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Consultation: Sedating antihistamines: proposed additional advisory statements for medicines

First-generation sedating oral antihistamines: alimemazine (trimeprazine), chlorphenamine, brompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, pheniramine, promethazine and triprolidine

25 September 2018

This consultation closed on 21 June 2018.

Invitation to comment

The TGA sought comments from interested parties on the wording of additional advisory statements for first-generation sedating antihistamines for oral use, for inclusion in the Required Advisory Statements for Medicine Labels (RASML) document.

The additional RASML advisory statements were proposed in order to ensure that health professionals, parents and carers were adequately cautioned against the use of first-generation sedating antihistamines in children, and particularly in children aged under 2 years of age.

The TGA also proposed to take this opportunity to make some editorial changes in order to harmonise the entries for each of these medicines as far as possible, to reduce the total number of entries needed to cover all eventualities, and to more clearly specify which substances are affected by these entries.

The proposed amended RASML class entries, showing the new RASML requirements in red text, are set out in Table 1, below (editorial changes are not tracked in this Table - for a full ‘tracked-changes’ version see Table 2 at the end of this document):

Table 1: Proposed amended RASML class-entries for medicines containing first-generation antihistamines (the proposed new statements that are the subject of this consultation are indicated by red text)
Column 1
Substance(s)
Column 2
Conditions
Column 3
Required statement(s)

Antihistamines (Entry 1 of 5), including:

  • Alimemazine (trimeprazine)
  • Chlorphenamine
  • Brompheniramine
  • Dexchlorpheniramine
  • Diphenhydramine
  • Doxylamine
  • Pheniramine
  • Promethazine
  • Triprolidine

when NOT separately specified in this table

In oral medicines:

  • which include dosage instructions for adults and children aged from 'x' years (where 'x' must not be less than 2)

when NOT separately specified in this table

  • either
    • This medication may cause drowsiness. If affected do not drive a vehicle or operate machinery. Avoid alcohol.

or

    • This medication may cause drowsiness and may increase the effects of alcohol. If affected do not drive a motor vehicle or operate machinery.
  • Do not give to children under 'x' years of age.
  • and (if 'x' < 12)
    • Do not give to children aged between 'x' and 11 years of age, except on the advice of a doctor, pharmacist or nurse practitioner.

Antihistamines (Entry 2 of 5), including:

  • Alimemazine (trimeprazine)
  • Chlorphenamine
  • Brompheniramine
  • Dexchlorpheniramine
  • Diphenhydramine
  • Doxylamine
  • Pheniramine
  • Promethazine
  • Triprolidine

when NOT separately specified in this table

In oral medicines:

  • which ONLY include dosage instructions for CHILDREN aged between 'x' and 'y' years (where 'x' must not be less than 2, and 'y'must not be more than 11)

when NOT separately specified in this table

  • This medication may cause drowsiness.
  • Do not give to children under 'x' yearsof age.
  • Do not give to children aged between 'x'and 'y' years of age, except on the advice of a doctor, pharmacist or nurse practitioner.

Antihistamines (Entry 3 of 5), including:

  • Alimemazine (trimeprazine)
  • Chlorphenamine
  • Brompheniramine
  • Dexchlorpheniramine
  • Diphenhydramine
  • Doxylamine
  • Pheniramine
  • Promethazine
  • Triprolidine

In oral medicines indicated for COUGH, COLD OR FLU:

  • which include dosage instructions for adults and children aged from 'x' years (where 'x' must not be less than 6)
  • either
    • This medication may cause drowsiness. If affected do not drive a vehicle or operate machinery. Avoid alcohol.

or

    • This medication may cause drowsiness and may increase the effects of alcohol. If affected do not drive a motor vehicle or operate machinery.
  • Do not give to children under 'x' years of age.
  • and (if 'x' < 12)
    • Do not give to children aged between 'x' and 11 years of age, except on the advice of a doctor, pharmacist or nurse practitioner.

Antihistamines (Entry 4 of 5), including:

  • Alimemazine (trimeprazine)
  • Chlorphenamine
  • Brompheniramine
  • Dexchlorpheniramine
  • Diphenhydramine
  • Doxylamine
  • Pheniramine
  • Promethazine
  • Triprolidine

In oral medicines indicated for COUGH, COLD OR FLU:

  • which ONLY include dosage instructions for CHILDREN aged between 'x' and 'y' years (where 'x' must not be less than 6 and 'y' must not be more than 11)
  • This medication may cause drowsiness.
  • Do not give to children under 'x' years of age.
  • Do not give to children aged between 'x' and 'y' years of age, except on the advice of a doctor, pharmacist or nurse practitioner.

Antihistamines (Entry 5 of 5), including:

  • Diphenhydramine
  • Doxylamine
  • Promethazine

In oral medicines indicated for SHORT TERM USE IN INSOMNIA:

  • which include dosage instructions for adults and children aged from 'x' years (where 'x' must not be less than 2)
  • This product should be taken on medical or pharmacist advice.
  • Do not give to children under 'x' years of age.
  • Not recommended for use by pregnant or breastfeeding women.
  • Do not take this medicine for more than a few days.
  • This preparation is to aid sleep. Drowsiness may continue the following day. If affected do not drive or operate machinery. Avoid alcohol.

The associated individual substance entries will also be updated accordingly.

Timetable

Documents released for consultation on Thursday, 24 May 2018.

Interested parties should respond by close of business Thursday, 21 June 2018.

Feedback will be released following consideration of submissions. (see 'What will happen').

About the consultation

The recent TGA Medicines Safety Update of 20 March 2018 has identified a need for additional mandatory advisory statements for labels of OTC medicines containing first-generation oral sedating antihistamines, for inclusion in the RASML.

With this consultation, the TGA is seeking comments on the proposed wording of these RASML advisory statements and some other editorial RASML changes, as detailed in this consultation document.

Through the consultation process, the TGA is requesting comments that will help ensure that the wording of the proposed advisory statements is appropriate and supports the quality use of the medicines; and that the label changes that would be required for these medicines are made in the most convenient, efficient and cost-effective way.

Background

Medicines Scheduling

The Standard for Uniform Scheduling of Medicines and Poisons (SUSMP) sets out the level of control on the availability of medicines in Australia. The majority of medicines that are included in the SUSMP fall under one of the following classifications: Schedule 2 - Pharmacy Medicine (available from a pharmacy without a prescription); Schedule 3 - Pharmacist Only Medicine (available from a pharmacist without a prescription); or Schedule 4 (Prescription Only Medicine). Medicines that are not included in the SUSMP are referred to as ‘unscheduled’ medicines (freely available from general retail outlets).

Medicines that are unscheduled or included in Schedules 2 or 3 of the SUSMP are collectively referred to either as ‘non-prescription medicines’, ‘over-the-counter medicines’ or 'OTC medicines'.

Advisory statements

Consumers rely on information from their health practitioner, pharmacist and medicine label in order to use medicines safely and effectively. However, the enhanced access and availability of OTC medicines means that consumers may not always receive comprehensive advice from a practitioner or pharmacist.

In the context of self-medication, the medicine label is the primary source of information for the consumer; so the label must contain the directions and advisory statements that are needed for safe and effective use of these medicines.

The TGA Labelling Orders require medicine labels to include 'warning statements' where these apply to the medicines, including any advisory statements specified in the instrument made under subsection 3(5A) of the Therapeutic Goods Act 1989 ('the Act'), as in force from time to time.

The Required Advisory Statements for Medicine Labels (RASML)

The RASML is registered on the Federal Register of Legislative Instruments under subsection 3(5A) of the Act, as the Medicines Advisory Statements Specification ('the Specification'). The RASML sets out the advisory statements that are required to be included on the labels of specified medicines.

The current version of the Specification is the Medicines Advisory Statements Specification 2017 (MASS 2017). The MASS 2017 incorporates two versions of the RASML (currently RASML No. 3 and RASML No. 4) as schedules 1 and 2, respectively, to allow for a transition period for adoption of new advisory statements onto medicine labels. RASML No. 3 is the current version. RASML No. 4 will come into effect on 1 January 2019.

The advisory statements required by the RASML are designed to inform consumers about specific risks related to the use of medicines that have been identified during development and evaluation of new medicines, or subsequent pharmacovigilance activities, testing, adverse event reports or from other scientific or clinical information.

The RASML permits the wording of the actual statements that are included on medicine labels to differ from the wording set out in the RASML, as long as the intent is the same.

First-generation oral sedating antihistamines for oral use – SUSMP scheduling and availability

First-generation antihistamines are available in a variety of doses and formulations. They are widely used for treatment of allergic conditions, as well as for symptomatic relief of ‘cough, cold and flu’, and for insomnia.

The following first-generation sedating antihistamines are included in Schedule 2 and/or Schedule 3 of the SUSMP (OTC medicines), subject to the requirement that they are not for treatment of children under 2 years of age:

  • Alimemazine (trimeprazine)
  • Chlorphenamine
  • Brompheniramine
  • Dexchlorphenamine
  • Diphenhydramine
  • Doxylamine
  • Pheniramine
  • Promethazine
  • Triprolidine

Proposed additional RASML statements - Background

1. Advisory statement: Do not give to children under 2 years of age

Currently, the Australian Regulatory Guidelines for OTC Medicines – Appendix 5 states that the labels of first-generation sedating antihistamines must display the  statement 'Do not give to children under 2 years of age' (or older, as applicable to the particular medicine).

Most of the affected products are already compliant with this requirement. However, the requirement is not currently included in the RASML.

The recent TGA Medicines Safety Update (MSU), Volume 9, No. 1, February-March 2018 included an article reminding health professionals that first-generation oral sedating antihistamines are not approved for use in children under 2 years of age. The reminder followed a coronial hearing of a fatal case involving an infant being given OTC promethazine oral liquid. While the death was not attributed to ingestion of promethazine, the incident raised the issue of the risk of respiratory depression when promethazine is given to infants. In regards to product labels the MSU article concluded that:

'In response to this safety concern, the TGA will be seeking to make the statement 'Do not give to children under two years of age' (which is currently a recommended statement in the applicable OTC guidelines) a mandatory warning statement on the labels of OTC liquid oral formulations of first-generation oral sedating antihistamines'.

Therefore, the TGA proposes that the RASML should now be updated to ensure that the warning appears more consistently on all of these products.

The statement 'Do not give to children aged between 2 and 11 years of age, except on the advice of a doctor, pharmacist or nurse practitioner' is also proposed, in line with the current RASML requirements applicable to these same medicines when labelled for cough, cold or flu.

As is always the case for the RASML, more restrictive statements will also fulfil these requirements (e.g. where a medicine is only labelled for adults and children 12 years and older, the single statement' Do not give to children under 12 years of age' will suffice). The RASML entries will be worded to try and make this as clear as possible.

2. Additional statement for paediatric-only products: This medication may cause drowsiness

For historical reasons, paediatric-only antihistamine substances other than cetirizine and levocetirizine are not currently subject to a RASML requirement for a sedation warning. However, the TGA considers that all paediatric-only sedating antihistamine products should be required to display a label statement advising care-givers that the medicine may cause drowsiness.

With this update, it is considered appropriate to now require the statement 'This medication may cause drowsiness' for all paediatric-only sedating-antihistamine medicines (as per the current requirement for cetirizine and levocetirizine).

Proposed editorial changes

The TGA proposes to take this opportunity to make some editorial changes, in order to harmonise the entries for each of these medicines as far as possible, as well as to reduce the total number of entries, and to more clearly specify which substances are affected by these entries.

In particular:

  • A list of substances covered by each of the class entries has been included in Column 1, together with the statement 'when NOT separately specified in this table'.
  • The wording in Column 2 restricts the scope of the entries to oral medicines only.
  • The wording 'not … paediatric preparations' has been replaced with '…medicines which include dosage instructions for adults and children…'
  • Due to the changes detailed above, there is no longer any need for the current list of Conditions in Column 2 of 'Antihistamines (Entry 1 of 5)' – so this text has been removed.
  • The current 'Entry 2 of 5' (applicable to '…preparations indicated for cough, cold or flu which DO NOT include dosage instructions for children aged under 12 years') has been merged with the corresponding 'adult and children' entry for cough, cold and flu preparations ('Entry 3 of 5'), which has been reworded accordingly (there is no change to the actual requirements).
  • The wording that refers to cases where 'x' is 11 has been removed from Column 3. This is considered justified on the basis that there are likely to be very few medicines for which 'x' is 11 years – and because the RASML already includes a note in regards to 'Permitted variation and combination of statements' that would cover this situation if it arises. It should be fairly obvious that the wording 'aged 11 years' would be the appropriate variation for 'aged between 11 and 11 years'.

As always, statement(s) that are more restrictive than the relevant RASML statement(s) will be considered to be compliant with the requirements.

Proposed changes (with change-tracking)

Table 2: Proposed amended RASML class-entries for medicines containing first-generation antihistamines: with change-tracking indicated by red text and strike through
Column 1 Substance(s) Column 2 Conditions Column 3 Required statement(s)
Antihistamines (Entry 1 of 5), including:
  • Alimemazine (trimeprazine)
  • Chlorphenamine
  • Brompheniramine
  • Dexchlorpheniramine
  • Diphenhydramine
  • Doxylamine
  • Pheniramine
  • Promethazine
  • Triprolidine

when NOT separately specified in this table

In oral medicines:

  • which include dosage instructions for adults and children aged from 'x' years (where 'x' must not be less than 2)

when NOT separately specified in this table

When included in a schedule to the SUSMP and NOT separately specified in the table and NOT:

  • Dermal or ocular or paediatric preparations; or
  • oral preparations of desloratadine, loratadine or fexofenadine; or
  • nasal preparations of azelastine
  • either
    • This medication may cause drowsiness. If affected do not drive a vehicle or operate machinery. Avoid alcohol.

    or

    • This medication may cause drowsiness and may increase the effects of alcohol. If affected do not drive a motor vehicle or operate machinery.
  • Do not give to children under 'x' years of age.
  • and (if 'x' < 12)
    • Do not give to children aged between 'x' and 11 years of age, except on the advice of a doctor, pharmacist or nurse practitioner.

Antihistamines (Entry 2 of 5), including:

  • Alimemazine (trimeprazine)
  • Chlorphenamine
  • Brompheniramine
  • Dexchlorpheniramine
  • Diphenhydramine
  • Doxylamine
  • Pheniramine
  • Promethazine
  • Triprolidine

when NOT separately specified in this table

Antihistamines (Entry 2 of 5)

In oral medicines:

  • which ONLY include dosage instructions for CHILDREN aged between 'x' and 'y' years (where 'x' must not be less than 2, and 'y'must not be more than 11)

when NOT separately specified in this table

In oral preparations indicated for cough, cold or flu which DO NOT include dosage instructions for children aged under 12 years

  • This medication may cause drowsiness.
  • Do not give to children under 'x' yearsof age.
  • Do not give to children aged between 'x'and 'y' years of age, except on the advice of a doctor, pharmacist or nurse practitioner.
  • either
    • This medication may cause drowsiness. If affected do not drive a vehicle or operate machinery. Avoid alcohol.

    or

    • This medication may cause drowsiness and may increase the effects of alcohol. If affected do not drive a motor vehicle or operate machinery.
    • Do not give to children under 12 years of age.

Antihistamines (Entry 3 of 5),, including:

  • Alimemazine (trimeprazine)
  • Chlorphenamine
  • Brompheniramine
  • Dexchlorpheniramine
  • Diphenhydramine
  • Doxylamine
  • Pheniramine
  • Promethazine
  • Triprolidine

In oral medicines indicated for COUGH, COLD OR FLU:

  • which include dosage instructions for adults and children aged from 'x' years (where 'x' must not be less than 6)

In oral preparations indicated for cough, cold or flu which include dosage instructions for adults and children aged from ‘x’ to 11 years (where ‘x’ is 6, 7, 8, 9, 10 or 11)

  • either
  • This medication may cause drowsiness. If affected do not drive a vehicle or operate machinery. Avoid alcohol.

or

  • This medication may cause drowsiness and may increase the effects of alcohol. If affected do not drive a motor vehicle or operate machinery.
  • Do not give to children under 'x' years of age.
  • and (if 'x' < 12)
  • Do not give to children aged between 'x'and 11 years of age, except on the advice of a doctor, pharmacist or nurse practitioner.
  • either (if ‘x’ is 11)
    • Do not give to children aged 11 years, except on the advice of a doctor, pharmacist or nurse practitioner.

    or (if ‘x’ is 6, 7, 8, 9 or 10)

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

Antihistamines (Entry 4 of 5),, including:

  • Alimemazine (trimeprazine)
  • Chlorphenamine
  • Brompheniramine
  • Dexchlorpheniramine
  • Diphenhydramine
  • Doxylamine
  • Pheniramine
  • Promethazine
  • Triprolidine

In oral medicines indicated for COUGH, COLD OR FLU:

  • which ONLY include dosage instructions for CHILDREN aged between 'x' and 'y' years (where 'x' must not be less than 6 and 'y' must not be more than 11)

In oral preparations indicated for cough, cold or flu which only include dosage instructions for children aged from ‘x’ years (where ‘x’ is 6, 7, 8, 9, 10 or 11)

  • This medication may cause drowsiness.
  • Do not give to children under 'x' years of age.
  • Do not give to children aged between 'x' and 11 'y' years of age, except on the advice of a doctor, pharmacist or nurse practitioner.

Antihistamines (Entry 5 of 5), including:

  • Diphenhydramine
  • Doxylamine
  • Promethazine

In oral medicines indicated for SHORT TERM USE IN INSOMNIA:

  • which include dosage instructions for adults and children aged from 'x' years (where 'x' must not be less than 2)

When indicated for short term use in insomnia

  • This product should be taken on medical or pharmacist advice.
  • Do not give to children under 'x' years of age.
  • Not recommended for use by pregnant or breastfeeding women.
  • Do not take this medicine for more than a few days.
  • This product should be taken on medical or pharmacist advice.
  • This preparation is to aid sleep. Drowsiness may continue the following day. If affected do not drive or operate machinery. Avoid alcohol.

Content of submissions

Submissions may address the proposed advisory statements and other identified issues. In addition, submissions might include:

  • Whether or not you support the wording of the advisory statement. If you do not support the wording of the statement you may make suggestions for an alternative acceptable to you.
  • An assessment of how the proposed change will impact on you. That is, what do you see as the likely benefits or costs to you (these may be financial or non-financial). If possible, please attempt to quantify these costs and benefits.

Enquiries

Enquiries should be directed via email to

What will happen

All submissions will be placed on this website unless marked confidential or indicated otherwise in the submission form (see Privacy information).

Submissions will be reviewed by the TGA and feedback on submissions will be provided through this website.

It is proposed that the advisory statements will be included in the next update to the RASML (‘RASML 5’), with an anticipated date of publication on the FRLI in January 2019, and an anticipated date of effect 18 months later (i.e. July 2020) to allow affected sponsors time to update their labels. However, the TGA will expect that all new medicines registered by the TGA from the date of publication of the outcomes of this current consultation will include all the requirements.

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