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Referred scheduling proposal
An application was submitted to amend the Schedule 2 of ibuprofen combined with paracetamol to increase the pack size from 12 to 24 dosage units or less.
Scheduling application
This was a general application. The applicant's proposed amendments to the Poisons Standard are:
Schedule 2 – Amend Entry
PARACETAMOL for therapeutic use:
- 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
1224 dosage units per pack
The applicant's reasons for the proposal are:
- Paracetamol and ibuprofen packed separately have been classified for many years as 'unscheduled' in packs of up to 24 dose units and as Schedule 2 in packs of up to 100 dose units. Two paracetamol/ibuprofen combination products have been approved by TGA and are currently marketed in Australia:
- Combination tablet 1 (paracetamol 500 mg with ibuprofen 150 mg) approved on 23 December 2013; and
- Combination tablet 2 (paracetamol 500 mg with ibuprofen 200 mg) approved on 4 July 2014.
- Fixed dose combinations of paracetamol and ibuprofen offer greater analgaesic efficacy at a lower dose while maintaining the acceptable safety profile of each active alone. These combination products are a logical replacement for codeine/paracetamol and codeine/ibuprofen combinations as noted in the Scheduling Delegate's interim decision in relation to codeine on 1 Oct 2015:
"The combination of two non-opioid analgaesics (ibuprofen plus paracetamol) appears to be more effective than the codeine-containing analgaesics (CCAs), with a number needed to treat (NNT) of 1.5. This combination would fill any gap left by the unavailability of CCAs over the counter, giving consumers access to a more effective analgaesic without requiring a prescription and without the risks of the marked variability in pharmacokinetics or abuse potential that are associated with codeine".
- However, the current 12 dose units pack size limit provides a significant incentive in terms of convenience and price for consumers to purchase separate packs of paracetamol and ibuprofen (20 tablets of paracetamol or 25 tablets of ibuprofen in the supermarket or 100 tablets of each in the pharmacy) then take them together.
- The problem with this approach is that the recommended daily doses of the separate analgaesics are higher (paracetamol 4000 mg and ibuprofen 1200 mg separately vs paracetamol 1500 mg and ibuprofen 600 mg together). While some people may be aware of these differences and compensate accordingly, others may be exposed to unnecessarily high doses of analgaesic. The proposed increase in pack size will lessen the impact of this imbalance in availability of the substances when presented for sale separately and together.
- Estimated total cumulative exposure to the combination product from launch to 29 February 2016 worldwide is 10,160,928 patients. The 29 February 2016 PSUR concludes that post-marketing data for company products containing ibuprofen and paracetamol supports the good safety profile of the product with a low incidence of adverse events in relation to the estimated cumulative exposure, and that the risk-benefit balance for the company products containing ibuprofen and paracetamol remains positive.
- The benefit/risk equation for the proposed 24 dose unit pack in Schedule 2 is positive, based on closer consistency with the maximum pack sizes in separate products, a reduction in the incentive for people to use separate products concurrently and the very low incidence of post-market adverse event reports in New Zealand and worldwide.
Current scheduling status
Paracetamol
Paracetamol is currently listed in Schedules 2, 3 and 4 in the Poisons Standard as follows:
Schedule 4
PARACETAMOL:
- when combined with aspirin or salicylamide or any derivative of these substances except when separately specified in these Schedules;
- when combined with ibuprofen in a primary pack containing more than 30 dosage units;
- in slow release tablets or capsules containing more than 665 mg paracetamol;
- in non-slow release tablets or capsules containing more than 500 mg paracetamol;
- in individually wrapped powders or sachets of granules each containing more than 1000 mg paracetamol;
- in tablets or capsules enclosed in a primary pack containing more than 100 tablets or capsules except in schedule 2;
- 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;
- for injection.
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:
- 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
- in tablets or capsules enclosed in a primary pack containing not more than 100 tablets or capsules; or
- 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
- 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
- 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
- in other preparations except:
- when included in Schedule 3 or 4; or
- in individually wrapped powders or sachets of granules each containing 1000 mg or less of paracetamol as the only therapeutically active constituent (other than phenylephrine and/or guaifenesin or when combined with effervescent agents) when:
- enclosed in a primary pack that contains not more than 10 such powders or sachets of granules,
- compliant with the requirements of the Required Advisory Statements for Medicine Labels,
- not labelled for the treatment of children 6 years of age or less, and
- not labelled for the treatment of children under 12 years of age when combined with phenylephrine and/or guaifenesin; or
- in tablets or capsules each containing 500 mg or less of paracetamol as the only therapeutically active constituent (other than phenylephrine and/or guaifenesin or when combined with effervescent agents) when:
- packed in blister or strip packaging or in a container with a child-resistant closure,
- in a primary pack containing not more than 20 tablets or capsules,
- compliant with the requirements of the Required Advisory Statements for Medicine Labels,
- not labelled for the treatment of children 6 years of age or less, and
- not labelled for the treatment of children under 12 years of age when combined with phenylephrine and/or guaifenesin.
It is also included under the entry PARACETAMOL in Appendix F with the following statements:
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).
Ibuprofen
Ibuprofen is currently listed in Schedules 2, 3 and 4 of the Poisons Standard as follows:
Schedule 4
IBUPROFEN except:
- when included in or expressly excluded from Schedule 2 or 3; or
- in preparations for dermal use.
Schedule 3
IBUPROFEN in divided preparations, each containing 400 mg or less of ibuprofen in a primary pack containing not more than 50 dosage units when labelled:
- with a recommended daily dose of 1200 mg or less of ibuprofen; and
- 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:
- in liquid preparations when sold in the manufacturer's original pack containing 8 g or less of ibuprofen; or
- in divided preparations, each containing 200 mg or less of ibuprofen, in packs of not more than 100 dosage units except when:
- as the only therapeutically active constituent (other than phenylephrine or when combined with an effervescent agent);
- packed in blister or strip packaging or in a container with a child-resistant closure;
- in a primary pack containing not more than 25 dosage units;
- compliant with the requirements of the Required Advisory Statements for Medicine Labels;
- not labelled for the treatment of children 6 years of age or less; and
- not labelled for the treatment of children under 12 years of age when combined with phenylephrine.
It is also included under the entry IBUPROFEN in Appendix F with the following statements:
Appendix F, Part 3
IBUPROFEN
Warning Statement:
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.]
Relevant scheduling history
Paracetamol and ibuprofen individually have a long scheduling history. Only the relevant scheduling history for paracetamol/ibuprofen combinations is presented below.
Paracetamol/ibuprofen combinations
In June 2010 the National Drugs and Poisons Scheduling Committee (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 Poison 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 ACMS 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 remains appropriate. The ACMS considered that the public health risk from advertising is that it 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 analgaesics to non-codeine combination analgaesics. 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 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.
Australian regulatory information
According to the TGA Ingredient Database, paracetamol is available for use as an:
- Active ingredient in biologicals, export only, over-the-counter and prescription medicines; and
- Excipient ingredient in biologicals, devices and prescription medicines.
According to the TGA Ingredient Database, ibuprofen is available for use as an:
- Active ingredient in biologicals, export only, over-the-counter and prescription medicines; and
- Excipient ingredient in biologicals, devices and prescription medicines.
The Australian Register of Therapeutic Goods (ARTG) has 836 entries for products containing paracetamol, and 250 entries for products containing ibuprofen listed. The products marketed vary in dose form, strength and quantity.
In the last 20 years there have been 3188 reported cases of adverse events related to paracetamol, and 1244 related to ibuprofen in the Database of Adverse Events Notification (DAEN) - Medicines: 1190 cases with the single suspected medicine being paracetamol with 120 cases reported death as the outcome, and 831 cases with the single suspected medicine being ibuprofen with 36 cases reported death as the outcome.
International regulations
One combination tablet (paracetamol 500 mg with ibuprofen 200 mg) was approved in the United Kingdom (Pharmacy medicine, 2010) and Poland (Pharmacy medicine, 2010). In New Zealand it was approved as a 'general sale' medicine in 2011 and in Australia it was listed on the ARTG in July 2014. It has also been approved as an over-the-counter medicine in Ukraine, Russia, Saudi Arabia, United Arab Emirates, Kuwait, Bahrain, Oman, Qatar and Yemen.
Another combination tablet (paracetamol 500 mg with ibuprofen 150 mg) was approved in New Zealand on 5 March 2009 and also listed on the ARTG in Australia on 23 December 2013.
Substance summary
Paracetamol is a p-aminophenol derivative that has analgaesic and antipyretic effects and has weak anti-inflammatory activity. It has been available in Australia since the 1970s and is marketed in many OTC medicine brands. Like ibuprofen it is indicated for the management of mild to moderate pain in conditions such as period pain, headache, muscular pain, dental pain, cold and flu symptoms, back pain, rheumatic pain and sinus pain and to reduce fever.
Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) used as an OTC medicine in the management of mild to moderate pain and inflammation in conditions such as period pain, headache, muscular pain, dental pain, cold and flu symptoms, back pain, arthritic pain and sinus pain. It is also used to reduce fever.
| Property | Ibuprofen | Paracetamol |
|---|---|---|
| CAS number | 15687-27-1 | 103-90-2 |
| Chemical structure |
|  |
| Molecular formula | C13H18O2 | C8H9NO2 |
| Molecular weight | 206.3 g/mol | 151.2 g/mol |
| IUPAC, common and/or other names | (RS)-2-(4-(2-Methylpropyl)phenyl)propanoic acid (IUPAC); α-Methyl-4-(isobutyl)phenylacetic acid, (±)-2-(4-isobutylphenyl)propanoic acid; isobutylphenylpropionic acid. | N-(4-hydroxyphenyl)acetamide (IUPAC); 4′-Hydroxyacetanilide; 4-Acetamidophenol, N-Acetyl-4-aminophenol; N-acetyl-p-aminophenol (APAP); acetaminophen. |
Pre-meeting public submissions
Three (3) submissions were received, one (1) in support and two (2) opposed.
Main points in support:
- Paracetamol and ibuprofen have a long history of use, and a well-documented, favourable safety profile.
- To avoid any unintentional overdose, the products should include specific labelling outlining the dose and any warnings, to facilitate its appropriate use.
- One submission noted that in New Zealand, combination paracetamol and ibuprofen products are suitable for general sale in packs of up to 20 dosage units.
Main points opposed:
- Combination ibuprofen/paracetamol products are a relatively new product and there is still a large degree of patient confusion regarding appropriate dosing.
- Typically, consumers will choose a combined ibuprofen/paracetamol product to treat pain when a single ingredient analgaesic is insufficient. These consumers should consult a pharmacist when requesting these combined products in a larger pack to investigate the potential for a more serious underlying cause.
- The availability of a larger pack size available as Schedule 2 will increase the probability of consumers self-managing more severe forms of pain.
- The risk of overdosing is high, and there is a need for ongoing patient education regarding the safe and appropriate use of these medicines.
The public submissions will be made available on the TGA website.
Summary of ACMS advice to the delegate
The committee recommended that the current scheduling of ibuprofen combined with paracetamol 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; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice were:
- A risk of overdosing on ibuprofen and paracetamol and an increased risk of potential adverse effects if the pack size of ibuprofen combined with paracetamol is increased in Schedule 2 from 12 dosage units to 24. The risk is mitigated by maintaining a pack size of 12 dosage units in Schedule 2.
- Pharmacist advice is likely to be significantly reduced if the pack size is increased from 12 to 24 dosage units in Schedule 2. 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.
- An increased risk of potential delay in consumers seeking health practitioner advice, confusion in the market and potential increase in duration of inappropriate use if the pack size is increased to 24 dosage units in Schedule 2.
- Adverse events of ibuprofen combined with paracetamol can be potentially severe. The adverse effects are liver damage, gastric ulcers, gastrointestinal bleeding, anaemia and melaena.
Delegate's considerations
The delegate considered the following regarding this proposal:
- Scheduling proposal
- ACMS advice
- Public Submissions received
- Section 52E of the Therapeutic Goods Act 1989
- Scheduling Policy Framework (SPF 2015)
- Other relevant information
Delegate's interim decision
The delegate's interim decision is that the current scheduling of ibuprofen combined with paracetamol remains appropriate.
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (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; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the interim decision are:
- the risks and benefits of the use of a substance:
- A risk of overdosing on ibuprofen and paracetamol and an increased risk of potential adverse effects if the pack size of ibuprofen combined with paracetamol is increased in Schedule 2 from 12 dosage units to 24. This risk is mitigated by maintaining the small pack size in Schedule 2.
- NPSMedicineWISE report that the NSW Poisons Information Centre has recorded a marked increase in calls about possible dosing errors with new combination paracetamol ibuprofen pain relievers since mid-2016.
- Pharmacist advice is likely to be significantly reduced if the pack size is increased from 12 to 24 dosage units in Schedule 2. 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.
- An increased risk of potential delay in consumers seeking health practitioner advice, confusion in the market and potential increase in duration of inappropriate use if the pack size is increased to 24 dosage units in Schedule 2.
- Potential increase in duration of inappropriate use.
- The small pack sizes might mitigate the risk and encourages consumers to have conversation with pharmacist.
- the purposes for which a substance is to be used and the extent of use of a substance:
- Same as for current 12 unit pack size.
- the toxicity of a substance:
- A 24 pack size increases the risk of harm from overdose (12 g paracetamol and 3600 to 4800 mg ibuprofen).
- Adverse events of ibuprofen combined with paracetamol can be potentially severe. The potential adverse effects are liver damage, gastric ulcers, gastrointestinal bleeding, anaemia and melaena.
- the dosage, formulation, labelling, packaging and presentation of a substance:
- Current pack of 12 dosage units is sufficient for initial use of combination analgesia.
- Need to maintain the maximum duration of 3 days statement.
- any other matters that the Secretary considers necessary to protect public health:
- Risk of consumer confusion in the market.
- Pharmacist intervention is required to deal with different types of pain.