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1.5. Interim decision in relation to Paracetamol + ibuprofen

Scheduling of chemicals and poisons
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1. Interim decisions on proposed amendments referred to the Advisory Committee on Medicines Scheduling (ACMS #28, November 2019)

1.5. Interim decision in relation to Paracetamol + ibuprofen

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision not to amend the current Poisons Standard in relation to paracetamol (in combination with ibuprofen).

Reasons for the interim decision (including findings on material questions of fact)

In this section: Applicant's scheduling proposal and reasons for the proposal | Current scheduling status | Scheduling history | Australian regulations | International regulations | Summary of pre-meeting public submissions | Summary of ACMS advice/recommendations to the Delegate | Delegate's considerations | Reasons for the interim decision

Applicant's scheduling proposal and reasons for the proposal

An application to amend the Schedule 2, Schedule 3 and Schedule 4 entries for paracetamol when in combination with paracetamol was considered.

The Applicant's proposed amendments to the Poisons Standard were:

Schedule 4 - Amend Entry

PARACETAMOL:

  1. when combined with aspirin or salicylamide or any derivative of these substances except when separately specified in these Schedules;
  2. when combined with ibuprofen in a primary pack containing more than 3050 dosage units;
  3. in slow release tablets or capsules containing more than 665 mg paracetamol;
  4. in non-slow release tablets or capsules containing more than 500 mg paracetamol;
  5. in individually wrapped powders or sachets of granules each containing more than 1000 mg paracetamol;
  6. in tablets or capsules enclosed in a primary pack containing more than 100 tablets or capsules except in schedule 2;
  7. in individually wrapped powders or sachets of granules enclosed in a primary pack containing more than 50 wrapped powders or sachets of granules except when included in Schedule 2;
  8. for injection;
  9. for the treatment of animals.

Schedule 3 - Amend Entry

PARACETAMOL when combined with ibuprofen in a primary pack containing 3050 dosage units or less except when included in or expressly excluded from Schedule 2.

Schedule 2 - Amend Entry

PARACETAMOL for therapeutic use:

  1. when combined with ibuprofen in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen in divided doses in a primary pack containing no more than 1230 dosage units per pack except in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen in divided doses in a primary pack containing no more than 12 dosage units per pack; or
  2. in tablets or capsules enclosed in a primary pack containing not more than 100 tablets or capsules; or
  3. in tablets or capsules enclosed in a primary pack containing more than 100 tablets or capsules intended only as a bulk medicine pack and labelled 'For dispensing only' and 'This pack is not to be supplied to a patient'; or
  4. in individually wrapped powders or sachets of granules enclosed in a primary pack containing not more than 50 wrapped powders or sachets of granules; or
  5. in individually wrapped powders or sachets of granules enclosed in a primary pack containing more than 50 wrapped powders or sachets of granules intended only as a bulk medicine pack and labelled 'For dispensing only' and 'This pack is not to be supplied to a patient'; or
  6. in other preparations except:
    1. when included in Schedule 3 or 4; or
    2. in individually wrapped powders or sachets of granules each containing 1000 mg or less of paracetamol as the only therapeutically active constituent (other than caffeine, phenylephrine and/or guaifenesin or when combined with effervescent agents) when:
  7. enclosed in a primary pack that contains not more than 10 such powders or sachets of granules,
  8. compliant with the requirements of the Required Advisory Statements for Medicine Labels,
  9. not labelled for the treatment of children 6 years of age or less, and
  10. not labelled for the treatment of children under 12 years of age when combined with phenylephrine and/or guaifenesin; or
    1. in tablets or capsules each containing 500 mg or less of paracetamol as the only therapeutically active constituent (other than caffeine, phenylephrine and/or guaifenesin or when combined with effervescent agents) when:
  11. packed in blister or strip packaging or in a container with a child-resistant closure,
  12. in a primary pack containing not more than 20 tablets or capsules,
  13. compliant with the requirements of the Required Advisory Statements for Medicine Labels,
  14. not labelled for the treatment of children 6 years of age or less, and
  15. not labelled for the treatment of children under 12 years of age when combined with caffeine, phenylephrine and/or guaifenesin.

Appendix F, Part 3

PARACETAMOL

Warning Statements: 97 (Adults: Keep to the recommended dose. Don't take this medicine for longer than a few days at a time unless advised to by a doctor); AND/OR 98 (Children and adolescents: Keep to the recommended dose. Do not give this medicine for longer than 48 hours at a time unless advised to by a doctor); 99 (If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 13 11 26; New Zealand 0800 764 766) or go to a hospital straight away even if you feel well because of the risk of delayed, serious liver damage); 100 (Do not take with other products containing paracetamol, unless advised to do so by a doctor or pharmacist).

Appendix H

PARACETAMOL.

Index

PARACETAMOL
cross reference: ASPIRIN, IBUPROFEN, METOCLOPRAMIDE, SALICYLAMIDE, CAFFEINE

Schedule 4
Schedule 3
Schedule 2
Appendix F, Part 3
Appendix H

The Applicant's main points provided in support of the proposed amendments were as follows:

  • This application proposes a logical sequence of controls on paracetamol/ibuprofen combinations based on pack size with 12 dosage units or less as 'exempted from scheduling', 13 to 30 dosage units or less as 'Pharmacy Medicine' (Schedule 2), 31 to 50 dosage units or less as 'Pharmacist Only Medicine' (Schedule 3) and larger pack sizes as 'Prescription medicine' (Schedule 4).
  • Paracetamol and ibuprofen used separately have long been recognised as safe and effective for the treatment of simple self-limiting pain. The risks that do exist are addressed by label warning statements with small packs being available for general sale and larger packs being available in Schedules 2 or 3.
  • The proposed pack sizes for the combination in terms of days' treatment per pack are broadly consistent with pack sizes currently available without prescription for paracetamol or ibuprofen used separately. Quantities of up to 17 days' supply may legitimately be required for short term treatment of intermittent pain over a period of time or where more than one person in a household uses the same medicine. This is currently the case for ibuprofen in Schedule 2 and is now being proposed for the combination in Schedule 3 where pharmacist advice represents a further level of safety.
  • The two 'originator' products approved by TGA (XXXXXXXXXXXXXX) have now been available in Australia since 2013/2014 and in New Zealand since 2011. During that time there have been no 'serious' adverse events reported to TGA or to Medsafe and the number of adverse reactions relative to sales has been small.
  • In New Zealand XXXXXXXXXXXXXXX have been available since 2011 as 'general sales' items in packs of 20 and as 'pharmacy medicine' items in packs of 100. In addition, the maximum daily dose of XXXXXX in Australia is less than half the maximum daily dose of XXXXXX and exactly half the maximum daily dose of XXXXXX in New Zealand.
  • It has been accepted that the risk of consumers confusing their temporary pain condition with more serious diseases or conditions is very small.
  • In recognition of the differences in approved dose between the two major brands of paracetamol/ ibuprofen (XXXXXXXXXXXXX) and between these products and paracetamol and ibuprofen used separately XXXXXXXXX proposes to draw attention to the '1 tablet dose' of XXXXX on the front of pack.
  • Combinations of paracetamol and ibuprofen are able to be supplied in pack sizes of up to 12 dosage units, with reasonable safety, without access to health professional advice and this small pack size falls outside the factors for Schedules 2, 3, 4 or 8 in the same way that small packs of paracetamol or ibuprofen used separately fall outside these factors.
  • Ongoing long-term treatment with any analgesic requires medical intervention. The proposed Schedule 4 pack of more than 50 dosage units will achieve this while enabling medical practitioners to prescribe larger quantities when appropriate.
Current scheduling status

Paracetamol

Paracetamol is currently listed in Schedules 2, 3 and 4 and Appendix F and H of the Poisons Standard as follows:

Schedule 4

PARACETAMOL:

  1. when combined with aspirin or salicylamide or any derivative of these substances except when separately specified in these Schedules;
  2. when combined with ibuprofen in a primary pack containing more than 30 dosage units;
  3. in slow release tablets or capsules containing more than 665 mg paracetamol;
  4. in non-slow release tablets or capsules containing more than 500 mg paracetamol;
  5. in individually wrapped powders or sachets of granules each containing more than 1000 mg paracetamol;
  6. in tablets or capsules enclosed in a primary pack containing more than 100 tablets or capsules except in Schedule 2;
  7. in individually wrapped powders or sachets of granules enclosed in a primary pack containing more than 50 wrapped powders or sachets of granules except when included in Schedule 2;
  8. for injection;
  9. for the treatment of animals.

Schedule 3

PARACETAMOL when combined with ibuprofen in a primary pack containing 30 dosage units or less except when included in Schedule 2.

Schedule 2

PARACETAMOL for therapeutic use:

  1. when combined with ibuprofen in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen in divided doses in a primary pack containing no more than 12 dosage units per pack; or
  2. in tablets or capsules enclosed in a primary pack containing not more than 100 tablets or capsules; or
  3. in tablets or capsules enclosed in a primary pack containing more than 100 tablets or capsules intended only as a bulk medicine pack and labelled 'For dispensing only' and 'This pack is not to be supplied to a patient'; or
  4. in individually wrapped powders or sachets of granules enclosed in a primary pack containing not more than 50 wrapped powders or sachets of granules; or
  5. in individually wrapped powders or sachets of granules enclosed in a primary pack containing more than 50 wrapped powders or sachets of granules intended only as a bulk medicine pack and labelled 'For dispensing only' and 'This pack is not to be supplied to a patient'; or
  6. in other preparations except:
    1. when included in Schedule 3 or 4; or
    2. in individually wrapped powders or sachets of granules each containing 1000 mg or less of paracetamol as the only therapeutically active constituent (other than caffeine, phenylephrine and/or guaifenesin or when combined with effervescent agents) when:
      1. enclosed in a primary pack that contains not more than 10 such powders or sachets of granules,
      2. compliant with the requirements of the Required Advisory Statements for Medicine Labels,
      3. not labelled for the treatment of children 6 years of age or less, and
      4. not labelled for the treatment of children under 12 years of age when combined with caffeine, phenylephrine and/or guaifenesin; or
    3. in tablets or capsules each containing 500 mg or less of paracetamol as the only therapeutically active constituent (other than caffeine, phenylephrine and/or guaifenesin or when combined with effervescent agents) when:
      1. packed in blister or strip packaging or in a container with a child-resistant closure,
      2. in a primary pack containing not more than 20 tablets or capsules,
      3. compliant with the requirements of the Required Advisory Statements for Medicine Labels,
      4. not labelled for the treatment of children 6 years of age or less, and
      5. not labelled for the treatment of children under 12 years of age when combined with caffeine, phenylephrine and/or guaifenesin.

Appendix F, Part 3

Warning Statements: 97 (Adults: Keep to the recommended dose. Don't take this medicine for longer than a few days at a time unless advised to by a doctor.); and/or 98 (Children and adolescents: Keep to the recommended dose. Don't give this medicine for longer than 48 hours at a time unless advised to by a doctor.); 99 (If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 13 11 26; New Zealand 0800 764 766) or go to a hospital straight away even if you feel well because of the risk of delayed, serious liver damage); 100 (Do not take with other products containing paracetamol, unless advised to do so by a doctor or pharmacist.)

Appendix H

PARACETAMOL.

Index

PARACETAMOL
cross reference: ASPIRIN, IBUPROFEN, METOCLOPRAMIDE, SALICYLAMIDE, CAFFEINE

Schedule 4
Schedule 3
Schedule 2
Appendix F, Part 3
Appendix H

Paracetamol is also included in Part 2 of the Poisons Standard as follows:

Part 2 - Control on medicines and poisons, section 2.4 - child-resistant closures

Paracetamol included in Schedule 4, when packed and labelled for the treatment of animals

Nominal capacity: All sizes

Ibuprofen

Ibuprofen is listed in Schedules 2, 3 and 4 and Appendix F and H of the Poisons Standard as follows:

Schedule 4

IBUPROFEN except:

  1. when included in or expressly excluded from Schedule 2 or 3; or
  2. in preparations for dermal use.

Schedule 3

IBUPROFEN:

  1. in divided preparations, each containing 400 mg or less of ibuprofen in a primary pack containing not more than 50 dosage units, when labelled:
    1. with a recommended daily dose of 1200 mg or less of ibuprofen; and
    2. not for the treatment of children under 12 years of age; or
  2. in a modified release dosage form, each containing 600 mg of ibuprofen in a primary pack containing not more than 32 dosage units, when labelled:
    1. with a recommended daily dose of 1200 mg or less of ibuprofen; and
    2. not for the treatment of children under 12 years of age;

    except when included in or expressly excluded from Schedule 2.

Schedule 2

IBUPROFEN in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen:

  1. in liquid preparations when sold in the manufacturer's original pack containing 8 g or less of ibuprofen; or
  2. in divided preparations, each containing 200 mg or less of ibuprofen, in packs of not more than 100 dosage units except when:
    1. as the only therapeutically active constituent (other than phenylephrine or when combined with an effervescent agent);
    2. packed in blister or strip packaging or in a container with a child-resistant closure;
    3. in a primary pack containing not more than 25 dosage units;
    4. compliant with the requirements of the Required Advisory Statements for Medicine Labels;
    5. not labelled for the treatment of children 6 years of age or less; and
    6. not labelled for the treatment of children under 12 years of age when combined with phenylephrine.

Appendix F, Part 3

IBUPROFEN

Warning Statements:

101: Don't use [this product/name of the product]:

If you have a stomach ulcer.

In the last 3 months of pregnancy. [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea.]

If you are allergic to (name of substance) or anti-inflammatory medicines

104: Unless a doctor has told you to, don't use [this product/name of the product]:

For more than a few days at a time.

With other medicines containing (name of substance) or other anti-inflammatory medicines.

If you have asthma.

If you are pregnant. [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea.]

Appendix H

IBUPROFEN.

Index

IBUPROFEN
cross reference: PARACETAMOL

Schedule 4
Schedule 3
Schedule 2
Appendix F, Part 3
Appendix H

Scheduling history

Paracetamol/ibuprofen combinations

In June 2010, the NDPSC considered the scheduling of a combination of ibuprofen and paracetamol and agreed that the current scheduling remained appropriate - Schedule 2 for combinations of up to 200 mg ibuprofen and 500 mg paracetamol in packs of up to 100 dosage units.

In February 2011, the Advisory Committee on Medicines Scheduling (ACMS) considered a proposal from the Advisory Committee on Non-Prescription Medicines (ACNM) that the Delegate/ACMS consider up-scheduling paracetamol/ibuprofen combinations (containing up to 500 mg paracetamol/200 mg ibuprofen) from Schedule 2 to Schedule 3. The ACNM had also recommended consideration of a maximum pack size for Schedule 3 paracetamol/ibuprofen combinations. The ACNM, in an assessment of an application to register a combination paracetamol/ibuprofen product, had raised concerns that the sponsor had not satisfactorily established the safety of the product, and considered that pharmacist intervention was needed to assist consumers with safe use of the combination. The ACMS recommended that the combination paracetamol/ibuprofen products that were in Schedule 2 should be rescheduled to Schedule 3, when in packs containing 30 dosage units or less, with larger packs to be included in Schedule 4. The Delegate agreed with the ACMS advice and in September 2011, the Poisons Standard was amended to move paracetamol combined with ibuprofen to Schedule 3 in pack sizes of 30 units or less and Schedule 4 (all other products).

In October 2012, the ACMS considered proposals to reschedule paracetamol 500 mg when combined with ibuprofen 200 mg from Schedule 3 to Schedule 2 in packs containing 12 dosage units or less and to also include Schedule 3 paracetamol when combined with ibuprofen in Appendix H. The ACMS recommended that the current scheduling of paracetamol in combination with ibuprofen remained appropriate, and that paracetamol in combination with ibuprofen should not be included in Appendix H. The reasons for opposing rescheduling to Schedule 2 included insufficient data to disprove the safety concerns with the combination, lack of evidence to support rescheduling, lack of long-term evidence of safety of the combination, potential for additive gastrointestinal side effects, potential for inadvertent misuse and no experience with use of paracetamol/ibuprofen combination products in Australia. The ACMS also considered that there were no public health benefits with inclusion of the combination in Appendix H, and that advertising could lead to inappropriate use. The Delegate agreed with the Committee's advice.

In March 2015, the ACMS considered a proposal to create a new entry for paracetamol/ibuprofen in Appendix H. The ACMS recommended that the current scheduling of paracetamol when combined with ibuprofen remained appropriate. The ACMS considered that the public health risk from advertising would be seen as first line therapy and that there was little evidence to support the applicant claim that an Appendix H entry would transfer demand from codeine combination analgesics to non-codeine combination analgesics. The Delegate agreed with the Committee's advice.

In November 2015, the ACMS considered a proposal to amend the Schedule 2 entry for paracetamol to include paracetamol when combined with ibuprofen in pack sizes of 12 dosage units or less. The ACMS supported the proposal on the basis of the well-established safety profile, low risk of diversion/abuse/addiction and that the medicine provides an effective option for short term use for moderate pain. Following an interim decision in alignment with committee advice and subsequent consideration of the submissions on the interim decision, the Delegate decided to vary the interim decision. In view of the dosage levels of paracetamol and ibuprofen, the Delegate considered it is more appropriate to limit the Schedule 2 entry to 12 dosage units per pack rather than 3 days' supply packs as this would ensure the total paracetamol available in the pack would not be excessive. The implementation date was 1 June 2016.

In July 2017, the ACMS considered a proposal to amend the Schedule 2 entry of paracetamol combined with ibuprofen to increase the pack size from 12 to 24 dosage units or less. The ACMS recommended that the current scheduling of paracetamol when combined with ibuprofen remains appropriate. The ACMS considered the risk of overdosing on ibuprofen combined with paracetamol, the risk of potential adverse effects if the Schedule 2 pack size increase, the reduction in pharmacist advice and the potential for increased delay in consumers seeking advice. The Delegate agreed with the Committee's advice and the scheduling remained unchanged.

In June 2018, the ACMS considered a proposal to amend the Schedule 3 and Schedule 4 entries for paracetamol combined with ibuprofen to increase the dosage units from 30 to 50. The ACMS recommended that the current scheduling of paracetamol when combined with ibuprofen remained appropriate. The Delegate agreed with the Committee's advice and stated in the final decision that increasing the pack size from 10 days' supply (30 tablets) to 17 days' supply (50 tablets) may encourage self-treatment of chronic pain, which is outside the approved acute short term pain indication. The availability of larger quantities of any analgesic increases the likelihood of misadventure. Consumers should only have access to clinically appropriate quantities.

Australian regulations

Paracetamol combined with ibuprofen

  • There are 24 medicines currently active on the Australian Register of Therapeutic Goods (ARTG)[87] that contain paracetamol combined with ibuprofen as active ingredients. There is one (1) prescription medicine and 23 non-prescription medicines.
  • The Medicines Advisory Statement Specification 2019 (RASML No. 5 - Schedule 1)[88] requires the following warning statements pertaining to paracetamol and ibuprofen to be included on the labelling. The RASML requirements for paracetamol products are:
    Substance(s) Conditions Required statements(s)

    Ibuprofen

    (Entry 5 of 6)

    		 In combination with paracetamol, in medicines for oral use

    Do not give to children under 12 years of age.

    Adults: Keep to the recommended dose. Do not take this medicine for longer than a few days at a time unless advised to by a doctor.

    Children and adolescents: Keep to the recommended dose. Do not give this medicine for longer than 48 hours at a time unless advised to by a doctor.

    Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage.

    Do not use if pregnant or trying to become pregnant.

    Do not use if you have a stomach ulcer.

    Do not use if you have impaired kidney function.

    Do not use if you have heart failure.

    Do not use if you are allergic to ibuprofen or other anti-inflammatory medicines.

    If you get an allergic reaction, stop taking and see your doctor immediately.

    Unless a doctor has told you to, do not use if you have asthma.

    Unless a doctor has told you to, do not use if you are aged 65 years or over.

    Do not take with other products containing paracetamol, ibuprofen, aspirin or other anti-inflammatory medicines or with medicines that you are taking regularly, unless advised to do so by a doctor or pharmacist.

    If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 13 11 26, New Zealand 0800 764 766) or go to hospital straight away even if you feel well because of the risk of delayed, serious liver damage.

    Paracetamol

    (Entry 3 of 3)

    		 In combination with ibuprofen, in medicines for oral use

    Do not give to children under 12 years of age.

    Adults: Keep to the recommended dose. Do not take this medicine for longer than a few days at a time unless advised to by a doctor.

    Children and adolescents: Keep to the recommended dose. Do not give this medicine for longer than 48 hours at a time unless advised to by a doctor.

    Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage.

    Do not use if pregnant or trying to become pregnant.

    Do not use if you have a stomach ulcer.

    Do not use if you have impaired kidney function.

    Do not use if you have heart failure.

    Do not use if you are allergic to ibuprofen or other anti-inflammatory medicines.

    If you get an allergic reaction, stop taking and see your doctor immediately.

    Unless a doctor has told you to, do not use if you have asthma.

    Unless a doctor has told you to, do not use if you are aged 65 years or over.

    Do not take with other products containing paracetamol, ibuprofen, aspirin or other anti-inflammatory medicines or with medicines that you are taking regularly, unless advised to do so by a doctor or pharmacist.

    If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 13 11 26, New Zealand 0800 764 766) or go to hospital straight away even if you feel well because of the risk of delayed, serious liver damage.
  • There has been one (1) reported case of adverse events related to paracetamol combined with ibuprofen in the Database of Adverse Event Notifications (DAEN),[89] with one (1) report where paracetamol combined with ibuprofen was the single suspected medicine. There were no reports of death associated with paracetamol combined with ibuprofen use.

Paracetamol

  • According to the TGA Ingredient Database,[90] paracetamol is:
    • Available for use as an active ingredient in biologicals, export only, over the counter and prescription medicines;
    • Available for use as an excipient ingredient in biologicals, devices and prescription medicines; and
    • Not available as an equivalent ingredient in any application.
  • There are 690 medicines currently active on the Australian Register of Therapeutic Goods (ARTG)[91] that contain paracetamol as an active ingredient. These include 138 prescription and 511 non-prescription medicines.
  • Paracetamol is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2019[92].
  • The Prescribing medicines in pregnancy database[93] classifies paracetamol as:
    Drug name Category Classification Level 1 Classification Level 2
    Paracetamol A Central Nervous System Analgesics and Antipyretics (see also non-steroidal anti-inflammatory agents)
    Category A - Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.
  • The Medicines Advisory Statement Specification 2019 (RASML No. 5 - Schedule 1)[94] requires the following warning statements pertaining to paracetamol to be included on the labelling. The RASML requirements for paracetamol products are:
    Substance(s) Conditions Required statements(s)

    Paracetamol

    (Entry 1 of 3)

    		 For the purpose of exclusion from the schedules to the Poisons Standard

    Adults: Keep to the recommended dose. Do not take this medicine for longer than a few days at a time unless advised to by a doctor.

    Children and adolescents: Keep to the recommended dose. Do not give this medicine for longer than 48 hours at a time unless advised to by a doctor.

    If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 13 11 26, New Zealand 0800 764 766) or go to hospital straight away even if you feel well because of the risk of delayed, serious liver damage.

    Do not take with other products containing paracetamol, unless advised to do so by a doctor or pharmacist.

    Paracetamol

    (Entry 2 of 3)

    		 In Schedule 2 or 3 to the Poisons Standard

    Adults: Keep to the recommended dose. Do not take this medicine for longer than a few days at a time unless advised to by a doctor.

    and / or

    Children and adolescents: Keep to the recommended dose. Do not give this medicine for longer than 48 hours at a time unless advised to by a doctor.

    If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 13 11 26, New Zealand 0800 764 766) or go to hospital straight away even if you feel well because of the risk of delayed, serious liver damage.

    Do not take with other products containing paracetamol, unless advised to do so by a doctor or pharmacist.

    Paracetamol

    (Entry 3 of 3)

    		 In combination with ibuprofen, in medicines for oral use

    Do not give to children under 12 years of age.

    Adults: Keep to the recommended dose. Do not take this medicine for longer than a few days at a time unless advised to by a doctor.

    Children and adolescents: Keep to the recommended dose. Do not give this medicine for longer than 48 hours at a time unless advised to by a doctor.

    Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage.

    Do not use if pregnant or trying to become pregnant.

    Do not use if you have a stomach ulcer.

    Do not use if you have impaired kidney function.

    Do not use if you have heart failure.

    Do not use if you are allergic to ibuprofen or other anti-inflammatory medicines.

    If you get an allergic reaction, stop taking and see your doctor immediately.

    Unless a doctor has told you to, do not use if you have asthma.

    Unless a doctor has told you to, do not use if you are aged 65 years or over.

    Do not take with other products containing paracetamol, ibuprofen, aspirin or other anti-inflammatory medicines or with medicines that you are taking regularly, unless advised to do so by a doctor or pharmacist.

    If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 13 11 26, New Zealand 0800 764 766) or go to hospital straight away even if you feel well because of the risk of delayed, serious liver damage.
  • The Database of Adverse Event Notifications (DAEN)[95] contains 4500 reports of adverse events for products containing paracetamol as an active ingredient, with 2014 reports where paracetamol was the single suspected medicine. There were 203 reports of deaths associated with paracetamol use.
  • As of 7 July 2019, there are currently no products containing paracetamol listed on the Public Chemical Registration Information System Search (PUBCRIS).[96]

Ibuprofen

  • According to the TGA Ingredient Database,[97] ibuprofen is:
    • Available for use as an active ingredient in biologicals, export only, over the counter and prescription medicines;
    • Available for use as an excipient ingredient in biologicals, devices and prescription medicines; and
    • Available as an equivalent ingredient in biologicals, export only and prescription medicines.
  • There are 240 medicines currently active on the Australian Register of Therapeutic Goods (ARTG)[98] that contain ibuprofen as an active ingredient. These include 20 prescription and 214 non-prescription medicines.
  • Ibuprofen is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2019[99].
  • The Prescribing medicines in pregnancy database[100] classifies ibuprofen as:
    Drug name Category Classification Level 1 Classification Level 2 Additional information
    Ibuprofen C Musculoskeletal System Non-steroidal anti-inflammatory drugs (NSAIDS) Non-steroidal anti-inflammatory (NSAIDs) agents inhibit prostaglandin synthesis and, when given during the latter part of pregnancy, may cause closure of the foetal ductus arteriosus, foetal renal impairment, inhibition of platelet aggregation, and delay labour and birth. Continuous treatment with NSAIDs during the last trimester of pregnancy should only be given on sound indications. During the last few days before expected birth, agents with an inhibitory effect on prostaglandin synthesis should be avoided.
    Category C - Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
  • The Database of Adverse Event Notifications (DAEN)[101] contains 1751 reports of adverse events for products containing ibuprofen as an active ingredient, with 1188 reports where ibuprofen was the single suspected medicine. There were 56 reports of deaths associated with ibuprofen use.
  • As of 7 July 2019, there are currently no products containing paracetamol listed on the Public Chemical Registration Information System Search (PUBCRIS).[102]
  • The Medicines Advisory Statement Specification 2019 (RASML No. 5 - Schedule 1)[103] requires the following warning statements pertaining to ibuprofen to be included on the labelling. The RASML requirements for ibuprofen products are:
    Substance(s) Conditions Required statements(s)

    Ibuprofen

    (Entry 1 of 6)

    		 For the purpose of exclusion from the schedules to the SUSMP, when the preparation is for oral use in adults and children aged 12 years and over.

    Do not use if you have a stomach ulcer.

    Do not use if you have impaired kidney function.

    Do not use if you have heart failure.

    Do not use if you are allergic to ibuprofen or other anti-inflammatory medicines.

    If you get an allergic reaction, stop taking and see your doctor immediately.

    Unless a doctor has told you to, do not use if you have asthma.

    Unless advised by your doctor or pharmacist, do not use with products containing ibuprofen, aspirin or other anti-inflammatory medicines or with medicines that you are taking regularly.

    Do not use for more than a few days at a time unless a doctor has told you to. Do not exceed the recommended dose. Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage.

    Do not use if trying to become pregnant, or during the first 6 months of pregnancy, except on doctor's advice. Do not use at all during the last 3 months of pregnancy.

    Unless a doctor has told you to, do not use if you are aged 65 years or over.

    Ibuprofen

    (Entry 2 of 6)

    		 When included in a schedule to the SUSMP for oral use in adults and children aged 12 years and over

    Do not use if you have a stomach ulcer.

    Do not use if you have impaired kidney function.

    Do not use if you have heart failure.

    Do not use if you are allergic to ibuprofen or other anti-inflammatory medicines.

    If you get an allergic reaction, stop taking and see your doctor immediately.

    Unless a doctor has told you to, do not use if you have asthma.

    Unless advised by your doctor or pharmacist, do not use with products containing ibuprofen, aspirin or other anti-inflammatory medicines or with medicines that you are taking regularly.

    Do not use for more than a few days at a time unless a doctor has told you to. Do not exceed the recommended dose. Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage.

    Do not use if trying to become pregnant, or during the first 6 months of pregnancy, except on doctor's advice. Do not use at all during the last 3 months of pregnancy.

    Ibuprofen

    (Entry 3 of 6)

    		 For the purpose of exclusion from the schedules to the SUSMP, for oral use in children under 12 years of age

    Do not use if you have a stomach ulcer.

    Do not use if you have impaired kidney function.

    Do not use if you have heart failure.

    Do not use if you are allergic to ibuprofen or other anti-inflammatory medicines.

    If you get an allergic reaction, stop taking and see your doctor immediately.

    Unless a doctor has told you to, do not use if you have asthma.

    Unless advised by your doctor or pharmacist, do not use with products containing ibuprofen, aspirin or other anti-inflammatory medicines or with medicines that you are taking regularly.

    Do not use for more than a few days at a time unless a doctor has told you to. Do not exceed the recommended dose. Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage.

    Do not use if trying to become pregnant, or during the first 6 months of pregnancy, except on doctor's advice. Do not use at all during the last 3 months of pregnancy.

    Ask your doctor or pharmacist before use of the medicine in children suffering from dehydration through diarrhoea and/or vomiting.

    Unless a doctor has told you to, do not use if you are aged 65 years or over.

    Unless a doctor has told you to, do not use in children 6 years of age or less.

    Ibuprofen

    (Entry 4 of 6)

    		 When included in a schedule to the SUSMP for oral use in children under 12 years of age

    Do not use if you have a stomach ulcer.

    Do not use if you have impaired kidney function.

    Do not use if you have heart failure.

    Do not use if you are allergic to ibuprofen or other anti-inflammatory medicines.

    If you get an allergic reaction, stop taking and see your doctor immediately.

    Unless a doctor has told you to, do not use if you have asthma.

    Unless advised by your doctor or pharmacist, do not use with products containing ibuprofen, aspirin or other anti-inflammatory medicines or with medicines that you are taking regularly.

    Do not use for more than a few days at a time unless a doctor has told you to. Do not exceed the recommended dose. Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage.

    Do not use if trying to become pregnant, or during the first 6 months of pregnancy, except on doctor's advice. Do not use at all during the last 3 months of pregnancy.

    Ask your doctor or pharmacist before use of the medicine in children suffering from dehydration through diarrhoea and/or vomiting.

    Ibuprofen

    (Entry 5 of 6)

    		 In combination with paracetamol, in medicines for oral use

    Do not give to children under 12 years of age.

    Adults: Keep to the recommended dose. Do not take this medicine for longer than a few days at a time unless advised to by a doctor.

    Children and adolescents: Keep to the recommended dose. Do not give this medicine for longer than 48 hours at a time unless advised to by a doctor.

    Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage.

    Do not use if pregnant or trying to become pregnant.

    Do not use if you have a stomach ulcer.

    Do not use if you have impaired kidney function.

    Do not use if you have heart failure.

    Do not use if you are allergic to ibuprofen or other anti-inflammatory medicines.

    If you get an allergic reaction, stop taking and see your doctor immediately.

    Unless a doctor has told you to, do not use if you have asthma.

    Unless a doctor has told you to, do not use if you are aged 65 years or over.

    Do not take with other products containing paracetamol, ibuprofen, aspirin or other anti-inflammatory medicines or with medicines that you are taking regularly, unless advised to do so by a doctor or pharmacist.

    If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 13 11 26, New Zealand 0800 764 766) or go to hospital straight away even if you feel well because of the risk of delayed, serious liver damage.

    Ibuprofen

    (Entry 6 of 6)

    		 In preparations for dermal use

    Do not use [this product/insert name of product] if you are allergic to ibuprofen or other anti-inflammatory medicines.

    If you get an allergic reaction, stop taking and see your doctor immediately.

    Unless a doctor or pharmacist has told you to, do not use [this product/insert name of product] with other medicines that you are taking regularly.
International regulations

XXXXX tablets (paracetamol 500 mg with ibuprofen 200 mg) have been approved as an over-the-counter medicine in many countries including the United Kingdom, Poland, New Zealand, Ukraine, Russia, Saudi Arabia, United Arab Emirates, Kuwait, Bahrain, Oman, Qatar and Yemen. It is Pharmacy Only in the United Kingdom and Poland and it is a 'general sale' medicine in New Zealand in pack sizes up to 20 dose units and 'pharmacy medicine' in pack sizes of up to 100 dose units. In the United Kingdom, XXXXX is available as a 'pharmacy' medicine in packs of up to 32 tablets.

XXXXXX tablets (paracetamol 500 mg with ibuprofen 150 mg) were approved in New Zealand in March 2009.

Summary of pre-meeting public submissions

In response to the notice published under regulation 42ZCZK advising of the proposed amendment, five (5) submissions were received. All submissions opposed the amendment.

The main points provided in opposition to the proposed amendment were:

  • In June 2016, these products were down-scheduling to facilitate Schedule 2 supply, which coincided with an increase in calls to the Poisons Information Centres regarding overdoses involving these medicines.[104] The Medical Journal of Australia also recently published an article on paracetamol poisoning-related hospitalisations and deaths, demonstrating an increasing rate of paracetamol poisoning and associated harms between 2004 and 2017.[105]
  • In 2018, the ACMS considered a proposal to amend the Schedule 3 entry for paracetamol, when combined with ibuprofen. The proposal sought to allow the Schedule 3 pack size to be increased from 30 dosage units (equivalent to 10 days' supply) to 50 dosage units (17 days' supply). The delegate's final decision published in November 2018 was to not amend the Poisons Standard on the basis that the perceived benefits of larger pack sizes from a convenience perspective were outweighed by the risks.[106]
  • In 2018, the TGA published an interim decisions NOT to amend the Poisons Standard in relation to available pack sizes of paracetamol combined with ibuprofen.[107] We support the interim decision and considers there is no additional clinical evidence to support increasing pack sizes within the various Schedules nor to exempt the smallest pack size to allow general sale in supermarkets. The reduction in scheduling infers a perceived safety around use of these medicines.
  • Although reduced maximum pack size of unscheduled paracetamol was implemented in Australia in 2013, there is no legal restriction on the number of packs that may be purchased in one transaction from non-pharmacy retail outlets, nor the means to generally monitor frequency of purchase.
  • The risks associated with poisoning from these products due to therapeutic errors, inappropriate usage, accidental paediatric exposures and particularly deliberate self-poisonings, far outweighs the few benefits associated with changes to existing schedules. Since the introduction of combined paracetamol+ibuprofen products the number of calls received at NSW PIC regarding these products has substantially increased each year with 2019 currently showing a proportional increase in call numbers compared to 2018.
  • The increasing number of calls regarding therapeutic errors also indicates ongoing confusion amongst the general public about the correct dosing of these products. Increasing the pack size available as an S2 medication and allowing pack sizes up to 12 to be unscheduled will further increase the likelihood of incorrect dosage. The availability of larger pack sizes may also mean therapeutic errors will continue for longer before the patient discusses their medication use with a health professional such as a pharmacist or doctor.
  • Existing marketed products containing paracetamol and ibuprofen combinations contain differing strengths and differing dose instructions that likely contribute to consumer confusion, highlighting the important need for accessibility to appropriate health professional review and counselling in the purchase of these products.
  • The maximum recommended daily adult dose of paracetamol is 4 g. Single oral doses of paracetamol above 10 grams or 200 mg/kg of bodyweight, whichever is lower, have a reasonable likelihood of causing liver toxicity and irreversible damage. The proposed increases in pack size from 30 to 50 tablets would increase the total amount of paracetamol from 10 g to 25 g and ibuprofen from 6 g to 10 g.
  • Ibuprofen should only be used with caution in consumers with coexisting medical conditions such as, asthma, heart conditions, gastrointestinal bleeding risk, or kidney disease and NSAIDS such as ibuprofen can interact with other medicines. Ongoing long-term treatment with any analgesic requires medical intervention especially when patients suffer additional conditions and already prescribed medicines that could interact with NSAIDs such as ibuprofen.
  • The existing scheduling already provides adequate and appropriate consumer access to these combination products. It represents an adequate measure to address the risks by limiting the quantities that can be purchased without health professional advice. It is considered that the existing measures assist in protecting the public from unintended harms. As such, the proposed amendment to the scheduling of paracetamol/ibuprofen containing products is not supported.
Summary of ACMS advice/recommendations to the Delegate

The Committee recommended that the current scheduling of paracetamol (in combination with ibuprofen) in the Poison Standard remains appropriate.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

52E(1) Considerations Reasons
a - the risks and benefits of the use of a substance

Risks:

  • The risks associated with paracetamol-ibuprofen combinations are those of each ingredient with the additional risk of consumer confusion and therapeutic error.
  • Pharmacist advice will not be available to mitigate risks of therapeutic error and inappropriate use if 12 dosage units are available for general sale (outside a pharmacy). As there are no limits on the number of unscheduled packs that may be purchased, the risk of intentional overdose is not mitigated. General sale also gives the impression of safety and paracetamol-ibuprofen combinations cannot be supplied with reasonable safety (SPF Handbook).
  • Pharmacist advice is also likely to be significantly reduced if the Schedule 2 pack size is increased from 12 to 30 dosage units. Pharmacist intervention is required to manage acute pain, including inflammation and/or aches and pains associated with colds and flu. The current pack size of 12 dosage units is sufficient for initial use of combination analgesia, given that the combination is only to be used for a few days.
  • The risk of increasing the Schedule 2 pack size would be potentially delaying consumers seeking further advice from a health practitioner.
  • Potential increase in duration of inappropriate use and accidental poisoning due to a larger than necessary quantity being supplied under Schedule 3.
  • Risk of co-administration with other NSAIDs and analgesics
b - the purposes for which a substance is to be used and the extent of use of a substance
  • Same as for the current Schedule 2 and Schedule 3 products. The substance is intended for use to provide temporary relief of acute pain and/or inflammation.
c - the toxicity of a substance
  • The toxicity is well-established. Potential for significant toxicity if medication is taken over and above the recommended dosage from both ingredients.
  • Adverse effects in overdose of ibuprofen combined with paracetamol can be potentially severe. The adverse effects are liver damage, gastric ulcers, gastrointestinal bleeding, anaemia and melaena. Single oral doses of paracetamol above 10 grams or 200 mg/kg of bodyweight, whichever is lower, have a reasonable likelihood of causing liver toxicity and irreversible damage.
  • The proposed 30 dosage unit and 50 dosage unit pack size in Schedules 2 and 3 respectively increases the risk of harm from overdose.
d - the dosage, formulation, labelling, packaging and presentation of a substance
  • The proposed warning statements for an unscheduled pack are the same as the Schedule 2 and 3 packs but without the availability of pharmacist advice.
e - the potential for abuse of a substance

Increasing evidence of deliberate and accidental overdose according to PIC (NSW)
f - any other matters that the Secretary considers necessary to protect public health
  • A previous application for paracetamol-ibuprofen combinations in 2018 was not approved based on the risks
  • There is a risk of consumer confusion in the market
  • Observed increasing trend in paracetamol overdoses
  • Pharmacist advice is required to deal with different types of pain and non-pharmacological management options.
Delegate's considerations

In making this interim decision, I have considered the following material:

  • The application to amend the current Poisons Standard with respect to paracetamol + ibuprofen;
  • Advisory Committee on Medicines Scheduling's advice;
  • The public submissions received by the first closing date;
  • Section 52E of the Therapeutic Goods Act 1989, in particular (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
  • The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
  • Scheduling Handbook (V 1.1, July 2019).
Reasons for the interim decision

I agree with the Committee's finding that the relevant matters of section 52E of the Therapeutic Goods Act 1989 are: (a) the risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

In my view, the relevant parts of the Scheduling Policy Framework (SPF) 2018 are the Scheduling Factors for Schedules 2, 3 and 4.

I have made an interim decision that the scheduling of paracetamol (in combination with ibuprofen) remains appropriate under Schedules 2, 3 and 4. I have set out my reasons below.

I have taken into account that the proposed increase in pack size is beyond the amount of medication required for acute pain and could encourage use of the medication for chronic pain. This does not meet the Scheduling Factors in the SPF (2018), especially for Schedule 2, which provides 'The use of the medicine is substantially safe for short term treatment and the potential for harm from inappropriate use is low'.

I have considered that currently there are different strengths and dosages of the combination packs available and that this is likely to cause significant confusion in the community. In particular, the proposal for larger pack sizes may have the potential to increase the risk of over-dosage, both inadvertent and deliberate. There is also likely to be an assumption amongst consumers that if a product is available in a general retail outlet then it is safe for use and can be taken in combination with any other over-the-counter products. I am of the view that this may lead to inadvertent overdose if someone is not aware that they are taking paracetamol and/or ibuprofen in a combination product.

I have also taken into account that paracetamol combined with ibuprofen is not generally a first-line therapy for pain. These medications both have significant risk profiles particularly when taken in larger doses than the recommended daily dosages. In particular, ibuprofen has multiple contraindications and drug-drug interactions. As a result, ibuprofen should be used with caution by a large sector of the community (e.g. those over 65, those who suffer from asthma, heart conditions, renal disease, and gastrointestinal bleeding or are pregnant).

I have considered that the NSW Poisons Information Centre (PIC) data has shown a significant increase in calls regarding potential over-dosage of these medications since they were down-scheduled in 2015 to Schedule 2 for packs of 12 or less. Further, NSW PIC has taken an increasing number of calls each year regarding these combination medications in relation to therapeutic errors, deliberate self-poisoning and accidental poisoning, with the number of deliberate self-poisonings reported by 15 September 2019 already exceeding that of 2018 or any year previously, and total number of incidents since 2014.

I am of the view that the Applicant has not presented any further objective clinical evidence for the proposal to increase the pack sizes since the previous application in 2018 and I am in agreement with my final decision from November 2018. I am not in agreement with the proposal that states that the increase pack size in Schedules 2, 3 and 4, as well as the exemption of the smaller packs, is in the interest of public health and that the risk of misuse and inappropriate use is minimal. In particular, the Applicant has not acknowledged that each individual medication has the potential for serious harm, and when combined, may have more side effects than one of the medications alone.

I note that all five pre-meeting public submissions opposed the scheduling proposal on the grounds that the risks outweigh the benefits for increased pack sizes.

The current scheduling allows for the availability of clinically appropriate quantities for the treatment of acute/short-term pain while larger pack sizes are outside the acute pain relief indication and could encourage self-treatment for chronic pain. There is an increased risk of therapeutic error, misuse or overdose with larger pack sizes, which could lead to significant medical conditions. Overall the risks of these medications outweigh the purported benefits of the proposal.

Footnotes

[87] Australian Register of Therapeutic Goods
[88] Therapeutic Goods (Medicines Advisory Statements) Specification 2019
[89] [3] Database of Adverse Event Notifications - medicines
[90] eBS
[91] Australian Register of Therapeutic Goods
[92] Therapeutic Goods (Permissible Ingredients) Determination (No. 4) 2019
[93] Prescribing medicines in pregnancy database
[94] Therapeutic Goods (Medicines Advisory Statements) Specification 2019
[95] Database of Adverse Event Notifications - medicines
[96] Public Chemical Registration Information System Search
[97] eBS
[98] Australian Register of Therapeutic Goods
[99] Therapeutic Goods (Permissible Ingredients) Determination (No. 4) 2019
[100] Prescribing medicines in pregnancy database
[101] Database of Adverse Event Notifications - medicines
[102] Public Chemical Registration Information System Search
[103] Therapeutic Goods (Medicines Advisory Statements) Specification 2019
[104] NPS Medicinewise (NSW June 2017). Dose confusion with paracetamol/ibuprofen combinations [cited 19 September 2019]
[105] [19] Cairns R et al., (2017). Paracetamol poisoning-related hospital admissions and deaths in Australia, 2004-2017. Me J Aust 211(5) 218-223
[106] Therapeutic Goods Administration. Final decisions amending, or not amending, the current Poisons Standard, November 2018. 29 Nov 2018. At: Final decisions amending, or not amending, the current Poisons Standard, November 2018
[107] ACSM #24. Publication of interim decisions proposing to amend, or not amend, the current Poisons Standard, September 2018: 1.6 Paracetamol combined with ibuprofen.

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