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Publication of interim decisions proposing to amend, or not amend, the current Poisons Standard, September 2018

Scheduling medicines and poisons

10 September 2018

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1.4 Codeine

1. Advisory Committee on Medicines Scheduling (ACMS #24)

Delegate's interim decision

The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is not to amend the current Poisons Standard in relation to codeine.

Reasons

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:

  1. the risks and benefits of the use of a substance:
    • Codeine is considered a weak opioid analgesic and antitussive. Risks include dependence, and harms associated with taking large quantities of combination analgesic products, predominantly in the context of over the counter (OTC) use.
    • As noted in the recent up-scheduling of codeine there is little evidence of efficacy at low doses (8-15 mg) so reducing the Schedule 4 dose to 12 mg is not appropriate.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Predominantly analgesia, with some use as an antitussive. As an analgesic codeine combination is widely used, for example over 12 million packets of Schedule 4 codeine products were sold in Australia in 2013.
  3. the toxicity of a substance:
    • Codeine is considered a weak opioid, there is the potential for toxicity with rapid metabolisers otherwise, codeine is considered to have lower potency compared with other opioids.[35]
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Combination products with up to 30 mg in a dose unit, compounded with another active ingredient. Formulations with codeine as a single ingredient are Schedule 8.
  5. the potential for abuse of a substance:
    • Codeine is a weak opioid analgesic. There is evidence of non-medical use and dependence with combination codeine products, though this evidence was generated during the period of time when codeine was widely available in an over-the-counter medication. Blinded abuse liability studies indicate that doses of 100 mg of codeine have a placebo like effects on abuse liability while higher doses (200 mg) were similar to tramadol and oxycodone in their abuse liability)above.35 This suggests that in a controlled blinded clinical trial a therapeutic dose of 60mg (2 x 30 mg codeine + 500 mg paracetamol) has lower abuse liability than therapeutic doses of tramadol or oxycodone.
  6. any other matters that the Secretary considers necessary to protect public health:
    • Given the recent rescheduling of codeine to delete the Schedule 3 entry was only implemented in February 2018, there is minimal experience and data to inform if additional regulatory measures are required.
    • Reporting systems currently in use, as well as those proposed for roll out in the coming months, already have the capability to capture Schedule 4 medicines such as codeine at the discretion of the jurisdictions.
    • The current scheduling of codeine as a prescription only medicine is now in alignment with many comparable international regulators.
    • Due to significant use of S4 codeine combination products there does not appear to be substantive evidence of significant diversion and abuse of combination codeine (more than 12 mg) analgesics in institutional healthcare to warrant the additional security and accountability measures a Schedule 8 status affords.
    • The significant economic and administrative burden of meeting the storage, distribution, supply and record keeping requirements for Schedule 8 medicines will increase costs which sponsors may not be able to absorb. This could impact product viability creating an access barrier to effective pain relief for patients.

Delegate's considerations

The delegate considered the following in regards to this interim decision:

  • The application to amend the current Poisons Standard with respect to codeine;
  • The advice received from the Advisory Committee on Medicines Scheduling (ACMS#24);
  • The public submissions received before the first closing date;
  • The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
  • Section 52E of the Therapeutic Goods Act 1989, in particular: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance and (f) any other matters that the Secretary considers necessary to protect public health.

Scheduling proposal

The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.

Background information for codeine

Delegate's referral to ACMS

An application was submitted to amend the Poisons Standard with respect to codeine. The application proposed to amend the Schedule 4 and Schedule 8 entries for codeine.

Applicant's scheduling proposal and reasons

Note

New text is shown as green, larger font, with a horizontal line above it.

Deleted text is shown as red, smaller font, with a strikethrough.

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

Schedule 4 - Amend Entry

CODEINE when compounded with one or more other therapeutically active substances:

  1. in divided preparations containing 3012 mg or less of codeine per dosage unit; or
  2. in undivided preparations containing 10.25 per cent or less of codeine.

Schedule 8 - Amend Entry

CODEINE alone or when compounded with one or more other therapeutically active substances:

  1. in divided preparations containing more than 12 mg of codeine per dosage unit; or
  2. in undivided preparations containing more than 0.25 per cent of codeine;

except when included in Schedule 4.

The applicant's reasons for the proposal were:

  • The application seeks to address scheduling inconsistencies highlighted in the Regulation Impact Statement (RIS). This will be achieved by moving high dose codeine-containing medicines and single ingredient 30 mg codeine into Schedule 8 where, as suggested by the RIS, these products belong.
  • By up-scheduling high dose codeine-containing medicines to Schedule 8, they will be monitored by State and Territory Real Time Monitoring systems such as DORA in Tasmania or SafeScript, soon to be implemented in Victoria. As the Victorian system will address system insufficiencies of the DORA platform it will easily be implemented in other states and territories with the assistance of funds recently announced by Minister Hunt.

Current scheduling status

Codeine is listed in Schedules 4 and 8 and Appendix K of the Poisons Standard as follows:

Schedule 4

CODEINE when compounded with one or more other therapeutically active substances:

  1. in divided preparations containing 30 mg or less of codeine per dosage unit; or
  2. in undivided preparations containing 1 per cent or less of codeine.

Schedule 8

CODEINE except when included in Schedule 4.

Appendix K

CODEINE.

Scheduling history

National Drugs and Poisons Schedule Committee (NDPSC): June 2008

The NDPSC agreed to form a Codeine Working Party to review the availability of all over the counter (OTC) combination analgesics containing codeine. This followed concerns raised at previous NDPSC meetings (June 2005, October 2005 and June 2007) of abuse of codeine from a codeine-ibuprofen combination analgesic product (by cutting a bi-layer tablet in half to access the codeine, or separating codeine from the product by simple dissolution in water).

NDPSC: February 2009

The NDPSC considered a report from the Codeine Working Party, together with findings from an evaluation of OTC codeine-containing analgesics, and agreed to foreshadow a proposal to re-schedule all OTC codeine to Schedule 3 (with suggestions to limit the maximum daily dose to 100 mg codeine, limit the maximum pack size to 5 days' supply, restrict divided preparations to 12 mg of codeine per dosage unit and restrict undivided preparations to 0.25% codeine). In addition, a member proposed to maintain a Schedule 2 entry for codeine with phenylephrine, if all other OTC codeine was included in Schedule 3. The NDPSC foreshadowed a proposal to include all OTC codeine (and not just analgesics) to encourage public comment.

NDPSC: June 2009

The NDPSC agreed that the current scheduling of OTC codeine combinations for coughs and colds remained appropriate (but with a pack size limit of 5 days' supply), and that all OTC combination analgesics containing codeine should be re-scheduled from Schedule 2 to Schedule 3 (with the maximum daily dose limited to 100 mg, the duration of treatment limited to 5 days, divided preparations restricted to 12 mg of codeine per dosage unit and undivided preparations restricted to 0.25% codeine) and that Schedule 3 codeine should not be included in Appendix H. The implementation date was to be 1 May 2010.

NDPSC: October 2009

Following consideration of June 2009 post-meeting submissions and further discussion, the NDPSC agreed to amend the pack size limit for Schedule 2 cough and cold preparations to a maximum of 6 days' supply. The NDPSC also confirmed the June 2009 resolution regarding the Schedule 3 entry for all OTC combination analgesics containing codeine. The implementation date remained as 1 May 2010. An editorial amendment was made to the Schedule 3 entry at the February 2010 NDPSC meeting.

Advisory Committee on Medicines Scheduling (ACMS): June 2011

The scheduling of codeine was considered as a part of the cold and cough preparation review, which looked at the use of these preparations for the treatment of children aged 2 to 12 years. Taking into consideration the advice from the ACMS, the delegate decided that there should be no change to the scheduling of codeine in cold and cough preparations.

ACMS: August 2015

The ACMS considered a proposal to re-schedule codeine with assistance from an independent external evaluation, public submissions and the original application. Consideration was given as to whether all current Schedule 3 preparations should be rescheduled to Schedule 4, or whether any rescheduling to Schedule 4 should only apply to combination analgesic products containing codeine. Consideration was also given to whether the Schedule 2 entry for codeine should be amended. The committee recommended that the Schedule 2 and Schedule 3 entries for codeine be deleted and that the Schedule 4 and Schedule 8 entries be amended to reflect this.

Delegate's Decision: November 2015

The delegate announced that a decision on the re-scheduling of codeine would be delayed to allow a more thorough consideration of the numerous submissions received from the pre-meeting and interim decision consultation periods and the broader implications to the then current products in the market.

Call for further submissions: December 2015

A notice was published on the TGA website calling for further submissions from interested parties on the proposed re-scheduling options for codeine. This call for further submissions was based on feedback received during the consultation periods.

Advisory Committee on the Safety of Medicines (ACSOM): March 2016

The ASCOM provided advice on products containing low dose codeine (8-15 mg codeine or codeine phosphate) that were available as a Schedule 2 and Schedule 3 medicine. The committee noted that the OTC availability of codeine-containing medicines supported a general misconception in the community that codeine is safe. It was also noted that there would need to be additional measures, such as education and possible up-scheduling, to achieve the desired outcome to reduce the risks associated with codeine.

ACMS: March 2016

The ACMS again considered the proposal to re-schedule codeine. The ACMS advised that their recommendation to up-schedule codeine from Schedule 2 and 3 to Schedule 4 from the August 2015 remains the same. The delegate agreed and made a final decision to up-schedule all medicines containing codeine to be Schedule 4 Prescription Only Medicines. This was published on the TGA website, along with the KPMG report and the RIS. As part of the final decision, an implementation date of 1 February 2018 was announced by the delegate, which provided more than a year for implementation. This balanced the needs of affected stakeholders while addressing the harms associated with these products.

Australian regulations

The Australian Register of Therapeutic Goods (ARTG) has 207 products that contain codeine, codeine phosphate hemihydrate or codeine phosphate sesquihydrate.

In the last 30 years there have been 1670 reported cases of adverse events related to codeine in the Database of Adverse Events Notification (DAEN) - Medicines: 634 cases with a single suspected medicine and 103 cases where death was the reported outcome.

According to the TGA Ingredient Database, codeine is:

  • Available for use as an Active Ingredient in: Biologicals, Prescription Medicines;
  • Available for use as an Excipient Ingredient in: Biologicals, Devices, Prescription Medicines; and
  • Not available as an Equivalent Ingredient in any application.

According to the TGA Ingredient Database, codeine phosphate hemihydrate 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, Export Only, Over the Counter, Prescription Medicines; and
  • Not available as an Equivalent Ingredient in any application.

According to the https://www.ebs.tga.gov.au/ TGA Ingredient Database, codeine phosphate sesquihydrate is:

  • Available for use as an Active Ingredient in: Biologicals, Prescription Medicines;
  • Available for use as an Excipient Ingredient in: Biologicals, Devices, Prescription Medicines; and
  • Not available as an Equivalent Ingredient in any application.

International regulations

Countries in Europe including Austria, Belgium, Germany and Italy, as well as the United States, Japan, Russia and the United Arab Emirates all require prescriptions for medicines containing codeine. In some other countries, including Hong Kong, Hungary and the Netherlands, OTC sale of cough linctus (containing codeine) is allowed, with all other medicines containing codeine requiring a prescription.

In July 2017, the new French Government announced that all medicines containing codeine would only be available via prescription.

In November 2017, Canada completed a public consultation on making codeine products Prescription Only.

In November 2017, Medsafe New Zealand made their recommendation that, from 31 January 2020, all codeine in combination medicines, both analgesics and those used for cough and colds, should be reclassified to prescription medicines with a proposed exception applying to medicines containing not more than 15 mg of codeine per unit, with a maximum daily dose not exceeding 90 mg of codeine for use as an analgesic and when sold in a pack of not more than three day's supply. Medsafe is also advocating for a national monitoring of all codeine-containing medicines, including restricted and prescription, subsidised and unsubsidised medicines.

In January 2018, the Kenya Pharmacy and Poisons Board (KPPB) announced that all medicines that contain codeine have been rescheduled from Pharmacy Only Medicines to Prescription Only Medicines in an effort to minimise the risk of overuse and addiction. In addition, the KPPB have given all marketing authorisation holders six months to change packages to include clear and prominently positioned warnings on the label.

Substance summary

Codeine and its salts, especially codeine phosphate, are given orally in the form of linctuses for the relief of cough, and as tablets for the relief of mild to moderate pain, often with a non-opioid analgesic such as aspirin, ibuprofen, or paracetamol. Codeine phosphate is also given by intramuscular injection for the relief of pain, in doses similar to those used orally; the intravenous, subcutaneous, and rectal routes have also been used.

For the relief of pain, codeine phosphate may be given in doses of 30 to 60 mg every 4 hours to a usual maximum of 240 mg daily.

To allay non-productive cough, codeine phosphate may be given in doses of 15 to 30 mg three or four times daily.

Codeine phosphate is also used as tablets or in mixtures for the symptomatic relief of acute diarrhoea in doses of 15 to 60 mg given three to four times daily.

Other codeine salts used include the hydrochloride, sulfate, camsilate, and hydrobromide. Codeine polistirex (a codeine and sulfonate diethenylbenzene-ethenylbenzene copolymer complex) is used in modified-release preparation.

Table 1.4: Chemical information of codeine
Property Codeine
CAS number 76-57-3
IUPAC and/or common and/or other names Morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-, (5-alpha,6-alpha)- (9CI); methylmorphine; codeine phosphate; codeine anhydrous; morphine monomethyl ether.
Chemical structure chemical structure of codeine
Molecular formula C18H21NO3
Molecular weight 299.4 g/mol

Pre-meeting public submissions

Nine (9) public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. Two (2) submissions were in support and seven (7) opposed to the proposed amendments.

The main points provided in support of the amendment were:

  • There is evidence of codeine medicines being associated with adverse health risks.[36]
  • Further restricting access to sub-therapeutic doses of codeine is consistent with the Choosing Wisely Australia recommendation advising against the use of low-dose codeine.
  • As federal and jurisdictional governments continually invest in real-time prescription monitoring systems which focus strongly on Schedule 8 medicines, this up-scheduling would empower clinicians to appropriately monitor codeine prescribing and supply to ensure optimal and safe patient care.

The main points provided in opposition of the amendment were:

  • The up-scheduling of Schedule 3 codeine to Schedule 4 on 1 February 2018 adequately addressed the inconsistencies in codeine scheduling. Further, there is no new evidence supporting additional up-scheduling.
  • Australia's codeine scheduling status is now in alignment with many other countries. No other country classifies codeine as a 'Controlled Substance (Schedule 8)' or equivalent. Further restricting products containing more than 12 mg of codeine to Schedule 8 will remove the international alignment Australia has recently achieved.
  • Both Schedule 4 and 8 products are prescription only medicines, requiring the clinical assessment of a medical practitioner and dispensing by a pharmacist. This presents further opportunity to clinically evaluate the appropriateness of the supply. The recent up-scheduling of all over the counter codeine products to prescription only and the potential for all codeine supplies to be included in real-time prescription monitoring systems provides significant and sufficient safeguards for patients in the community.
  • There does not appear to be substantive evidence of significant diversion and abuse of combination codeine (more than 12 mg) analgesics in institutional healthcare to warrant the additional security and accountability measures a Schedule 8 status affords.
  • The risk to patient safety was mitigated through consideration of formulation (single active ingredient only versus combination), the amount of codeine per dosage unit and total amount of codeine per pack. The single ingredient products remain in Schedule 8 and combination products containing codeine when compounded with one or more other therapeutically active substances are in Schedule 4.
  • The distinction between codeine being used as a single active ingredient or compounded in a divided preparation product provides a degree of mitigation of risk and is adopted for other substances.
  • The significant economic and administrative burden of meeting the storage, distribution, supply and record keeping requirements for Schedule 8 medicines will increase costs which sponsors may not be able to absorb. This could impact product viability creating an access barrier to effective pain relief for patients.
  • Storage of Schedule 8 medicines:
    • Schedule 8 medications carry significantly greater requirements for secure storage, chain of custody and record keeping due to the potential for diversion and abuse through the supply chain.
    • The stringent controls and record keeping required to manage the storage, distribution and supply of Schedule 8 goods will warrant significant investment in infrastructure and logistics considering the product volumes, which in turn will increase the cost of goods and potentially impact product viability.
    • The increased cost burden will need to cover vault storage requirements, additional vigilance on picking and inventory validation activities as well as higher costs of a premium freight service. These additional costs incurred via wholesale channels may further impact the product price point and potentially patient access. The additional financial costs will also impact numerous parts of the medicine supply chain including wholesalers, pharmacies, aged care facilities, consumers and the Commonwealth through increased Controlled Drug dispensing fees.
    • One submission outlined that in excess of $1.5 million would be required to expand their current Schedule 8 storage facilities. This expense would have significant impact on the cost of the goods and would likely result in product discontinuation.
    • As current storage facilities are insufficient this would result in stock shortages.
    • Previous experience with up-scheduling a product to Schedule 8 saw a more than 50% decline in sales. This was not attributed to lack of need but rather to the preferred ease of prescribing a Schedule 4 medicine.
    • Pharmacies must store Schedule 8 medicines in a Controlled Drug safe that meets jurisdictional requirements. Such medicine safes have a limited storage capacity and with more Schedule 8 medicines being prescribed, pharmacies must assess and resolve the storage requirements. Replacing a safe or installing an additional one can be costly, and some pharmacies may not have the space for such measures without a significant refit of the dispensary.
    • The additional legislative requirements regarding Schedule 8 medicine storage receptacles are likely to be problematic for many health services if they are faced with also including these high volume codeine combination products in existing safes. Overcrowding of existing Schedule 8 safes to accommodate the additional products (in high volumes in some instances) may potentially lead to unintended negative patient outcomes relating to medication selection errors, a known risk with other higher potency Schedule 8 opioids.
  • Additional security and accountability measures will ultimately detract from available time to deliver existing healthcare services to patients in need.
    • The proposed re-scheduling will have a negative impact on health professional productivity and physical work environments within institutional healthcare settings which would result from the additional regulatory and administrative burden.
    • An additional estimated 28,000 transactions per annum would need to be recorded by pharmacists through controlled drug registers for predominantly hospital and residential care supplies. There would also be flow-on transactional requirements for nursing staff within the health care facilities. Additionally, there would also be more time taken to periodically count and reconcile register and physical stock balances.
    • Acute care and aged care facilities will be significantly affected with facilities requiring extra security for the storage of the additional Schedule 8 medicines as well as the administrative burden for staff in storing, handling, administering and recording.
    • Schedule 8 medicines will require a separate prescription thereby affecting the National Residential Medication Chart.
  • The simulation and modelling conducted for the RIS for the low dose codeine rescheduling scenarios do not apply to higher dose codeine medicines and further up-scheduling was not included as part of the RIS recommendations. In particular, the significant economic impacts of managing the supply of Schedule 8 medicines, due to the strict storage, distribution and record keeping requirements, represents a completely different set of scenarios to those considered in the previous RIS and requires a new assessment.
  • Sponsors may cancel their products as a result of the up-scheduling. The use of alternative prescription medicines are likely to increase which may result in the manufacturers not being able to meet demand and patients being unable to readily access alternative analgesics.
  • Real time reporting:
    • Codeine medicines should be subject to Real Time Monitoring and it is unnecessary to up-schedule to Schedule 8 for this to occur.
    • The Tasmanian Drugs and Poisons Information System Online Remote Access (DORA) currently considers codeine as a relevant substance for real-time reporting, and Schedule 4 codeine is expected to be included in SafeScript in Victoria.
    • The COAG Health Council announced[37] that federal, state and territory Health Ministers agreed to progress national real time prescription monitoring as a federated model with jurisdictions committed to progressing development and adaptation of systems to connect to and interface with Commonwealth systems to achieve a national solution.
  • The Medicines Classification Committee in New Zealand have proposed to down schedule codeine as a single ingredient for sale over the counter from 31 January 2020. Down-scheduling codeine from Schedule 8 to Schedule 4 may address the inconsistencies with codeine.
  • One submission proposed to amend the Schedule 8 entry to include divided preparations containing more than 30 mg of codeine per dosage unit and in undivided preparations containing more than 1 per cent of codeine.

ACMS advice

The committee recommended that the current scheduling of codeine 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 extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

  1. risks and benefits of the use of a substance:
    • Codeine is considered a weak opioid analgesic and antitussive. Risks include dependence, and harms associated with taking large quantities of combination analgesic products, predominantly in the context of OTC use.
  2. the purpose for which a substance is to be used and the extent of use:
    • Predominantly analgesia, with some use as an antitussive. As an analgesic codeine combination is widely used, for example over 12 million packets of S4 codeine products were sold in Australia in 2013.
  3. the toxicity of a substance:
    • Codeine is considered a weak opioid, there is the potential for toxicity with rapid metabolisers otherwise, codeine is considered to have lower potency compared with other opioids.[35]
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Combination products with up to 30mg in a dose unit, compounded with another active ingredient. Formulations with codeine as a single ingredient are Schedule 8.
  5. the potential for abuse of a substance:
    • Codeine is a weak opioid analgesic. There is evidence of non-medical use and dependence with combination codeine products, though this evidence was generated during the period of time when codeine was widely available in an over-the-counter medication. Blinded abuse liability studies indicate that doses of 100mg of codeine have a placebo like effects on abuse liability while higher doses (200mg) were similar to tramadol and oxycodone in their abuse liability)above.35 This suggests that in a controlled blinded clinical trial a therapeutic dose of 60mg (2 x 30mg codeine + 500mg paracetamol) has lower abuse liability than therapeutic doses of tramadol or oxycodone.
  6. any other matters that the Secretary considers necessary to protect public health:
    • Given the recent rescheduling of codeine to delete the Schedule 3 entry, there is minimal experience and data to inform if additional regulatory measures are required.

Footnotes

How to access a pdf document

  1. Babalonis S, Lofwall MR, Nuzzo PA, Siegel AJ, Walsh SL. Abuse Liability and Reinforcing Efficacy of Oral Tramadol in Humans. Drug and alcohol dependence. 2013;129(1-2):116-124. doi:10.1016/j.drugalcdep.2012.09.018.
  2. TGA. (2018). Codeine information hub: Codeine use can be harmful and Shaheed, C. A., Maher, C. G., & McLachlan, A. (2016). Investigating the efficacy and safety of over-the-counter codeine containing combination analgesics for pain and codeine based antitussives.
  3. COAG Health Council Communique 13 April 2018 (pdf,225kb)
  4. Minutes of the 59th meeting of the Medicines Classification Committee held in Wellington on Tuesday 7 November 2017

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