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Submissions received: Sedating antihistamines - proposed additional advisory statements for medicines

25 September 2018

The TGA would like to thank the respondents who have submitted written comments or made submissions in response to the consultation paper. Sedating antihistamines: proposed additional advisory statements for medicines.

A total of 4 submissions were received.

All submissions that gave permission to be published on the TGA website are available below in PDF format.

Submissions

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The respondents supported the new warning statements, but some respondents raised issues in regards to the presentation of the proposed statements, as well as issues in regards to the existing RASML Entries for antihistamines.

Summary of broad issues reported

The following sets out in brief the issues identified from the submissions received, and the TGA's response.

1. Entries 1, 2, 3 and 4: wording of the text in columns 1 and 2

Summary of issue

A respondent noted some inconsistencies in the wording of columns 1 and 2 for Entries 1, 2, 3 and 4.

TGA response

As suggested by the respondent, Entries 1, 2, 3 and 4 will be amended to all include the words 'when NOT separately specified in this Table' in column 1. The lead-in text in column 2 for Entries 1 and 2 will also be modified, as suggested, to specifically exclude use for 'cough, cold or flu' from the scope of the entries (this will replace the current wording 'when NOT separately specified in this table' in column 2 of these entries, as these words were intended to have the same effect).

2. Entry 5: wording in column 1

Summary of issue

A respondent suggested deleting the word 'including' in column 1 of Entry 5, given that the indication 'for short term use in insomnia' applies solely and specifically to the three substances listed.

TGA response

Use of the word 'including' prefacing the list of specific substances in column 1 is a convention used in all RASML class entries. This is intended allow the entry to also apply to additional substances that might come under the scope of the entry (e.g. due to down-scheduling or a new registration) even if they are not included by name in the list. The respondent's comments about this particular case are acknowledged; however, at this time the TGA prefers to keep the wording consistent with the general RASML convention.

3. Advisory statements in regards to use in pregnancy

A respondent suggested that the existing statement ‘Not recommended for use by pregnant or breastfeeding women’, in Entry 5, should be amended so that it does not appear to conflict with the Category A pregnancy categorisation for doxylamine and diphenhydramine.

Both doxylamine and diphenhydramine are in Category A of the TGA Prescribing Medicines in Pregnancy Database, whereas promethazine is in Category C.

The respondent is concerned that ‘confusion sometimes occurs when specialists or GPs advise pregnant women to take doxylamine or diphenhydramine for severe nausea & vomiting in pregnancy, advising them that it is an OTC medicine, which they then purchase from the pharmacy. Women (justifiably) are then concerned and confused by the medicine label statement 'Not recommended for use by pregnant women' or 'Do not use if you are pregnant'.

TGA response

The TGA agrees that the entry should be amended to harmonise with other Australian requirements in regards to use of these substances in pregnancy. However, the TGA considers that the statements proposed by the respondent, beginning with 'Do not use …', are actually more restrictive than the current statement (beginning with 'Not recommended for use …').

If this aspect of the entry is to be updated, it is logical that the entry should also be harmonised with the relevant requirements of Therapeutic Goods Order No. 92 Standards for labels of non-prescription medicines (TGO 92), which will come into effect on 1 September 2020.

Paragraph 8(k)(i) of TGO 92 requires medicines containing Pregnancy Category B or C substances (e.g. promethazine) to be labelled with the statement ‘If pregnant or likely to become pregnant, consult a pharmacist or doctor before use’, or words to this effect.

The TGA therefore proposes to change the date of effect of the new RASML to 1 September 2020, to harmonise with the date of effect of TGO 92 (this is two months later than the previously proposed date of 1 July 2020 for the new RASML). With the proposed new date of effect of 1 September 2020, the changes to this RASML entry will not result in any new requirements for any medicines. These RASML changes will clarify and harmonise the current requirements (noting that ‘words to the same effect’ are permitted by both the RASML and TGO 92).

Consequently, Antihistamines Entry 5 of 5 will be updated as follows (changes are indicated by red text):

Column 1
Substance(s)
Column 2
Conditions
Column 3
Required statement(s)

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)

Note: Antihistamine medicines indicated for sedation that include dosage instructions solely for children aged between 11 and 2 years are subject to 'Antihistamines (Entry 2 of 5)'

  • This product should be taken on medical or pharmacist advice.
  • Do not give to children under 'x' years of age.
  • If the substance is in pregnancy category B or C,
    • If pregnant or (likely/trying) to become pregnant, or if breastfeeding, consult a doctor or pharmacist before use
  • If the substance in is pregnancy category A, either
    • Not recommended for use by pregnant or breastfeeding women.
      or
    • If pregnant or breastfeeding, consult a doctor or pharmacist before use
  • 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 additional note in column 2, 'Note: Antihistamine medicines indicated for sedation that include dosage instructions solely for children 11 years of age and under are subject to 'Antihistamines (Entry 2 of 5)', is intended to clarify the TGA's existing interpretation of the requirements for 'paediatric-only' products that include indications for sedation.

4. Proposal for additional actions in regards to children 2-5 years of age

Summary of issue

A respondent (the NSW Poisons Information Centre [NSWPIC]) expressed concern about increasing numbers of accidental and therapeutic error exposures to sedating antihistamines in children 2- 5 years of age. The respondent was particularly concerned that a Schedule 2 brompheniramine/phenylephrine oral liquid (indicated for allergic rhinitis) is being used off-label for 'cough and cold' indications in children under 6 years of age.

The respondent reported that, for the six-week period 01/05/18 - 11/06/18, twenty-one (21) 2 - 5 year olds either presented to hospital or required referral to hospital after using this product. For 12 of these the intended use was reported as 'runny nose, cough and cold'.

The respondent suggested a number of measures that could help address this issue, including requirements for location and prominence of the currently proposed warnings, or additional requirements for products currently permitted for use in children 2 - 5 years of age to the effect that the products should not be used to relieve the symptoms of cold and flu in children under 6 years of age.

The respondent also suggested that the SUSMP scheduling of the products (Schedule 2) should be reviewed.

TGA response

The TGA proposes to carry out an additional safety investigation on this issue in order to address this ongoing concern. Any changes that might be proposed as a result of this investigation will be the subject of separate consultation.

5. Other issues

Summary of issues

A respondent suggested that the proposed warning statements should be included in the Product Information and Consumer Medicines Information (CMI) for these medicines, and that all medicine boxes should contain a CMI leaflet.

Another respondent suggested that in future, the need to implement changes to warning statements or label requirements should be identified by considering the RASML and ARGOM documents concurrently.

TGA response

Most of the affected products are included in Schedule 3 of the SUSMP, and therefore required to have a CMI. However, TGA will continue to check that the CMI documents presented for review include the required advice (as already required by the ARGOM). The TGA will also continue to require that the Schedule 3 medicines either include a pack insert or a label statement advising consumers how to obtain Consumer Medicine Information.

The TGA will continue to consider the need for RASML statements when considering updates to the ARGOM in the future (and vice versa).

Final proposal

Advisory statements for medicines containing first-generation antihistamines

The following advisory statements will be included in the Required Advisory Statements for Medicine Labels (RASML) document when it is next updated (NB: the proposed date of effect for these changes is 1 September 2020).

Existing requirements are indicated by black. Changes that result in new requirements, or that are intended to clarify the intent of existing requirements, 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

when NOT separately specified in this Table

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

when NOT separately specified in this Table

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)

Note: Antihistamine medicines indicated for sedation that include dosage instructions solely for children aged between 11 and 2 years are subject to 'Antihistamines (Entry 2 of 5)'

  • This product should be taken on medical or pharmacist advice.
  • Do not give to children under 'x' years of age.
  • If the substance is in pregnancy category B or C,
    • If pregnant or (likely/trying) to become pregnant, or if breastfeeding, consult a doctor or pharmacist before use
  • If the substance in is pregnancy category A, either

    or

    • Not recommended for use by pregnant or breastfeeding women.
    • If pregnant or breastfeeding, consult a doctor or pharmacist before use
  • 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.