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Scheduling delegate's final decisions, June 2017

Scheduling medicines and poisons

29 June 2017

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1.4 Ibuprofen

Part A - Final decisions on matters referred to an expert advisory committee

Advisory Committee on Medicines Scheduling (ACMS #20)

1.4 Ibuprofen

Referred scheduling proposal

An application was submitted with the following proposal to amend the Schedule 3 entry for ibuprofen to include a modified release dosage form of 600 mg of ibuprofen per dosage unit in packs of 32 or less 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;

and include in Appendix H ibuprofen 600 mg in modified release dosage form.

Current scheduling status

In monotherapy preparations, ibuprofen is included in Schedules 4, 3 and 2 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 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;

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.

It is also included in Appendix F, Part 3 under the entry:

IBUPROFEN:

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.]

  • Ibuprofen is listed in Schedule 4 when in compounded products with paracetamol, in a primary pack containing more than 30 dosage units.
  • Ibuprofen is listed in Schedule 3 when in compounded products with paracetamol in a primary pack containing 30 dosage units or less except when included in Schedule 2.
  • Ibuprofen is also listed in Schedule 2 when compounded in products with paracetamol 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.
Scheduling history

In November 1985, the National Health and Medical Research Council (NHMRC) considered a request to change to Schedule 2 (currently in Schedule 4 of UPS) as Ibuprofen was not scheduled in Victoria. It was agreed there were anaphylactic problems with people sensitive to aspirin. It was decided not to alter the scheduling.

In November 1987 the NHMRC considered a request to move ibuprofen from Schedule 4 to Schedule 2 with pack size restrictions. The committee was of the opinion that there was a place for ibuprofen outside Schedule 4. Recommendation for a new Schedule 3 entry with pack size restrictions of less than 50 tablets or capsules (200 mg).

In May 1995, the NDPSC considered proposal for a new Schedule 2 entry for ibuprofen and agreed to a new entry. Schedule 4 entry amended. New Schedule 2 for ibuprofen in divided preparations for oral use containing 200mg or less with a recommended dose of 1200mg or less.

In November 1998, the NDPSC considered an application for ibuprofen liquid suspension 100 mg/5 mL to be rescheduled from Schedule 4 to Schedule 2. Overall, the committee considered that a Schedule 3 classification was more appropriate for this formulation, and agreed that the Poisons Standard be amended accordingly. The committee agreed that a maximum daily dose should be stipulated, but because the proposed pack size was 200 mL (maximum of 4 g ibuprofen) a restriction on total content was not required for this classification. A new entry for Schedule 3 was agreed in undivided preparations for oral use when labelled with a recommended daily dose of not more than 1200 mg of ibuprofen.

In May 2000, the NDPSC considered a proposal to amend the Schedule 2 entry for ibuprofen to include oral liquid preparations containing more than 20 mg/1 mL. The committee considered the safety profile of ibuprofen and that Schedule 2 is appropriate when used in analgesic dose for minor and temporary ailments for short periods. The committee was seeking consistency with divided dose formulations.

In June 2003, the NDPSC considered a proposal to exempt ibuprofen from scheduling in divided preparations containing 200 mg or less of ibuprofen per dosage unit in packs containing 24 or less dosage units when labelled with a maximum recommended daily dose of 1200 mg of ibuprofen. The NDPSC decided to exempt ibuprofen from scheduling as requested, but with an amended maximum pack size (25 dosage units) and additional restrictions as follows: ibuprofen as the only therapeutically active constituent other than an effervescent agent; and requirements for label warnings (consistent with Appendix F warnings for Schedule 2 ibuprofen). The minutes note that the NDPSC had agreed that the schedule wording should be comparable with that of the current aspirin and paracetamol entries.

In October 2003, following consideration of further public submissions, the NDPSC made some amendments to the label warning statements required for ibuprofen when exempted from scheduling, in particular, by adding warnings not to use the product unless advised by a doctor in children ages 6 years or less, or by people aged 65 years or over.

The NDPSC subsequently made some editorial amendments to the Schedule 2 exemption in June 2004 and February 2005.

In August 2010 the NDPSC considered the scheduling of paracetamol in combination with ibuprofen in June 2010. At that time, divided dose combinations containing up to 200 mg ibuprofen + 500 mg paracetamol were included in Schedule 2 (when labelled with a maximum daily dose of 1200 mg ibuprofen, and in packs of up to 100 dosage units). The NDPSC recommended, and the delegate confirmed, that the scheduling of ibuprofen and paracetamol that was current at that time remained appropriate.

In June 2011 the 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.

In February 2013 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 June 2012, the ACMS considered a submission to reschedule ibuprofen from Schedule 2 to unscheduled when in divided preparations containing 200 mg or less of ibuprofen in fixed dose combination with 5 mg or less of phenylephrine, in packs containing not more than 25 tablets. ACMS advised the delegate that ibuprofen in combination with phenylephrine should be exempt from scheduling, as requested. The delegate decided to also restrict the scheduling exemption to use for the treatment of adults and children aged 12 years of age and over.

In November 2015, the ACMS considered a submission 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 advised that paracetamol should be included in Schedule 2 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 pack of not more than 3 day supply. The delegate agreed with the ACMS and made an interim decision based on the ACMS advice. After deferring their final decision to give consideration to a late submission received during the interim decision consultation period, the delegate decided to vary their decision. In view of the dosage levels of paracetamol and ibuprofen the delegate considers it is more appropriate to limit the Schedule 2 part a) 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.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:

Schedule 3 – Proposed Amendment

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:

  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;

IBUPROFEN in a modified release dosage form containing 600 mg of ibuprofen per dosage unit in packs of 32 or less dosage units when labelled:

  1. with recommended daily dose of 1200 mg or less; and
  2. not for the treatment of children under 12 years of age.

except when included in or expressly excluded from Schedule 2.

Appendix H – Proposed New Entry

Ibuprofen 600 mg in a modified release dosage form

The applicant's reasons for the request are:

  • The total daily dose of ibuprofen 600 mg IR/ER does not exceed 1200 mg and is therefore identical with that already approved for non-prescription ibuprofen 200 mg and 400 mg IR products.
  • Ibuprofen 600 mg IR/ER is bioequivalent to ibuprofen 200 mg IR tablets after single and multiple doses in terms of AUCL, AUCI, AUC0-12h, and overall Cmax.
  • The human safety profile for ibuprofen 600 mg IR/ER tablet is favourable and similar to that observed for ibuprofen 200 mg IR.
  • The new formulation approximates the immediate release characteristics of an ibuprofen 200 mg tablet, combined with extended release properties to maintain plasma concentrations adequate to provide up to 12 hours of pain relief with less frequent dosing.
  • Ibuprofen 600 mg IR/ER is efficacious for up to 12 hours in a model of dental pain, and this efficacy is sustained over multiple doses.
  • The non-prescription availability of ibuprofen 600 mg IR/ER as Schedule 3 provides an alternative option not only to the limited range of non-prescription modified release analgesics available in the market for short-term use but also to existing immediate release analgesic products that fall short of providing longer lasting relief from persistent pain conditions likely to last for more than 6 hours.
  • Creating a Schedule 3 and Appendix H entry of ibuprofen 600 mg IR/ER is consistent with the current scheduling status of comparable non-prescription analgesics namely, naproxen 600 mg modified release, diclofenac 25 mg immediate release and paracetamol 665 mg sustained release that are permitted to be advertised as a result of inclusion in Appendix H or in the case of paracetamol, inclusion in Schedule 2.
  • Ibuprofen 400 mg IR is currently included in Schedule 3, however, the information in this application is specific and relevant only to ibuprofen 600 mg IR/ER and does not translate to ibuprofen 400 mg IR. Hence, the proposal to include ibuprofen in Appendix H with specific conditions by stipulating the dosage strength and form, i.e. ibuprofen 600 mg in a modified release dosage form. This approach is consistent with the dimenhydrinate inclusion in Appendix H, which has specific conditions applied stipulating the indication of use that the product can only be advertised for.
  • The non-prescription availability and advertising of ibuprofen 600 mg IR/ER as a Schedule 3 medicine provides significant benefits are listed below:
    • The non-prescription approval of ibuprofen 600 mg IR/ER would provide an alternative option to a limited range of modified release analgesics available in the market for short term use and existing immediate release analgesics that fall short of providing sustained effect for longer lasting (more than 6 hours) pain conditions.
    • Improved access to a treatment option that provides rapid and extended analgesic relief over 12 hours reducing the frequency of dosing for those consumers who cannot optimally manage their persistent pain lasting for more than 6 hours with existing immediate release analgesics.
    • Breakthrough pain that can occur with short-acting analgesics in addition to the need to wake during the night to take a medication can be avoided with the use of ibuprofen 600 mg IR/ER.
    • Quality Use of Medicines principles will be supported by advertising and consumer programmes which are effective communication tools to educate consumers on this new dosage form, drive familiarity of appropriate use and encourage consumers to consult a pharmacist.
    • Consultation with a pharmacist will ensure appropriate and quality use of the product and improved clinical outcomes for consumers including those currently accessing analgesics for self-selection from grocery and pharmacy channels who may not be optimally managing their pain condition.
    • Cost savings associated with the use of ibuprofen 600 mg IR/ER over immediate release formulations and economic benefits resulting from self-care and use of professional pharmacy resources.
  • Suggested measures to manage potential risks associated with Schedule 3 entry and advertising ibuprofen 600 mg IR/ER (i.e. misuse, overdose, accidental ingestion, drug interactions, delay in treatment of an underlying condition, prolonged use) include:
    • Mandatory requirement for pharmacist intervention at the point of sale ensures that only consumers who have pain lasting for more than 6 hours have access to and use ibuprofen 600 mg IR/ER for the shortest period of time and inappropriate use for transient pain does not occur.
    • Consumer labelling contains necessary information to ensure correct and safe use of the medicine. The front/ main panel includes dosing-related statements, an entirely unique feature that differentiates the product from other non-prescription analgesics to emphasise correct dosing ensuring safe use of the product).
    • Implementation of education programs, resources and promotional materials (facilitated by inclusion in Appendix H) to educate consumers on the difference between persistent and transient pain ensuring appropriate and quality use of ibuprofen 600 mg IR/ER.
    • Education programs for pharmacists to supplement current resources to help increase their awareness of a new dosage form of ibuprofen and ensure that request for the product by consumers is managed appropriately.
Australian regulatory information

A search of the ARTG[14] returned 240 entries for ibuprofen containing products. The ibuprofen products are approved for treatment of infants to adults and come in multiple dosage strengths and forms. Dosage strength and forms include 200 mg and 400 mg capsules, gel capsule, liquid capsule, 200 mg and 400 mg tablets and film coated tablets, 20 mg/1 ml, 40 mg/1 ml, 100 mg/5 ml oral liquids, 200 mg and 400 mg effervescent granules, 100 mg chewable tablets.

In addition to the oral forms there are 50 mg/g topical gels and 400 mg and 800 mg vials for injection.

Combination products include ibuprofen with codeine, ibuprofen with paracetamol and ibuprofen with pseudoephedrine. The ARTG also included entries for ibuprofen lysine 324 mg tablets and capsules as well as ibuprofen sodium dihydrate 256 mg capsule and tablet.

A search of the Database for Adverse Events Notifications (DAEN) between January 1985 and August 2016 resulted in 1229 cases related to ibuprofen with 819 cases with a single suspected medicine. Of these 36 cases were reported to have resulted in death.[15]

International regulations

There is no modified-release OTC ibuprofen product in New Zealand. Medsafe[16] regulates ibuprofen up to 200 mg for external use and oral use with pack size restrictions for general sale and/or pharmacy only depending on dose unit number or total ibuprofen amount. Up to 400 mg in single dose form in packs of less than 50 dose units are restricted without consent of the Minister or the Director-General. Dosages over 400 mg are considered prescription medicines. An 800 mg ibuprofen sustained release tablet is prescription-only in New Zealand.

In February 2016, Health Canada[17] switched a modified release oral dosage form that provides 600 mg or less per dosage unit of ibuprofen to non-prescription status. This is available as 'Advil 12 Hour', containing 'ibuprofen extended release tablets BP, 600 mg'. This appears to be the formulation proposed in the current scheduling request.[18]

February 2016: Health Canada updated its Summary Safety Review of prescription ibuprofen to investigate the link between ibuprofen at high doses and serious heart and stroke events[19].

The UK has 200 mg ibuprofen modified release products available OTC, and an 800 mg sustained‑release tablet available by prescription.

In the USA, 800 mg ibuprofen prolonged release tablets are available by prescription.

Substance summary

Ibuprofen is a white or almost white, crystalline powder or colourless crystals. It is practically insoluble in water, freely soluble in acetone, in methanol and in methylene chloride. It dissolves in dilute solutions of alkali hydroxides and carbonates. The molecular weight of ibuprofen is 206.3, molecular formula C13H18O2.

Chemical structure of ibuprofen

Figure 1.4: Structure of ibuprofen

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) used as an analgesic, antipyretic, and anti-inflammatory. It decreases synthesis of pain- and inflammation-promoting prostaglandins via non-selective inhibition of both cyclo-oxygenase (COX), COX-1 and COX-2 enzymes. It has been extensively studied, and its efficacy and safety profile in humans following oral administration is well-established.

Numerous oral non-prescription ibuprofen formulations are now available (including tablets, capsules, liquigels, and oral suspension), with various dosage strengths. These 'immediate release' (IR) non-prescription dose forms are indicated for the management of mild to moderate pain and inflammation in conditions such as dysmenorrhoea, headache including migraine, postoperative pain, dental pain, musculoskeletal and joint disorders and soft-tissue disorders such as sprains and strains. It is also used to reduce fever. The currently recommended non-prescription ibuprofen oral dose for pain and/or fever in adults is 200 – 400 mg every 4 to 6 hours as needed, with a maximum daily dose of 1200 mg.

Pre-meeting public submissions

Two (2) submissions were received. Both supported the scheduling proposal. The main points were:

  • Ibuprofen has well-characterised safety profile. The rescheduling would be consistent with other comparable analgesic substances and risks are mitigated via the intervention of a pharmacist (i.e. Schedule 3 criteria).
  • This proposal aligns with other recent NSAID rescheduling decisions.
  • Permitting advertising would have benefits for both consumers and pharmacists with increasing awareness of Schedule 3 medicines in general.

The public submissions will be made available on the TGA website.

Summary of ACMS advice to the delegate

The committee advised that the Schedule 3 entry for ibuprofen be amended as follows:

Schedule 3 – Amend Entry

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.

Appendix H – New Entry

IBUPROFEN

The committee also recommended an implementation date of 1 October 2017.

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 comprised the following:

  • This will give consumers access to a product for pain relief that is longer-lasting than currently available products.
  • The potential for abuse and toxicity are low and in line with existing ibuprofen products.
  • Pharmacist intervention, CMI and TGA mandated RASML warning statements will assist consumers with managing any risks.
  • There is a public health interest to inform consumers about pain relief options through advertising.
Delegate's considerations

The delegate considered the following in regards to 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 to amend the Schedule 3 entry for ibuprofen. The proposed Schedule entry is as follows:

Schedule 3 – Amend Entry

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.

Appendix H – New Entry

IBUPROFEN

The proposed implementation date is 1 October 2017.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (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 reasons for the interim decision are the following:

  • The delegate acknowledges the committee's advice.
  • This will give consumers access to a product for pain relief that is longer-lasting than currently available products.
  • The potential for abuse and toxicity are low and in line with existing ibuprofen products.
  • Pharmacist intervention, CMI and TGA mandated RASML warning statements will assist consumers with managing any risks.
  • There is a public health interest to inform consumers about pain relief options through advertising.
Public submissions on the interim decision

One (1) public submission was received which supported the interim decision for ibuprofen.
The main points were:

  • Ibuprofen has well-characterised safety profile. The rescheduling would be consistent with other comparable analgesic substances and risks are mitigated via the intervention of a pharmacist (i.e. Schedule 3 criteria).
  • Permitting advertising would have benefits for both consumers and pharmacists with increasing awareness of Schedule 3 medicines in general.
Delegate's final decision

The delegate notes the submission in support of the interim decision and as no new evidence has been received to alter the interim decision; the delegate has confirmed that the final decision and reasons for the final decision are in keeping with those for the interim decision.
The delegate's final decision is to amend the Schedule 3 entry for ibuprofen. The implementation date is 1 October 2017.


Footnotes

14 Therapeutic Goods Administration Search results

15 Database of Adverse Event Notifications - medicines

16 Database of Medicine Classifications

17 Notice - Prescription Drug List (PDL): Ibuprofen

18 Advil Frequently Asked Questions

19 Summary Safety Review - Prescription Oral Ibuprofen (Non-Steroidal Anti-inflammatory Drug) - Risk of Serious Heart and Stroke Adverse Events at High Doses

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