Introduction
This OTC Medicine Monograph outlines the requirements for Australian market authorisation of oral medicines containing paracetamol as a single active ingredient when applied for as an OTC New Medicine N2 application. Proposed medicines must comply with all aspects of the monograph relevant to their strength and dosage form to qualify for evaluation as an N2 application.
This monograph should be read in conjunction with the document Requirements for OTC new medicine N2 applications.
Active substance
This monograph only applies to medicines containing paracetamol (CAS no. 103-90-2).
Dosage forms and strengths
Acceptable dosage forms and strengths are shown in the table below.
| Active substance | Dosage strengths | Dosage forms (excludes modified release dosage forms) |
|---|---|---|
| Paracetamol | 250 mg | Soluble tablet |
| 500 mg |
Tablet (uncoated, film coated, gelatin coated, soluble, effervescent) Capsule |
|
| 500 mg | Oral powder | |
| 600 mg | Oral powder | |
| 1000 mg | Oral powder | |
| 24 mg/mL (120 mg/5 mL) | Oral liquid or suspension | |
| 48 mg/mL (240 mg/5 mL) | Oral liquid or suspension | |
| 100 mg/mL | Oral liquid |
Indications
Therapeutic indications for inclusion in the Australian Register of Therapeutic Goods (ARTG)
Temporary relief of pain associated with headache, migraine headache, tension headache, sinus pain, toothache, dental procedures, backache, muscular aches and pains, arthritis, osteoarthritis, rheumatic pain, period pain, fibrositis, neuralgia, sore throat, tennis elbow, and colds and flu. Reduces fever.
For paediatric formulations, in addition to the indications above that are appropriate to the age group, the following indications would be acceptable: relief of pain associated with teething, earache and/or immunisation.
Label indications
All or most of the indications listed above should be included as label indications, as appropriate, depending on the intended age group. Label indications must not be restricted to, or emphasise, a single indication or subset of indications (e.g. cold and flu symptoms only, period pain only or headache only). Terms should be exactly as specified above and qualified by the words "temporary relief of pain associated with...".
Directions for use
Adults and children 12 years and over
Directions for use must be as shown in the table below.
| Dosage form & strength | Single dose | Dose interval | Maximum daily dose |
|---|---|---|---|
| 500 mg tablets, capsules, oral powder | 1-2 tablets, capsules or sachets | every 4-6 hours, as necessary | 8 tablets in 24 hours |
| 600 mg oral powder | 1 sachet | every 4-6 hours, as necessary | 6 sachets in 24 hours |
| 1000 mg oral powder | 1 sachet | every 4-6 hours, as necessary | 4 sachets in 24 hours |
- For soluble and effervescent tablets and oral powders, appropriate instructions for preparation of the dose form must be included.
- Include the statement Do not give to children under x years (where 'x' years is the youngest age for which dosage instructions are included on the labels).
Liquid dose products for children 1 month to 12 years
Dosages must be as shown in the table below.
| Age | Average body weight (kg) | Single dose (mL) 24 mg/mL oral liquid | Single dose (mL) 48 mg/mL oral liquid | Single dose (mL) 100 mg/mL oral liquid |
|---|---|---|---|---|
| 1-3 months | 4-6 | - | - | 0.6-0.9 mL |
| 3-6 months | 6-8 | - | - | 0.9-1.2 mL |
| 6-12 months | 8-10 | - | - | 1.2-1.5 mL |
| 1-2 years | 10-12 | 6-8 mL | 3-4 mL | 1.5-1.8 mL |
| 2-3 years | 12-14 | 8-9 mL | 4 mL | - |
| 3-4 years | 14-16 | 9-10 mL | 4-5 mL | - |
| 4-5 years | 16-18 | 10-11 mL | 5-6 mL | - |
| 5-6 years | 18-20 | 11-13 mL | 6 mL | - |
| 6-7 years | 20-22 | 13-14 mL | 6-7 mL | - |
| 7-8 years | 22-25 | 14-16 mL | 7-8 mL | - |
| 8-9 years | 25-28 | 16-18 mL | 8-9 mL | - |
| 9-10 years | 28-32 | 18-20 mL | 9-10 mL | - |
| 10-11 years | 32-36 | 20-23 mL | 10-11 mL | - |
| 11-12 years | 36-41 | 23-26 mL | 11-13 mL | - |
Doses should be given every 4-6 hours as necessary, with no more than four doses in 24 hours.
- Doses must be presented on the labels with ages (in months or years), weights (kg) and volumes (mL). Dosage instructions must also include advice consistent with the following:
- If you know that your child's weight is less than the weight corresponding to their age in the table, choose the dose for their weight.
- A medicine label could include only a subset of the age groups - for example, dosing for ages 1-5 years or 6-12 years only.
- Where dosage instructions for children under 6 months of age are included, the dosage instructions should clearly advise that the medicine only be given to this age group following the advice of a doctor.
- Labels must state the maximum daily dose - for liquid preparations that include doses for more than one age group, this should be stated as: Do not give more than 4 doses in 24 hours.
- The dosage instructions must include the following statement:
- Do not give to children under x years [or months] (where 'x' years / months is the youngest age for which dosage instructions are included on the labels).
- For 100 mg/mL strength liquid products, a measuring device that can accurately deliver the required doses must be included - see Container/measuring device below.
- A statement to 'Shake the bottle before use' must be included for oral suspensions.
- Instructions on how to use a supplied measuring device may be included if necessary. Requirements for measuring devices are included under Container/measuring device.
Solid dose products for paediatric use
Solid dosage forms, strengths and dosages are acceptable for paediatric use only as specified in the table below.
| Dosage form and strength | Age (years) | Average weight (kg) | Single dose (tablets) | Dose interval | Maximum daily dose |
|---|---|---|---|---|---|
| 250 mg soluble tablets | 2-3 | 12-14 | ½-1 tablet | every 4-6 hours, as necessary | 4 doses in 24 hours |
| 3-7 | 14-22 | 1 tablet | every 4-6 hours, as necessary | 4 doses (4 tablets) in 24 hours | |
| 7-10 | 22-32 | 1-2 tablets | every 4-6 hours, as necessary | 4 doses in 24 hours | |
| 10-12 | 32-41 | 2 tablets | every 4-6 hours, as necessary | 4 doses (8 tablets) in 24 hours | |
| 500 mg tablets/ capsules | 7-12 | 22-41 | ½-1 tablet or 1 tablet* or 1 capsule | every 4-6 hours, as necessary | 4 tablets/capsules in 24 hours |
- * 1 tablet single dose may be specified if the tablet is not divisible.
- Half tablet doses are only acceptable if tablets are scored and can appropriately deliver the intended dose (see Requirements for OTC new medicine N2 applications; Control of finished product).
- 250 mg soluble tablets with directions for use in children 12 years and under must include both ages and weights in the dosing instructions as above.
- For 500 mg tablets/capsules that include dosage for children aged 7-12 years, in addition to adults and children aged 12 years and over, average weight may be omitted from the dosage instructions.
- For soluble tablets, where more than one paediatric age group is specified, the maximum dose should be stated in numbers of tablets for each age group, or as Do not give more than 4 doses in 24 hours. For 500 mg tablets/capsules, the maximum paediatric dose should be specified in number of tablets/capsules (i/e. 4 tablets in 24 hours).
- The dosage instructions must include the following statement:
- Do not give to children under x years (where 'x' years / months is the youngest age for which dosage instructions are included on the labels).
Labels
Labelling must comply with all relevant Australian requirements, as detailed in the document Requirements for OTC new medicine N2 applications, including all required warning statements.
Quality requirements
In addition to the quality requirements outlined in the document Requirements for OTC new medicine N2 applications, the following specific requirements apply to paracetamol monograph medicines:
Active premixes
Where paracetamol is sourced by the finished product manufacturer as part of an active premix[1], the finished product manufacturer must, as a minimum, control the premix for appearance/description, identification (one chromatographic and one non-chromatographic test), assay, related substances, residue on ignition or sulfated ash, and heavy metals. The limits applied should be taken from either the BP or USP monograph for paracetamol/acetaminophen (with all limits to be taken from the same monograph), adjusted where necessary to account for the presence of excipients in the mixture (for example, assay). Additional requirements in relation to active premixes are specified in the document Requirements for OTC new medicine N2 applications.
Finished product specifications
In addition to other requirements specified in the document Requirements for OTC new medicine N2 applications, the finished product specifications must comply, at a minimum, with the relevant set of requirements below.
The requirements below include all relevant BP general monograph/USP General Chapter requirements and TGO 78 requirements. Further reference to these is not required. References to pharmacopoeial monographs below refer to the current monograph at time of application.
Tablets
The tests and limits in the BP monograph Paracetamol Tablets with the addition of:
- tablet appearance
- uniformity of dosage units (BP)
- microbiological quality, in compliance with TGO 77.
Soluble tablets
The tests and limits in the BP monograph Soluble Paracetamol Tablets with the addition of:
- tablet appearance
- uniformity of dosage units (BP)
- dissolution (900 mL phosphate buffer pH 5.8, paddle at 50 rpm, NLT 70% after 45 minutes)
- microbiological quality, in compliance with TGO 77.
Capsules
The tests and limits in the BP monograph Paracetamol Capsules with the addition of:
- capsule appearance
- uniformity of dosage units (BP)
- microbiological quality as required by USP, BP and Ph Eur and in compliance with TGO 77.
Oral suspensions
The tests and limits in the BP monograph Paracetamol Oral Suspension with the addition of:
- suspension appearance
- dissolution (900 mL phosphate buffer pH 5.8, paddle at 50 rpm, NLT 70% after 45 minutes)
- content of 4'-chloroacetanilide[2] (NMT 10 ppm wrt paracetamol)
- content of unspecified impurities2 (any individual NMT 0.1% wrt paracetamol, total NMT 0.5% wrt paracetamol)
- content of any preservatives included in the formulation
- microbiological quality, in compliance with TGO 77.
or
The tests and limits in the BP monograph Paediatric Paracetamol Oral Suspension with the addition of:
- suspension appearance
- dissolution (900 mL phosphate buffer pH 5.8, paddle at 50 rpm, NLT 70% after 45 minutes);
- content of any preservatives included in the formulation
- microbiological quality, in compliance with TGO 77.
or
The tests and limits in the USP monograph Acetaminophen Oral Suspension with the addition of:
- suspension appearance
- dissolution (900 mL phosphate buffer pH 5.8, paddle at 50 rpm, NLT 70% after 45 minutes)
- content of 4'-chloroacetanilide2 (NMT 10 ppm wrt paracetamol)
- content of unspecified impurities2 (any individual NMT 0.1% wrt paracetamol, total NMT 0.5% wrt paracetamol)
- content of any preservatives included in the formulation
- microbiological quality, in compliance with TGO 77.
Oral solutions
The tests and limits in the BP monograph Paediatric Paracetamol Oral Solution with the addition of:
- solution appearance
- content of 4'-chloroacetanilide2 (NMT 10 ppm wrt paracetamol)
- content of unspecified impurities2 (any individual NMT 0.1% wrt paracetamol, total NMT 0.5% wrt paracetamol)
- content of any preservatives included in the formulation
- microbiological quality, in compliance with TGO 77.
or
The tests and limits in the USP monograph Acetaminophen Oral Solution with the addition of:
- solution appearance
- content of 4-aminophenol[3] (NMT 0.5% wrt paracetamol)
- content of 4'-chloroacetanilide1 (NMT 10 ppm wrt paracetamol)
- content of unspecified impurities1 (any individual NMT 0.1% wrt paracetamol, total NMT 0.5% wrt paracetamol)
- content of any preservatives included in the formulation
- microbiological quality, in compliance with TGO 77.
Powders for oral solution
The following tests/limits:
- powder appearance
- solution appearance
- identification (as for Paracetamol Tablets BP)
- suitable test and limit for pH of solution
- dissolution (using conditions and limits for Paracetamol Tablets BP )
- uniformity of dosage units (BP)
- assay3 (90.0-110.0% LC)
- impurities (as for Paracetamol Tablets BP)
- microbiological quality, in compliance with TGO 77.
Container/measuring device
- Paracetamol products must be sold in containers that comply with Therapeutic Goods Order No 80, Child Resistant Packaging Requirements for Medicines.
- If a measuring device is to be supplied with the medicine, calibrations must be exclusively in metric units and must allow all the doses shown on the labels to be measured accurately. Details of the calibrations on the measuring device must be provided with the submission (a sample may also be requested). Further considerations and requirements regarding measuring devices are detailed in ARGOM Appendix 2 - Guidelines on quality aspects of OTC applications, Section 8: Finished product container
| Version | Description of change | Author | Effective date |
|---|---|---|---|
| V1.0 | Original publication | OTC Medicines Evaluation/Office of Medicines Authorisation | 06/09/2013 |
| V1.1 | Addition of footnote to information about active premixes | COMB | June 2021 |
Footnotes
| [1] | For more information on proprietary ingredient mixtures that contain an active ingredient see Streamlining proprietary ingredient categories. |
|---|---|
| [2] | Use assay methods specified for Paediatric Paracetamol Oral Suspension BP, or alternative equivalent or superior methods. Methods must be appropriately validated as described in Requirements for OTC new medicine N2 applications. |
| [3] | Use assay method specified for Acetaminophen Oral Suspension USP or Paediatric Paracetamol Oral Suspension BP, or an alternative equivalent or superior method. The method must be appropriately validated as described in Requirements for OTC new medicine N2 applications. |
| [4] | Use assay methods specified for Paracetamol Tablets BP or Acetaminophen Tablets USP, or alternative equivalent or superior methods. Methods must be appropriately validated as described in Requirements for OTC new medicne N2 applications. |