Publication of interim decisions amending, or not amending, the current Poisons Standard, June 2018

Scheduling medicines and poisons

7 June 2018

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1.1 Diclofenac

1. Advisory Committee on Medicines Scheduling (ACMS #23)

1.1 Diclofenac

Delegate's interim decision

The delegate's interim decision is to amend the Schedule 2 entry for diclofenac in the Poisons Standard to read as follows:

Schedule 2 - Amend Entry

DICLOFENAC when:

  1. in divided preparations for oral use containing 12.5 mg or less of diclofenac per dosage unit in a pack containing 20 or less dosage units and labelled with a recommended daily dose of 75 mg or less of diclofenac; or
  2. in preparations for dermal use containing 4 per cent or less of diclofenac except in preparations for dermal use containing 2 per cent or less of diclofenac or for the treatment of solar keratosis; or
  3. in transdermal preparations for topical use containing 140 mg or less of diclofenac.
Proposed implementation date: 1 October 2018

The delegate considers the Committee's proposed implementation date of 1 October 2018 as being reasonable and appropriate in the circumstances.

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:
    • The delegate agrees with the Committee's advice that use of this substance creates the potential for a very slight increase in cardiovascular toxicity when compared to diclofenac 1% gel. However, noting that the daily dose is the same for both gels, the risk posed by the 2% gel is no greater than the risk posed by the 1% gel.
    • The delegate agrees with the Committee' advice that there are a number of benefits of associated with having the 2% gel more accessible to consumers:
      • The 2016 Cochrane Systemic review demonstrates proven efficacy[1] at the proposed dose with adverse effect profile that is comparable to placebo and much reduced systemic toxicity compared to oral diclofenac;
      • Serious adverse events are rare and the likelihood of adverse effects with the topical product is lower than with oral products and is no greater than for the same daily dose using the 1% product.
      • Use of the gel reduces use of other oral NSAIDs;
      • Use of the gel results in significantly lower peak serum levels compared to oral products; and
      • The 2% gel has the added advantage over the 1% gel because it only has to be used twice a day as opposed to four times a day. This improves likelihood of patient compliance and usability.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Temporary (up to 3 weeks) relief of local pain and inflammation (swelling and redness) that may occur in mild forms of osteoarthritis of the knees and fingers.
    • Topical use for mild pain associated with osteoarthritis in the fingers and knees.
  3. the toxicity of a substance:
    • similar to the 1% gel and known NSAID toxicity according to the instructions of use;
    • has significantly lower peak serum levels compared to oral products; and
    • there has been large use in the UK and New Zealand with no significant issues.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • daily dosage of 2% gel when used as indicated is the same as for the 1% gel;
    • the potential for confusion between products can be effectively mitigated by appropriate labelling and packaging; and
    • 2% diclofenac gel, labelling states 12 hourly, not to use for more than 3 weeks and to cease use after 7 days if condition gets worse or no better.
  5. the potential for abuse of a substance:
    • Does not appear to have an abuse potential.
Scheduling proposal

The pre-meeting scheduling proposal for diclofenac was published on the TGA website on 21 December 2017 at Consultation: Proposed Amendments to the Poisons Standard - ACCS, ACMS and Joint ACCS-ACMS meetings, March 2018.

Background information for diclofenac
Referred scheduling proposal

An application was submitted to amend the Poisons Standard with respect to diclofenac. The application proposes to amend the Schedule 2 entry for diclofenac to exempt preparations for dermal use containing 2% or less of diclofenac from the Poisons Standard, except when labelled for the treatment of solar keratosis.

Scheduling application

The proposed amendments to the Poisons Standard are:

Schedule 2 - Amend Entry

DICLOFENAC when:

  1. in divided preparations for oral use containing 12.5 mg or less of diclofenac per dosage unit in a pack containing 20 or less dosage units and labelled with a recommended daily dose of 75 mg or less of diclofenac;
  2. in preparations for dermal use containing 4 per cent or less of diclofenac except in preparations for dermal use containing 2 per cent or less of diclofenac or for the treatment of solar keratosis; or
  3. in transdermal preparations for topical use containing 140 mg or less of diclofenac.

The applicant's reasons for the proposal are:

  • Dermal preparations containing 1% or less of diclofenac have been exempt from scheduling since February 2000. Diclofenac gel 2% (equivalent to diclofenac diethylammonium (DDEA) 2.32%) has been marketed in Australia as a Schedule 2 product for over 3 years. The date of first supply was June 2014.
  • Globally, there is an accumulating history of use of the Diclofenac 2% gel formulation:
    • Diclofenac 2% gel was first registered in May 2011. As of 2017, 67 countries had received marketing approval for Diclofenac 2% gel.
    • Sales data indicate that from first marketing through to 31 July 2016, approximately 45.2 million patients have been exposed to the sponsor's Diclofenac 2% gel.
    • Diclofenac 2% gel is unscheduled and approved for general sale in two major markets - New Zealand (NZ) (authorised July 2013) and the United Kingdom (UK) (authorised 2013).
  • The Advisory Committee on Medicines Scheduling (ACMS) reviewed a scheduling proposal to exempt Diclofenac 2% gel from scheduling in May 2014. The decision was to retain the Schedule 2 status. The reasons cited were:
    • The formulation had not been available for wider community use;
    • Lack of evidence of safety from the wider use in the community;
    • Potential for confusion arising from the different dosing regimen from the current (1%) product; and
    • In-pharmacy scheduling status in other markets such Switzerland, UK, Ireland and Canada.
  • Significant changes have occurred since this prior submission:
    • There has been increased availability globally;
    • The Cochrane Collaboration has published new efficacy/safety reviews; and
    • There has been sufficient in-market use to enable a direct comparison of safety reporting data for the 1% and 2% strength gels.
  • There is long standing prior precedence from other topical products to have the same active ingredients at different strengths in a general sales environment in Australia (e.g. rubefacient products containing methyl salicylate). These products are used for the same indication as diclofenac gel 2%, alleviating concerns about the potential for dose confusion.
  • There is now sufficient additional safety information addressing the reasons cited by the ACMS in May 2014 for having retained the Schedule 2 status.
  • Three recent Cochrane reviews, (Derry , 2015, Derry et al., 2016, Derry et al., 2017) provide high quality evidence showing a lack of systemic safety problems with topical non-steroidal anti-inflammatory drugs (NSAIDs). The Cochrane reviews support the view that the lack of systemic problems makes topical NSAIDs particularly useful for those individuals unable to tolerate oral NSAIDs or for those in whom oral NSAIDs are contraindicated (e.g. due to older age). Thus unscheduled availability is highly beneficial due to the absence of systemic safety concerns.[2,3,4]
  • Topical NSAIDs are universally recommended across international and national guidelines for knee and hand osteoarthritis, generally ahead of oral NSAIDs or opioids for pain relief, due to their superior safety profile (Rannou et al., 2016).[5]
  • Non-adherence to available pharmacological treatments is a problem that has the potential to impact on population health and expenditure (Laba et al., 2013).[6] Importantly, when making decisions about the use of topical and oral NSAIDs, patients with osteoarthritis perceive medications that do not fit in with their lifestyle to be less effective than those that do (Carnes et al., 2008).
  • The data provided within the application support the efficacy and safety of Diclofenac 2% gel when used as directed. The Diclofenac 2% gel formulation provides the same total daily dose of diclofenac as the DDEA 1.16% gel in fewer doses.[7]
  • The indications for use of Diclofenac 2% gel are the same as those for other topical analgesics currently available for general sale. Any potential risks with Diclofenac 2% gel are extremely low and are no different to those associated with DDEA 1.16% gel or other topical analgesics that are already available for general sale.
  • The evidence, combined with favourable labelling provisions (name, indication, label colour and an in-pack Patient Information Leaflet), supports the proposal that Diclofenac 2% gel be down-scheduled from Pharmacy-only to general sales.
Current scheduling status

Diclofenac is listed in Schedules 2, 3 and 4, as well as Appendices F and H of the Poisons Standard as follows:

Schedule 2

DICLOFENAC when:

  1. in divided preparations for oral use containing 12.5 mg or less of diclofenac per dosage unit in a pack containing 20 or less dosage units and labelled with a recommended daily dose of 75 mg or less of diclofenac;
  2. in preparations for dermal use containing 4 per cent or less of diclofenac except in preparations for dermal use containing 1 per cent or less of diclofenac or for the treatment of solar keratosis; or
  3. in transdermal preparations for topical use containing 140 mg or less of diclofenac.

Schedule 3

DICLOFENAC in divided preparations for oral use containing 25 mg or less of diclofenac per dosage unit in a pack containing 30 or less dosage units except when included in Schedule 2.

Schedule 4

DICLOFENAC except:

  1. when included in Schedule 2 or 3; or
  2. in preparations for dermal use unless:
    1. for the treatment of solar keratosis; or
    2. containing more than 4 per cent of diclofenac.

Appendix F, Part 3

Warning Statements: 101, 104

Appendix H

DICLOFENAC.

Scheduling history

The scheduling history for diclofenac in dermal preparations is outlined below.

In March 1981, diclofenac was first included in Schedule 4.

In February 1997, the National Drugs and Poisons Schedule Committee (NDPSC) rescheduled diclofenac from Schedule 4 to Schedule 2 in dermal preparations (creams) containing 1 per cent or less of diclofenac. This decision was based on the safety profile of a 1 per cent formulation and the then approved indications for use in readily recognised conditions (minor pain relief), which did not include treatment of solar keratosis.

In August 1999, the NDPSC decided that the scheduling of diclofenac in dermal preparations remained appropriate after considering recommendations from the Trans-Tasman Harmonisation Working Party to exempt diclofenac for dermal use.

In November 1999, the NDPSC deferred consideration of the scheduling of diclofenac in dermal preparations.

In February 2000, the NDPSC exempted dermal preparations of diclofenac from scheduling based on additional safety data.

In March 2011, following advice from the December 2010 ACMS meeting, the delegate included dermal preparations containing more than 1 per cent of diclofenac or preparations for the treatment of solar keratosis in Schedule 4.

In February 2012, following advice from the October 2011 ACMS meeting, the delegate rescheduled dermal preparations containing more than 1 per cent and up to 4 per cent or less of diclofenac to Schedule 2, except when for the treatment of solar keratosis. The delegate also confirmed that Schedule 4 remained appropriate for preparations containing more than 4 per cent of diclofenac, that preparations containing 1 per cent or less of diclofenac would remain unscheduled and that preparations for use in solar keratosis would remain in Schedule 4.

In February 2013, following advice from the October 2012 ACMS meeting, the delegate included transdermal preparations for topical use containing 140 mg or less of diclofenac in Schedule 2, with an implementation date of 1 May 2013.

In a final decision published in June 2013, the delegate considered a proposal to exempt diclofenac when presented in a transdermal drug delivery system containing 140 mg or less of diclofenac. The decision was that the scheduling was appropriate, as there was no clinical or marketing experience with this formulation in Australia, and Schedule 2 allows for access to professional advice at the time of purchase.

In July 2014, following the advice from the March 2014 ACMS meeting, the delegate decided that the scheduling of diclofenac remained appropriate and decided not to exempt dermal use preparations containing 2 per cent or less of diclofenac from scheduling. The delegate noted that a diclofenac 2 per cent topical solution is a Prescription Only Medicine in the United States of America.

Australian regulations

The Australian Register of Therapeutic Goods (ARTG) has 99 products listed that contain diclofenac, diclofenac diethylamine, diclofenac potassium and diclofenac sodium. The products marketed include topical preparations, immediate and modified realise capsules and tablets, eye drops and suppositories with varying strengths and quantities.

Diclofenac does not appear in the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2018, as it is a scheduled ingredient and is not eligible for use in ARTG listed medicines.

In the last 30 years there have been 1935 reported cases of adverse events related to diclofenac in the Database of Adverse Events Notification (DAEN) - Medicines: 1194 cases with a single suspected medicine and 43 cases where death was a reported outcome.

According to the TGA Ingredient Database, diclofenac diethylamine is available for use as an:

  • Active ingredient in: Biologicals, Export Only, Over The Counter, Prescription Medicines; and
  • Excipient ingredient in: Biologicals, Devices, Prescription Medicines.

Diclofenac is not an approved active constituent with APVMA. One product had been registered with APVMA. However, this product was discontinued in November 1991.

International regulations

Canada

Health Canada regulates diclofenac as a prescription and over-the-counter medicine.

NZ

Ingredient Conditions (if any) Classification
Diclofenac

in preparations for the treatment of solar keratosis;

except when specified elsewhere in this schedule;

except in preparations for external use other than for the treatment of solar keratosis

Prescription
Diclofenac in solid dose form in medicines containing 25 milligrams or less and more than 12.5 milligrams per dose form in packs containing not more than 30 tablets or capsules Restricted
Diclofenac in solid dose form in medicines containing 12.5 milligrams or less per dose form in packs containing not more than 30 tablets or capsules and with a recommended daily dose of not more than 75 milligrams Pharmacy Only
Diclofenac in preparations for external use other than for the treatment of solar keratosis General Sale

United States of America (USA)

The USA Food and Drug Administration regulate diclofenac in varying dose forms as prescription medicines.

UK

The UK regulates diclofenac as a:

  • Prescription only medicine including varying strengths of immediate and modified release capsules and tablets, eye drops, ampoules, topical preparations, patches and suppositories;
  • Pharmacy only medicine including cutaneous spray 4% and medical plaster; and
  • General sales list medicine including emulgel 1.16% and 2.32% (active substance diclofenac diethylammonium).
Substance summary

In the 2% gel, diclofenac is present in its diethylammonium form [diclofenac diethylammonium (DDEA)].

Table 1.1A: Chemical information for DDEA
Property DDEA
CAS number 78213-16-8
Chemical structure chemical structure of diclofenac diethylamine
Molecular formula C14H11Cl2NO2.C4H11N (or C18H22Cl2N2O2)
Molecular weight 369.3 g/mol
IUPAC and/or common and/or other names

diclofenac diethylammonium (DDEA);

Diclofenac diethylamine;

2-((2,6-Dichlorophenyl)amino)benzeneacetic acid, compd. with N-ethylethanamine;

N-ethylethanaminium{2-[(2,6-dichlorophenyl)amino]phenyl}acetate;

Benzeneacetic acid, 2-((2,6-dichlorophenyl)amino)-, compd. with N-ethylethanamine (1:1);

N-Ethylethanamine 2-[(2,6-dichlorophenyl)amino]

Action and use Cyclo-oxygenase (COX) inhibitor; analgesic; anti-inflammatory
Description A white to light beige, crystalline powder
Solubility Sparingly soluble in water and in acetone; freely soluble in ethanol (96%) and in methanol; practically insoluble in 1M sodium hydroxide
Pre-meeting public submissions

Four (4) public submissions were received, two (2) in support and two (2) opposed.

The main points provided in support of the amendment were:

  • Topical diclofenac is a safe and effective analgesic. The safety profile of 2% diclofenac gel is comparable to the 1% gel and can be supplied with reasonable safety without access to a health professional.
  • The proposed 2% diclofenac gel requires less frequent dosing than the unscheduled 1% gel and will be easily differentiated from each other by labelling. The less frequent application will also lead to better adherence and better outcomes.
  • Since the last consideration to exempt 2% diclofenac gel from scheduling in May 2014, new evidence highlights the safety from wider use. Recent TGA reviews have also shown that topical diclofenac has a well-characterised and favourable safety profile.
  • There is no evidence of dependence or abuse.
  • 2% diclofenac gel is unscheduled in NZ and the UK and international misuse is rare.
  • Exempting 2% diclofenac gel from scheduling does not affect regulation of the product. Products will continue to be regulated in relation to its manufacturing, composition, packaging and advertising. The only change will be consumer access.

The main points provided in opposition of the amendment were:

  • The TGA's full safety review of diclofenac in 2013 concluded that a conservative approach for topical diclofenac products is warranted. Further, research literature could not be located where the safety of topical 3% diclofenac was specifically examined.
  • The Australian Product Information for topical 3% diclofenac makes reference to serious systemic side effects.
  • Concomitant administration of diclofenac gel with oral NSAIDs or aspirin may result in increased adverse NSAID effects. Guidelines for prescribing indicate only one non-aspirin NSAID should be used at any time.
  • Given the up-scheduling of combination codeine products, consumers will be seeking alternative products for relief of pain and consultation in a pharmacy would be appropriate to ensure quality use of medicines.
  • The dosage guidelines for 2% diclofenac gel are different to 1% gel. The 2% concentration gel is applied half as often. Having potentially two types of unscheduled products available at different strengths increases the risk of medicine overuse and associated risks.
  • Risks associated with 2% diclofenac gel are best mitigated with consumers having discussions regarding the safe and appropriate use of these medicines with pharmacy staff.
  • Based on currently available information and evidence, the proposal of exempting dermal diclofenac from 1% to 2% is not supported.

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

Summary of ACCS advice to the delegate

The committee recommended that the Schedule 2 entry for diclofenac be amended in the Poisons Standard as follows:

Schedule 2 - Amend Entry

DICLOFENAC when:

  1. in divided preparations for oral use containing 12.5 mg or less of diclofenac per dosage unit in a pack containing 20 or less dosage units and labelled with a recommended daily dose of 75 mg or less of diclofenac;
  2. in preparations for dermal use containing 4 per cent or less of diclofenac except in preparations for dermal use containing 12 per cent or less of diclofenac or for the treatment of solar keratosis; or
  3. in transdermal preparations for topical use containing 140 mg or less of diclofenac.

The committee also provided the following comments regarding the regulation of products including diclofenac gel:

  • That the different strength unscheduled packs of diclofenac should be well differentiated;
  • Undertake a literature review and publish a consultation for updates to Required Advisory Statements for Medicine Labels (RASML); and
  • Amend the Patient Information leaflet to include the risk of use in patients with cardiovascular disease (perhaps through the next RASML update).

The committee also recommended an implementation date of 1 October 2018.

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; and (e) the potential for abuse of a substance.

The reasons for the advice included:

  1. the risks and benefits of the use of a substance:
    • Risks: a potential for a very slight increase in cardiovascular toxicity. However, it is the same for the 1% gel, which is also exempt.
    • Benefits:
      • Proven efficacy (Derry et al., 2016[8] Cochrane Systematic Review) at the proposed dose with adverse effect profile that is comparable to placebo and much less (but not no) systemic toxicity compared to oral diclofenac;
      • Reduces use of other oral NSAIDs; and
      • Improved adherence - twice a day vs four times a day.
      • Serious adverse events are rare and the likelihood of adverse effects with the topical product is lower than with oral products.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Temporary (up to 3 weeks) relief of local pain and inflammation (swelling and redness) that may occur in mild forms of osteoarthritis of the knees and fingers.
    • Topical use for mild pain associated with osteoarthritis in the fingers and knees.
  3. the toxicity of a substance:
    • As per 1% gel and known NSAID toxicity according to the instructions of use.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • The two products (2% and 1% gel) are insufficiently differentiated. Patient Information Leaflet should mention slight risk of cardiovascular toxicity as per oral diclofenac.
    • 2% diclofenac gel, labelling states 12 hourly, not to use for more than 3 weeks and to cease use after 7 days if condition gets worse or no better.
  5. the potential for abuse of a substance:
    • Does not appear to have an abuse liability.
  6. any other matters that the Secretary considers necessary to protect public health
    • Nil.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • ACMS advice;
  • Public submissions received;
  • Scheduling Policy Framework (SPF 2018); and
  • Section 52E (1) 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; and (e) the potential for abuse of a substance.

Footnotes

  1. Derry, S., P. Conaghan, J. A. Da Silva, et al., Topical NSAIDs for chronic musculoskeletal pain in adults; 2016 Cochrane Database Syst Rev 4,Cd007400.
  2. Derry, S., R. A. Moore, H. Gaskell, et al., Topical NSAIDs for acute musculoskeletal pain in adults; 2015 Cochrane Database Syst Rev (6),CD007402.
  3. Derry, S., P. Conaghan, J. A. Da Silva, et al., Topical NSAIDs for chronic musculoskeletal pain in adults; 2016 Cochrane Database Syst Rev 4,Cd007400.
  4. Derry, S., P. J. Wiffen, E. A. Kalso, et al., Topical analgesics for acute and chronic pain in adults - an overview of Cochrane Reviews; 2017 Cochrane Database Syst Rev 5,Cd008609.
  5. Rannou, F., J.-P. Pelletier and J. Martel-Pelletier. Efficacy and safety of topical NSAIDs in the management of osteoarthritis: Evidence from real-life setting trials and surveys; 2016 Seminars in Arthritis and Rheumatism 45(4),S18-S21.
  6. Laba, T.-L., J.-a. Brien, M. Fransen, et al., Patient preferences for adherence to treatment for osteoarthritis: the Medication Decisions in Osteoarthritis Study (MEDOS); 2013 BMC Musculoskeletal Disorders 14(1),160.
  7. Carnes, D., Y. Anwer, M. Underwood, et al., Influences on older people's decision making regarding choice of topical or oral NSAIDs for knee pain: qualitative study; 2008 BMJ : British Medical Journal 336(7636),142-145.
  8. Derry, S., P. Conaghan, J. A. Da Silva, et al., Topical NSAIDs for chronic musculoskeletal pain in adults; 2016 Cochrane Database Syst Rev 4,Cd007400.

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