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ARGOM Appendix 5: Guidelines on OTC applications for specific substances

Version 1.0

12 October 2012

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P-Q

Note: This guidance document contains references to warning statements that are being included in the current updating of the RASML document. Warning statements marked with an (*) which are included in the updated version of the RASML document will be removed from this guidance document once the updated RASML is implemented.

Paediatric products

This guideline applies to medicines that are indicated for use in children (including products that are intended for use in both adults and children). Where label statements are specified, the wording may be varied provided the intent remains the same.

Where the TGA has not previously approved a substance for use in children, or in children in a specific age group, sponsors will be required to submit clinical data to justify the efficacy and safety of that substance in the requested age group. In some cases, a justification based on specific pharmacokinetic data and safety data relevant to the requested age group may be acceptable.

Where product labels only include doses for adults and/or children over a particular age (e.g. adults and children 12 years and over; adults and children 6 years and over; children 6-12 years), the labels should include a statement such as "Do not give to children under xx years/months".

Where the labels do not include doses for children under a particular age, inclusion of a label statement such as "Do not give to children under xx years except on medical advice" or "Not recommended for use in children under xx years/months except on the advice of a doctor (or pharmacist)" is only acceptable if the product has an approved published Product Information that the doctor (or pharmacist) can refer to in determining the appropriate dose for this age group.

Use in children under 6 months of age

Medicines generally should not be administered to children under 6 months of age except on the advice of a doctor because:

  • serious illnesses in this age group often produce subtle or non-specific symptoms. Sedative, antipyretic and other drugs may confuse the clinical picture, delaying correct diagnosis and treatment; and
  • correct dosage calculation based on weight is essential for many medicines for use in this age group.

Unless otherwise justified, where dosage instructions for children under 6 months of age are included on the labelling, the dosage instructions should advise (at the beginning of the directions for use in this age group) that the product is only to be given in this age group following the advice of a doctor.

In the case of products which are not absorbed systemically and are used for self-limiting conditions (e.g. simethicone 'wind' drops), inclusion of a statement such as the following may be considered:

  • Seek the advice of a doctor or pharmacist before using for the first time in children under 6 months of age.

Paediatric cough, cold and flu products

A review by the TGA of OTC cough and cold medicines for children aged 2-12 years has concluded that, in light of the current lack of evidence of efficacy and the historical profile of adverse drug reactions (ADRs) in Australia and overseas, it is likely that the risks associated with the use of cough and cold preparations in children outweigh the benefits for children below the age of 6 years. There is currently a lack of evidence of efficacy for cough and cold medicines in children aged 6 to 12 years of age. Additionally, the historical profile of adverse drug reactions indicates that there are potential risks involved in use of these medicines in that age group.

Following this review, the TGA has agreed that OTC cough and cold products containing any of the following ingredients should not be used for the treatment of children under 6 years of age, and should only be administered to children aged 6-11 years on the advice of a doctor, pharmacist or nurse practitioner

  • bromhexine
  • brompheniramine
  • carbetapentane
  • chlorpheniramine
  • codeine
  • dexchlorpheniramine
  • dextromethorphan
  • dihydrocodeine
  • diphenhydramine
  • doxylamine
  • guaiphenesin
  • ipecacuanha
  • oxymetazoline
  • peniramine
  • phenylephrine
  • pholcodine
  • promethazine
  • pseudoephedrine
  • senega and ammonia
  • triprolidine
  • xylometazoline

The following table provides guidance for statements required for labels of cough, cold and flu products.

Table 2. Statements required for labels of cough, cold and fly products.
Labels of products Statements
Which include dosage instructions for children aged from 6 years

Do not give to children under 6 years of age.

and

Do not give to children aged between 6 and 11 years, except on the advice of a doctor, pharmacist or nurse practitioner.

Which include dosage instructions for children aged from 'x' years, where 'x' is 7, 8, 9, 10 or 11 years

Do not give to children under 'x' years of age.

and

Do not give to children aged between 'x' and 11 years, except on the advice of a doctor, pharmacist or nurse practitioner.

or

Do not give to children aged 11 years, except on the advice of a doctor, pharmacist or nurse practitioner.

Which does not include dosage instructions for children aged under 12 years

Do not give to children under 12 years of age.

Registration of single active ingredient products for relief of specific symptoms of colds and flu in children aged under 2 years may be acceptable. For example, OTC analgesic products containing ibuprofen or paracetamol for relief of pain and discomfort and/or reduction of fever associated with colds and flu may be registered, provided those products comply with the ARGOM guideline on 'Ibuprofen' or 'Paracetamol'.

Paediatric products containing sedating antihistamines (other than cough, cold and flu products)

OTC products containing sedating antihistamines (including chlorpheniramine, brompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, pheniramine, promethazine, trimeprazine, triprolidine) that are approved for paediatric use for indications other than coughs, colds and flu (e.g. for use in allergic conditions, as an antiemetic and/or sedation) must not include directions for use in children under 2 years of age on the labelling or Product Information. Any product containing a sedating antihistamine and indicated for children under 2 years is only available as a 'Prescription only medicine' (Schedule 4 of the SUSMP).

The following table provides guidance for statements required for labels of products containing sedating antihistamines that are approved for paediatric use for allergic conditions and/or as an anti-emetic.

Table 3. Statements required for labels of products containing sedating antihistamines approved for paediatric use for allergic conditions and/or as an anti-emetic.
Labels of products Statements
Which include dosage instructions for children aged from 2 years Do not give to children under 2 years of age.
Which include dosage instructions for children aged from 'x' years, where 'x' is 3, 4, 5, 6, 7, 8, 9, 10 or 11 years Do not give to children under 'x' years of age.
Which does not include dosage instructions for children aged under 12 years Do not give to children under 12 years of age.

The statements contained in the above table must be placed together with the corresponding dosage instructions for allergies and/or anti-emetic use.

Additional requirements for paediatric products containing sedating antihistamines that include indications for sedation

OTC products containing some sedating antihistamines (e.g. diphenhydramine, promethazine, trimeprazine) may be approved for short-term use for sedation. This may be in addition to other indications (e.g. for use in allergic conditions and/or as an anti-emetic).

The labels of OTC products containing sedating antihistamines that are approved for indications that include short-term use for sedation in children must include advice that the products should only be used for sedation in children aged 2-11 years on the advice of a doctor or pharmacist.

The following table provides guidance for statements required for labels of products containing sedating antihistamines that include indications for sedation.

Table 4. Statements required for labels of products containing sedating antihistamines that include indications for sedation.
Labels of products Statements
Which include dosage instructions for sedation in children aged from 2 years

Do not give to children under 2 years of age.

and

Do not give to children aged between 2 and 11 years for sedation, except on the advice of a doctor or pharmacist.

Which include dosage instructions for children aged from 'x' years, where 'x' is 3, 4, 5, 6, 7, 8, 9, 10 or 11 years

Do not give to children under 'x' years of age.

and

Do not give to children aged between 'x' and 11 years, except on the advice of a doctor, pharmacist or nurse practitioner.

or

Do not give to children aged 11 years, except on the advice of a doctor, pharmacist or nurse practitioner.

The statements contained in the above table must be placed together with the corresponding dosage instructions for sedation.

See also 'Antihistamines - Use as hypnotics'

Solid dose products for paediatric use

In general, products in solid dosage forms (e.g. tablets, capsules) should not be labelled for use in children aged 6 years and under, because of the danger of inhalation. Where other presentations more suitable for use in this age group are available (e.g. oral liquid products, chewable tablets or dissolve in the mouth formats), the dosage instructions on the label of the solid dosage form could advise of the availability of these other presentations.

Chewable tablets and 'dissolve in the mouth' dosage forms may be indicated for use in children aged 2 years and over:

  • For chewable tablets, the dosage instructions should clearly state that the tablets are intended to be chewed, and should not be swallowed whole. The directions for use should also advise that the tablets should not be given to children unless the parent or carer is sure the child can chew the tablets.
  • For 'dissolve in the mouth' dosage forms, the dosage instructions should clearly state that the product is intended to be dissolved in the mouth, and should not be swallowed whole. The directions for use should also advise that the product should not be given to children unless the parent or carer is sure the child is able to dissolve the product in the mouth.

If an alternative presentation is not available, and a solid dose product (that is not a chewable tablet, 'dissolve in the mouth' dosage form or other format that is not intended to be swallowed whole) is indicated for use in children, the label should include appropriate dosage instructions for use in children. For example, if appropriate and the formulation permits, the label could advise that the tablets should be crushed or capsules emptied and the contents mixed with water, jam or honey before administering to young children or any individual who has difficulty swallowing tablets or capsules.

See also 'Anaesthetic lozenges', 'Chest rubs', 'Corn treatments', 'Diarrhoea treatments', 'Fluoride supplements', 'Ibuprofen', 'Paracetamol' and 'Teething products'

Paracetamol

Indications

Sponsors may use indications consistent with any or all of the representative indications set out below, as appropriate to a particular product, without the need to supply supporting efficacy data:

  • For the temporary relief of pain (and discomfort) associated with:
    • headache
    • osteoarthritis
    • migraine headache
    • rheumatic pain
    • tension headache
    • menstruation/period pain
    • sinus pain
    • fibrositis
    • toothache
    • neuralgia
    • dental procedures
    • sore throat
    • backache
    • tennis elbow
    • muscular aches and pains
    • colds and flu
    • arthritis
  • Reduces fever and/or the discomfort associated with fever

For paediatric formulations, relief of pain and discomfort associated with teething, earache and immunisation may be added to any of the above, as appropriate to the age group.

Sponsors may propose other indications but should contact the TGA for advice on whether data will be required to support the safety and efficacy of the product for those indications.

Combination OTC analgesic products that contain paracetamol and codeine may include claims of 'strong' or 'powerful' pain relief (or similar). These claims will not be accepted for products that contain paracetamol as the only analgesic agent, or paracetamol in combination with another analgesic agent, unless the claims are justified on the basis of clinical efficacy data.

As fever is a normal and generally beneficial response to infection, no elaboration to the words "reduces fever" will be accepted except in the context of duration of treatment, relief of discomfort associated with fever or examples of conditions where fever may occur.

Dose

Adult dosage

Adult dosage recommendations (adults and children 12 years and over):

  • 500 to 1000 mg every four to six hours as necessary. Dosage should not exceed 4 g (expressed on the label as number of units, for example tablets) in 24 hours.
Paediatric dosage

Paediatric dosage recommendations (1 month to 12 years, see also Table 5):

  • The dose should be based on 15 mg/kg, with the understanding that dosing with solid dose products in children is less flexible than with liquid products.
  • Doses should be given every four to six hours as required with not more than four doses in 24 hours.
  • The total daily dose should not exceed 60 mg/kg except on medical advice.

The labels should advise that the product should not be administered for more than 48 hours except on medical advice, and (where doses are included for children aged from one month) that administration to children under one month is not recommended.

Labels could include appropriate discrete doses (consistent with the table below), instead of dosage ranges. For example, for children aged 1-3 years, the label could include a dose equivalent to 180 mg (rather than a dosage range, such as 150-210 mg).

Wider age ranges (e.g. 1-3 years) could be used on product labelling where appropriate.

Table 5. Paracetamol dosage for children aged 1 month to 12 years.
Age Average body weight (kg) Single dose (mg)
1 - 3 months 4 - 6 60 - 90
3 - 6 months 6 - 8 90 - 120
6 - 12 months 8 - 10 120 - 150
1 - 2 years 10 - 12 150 - 180
2 - 3 years 12 - 14 180 - 210
3 - 4 years 14 - 16 210 - 240
4-– 5 years 16 - 18 240 - 270
5 - 6 years 18 - 20 270 - 300
6 - 7 years 20 - 22 300 - 330
7 - 8 years 22 - 25 330 - 375
8 - 9 years 25 - 28 375 - 420
9 - 10 years 28 - 32 420 - 480
10 - 11 years 32 - 36 480 - 540
11 - 12 years 36 - 41 540 - 615
Paediatric dosage - Liquid dose products

Where possible, dose volumes of liquid products should be expressed in whole numbers of mL. Doses should be presented with age, weight and volumes unless otherwise justified.

Recommended doses should be able to be measured using commonly available metric measuring devices or an appropriate measuring device provided with the product. There may be instances where doses need to be slightly different from the recommended milligram doses given above, depending on the paracetamol concentration of the product, and/or calibrations on dosing devices.

Sponsors intending to supply measuring devices with the product should refer to ARGOM Appendix 2 – Guidelines on quality aspects of OTC application: Section 8 Finished product container. Calibrations on measuring devices should be exclusively in metric units and should allow all the doses shown on the labels to be measured accurately. A sample of the proposed measuring device, or information on the calibrations intended for the measuring device, should be provided with the submission.

Dosage instructions could 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.
Paediatric dosage - Solid dose products

Solid dose products that are intended to be swallowed whole should not include directions for use by children aged 6 years and under. Recognising that dosing with solid dose products is less flexible than with liquid products, these products could include a dose of 250 to 500 mg every 4-6 hours as necessary, with no more than four doses in 24 hours, for children aged 7-12 years.

Solid dosage forms that are specially designed and suitable for administration to younger children (e.g. chewable tablets) may be indicated for use in children from two years of age.

Product strength and pack size - liquid preparations

Sponsors may supply any or all of the following strengths of paracetamol liquid without the need for justification: 24 mg/mL, 48 mg/mL, 50 mg/mL and 100 mg/mL. Deviation from these strengths requires justification.

While not prohibited, the introduction of pack sizes larger than 200 mL will require justification.

Differentiation of strengths

Sponsors should give close consideration to the labelling and presentation of different strength liquid and solid dose paracetamol products, with the aim of minimising the possibility that the wrong dose may accidentally administered or taken.

Combination products

Products containing paracetamol together with one or more other active ingredients which are similar to existing registered products will usually not require efficacy or safety data, provided they comply with the guideline on fixed dose combination products (see ARGOM Appendix 1 – Guidelines on efficacy and safety aspects of OTC application: Section 9 Fixed dose combination products). Where new combinations are proposed (i.e. combinations and/or strengths that are not included in the ARTG for supply in Australia), the safety and efficacy of the combination will need to be justified.

Due to the lack of flexibility when dosing with combination products, and because the majority of patients require more than 500 mg of paracetamol for effective analgesia, products should be formulated so that doses of other ingredients are at safe and effective levels when at least 600 mg of paracetamol is taken.

See also 'Paediatric products'.

Phenylalanine

See 'Aspartame'

Phenylephrine

See 'Decongestant products, oral'

Povidone-iodine/iodine - dermal

Products for dermal use should contain a statement such as:

  • *If skin irritation or rash occurs, discontinue use immediately.

Pseudoephedrine

See 'Decongestant products, oral'

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