1.4. Interim decision in relation to paracetamol (liquid formulations)

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

1.4. Interim decision in relation to paracetamol (liquid formulations)

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the paracetamol (liquid formulations) as follows:

Proposed date of effect of the proposed amendment

1 June 2020

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 and Schedule 4 entries for paracetamol was considered. The proposal sought to set limits on the volume of liquid paracetamol available for oral use.

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

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

• The paracetamol entries in Schedules 2, 3 and 4 of the Poisons Standard aim to minimise the risk of accidental poisoning by limiting the total dose in a pack. However, there is no limit on the amount of paracetamol that can be supplied in the liquid form in Schedule 2.
• A product containing large quantities of paracetamol, particularly in liquid form, carries a potential for significant human toxicity (including delayed irreversible hepatotoxicity) if the product is accidently ingested or deliberately misused.
• In view of the known risks of paracetamol toxicity to humans (the acute toxic effects include hepatic and renal tubular necrosis) and in the interests of public health, it is appropriate to limit the volume or maximum paracetamol mass in Schedule 2 paracetamol liquid preparations.
• Liquid paracetamol products are marketed in formulations containing:
  • 24 mg/mL paracetamol in 50, 100, 200 and 500 mL pack sizes;
  • 48 mg/mL paracetamol in 50, 100, 200 and 500 mL pack sizes;
  • 50 mg/mL paracetamol in 60, 100, 200 and 1000 mL pack sizes;
  • 100 mg/mL paracetamol in 5 and 20 mL pack sizes; and
  • 32.5 mg/mL paracetamol + 1 mg/mL dextromethorphan in 120, 240 and 360 mL pack sizes (intended primarily for use in children, are currently available as a Pharmacy Medicine (Schedule 2)).

Current scheduling status

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

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

Scheduling history

At the February 1977 and May 1977 meetings of the Poisons Scheduling Committee (PSC), consideration was given to a report from the Analgesics Working Party which had been convened by the Medicines Advisory Committee to determine whether specific analgesics, including paracetamol, should be restricted in their availability and if so, by what means. The Committee also considered whether paracetamol and other analgesics and their derivatives should be available over the counter (OTC) when supplied as a single substance only with pack size restrictions and supplied in strip packs or in containers with suitable child resistant closures. The Committee agreed that a new Schedule 2 entry be created for paracetamol:

• In tablets or capsules each containing 500 milligrams or less of paracetamol as the only therapeutically active constituent;
• The tablets or capsules supplied in blister or strip packaging or in containers with suitable child resistant closures; and
• In a primary pack containing not more than 20 such tablets or capsules; or
• In individually wrapped powders each containing 250 milligrams or less of paracetamol as the only therapeutically active constituent provided such individually wrapped powders were packed in a primary pack containing not more than 10 such powders.

In November 1978, the PSC considered a request that warning statements should appear on scheduled and unscheduled analgesics including paracetamol. The Committee agreed that the following warning statements for paracetamol, aspirin and salicylamide be adopted:

'WARNING - THIS MEDICATION MAY BE DANGEROUS WHEN USED IN LARGE AMOUNTS OR FOR A LONG PERIOD'

or

'CAUTION - THIS PREPARATION IS FOR THE RELIEF OR MINOR AND TEMPORARY AILMENTS AND SHOULD BE USED STRICTLY AS DIRECTED. PROLONGED USE WITHOUT MEDICAL SUPERVISION COULD BE HARMFUL.'

In May 1979, the PSC considered advice regarding inconsistencies relating to the dose and quantity paracetamol, aspirin and salicylamide present in powders and tablets available over the counter. This was based on the premise that the public had a misunderstanding that one powder sachet was the therapeutic equivalent to two tablets. The PSC agreed that the case was reasonable and recommended that the quantity of paracetamol in individually wrapped powders available in Schedule 2 be increased from 250 mg to 1000 mg.

In May 1981, the PSC considered requests to review the existing Schedule 2 entries for the powder form of analgesics, including paracetamol, to allow the use of effervescent dose forms; to reduce the net content of each dose; and to increase the number of doses per pack from 12 to 24. The PSC agreed that while alternative formulations were acceptable, increasing the number of doses per pack (decreased contents not withstanding) was seen as contrary to the spirit of previous recommendations designed to discourage excessive analgesic consumption.

In February 1989, the National Drugs and Poisons Schedule Committee (NDPSC) were made aware of a new paediatric flavoured 80 mg paracetamol tablet being sold as an unscheduled item through non-pharmacy retail outlets. As a result, the NDPSC considered the unrestricted promotion of unscheduled flavoured paediatric paracetamol tablets. The NDPSC made a foreshadowed recommendation to include paediatric flavoured dose forms of paracetamol in Schedule 2. The foreshadowed recommendation was confirmed at the November 1989 meeting.

In August 1993, the NDPSC gave consideration to the Schedule 2 paracetamol entry which prevented the marketing of any industrial product containing paracetamol, even at very low concentrations. The NDPSC amended the Schedule 2 entry for paracetamol to include the words 'for therapeutic use'.

In May 1998, the NDPSC considered a request to make paracetamol a Pharmacy Only medicine due to problems with overdoses. The NPPSC agreed that restricting paracetamol to pharmacies would have no substantial effect on deliberate paracetamol poisonings and the scheduling of OTC paracetamol remained unchanged.

In May 2001, the NDPSC considered an application to vary the dose limit for paracetamol in Schedule 2 to exempt a modified release paracetamol product containing 665 mg paracetamol per caplet with 18 caplets per pack. Whilst the NDPSC recognised that sustained release paracetamol may have an advantage over immediate release preparations in terms of reduced dosing frequency, they were concerned that the changed dosage regime, combined with the pharmacokinetics of the new formulation, would lead to an increase in overdose with paracetamol. The NDPSC was of the view that there was a need to assess the safety-in-use for the new dosing regimen and in the treatment of pain in chronic conditions such as osteoarthritis, given the pharmacokinetic profile of sustained release paracetamol and the shift in demographic from the healthy volunteers to an older age group. Consequently, the NDPSC did not agree to vary the Schedule 2 exemption of 500 mg paracetamol limit.

In October 2003, the NDPSC considered the Medicines Evaluation Committee's (MEC) package of warning statements for over the counter paracetamol and subsequent inclusion of paracetamol in Appendix F of the Poisons Standard. The NDPSC agreed to this proposal and the consequential amendments to the Schedule 2 entry for paracetamol. It was also agreed that the effective date would be 1 May 2005.

In October 2006, the NDPSC considered a recommendation arising from the June 2006 Medicines Classification Committee (MCC) meeting with respect to harmonising the Schedule 2 entry for paracetamol with New Zealand. The NDPSC considered the requirement for Schedule 2 (Pharmacy Only) tablets or capsules containing over 500 mg and up to 665 mg of paracetamol to be in slow release form only. After discussion of the request and the reasons behind it, the NDPSC agreed to foreshadow consideration of the scheduling of paracetamol at the February 2007 meeting.

In February 2007, the NDPSC noted the safety concerns surrounding the potential for overdose and toxicity with immediate release does of paracetamol over 500 mg. With consideration to these safety concerns and in order to harmonise with New Zealand, the NDPSC agreed that slow release paracetamol with >665 mg should remain in Schedule 4 and also agreed to lower the non-slow release cut-off to >500 mg.

In February 2008, the NDPSC considered a proposal to include paracetamol for injection in Schedule 4 of the Poisons Standard. The NDPSC agreed that there were certain circumstances where the use of injectable paracetamol was appropriate and that use of a substance as an injectable required clinical input and supervision. It was agreed that the Schedule 4 entry for paracetamol be amended accordingly.

In May 2012, the ACMS considered a proposal to further restrict the pack size requirements for paracetamol to be exempt from scheduling. The ACMS recommended and the Delegate agreed for Australia to harmonise with New Zealand and restrict the exempt pack size requirements for paracetamol to packs containing 10 g or less of paracetamol. The full reasons for this decision can be found on the TGA website.

In March 2016, the ACMS considered an application to restrict the pack size requirements of paracetamol available in a pharmacy. The Delegate made a final decision to limit the pack size of paracetamol available from a pharmacy to no more than 100 tablets or capsules per pack and no more than 50 wrapped powders or sachets of granules per pack for domestic supply. In addition, bulk pack sizes of paracetamol were specifically limited for supply only to hospitals, nursing homes and pharmacies for dispensing purposes. The full reasons for this decision can be found on the TGA website.

In March 2019, the ACMS and the Joint Advisory Committee on Chemicals and Medicines Scheduling (Joint ACCS-ACMS) considered proposals to amend the Schedule 4 entry for paracetamol with respect to slow release paracetamol and to create a new scheduling entry for a concentrated liquid paracetamol formulation for the animal treatment, respectively. The Delegate's interim decisions, published on the TGA website on 6 June 2019, were to: (i) replace the words 'slow release' with 'modified release'^[53]; and (ii) include paracetamol for the treatment of animals in Schedule 4^[54] of the Poisons Standard. In addition, a new listing will be created in Part 2 - Control on medicines and poisons, section 2.4 - child-resistant closures as follows: 'Paracetamol included in Schedule 4, when packed and labelled for the treatment of animals. Nominal capacity: All sizes'^[55]. The final decision was published on the TGA website on 22 August 2019.

Australian regulations

• According to the TGA Database,^[56] paracetamol is:
  • Available for use as an Active Ingredient in: Biologicals, Export Only, Over the Counter, Prescription medicines;
  • Available for use as an Excipient Ingredient in: Biologicals, Devices, Prescription medicines; and
  • Not available as an Equivalent Ingredient in any application.
• There are 716 medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[57] that contain paracetamol as the sole active ingredient or in combination products. Of these 716 products, 49 are oral liquid preparations which include 3 prescription (Schedule 4) and 46 non-prescription medicines (Schedule 2).
• Liquid paracetamol preparations on the ARTG:

  Dosage form	Total	Prescription medicines	Non-prescription medicines
  Oral liquid	12	1	11
  Oral liquid, solution	19	1	18
  Oral liquid, suspension	18	1	17

• Liquid paracetamol products are marketed in formulations containing:
  • 24 mg/mL paracetamol in 50, 100, 200 and 500 mL pack sizes;
  • 48 mg/mL paracetamol in 50, 100, 200 and 500 mL pack sizes;
  • 50 mg/mL paracetamol in 60, 100, 200 and 1000 mL pack sizes;
  • 100 mg/mL paracetamol in 5 and 20 mL pack sizes; and
  • 32.5 mg/mL paracetamol + 1 mg/mL dextromethorphan in 120, 240 and 360 mL pack sizes (intended primarily for use in children, are currently available as a Pharmacy Medicine (Schedule 2)).
• 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^[58].
• The Prescribing medicines in pregnancy database^[59] 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)^[60] requires the following warning statements pertaining to paracetamol to be included on the labelling. The RASML requirements for paracetamol products are:

  Column 1 Substance(s)	Column 2 Conditions	Column 3 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)^[61] contains one hundred and eight (108) reports of adverse events for products containing paracetamol as an active ingredient that are targeted to children, with ninety-nine (99) reports where paracetamol was the single suspected medicine. Of these 99 cases:
  • 9 involved accidental overdose/poisoning;
  • involved the accidental exposure to products by children;
  • involved use of products in unapproved indications/off label use;
  • involved the incorrect dose or administration rate being administered;
  • 1 incorrect drug administration rate;
  • 1 involved hepatotoxicity; and
  • 2 reports of deaths associated with paracetamol use resulting from overdose and sudden infant death syndrome.
• As of 20 June 2019, there are currently no products containing paracetamol listed on the Public Chemical Registration Information System Search (PUBCRIS).^[62]

International regulations

• Paracetamol is registered with the European Chemical Agency (ECHA)^[63] for a variety of uses including pharmaceutical, laboratory and industrial.
• Paracetamol is on the World Health Organisation's List of Essential Medicines,^[64] which lists the most effective and safe medicines needed in a health system.
• In Sweden, oral solutions of 24 mg/mL paracetamol are available at non-pharmacy outlets and at pharmacies in 100 mL pack sizes.^[65]
• In Ireland, dosage instructions for liquid paracetamol, 120 mg/5mL, were increased in March 2012 from two single bands (3 months to 1 year and 1 year to 6 years) to four separate age bands (3‐6 months, 6‐24 months, 2‐4 years and 4‐6 years) with one dose recommended for each age band.^[66] Oral liquid paracetamol, 50 mg/mL, is available as a non-pharmacy medicine (60 mL pack size) and a pharmacy medicine (240 mL pack size).^[67]
• In the United States (U.S.), acetaminophen (paracetamol) is available in OTC and prescription medicines.^[68] On December 22 2011, The U.S. Food and Drug Administration (FDA) informed the public that an additional concentration of liquid acetaminophen marketed for 'infants' (160 mg/5 mL) became available at local stores. Until then, liquid acetaminophen marketed for 'infants' was only available in 80 mg/0.8 mL or 80 mg/mL concentrations. Having two very different concentrations of liquid acetaminophen on the market increased the likelihood for dosing confusion and medication errors involving unintentional overdoses in children. In order to prevent possible dosing confusion between products with different concentrations of acetaminophen, many (but not all) U.S. manufacturers decided to voluntarily change the liquid acetaminophen marketed for infants to make it the same concentration as the product used for older children.^[69]
• In the United Kingdom (UK), paracetamol is included on the General Sales List (GSL)^[70] and is available in small quantities off the shelf with no pharmacy training required to sell. The largest pack size of paracetamol available in shops without a pharmacist is 16 tablets, but pharmacies can sell packs of 32 tablets. In 2011, new paediatric paracetamol dosing instructions were introduced in the UK. The UK paediatric paracetamol dosage system^[71] has a larger number of narrower age bands and defines a single dose per age band. Schedule 15 (Requirements for specific products subject to general sale) of the UK Human Medicines Regulation 2012,^[72] restricts liquid paracetamol pack sizes available for general sale to: (i) 160 mL for preparation intended for persons over 12 years of age; and (ii) individual unit doses of not more than 5 mL each, to a maximum of 20 unit doses for preparations intended for persons aged less than 12 years old.
• In New Zealand (Medicines and Medical Devices Safety Authority (MEDSAFE)),^[73] paracetamol, depending on its presentation, is available as a Prescription, Restricted (Pharmacist-Only), Pharmacy Only or General Sales medicine. Liquid paracetamol for children and infants over three months is available in two strengths: 120 mg/5 mL and 250 g/5 mL, with individual doses based on body weight. For infants younger than three months or where an infant or child weighs 5 kg or less, a doctor must be seen first.^[74]
• In Canada, acetaminophen (paracetamol), when recommended for administration by intravenous injection, is on Health Canada's Prescription Drug List^[75] for human use and veterinary use. It is also available as an OTC medicine and in some presentations is classed as a narcotic under Canada's Controlled Substances Act (CDSA).^[76]

Summary of pre-meeting public submissions

In response to the notice published under regulation 42ZCZK advising of the proposed amendment, eight (8) submissions were received. One (1) submission requested clarification of the scheduling proposal, two (2) submissions supported the amendment, four (4) submissions opposed the amendment and one (1) submission made comment only.

The main points provided in the submission requesting clarification of the proposed scheduling amendment were:

• The proposed limits on concentration, total volume and total mass per container do not appear to be mathematically logical or feasible.
• The wording suggests the upper limits in concentration, total volume and total mass per container must all be met (i.e. not exceeded).

The main points provided in support of the proposed amendment were:

• Paracetamol is the most widely used over-the-counter analgesic agent in the world. It is involved in a large proportion of accidental paediatric exposures and deliberate self-poisonings. Australia should review the current situation of paracetamol availability and work to bring it in line with overseas jurisdictions which have restricted non-pharmacy paracetamol availability (pack sizes and/or maximum paracetamol mass). In the UK, reduced pack sizes of paracetamol led to a reduction in deaths resulting from paracetamol overdose^[77] and it is relevant to also consider pack sizes of all forms of paracetamol freely available for public purchase.
• It is appropriate to limit the volume or maximum paracetamol mass in Schedule 2 paracetamol liquid preparations, as this will ensure that purchasers of paracetamol liquid preparations will have the benefit of a pharmacist's guidance on appropriate dosage and precautions, provided either directly or under the direction of that pharmacist.
• A product containing large quantities of paracetamol, particularly in liquid form, carries a potential for significant human toxicity (including delayed irreversible hepatotoxicity) if the product is accidently ingested or deliberately misused. While strongly supporting the introduction of a limit on the amount of paracetamol that can be supplied in the liquid form in Schedule 2, it would be preferable for a limit of 10 g paracetamol per container of liquid preparation in Schedule 2 to be implemented as this is a clearly defined toxic dose in adults. In children the toxic dose is >200mg/kg/24 hours which for a 10 kg child equates to only 2 g.
• Restricting the amount of paracetamol that can be supplied in Schedule 2 to a maximum 10g paracetamol per container of liquid would help to reduce the likelihood of massive paracetamol poisonings from both accidental paediatric exposures and single impulsive purchases, while having minimal impact on access to affordable OTC liquid paracetamol.
• Since January 2014, NSW Poisons Information Centre (PIC) has received in excess of 6800 calls regarding accidental exposures to liquid paracetamol. More than 6220 of these exposures involved children under the age of 5 years. Of these calls 1828 patients were either in or referred to hospital and 1629 of these patients were under the age of 5 years. Hospital referral was due to concerns a toxic dose of paracetamol may have been ingested by the child. 200 mL bottles of paracetamol were much more likely to be implicated in hospital referrals compared with 100ml or smaller bottles.
• In a sample period of calls (23-06-2018 to 02-09-2019) NSW PIC received 684 calls regarding accidental exposures to liquid paracetamol of which 642 calls involved children under the age of 5 years. 205 patients were either in or referred to hospital during this period due to concerns they had ingested a toxic dose of paracetamol and 196 (95.6%) of these patients were under the age of 5 years.
• There is growing evidence from multiple sources that the rate of deliberate self-harm, including deliberate self-poisoning, is increasing amongst young people^[78],^[79],^[80] and that this behaviour is starting at a younger age. In 2018, NSW PIC received 239 calls regarding deliberate self-poisoning with paracetamol in children aged 14 years and under. In 2019 up until mid-September, NSW PIC received 155 calls regarding deliberate self-poisoning with paracetamol in children aged 14 years and under. While most self-poisonings involved paracetamol in tablet form, the concern is that liquid paracetamol may become an increasingly popular self-harm option for younger people due to the relevant ease of ingestion of liquid formulations.

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

• The wording of the amendment as proposed is confusing and unclear and appears to contain a mathematical error that will have a significant but unnecessary impact on existing liquid paracetamol products currently available in Schedule 2. It would remove from Schedule 2 and force into Schedule 4, all 100 mg/L 'infant drops' products, all pack sizes greater than 100 mL and the combination product (paracetamol plus dextromethorphan), which cannot meet the TGA proposal.
• While not in principle opposed to setting a limit on the total amount (volume) of paracetamol that is available per container of liquid preparations to bring them in line with solid dose formulations, no meaningful, evidence-based public health rationale has been presented to support removal of any of these products from the market through re-scheduling. Further, practical issues supporting the need for age-appropriate dose volumes should be considered before any changes are made to the currently available dosage strengths.
• The proposal is inconsistent with both the paracetamol N2 OTC risk categorisation (N1 and N2 classifications are deemed to pose negligible risk) and the Australian Regulatory Guidelines for over the counter medicines (ARGOM) documents issued by the TGA. Liquid paracetamol preparations at dose strengths of 24 mg/mL, 48 mg/mL and 100 mg/mL are permitted under the N2 classification while the ARGOM allows sponsors to supply any of the following strengths of liquid preparations of paracetamol without the need for justification: 24 mg/mL, 48 mg/mL, 50 mg/mL and 100 mg/mL. Deviation from these strengths requires justification.
• Analysis of the DAEN database (1971-2019) corroborates the published data, with only 4 cases of overdose and 8 cases of accidental overdose reported in the last 48 years. Clearly existing measures - the mandatory child-resistant closures, detailed dosing instructions for all ages, clear labelling design, and accurate, age-appropriate measuring devices - are an effective means of protecting Australian consumers.
• While supportive of amendments to the Poisons Standard that would limit the pack size of paracetamol liquid within Schedule 2, the proposed amendment could lead to unintended consequences by limiting pack sizes and strengths available within pharmacies or for general sale. It is suggested that a 5 g maximum per container of liquid paracetamol is appropriate for Schedule 2. Inclusion of larger pack sizes (e.g. up to 25 g paracetamol) in Schedule 3 would allow for continued access to larger volume pack sizes by adult consumers with swallowing difficulties whom rely on liquid medicine formulations.
• It is suggested that a 5 g maximum per container of liquid paracetamol is appropriate for Schedule 2. Inclusion of larger pack sizes (e.g. up to 25 g paracetamol) in Schedule 3 would allow for continued access to larger volume pack sizes by adult consumers with swallowing difficulties whom rely on liquid medicine formulations.
• Dose volume is an important aspect of the acceptability of paediatric liquid preparations. Recognising that 'High-dose volumes pose a risk of incomplete ingestion and, thus, underdosage,' the WHO recommends 'Efforts should, therefore, be made during pharmaceutical development to minimize the dose volume while recognizing the need to ensure accurate measurements of the dose over the anticipated range'.^[81] Concerns around dose volume and dosing accuracy have been mitigated with the currently available range of liquid paracetamol age-specific dose strengths and corresponding age-appropriate dosing devices available in Australia. It is questionable whether eliminating 11 of the 17 of the currently available liquid paracetamol dose/pack size permutations and forcing consumers to purchase pack sizes that are not age-appropriate or do not contain an age-appropriate dosing device has any tangible value in mitigating the risk of harm from these products.
• There is a potential for paracetamol to be misused, but this is often inadvertent rather than intentional especially with liquid presentations used for children. As noted in the NPS MedicinesWise article on the 'Safe and appropriate use of paracetamol: closing the consumer knowledge gap',^[82] knowledge gaps in carers of young children may contribute to unintentional misuse and overdose of paracetamol. In a cross-sectional study performed in the USA, only 38% of participants correctly selected and measured the appropriate paracetamol dose for infants or children. Knowledge gaps with respect to paracetamol use in children included:
  • the perception that paracetamol is a safe medicine;
  • an uncertainty around appropriate indications;
  • a lack of awareness of strengths and formulations; and
  • the methods used to measure the correct dose.
• If the intent of the proposal is to correct omission of liquids in the Schedule 2 paracetamol entry by specifying an upper limit to the total dose of paracetamol available in liquid preparations, this can be achieved by revising the wording of the proposed amendment to Schedule 2 to read as follows: 'Liquid preparations for oral use containing no greater than 50mg per mL or paracetamol in 100 mL with a maximum of 50 g paracetamol per container'. Of the three numerical requirements in the proposal, only a 50 g total cut-off would permit the existing products to continue as Schedule 2. Any other upper limit apart from 50 g would need to be justified in terms of the need for the limit and the scientific basis for the limit chosen.

The main points of the submission that made comment only were:

• Under 'Reasons for Proposal', the available paracetamol liquid preparations are listed, including: '32.5 mg/mL paracetamol + 1 mg/mL dextromethorphan… (intended primarily for use in children, are currently available as a Pharmacy Medicine (Schedule 2))'. For the purposes of accuracy of the public record, XXXX wishes to clarify that it is incorrect to state that this product was 'intended primarily for use in children'. The labelling dosage instructions limits use to adults and children 12 years and over, and also included on the label is the warning statement 'Do not use this product in children under 12 years of age'.

Summary of ACMS advice/recommendations to the Delegate

The Committee recommended that the current Schedule 3 and Schedule 2 entries for paracetamol be amended in the Poisons Standard as follows:

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included (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.

The reasons for the advice included:

52E(1) Considerations	Reasons
a - the risks and benefits of the use of a substance	Risks: The risks of paracetamol are well known. Paracetamol is involved in deliberate self-poisoning and is the single most commonly used drug in overdoses leading to hospital presentations. Risks from overdose - either deliberate or accidental - can include severe and life threatening hepatotoxicity. Benefits: Paracetamol has an established safety profile at therapeutic doses and it is widely used in the community. When used according to label instructions and for short duration, paracetamol has analgesic properties and provides relief of mild to moderate pain. Paracetamol is generally first line therapy used in the community.
b - the purposes for which a substance is to be used and the extent of use of a substance	Analgesia and used for fever
c - the toxicity of a substance	Well established safety and toxicity profile. Toxicity is dose and patient weight dependent
d - the dosage, formulation, labelling, packaging and presentation of a substance	Paracetamol is currently available in tablet and liquid formulations.
e - the potential for abuse of a substance	Not applicable for single ingredient paracetamol preparations. Paracetamol is the most commonly taken drug in overdose.
f - any other matters that the Secretary considers necessary to protect public health	Liquid paracetamol has not previously had an upper limit in any schedule entry in the Poisons Standard.

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;

• 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) 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 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 Schedule 2 and 3.

I have made an interim decision to amend the Schedule 2 and 3 entries of paracetamol in the Poisons Standard and I have set out my reasons below.

Liquid paracetamol is available in different strengths and formulations (including baby drops, elixirs and suspensions) that are intended for use in babies, infants, children and adults for the temporary relief of pain and fever. Liquid formulations containing paracetamol at 24, 48, 50 and 100 mg/mL, which are intended primarily for use in children, are currently available as Pharmacy Medicines (Schedule 2). In March 2019, the Joint ACCS-ACMS #21 considered a proposal to amend the Poisons Standard with respect to paracetamol for animal use. Separate to this discussion, it was proposed that the Schedule 2 entry for paracetamol should be amended to restrict the volume of liquid paracetamol available for human use. In the interim decision^[84] published on the TGA website on 6 June 2019, the Delegate at that time stated that, 'In relation to the separate matter of paracetamol for human use, a future delegate initiated application was appropriate to restrict the volume of liquid paracetamol available for human use in Schedule 2.'

At present, there is no limit on the amount of paracetamol that can be supplied in the liquid form in Schedule 2. While the therapeutic doses of paracetamol are considered safe, unintentional and intentional exposure to high doses results in severe toxic effects. Paracetamol overdose is the leading cause of paediatric acute liver failure in Australia and New Zealand with affected children receiving excess paracetamol for a variety of reasons, including too frequent administration, co-administration with other medicines containing paracetamol and prolonged administration of regular paracetamol doses (for a period of up to 24 days).^[85]

I note that there is a high prevalence of accidental paracetamol poisoning in the community, in both adults and children. Data from the NSW PIC shows a considerable number of calls have been received regarding accidental exposures to liquid paracetamol since 2014. However, while a product containing large quantities of paracetamol, particularly in liquid form, may carry potential for significant human toxicity if the product is accidently ingested or deliberately misused, there is no clear evidence that the size of the bottle is contributing to the risks of harm. Further, I have seen no clear evidence that liquid paracetamol has been used for self-harm, with most evidence of harm relating to paracetamol in tablet preparations.

Paracetamol is one of the most commonly used OTC analgesic which is perceived as a safe medicine by consumers. While paracetamol has well established safety and toxicity profiles, it can have a narrow safety margin. Therefore, I am of the view that it is appropriate to restrict liquid paracetamol preparations available under Schedule 2. Even though there is presently no meaningful, evidence-based public health rationale to support such a restriction, comments received in response to the pre-meeting public consultation, gave in principle support provided any scheduling changes did not restrict access to existing pack sizes and strengths currently available within pharmacies or for general sale. I note the ambiguity in the scheduling amendment as proposed which included both a concentration cut-off (50 mg/mL) and two different weight cut-offs (5 g and 50 g). Given the lack of evidence of harm as previously discussed, I do not support a concentration cut-off. A concentration cut-off will do nothing to limit current pack size availability and would remove infant drop preparations from Schedule 2 sale. I have decided therefore to limit the total amount of paracetamol that is available per container of liquid paracetamol.

Based on the maximum toxic dose of paracetamol for adults (toxic dose in adults equates to 10 g paracetamol), a 10 g paracetamol weight limit per pack would be consistent with international standards and would remove the 500 mL paediatric formulation pack size and 1000 mL adult formulation pack size from Schedule 2. Whilst this weight limit is unlikely to have a significant impact on paediatric poisonings which can occur at 2 g, it has the potential to reduce the likelihood of significant paracetamol poisonings from both accidental paediatric exposures and single impulsive purchases, while having minimal impact on access to affordable over the counter (OTC) liquid paracetamol preparations. Furthermore, a maximum of 10 g of paracetamol per container in Schedule 2 would not limit access to essential medicines for families that use the 200 mL bottles and will ensure continued access to larger quantities for adults with genuine needs for liquid preparations (e.g. adults who cannot swallow tablets).

Paracetamol is used widely in the community for children, has a favourable risk and safety profile when used within recommended doses and is often used as a first-line therapy. However, there is a potential for paracetamol to be misused, but this is often inadvertent rather than intentional especially with liquid presentations used for children. As noted in the NPS MedicinesWise article on the 'Safe and appropriate use of paracetamol: closing the consumer knowledge gap',^[86] knowledge gaps in carers of young children may contribute to unintentional misuse and overdose of paracetamol. Two important aspects which impact the safe use of liquid paracetamol paediatric preparations are dose volume and dose accuracy. Concerns around dose volume and dosing accuracy have been mitigated with the currently available range of liquid paracetamol age-specific dose strengths and corresponding age-appropriate dosing devices available in Australia. Implementation of a 10 g paracetamol weight limit per pack will minimise the impact on these currently available paediatric liquid preparations ensuring care-givers will continue to have readily available access to these age-appropriate treatment options while still ensuring that a reasonable maximum limit is set for the availability of liquid paracetamol under Schedule 2 in order to minimise risks to public health. While no clear evidence has been presented that bottle size is a contributing factor in paracetamol poisoning, a product containing large quantities of paracetamol, particularly in liquid form, may carry potential for significant human toxicity if the product is accidently ingested or deliberately misused. However, I am satisfied that potential risks associated with preparations containing greater than 10 g paracetamol per pack can be adequately controlled through pharmacist counselling via a Schedule 3 listing unless otherwise scheduled (e.g. for veterinary use).

The Scheduling Policy Framework aims to facilitate access to medicines and other chemicals while minimising risk to public health. In view of the known risks of paracetamol toxicity to humans (the acute toxic effects include hepatic necrosis and renal tubular necrosis), and in the interests of public health, it is appropriate to limit the amount of paracetamol in Schedule 2 paracetamol liquid preparations to 10 g, with preparations above 10 g of paracetamol included in Schedule 3.

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