/etc.) every 4-6 hours.
  2. For doses where more than 1 dosage unit is recommended (e.g. 325mg and 500mg strengths):
    • If pain or fever does not improve after one (1) (caplet/tablet/etc.), take two (2) (caplets/tablets/etc.) at next dose.
  3. For all doses: Do not take more than 4000 mg (or X tablets/mL/doses) per day.

5.2 Dosages for Children under 12 years

The age-related dosing is provided as per the Food and Drug Regulations (C.01.024) for use when the weight of a child is unknown. The weight-related dosing is also provided.

Table 3: Dosages for Children Under 12 years of Age Footnote k,Footnote l,Footnote m
Age (Years) Single Dose Maximum Daily Dose
mg X 80 mg X 160 mg X 325 mg mg X 80 mg X 160 mg
11 to under 12 480 6 3 1 ½ 2400 30 15
9-10 400 5 2 ½ 1 ¼ 2000 25 12 ½
6-8 320 4 2 1 1600 20 10
4-5 240 3 1 ½   1200 15
2-3 160 2 1   800 10 5
Age (Months)              
12-23 120 1 ½     600 7 ½  
4-11 80 1     400 5  
0-3 40 ½     200  
 
Table 4: Dosages for Children based on WeightFootnote n
Body Weight Single Dose (mg) Maximum Daily Dose (mg)
Pounds (lbs) Kilograms (kg)
72-95 32.0-43.9 480 2400
60-71 27.0-31.9 400 2000
48-59 22.0-26.9 320 1600
36-47 16.0-21.9 240 1200
24-35 11.0-15.9 160 800
18-23 8.0-10.9 120 600
12-17 5.5-7.9 80 400
6-11 2.0-5.4 40 200

Dosage directions for children under 12 years of age must state:

  1. For all doses: Do not take more than XX mg (or X tablets/mL/doses) per day.

5.3 Dosing Considerations

  1. The quantitative declaration of the medicinal ingredients on any panel of the inner and outer labels should be prominently displayed and should be further identified by the therapeutic class or indication listed under Section 4.1, e.g.: "Medicinal Ingredient: Acetaminophen (analgesic/antipyretic) 325 mg"; "Medicinal Ingredient: Acetaminophen (pain reliever/fever reducer) 325 mg".
  2. The labels should declare the recommended single and maximum daily dose, as well as the dosing interval for the product. Maximum daily dose may be expressed as: "Do not take more than XX mg (or X tablets/mL/doses) per day."
  3. For liquid formulations, if a measuring device is provided, the following statement should be included with the directions for use: "Use only the measuring device provided."

5.4 Combinations

Applicants should apply outside of the labelling standard if they wish to combine acetaminophen with medicinal ingredient(s) other than caffeine and/or codeine.

6. WARNINGS

6.1 For outer and inner labels of all acetaminophen products

  • KEEP OUT OF THE REACH OF CHILDREN. C.01.029 (1)Footnote o,Footnote p
  • This package contains enough drug to seriously harm a child (if greater than 3.2 grams of acetaminophen in the package). C.01.029 (2)(c)o, p
  • DO NOT USE with other drugs containing acetaminophen. If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist.
  • DO NOT USE if you are allergic to acetaminophen or any other ingredient in this product
  • Liver warning Footnote q(should be bold font type and in red text):This product contains acetaminophen. Maximum daily dose is X <tablets/caplets> (XX mg) in 24 hoursFootnote r. Severe or possibly fatal liver damage may occur if you take:
    • more than the recommended dose in 24 hours;
    • with other drugs containing acetaminophen;
    • while drinking three (3) or more alcoholic drinks every day.

    Symptoms of liver damage may include:

    • yellowing of the skin/eyes, dark urine;
    • nausea, vomiting, stomach pain;
    • unusual tiredness, and/or loss of appetite.
  • Allergy alert: acetaminophen may cause serious skin reactions. Symptoms may include:
  • skin reddening, blisters, rash.

If any of the above noted symptoms occur, stop use and seek medical help right away.

Ask a doctor before use if you:

  • have a liver disease.

Ask a doctor or pharmacist before use if you:

  • are taking Warfarin-containing blood thinning drugs;
  • are pregnant or breast feeding.

Stop use and ask a doctor if:

  • pain lasts for more than five (5) days Footnote s;
  • fever lasts for more than three (3) days r.

In Case of Overdose: Call a Poison Control Centre or a healthcare professional immediately, even if you do not notice any signs or symptoms. Early symptoms of liver damage may seem like the flu, or you may have nausea, vomiting, stomach pain, loss of appetite, yellowing of the skin/eyes and dark urine.

6.2 Additional Warnings for combinations with 65 mg caffeine

  • Avoid other caffeine containing products. Too much caffeine may cause rapid heart rate, nervousness or sleeplessness.
  • Ask a doctor or pharmacist before use if you have high blood pressure, glaucoma, or overactive bladder syndrome.

6.3 Additional Warnings for combinations with codeine

  • DO NOT USE if you:
    • are allergic to codeine or other opioids;
    • are in your last trimester of pregnancy or breast-feeding. Codeine may cause serious harm to a breastfed baby;
    • have difficulty breathing, have asthma, chronic lung disease or other chronic breathing problems;
    • have suffered head injury;
    • are at risk of blocked intestines;
    • suffer from seizures.
  • The following warning must appear conspicuously on the principal display panel of the inner and outer label:

"This preparation contains codeine and should not be administered to children except on the advice of a physician, dentist or nurse practitioner." (Section 36(1) of the Narcotic Control Regulations).

Ask a doctor before use if you:

  • are taking other medications that can make you sleepy or less alert, for example: narcotic analgesics, sedating antihistamines; or anti-depressants, other prescription drugs, three (3) or more alcoholic drinks every day; or you have recently had surgery under general anaesthesia.

Stop use and ask a doctor if you:

  • feel sedated or drowsy, confused, have shallow breathing or have severe constipation.

7. Product Facts Table: Recommended (Not Mandatory)

Product FactsFootnote t

Active ingredient (in each dosage unit)
Acetaminophen XX mg
Purpose
Pain reliever or fever reducer

Uses

  • Temporarily relieves fever
  • Temporarily relieves minor aches and pain due to:
    • headache/migraine
    • arthritis or rheumatism
    • pre-menstrual/menstrual cramps
    • muscular sprains and strains
    • toothache
    • common cold and flu
    • immunization

Warnings

Liver warning: This product contains acetaminophen. Maximum daily dose is X <tablets/caplets> (XX mg) in 24 hours. Severe or possibly fatal liver damage may occur if you take:

  • more than the recommended dose in 24 hours;
  • with other drugs containing acetaminophen;
  • while drinking 3 or more alcoholic drinks every day.

Symptoms of liver damage may include:

  • yellowing of the skin/eyes, dark urine;
  • nausea, vomiting, stomach pain;
  • unusual tiredness, and/or loss of appetite.

Allergy alert: Acetaminophen may cause serious skin reactions. Symptoms may include:

  • skin reddening, blisters, rash.

If any of the above noted symptoms occur, stop use and seek medical help right away.

Do not use

  • with any other drug containing acetaminophen. If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist.
  • if you are allergic to acetaminophen or any other ingredient in this product.

Ask a doctor before use if you have liver disease

Ask a doctor or pharmacist before use if you are taking blood thinning drug warfarin

Stop use and ask a doctor if

  • pain lasts for more than 5 days
  • fever lasts more than 3 days

If pregnant or breastfeeding, ask a healthcare professional before use.

Keep out of reach of children. This package contains enough drug to seriously harm a child (if greater than 3.2 grams of acetaminophen in the package).
Overdose warning: Call a Poison Control Centre or a healthcare professional immediately, even if you do not notice any signs or symptoms. Early symptoms of liver damage may seem like the flu, or you may have nausea, vomiting, stomach pain, loss of appetite, yellowing of the skin/eyes and dark urine.

Directions

Adults and children 12 years and over
Do not take more than directed (see liver and overdose warnings)

  • Take one (1) (tablet/caplet/etc.) every 4-6 hours.
  • If pain or fever does not respond to one (1) (tablet/caplet/etc.), take two (2) (tablets/caplets/etc.) at next dose.
  • Do not take more than X mg (xx tablets) in 24 hours.

Other information

Inactive ingredients  <List all NMIs>

Questions? Concerns? Call 1-877-XXX-XXXX

8. Other Requirements

8.1 For all products

Declaration of acetaminophen on the product label:

  • Principal display panel:
    • For single ingredient products:
      • "Contains Acetaminophen" should appear in bold font type, font size 10 and in red text in the top right corner of the label.
  • For multi-ingredient products:
    • "Contains Acetaminophen and other Ingredients" should appear in bold font type and font size 10 in the top right corner of the label. In addition, the text for "Contains Acetaminophen" should appear in red.

Declaration of acetaminophen on the Product Facts Table:

  • Acetaminophen should appear in bold font type and highlighted.

Declaration of ingredients for all products:

Section C.01.004 of the Food and Drug Regulations indicates that for single ingredient products and/or products for which a compendial standard exists, the following must be shown on the inner and outer labels:

  • the proper name on the principal display panel immediately preceding or following the brand name in a font size not less than half (1/2) the size of the brand name.
  • a quantitative list of the medicinal ingredients by their proper names, or common names if they have no proper names.
  • a qualitative list of non-medicinal ingredients clearly distinguished from the medicinal ingredients.

Health Canada's Guidance Document: Labelling of Pharmaceutical Drugs for Human Use should be consulted for applicable labelling requirements.

  • At least one of the package sizes available for sale must be provided in a child resistant package and the outer label of all containers that are not child resistant shall carry a statement that the drug is also available in a child resistant package. C.01.031(a)(ii),(b)p
  • For adult use only products containing more than two (2) or three (3) times the standard adult dosage unit or for products that recommend dosages in excess of 650 mg per single dose, and/or 4 grams per day, the label must state that the product is to be used only on the advice of a doctor. (C.01.025)
  • For children's use only products:
    • the drug is to be packaged in a child resistant container. C.01.031(a)(i);
    • the package size is limited to no more than 1.92 grams in the 80 mg dosage units or 3.2 grams in the 160 mg dosage units. C.01.037(c)(d);
    • the word "Children" or "Infants" must appear in bold font type on the principal display panel of all labels to help prevent dosing errors.

Legibility:

Although no specific type size is mentioned in the Food and Drug Regulations, Section A.01.016specifies that all information required to appear on a label must be:

  • Clearly and prominently displayed, and
  • Readily discernible to the purchaser or consumer under the customary conditions of purchase and use.

A person with normal vision, or those with corrective glasses that restore normal vision, should be able to read the information without straining. The colour, contrast, the position, and the spacing of the information are all to be taken into consideration in complying with these requirements.

8.2 For products containing codeine

  • The active ingredients of products containing codeine must appear conspicuously on the principal display panel of the inner and outer label (Section 36(1) of the Narcotic Control Regulations).
  • The inner and outer labels shall show on the upper left quarter of the principal display panel of the label, the symbol "N" in a colour contrasting with the rest of the label or in type not less than half (1/2) the size of any other letters used thereon.

9. SPECIFICATIONS

This labelling standard describes those requirements that are specific to this class of drug.

  • Products must comply with the requirements in the Food and Drugs Act and associated Regulations. It is also noted that all products are subject to Part C, Division 2 of the Food and Drug Regulations.
  • All ingredients (medicinal and non-medicinal) and finished product specifications must meet or exceed the standards described in the publications referred to in Schedule B of the Food and Drugs Act, or equivalent standards.
  • Where no Schedule B monograph exists for the finished product's dosage form, specifications should be similar to those of a comparable compendial dosage form demonstrating the product's identity, potency, purity and quality.
  • Finished product specifications should include tests for identification and an assay with suitable limits for the medicinal ingredient(s). The specifications for all dosage forms should include a description of the dosage form, including organoleptic properties as well as physico-chemical testing (e.g. pH, specific gravity, viscosity), appropriate to the dosage form. Where antimicrobial preservatives are added, an assay with suitable limits should be included. Antimicrobial preservative effectiveness should be determined in order to establish that the product is capable of resisting microbial contamination.
  • Any change to the manufacturing process that impacts the safety and efficacy of the ingredients, such as the use of novel technology (e.g. nanotechnology), requires supporting data and will be reviewed outside the labelling standard.

10. Non-medicinal Ingredients

Non-medicinal ingredients must be chosen from the current Natural Health Products Ingredients Database (NHPID) and must meet the limitations outlined in that database, the Food and Drug Regulations (FDR), and/or the Herbs used as Non-medicinal Ingredients in Nonprescription Drugs for Human Use, when relevant.

11. Special Notes

Codeine, although meeting the definition of a natural health product under Schedule 1 of the NHPR, is excluded under Schedule 2 of the NHPR since it is subject to the Controlled Drugs and Substances Act.

Products making different dosing recommendations or using different dosage units of acetaminophen other than those listed in Tables 1-4 will require an application to be filed outside the labelling standard. Sufficient supporting data, demonstrating the safe and effective use of such a product, will need to be submitted for assessment.

Submissions for combinations of various strengths of acetaminophen, codeine and/or caffeine may require additional supporting data to demonstrate that the combination has a therapeutic advantage over existing products and that the enhanced benefit justifies the potential increased risk that may be associated with the new combination (Zhang WY and Po AL, 1996; Mitchell et al, 2008; Martell BA, 2007). As such, combinations other than those listed under section 2 will require an application to be filed outside the labelling standard.

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  42. United States Food and Drug Administration: FDA Warning on Codeine Use by Nursing Mothers, August 17, 2007. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108968.htm
  43. USP-DI® 2007, 27th Edition, Thomson Micromedex; 2007.
  44. Zhang Wei-Ya. A Benefit-Risk Assessment of Caffeine as an Analgesic Adjuvant. Drug Safety, 2001;24(15):1127-1142.
  45. Zhang WY, Po AL. Analgesic Efficacy of paracetamol and its combination with codeine and caffeine in surgical pain a meta-analysis. Journal of Clinical Pharmacy and Therapeutics, 1996;21:261-282.
  46. Zimmerman H J, Maddrey WC. Acetaminophen (Paracetamol) Hepatoxicity With Regular Intake of Alcohol: Analysis of Instances of Therapeutic Misadventure. Hepatology 1995;22(3):767-772.

Footnotes

Footnote 1

Note that for a liquid dosage form, a standard adult dosage unit is 325 milligram per teaspoon (5 millilitres). C.09.022 (7).

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Footnote 2

C.09.024 of the Food and Drug Regulations.

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Footnote 3

C.09.022 (1),(2) of the Food and Drug Regulations.

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Footnote 4

Codeine may be combined with Caffeine (15 milligram) and a dosage unit of acetaminophen. Caffeine at 65 milligram can be combined with a dosage unit of acetaminophen. Any other combination will be reviewed outside the labelling standard.

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Footnote 5

Pediatric preparations containing codeine are not acceptable under this labelling standard.

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Footnote 6

Section 36. (1) of the Narcotic Control Regulations.

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Footnote 7

C.01.024, C.01.025, C.09.022(1),(2) of the Food and Drug Regulations.  All other recommended doses or dosage units fall outside the scope of this labelling standard.

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Footnote 8

AHFS® 2009; Hersh et al, 2000; Moore et al, 2008; Repchinsky et al., 2002.

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Footnote 9

C.01.021 of the Food and Drug Regulations.

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Footnote 10

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Acetaminophen and caffeine:

  • Single dose (1 or 2 dosage units): 65 milligrams caffeine in combination with 500 milligrams acetaminophen every 4 - 6 hours (Hersh et al, 2000; Ali et al, 2007; Sawynok J and Yaksh TL, 1993; Zhang Wei-Ya, 2001).
  • Maximum daily dose: 520 milligrams caffeine/day.

Footnote11

C.01.024 of the Food and Drug Regulations.

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Footnote 12

Dosing interval: Every 4-6 hours. (AHFS, 2009; Repchinsky et al., 2002)

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Footnote 13

Solid dosage forms, for which half (1/2) or quarter (1/4) doses are recommended, must be adequately scored to ensure proper dosage.

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Footnote 14

Temple, 1983.

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Footnote 15

Must be preceded by a prominently displayed symbol that is octagonal in shape, conspicuous in colour and on a background of a contrasting colour. C.01.029 (3)

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Footnote 16

Above highlighted itemsdo not apply if the product is in an effervescent, suppository or powder form; or packaged in a non-reclosable package containing not more than two adult standard dosage units per package. C.01.031.2(c),(d),(f)

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Footnote 17

Health Canada, Summary Safety Review - Acetaminophen - Liver Injury, July 9, 2015.

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Footnote 18

C.09.011 (b), C.01.024 (3)(b) of the Food and Drug Regulations.

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Footnote 19

C.09.011(a) of the Food and Drug Regulations.

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Footnote 20

The regulatory amendment for a Fact Table for non-prescription drug products would come into force three years after the day of registration in Canada Gazette Part II (June 13, 2017). Next link will take you to another Web site http://gazette.gc.ca/rp-pr/p2/2014/2014-07-02/html/sor-dors158-eng.php

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