Submissions and TGA response: Review of cardiovascular safety of non-steroidal anti-inflammatory drugs and Safety review of diclofenac

16 November 2015

The TGA would like to thank the respondents who made submissions in response to this consultation: Review of cardiovascular safety of non-steroidal anti-inflammatory drugs and Safety review of diclofenac.

The reviews covered eight non-steroidal anti-inflammatory drugs (NSAIDs): diclofenac, naproxen, ibuprofen, celecoxib, etoricoxib, indomethacin, meloxicam and piroxicam.

Submissions received

Eleven submissions were received from product sponsors and other organisations. The following nine organisations provided consent for publication of all or part of the submission on the TGA website:

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  1. Consultation submission: Alphapharm Pty Ltd (pdf,186kb)
  2. Consultation submission: Australian Self-Medication Industry (pdf,277kb)
  3. Consultation submission: NSW Therapeutic Advisory Group (pdf,407kb)
  4. Consultation submission: New Zealand Self-Medication Industry (pdf,33kb)
  5. Consultation submission: Pharmaceutical Society of Australia (pdf,97kb)
  6. Consultation submission: Pharmacy Education Online (pdf,97kb)
  7. Consultation submission: The Pharmacy Guild of Australia (pdf,1.28Mb)*
  8. Consultation submission: Reckitt Benckiser Australia (pdf,238kb)
  9. Consultation submission: Society of Hospital Pharmacists of Australia (pdf,343kb)

Summary of submissions

These submissions focused on the over-the-counter (OTC) non-steroidal anti-inflammatory drugs (NSAIDs), and the general consensus reflected in the submissions received is as follows:

  • For OTC topical NSAIDs:
    • The cardiovascular and hepatotoxicity risks associated with NSAIDs do not apply to topical NSAIDs and no changes need to be made to their availability, scheduling or labelling.
  • For OTC oral NSAIDs:
    • No changes need to be made to the availability or scheduling of OTC oral NSAIDs, and there is no need to mandate inclusion of the Consumer Medicine Information (CMI) (or equivalent) document as a package insert.
    • Additional cardiovascular safety statements (and hepatic safety statements for diclofenac) need to be included on the labelling of existing products and incorporated into the Required Advisory Statements for Medicine Labels (RASML) to ensure that the same warnings are on the labels of products registered in the future. However, before requiring amendments to labelling, the TGA should consult further with stakeholders on the precise wording to be used, and the TGA should allow an adequate transition period for the implementation of the changes.
    • There should be a coordinated, collaborative program of information dissemination through appropriate media to health professionals and consumers to raise awareness of the cardiovascular and hepatic risks associated with the use of NSAIDs and their appropriate management.

TGA response

The TGA concurs with the general consensus above, and it has implemented the results of the reviews and the consultation process as follows:

Affected drugs

The reviews and submissions focused on the eight NSAIDs listed above, but the TGA has subsequently considered the references in the review reports to other structurally and/or pharmacologically similar NSAIDs available in Australia, namely, flurbiprofen, ketoprofen, ketorolac trometamol, mefenamic acid, sulindac and tiaprofenic acid, and concluded that the same cardiovascular safety risks probably apply to those drugs as well, and therefore, any changes should apply to all 14 NSAID drugs.

Labelling

In February 2015, the TGA conducted a further consultation with stakeholders on the wording of the warning statement about cardiovascular and hepatotoxicity risks that should be added to the labelling of OTC NSAIDs and that should be incorporated into the RASML. The submissions and TGA response were subsequently published on the TGA website.

After consideration of the submissions received, the TGA concluded that it would be appropriate and sufficient to modify the RASML statement:

"Do not use for more than a few days at a time unless a doctor has told you to. Do not exceed the recommended dose. Excessive use can be harmful." (or words to that effect)

to:

"Do not use for more than a few days at a time unless a doctor has told you to. Do not exceed the recommended dose. Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage." (or words to that effect)

In May 2015, a new condition was imposed on sponsors of OTC oral NSAIDs requiring them to amend their labelling of all new batches released into the Australian market from 1 July 2016 to include this longer warning statement.

The date for implementation of the labelling change was designed to allow sufficient time for sponsors to amend labels and manufacture and label stock with the amended labels.

A few sponsors requested and were granted an extension of time until 1 January 2017 to implement the change for their products for logistical reasons.

After the implementation date, wholesalers, pharmacies and other retailers with stock of previously released batches not carrying the new warning statement can sell that stock through to the end of its shelf life.

OTC oral NSAIDs registered in the Australian Register of Therapeutic Goods (ARTG) in the future will be required to carry the longer warning statement.

Scheduling

The TGA concluded that the current scheduling and availability of OTC NSAIDs are appropriate and that the addition of stronger label warnings on the labels should be sufficient to alert and inform consumers about the risks associated with excessive use of those products. Thus no changes to scheduling are proposed at this time.

Health professional and consumer awareness

In April 2015 the TGA published a Medicine Safety Update article advising health professionals of the outcomes of the NSAID reviews.

The TGA has also worked with the sponsors of the innovator brands of prescription-only and pharmacist-only NSAIDs to ensure that their Product Information (PI) documents are amended to reflect the conclusions of the reviews.

Sponsors of generic brands of prescription-only medicines are required to bring their PI documents into line with safety information added to the PIs of the corresponding innovator brands.

All sponsors are also required to align the safety information in their Consumer Medicine Information (CMI) documents with their PI documents.

In 2016 the TGA intends to work with stakeholders in the planning and implementation of a communication strategy to raise awareness among health professionals and the general public concerning the cardiovascular and hepatotoxicity risks associated with NSAIDs.