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Submissions and TGA response: Non-steroidal anti-inflammatory drugs (diclofenac, flurbiprofen, ibuprofen, ketoprofen, mefenamic acid and naproxen): proposed additional advisory statement for medicines

11 June 2015

The TGA would like to thank the respondents who have submitted written comments or made submissions in response to the consultation: Non-steroidal anti-inflammatory drugs (diclofenac, flurbiprofen, ibuprofen, ketoprofen, mefenamic acid and naproxen) for oral use: proposed additional advisory statements for medicines.

Submissions received

Eleven submissions were received. The following submissions provided consent for publication on the TGA website:

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Summary of issues reported and TGA response

The following sets out in brief the broad issues identified from the submissions received, and the TGA's response.

1. Proposed advisory statement for oral OTC medicines containing diclofenac, flurbiprofen, ibuprofen, ketoprofen, mefenamic acid or naproxen

Summary of issues

The majority of the respondents supported the RASML advisory statements as proposed.

However, a confidential submission noted that liver damage is a documented side effect of all non-steroidal anti-inflammatory drugs (NSAIDs), not just of diclofenac. Consequently the submission proposed that the hepatotoxicity risk associated with excessive use of diclofenac should be included on the labelling of all OTC oral NSAID products.

Two respondents also questioned the appropriateness of the proposed advisory statements on the labels of paediatric-specific products. The respondents maintained that the prevalence of cardiovascular risk factors is lower in children under 12 years of age than in adults, and that children are less likely to take these medicines for long periods or at higher doses than needed. It was suggested that inclusion of these statements in the RASML paediatric specific entries might cause unwarranted alarm for parents or caregivers.

In addition, some respondents asked for TGA clarification in regards to the scope for alternative wording. In particular, some respondents questioned whether 'similar' wording already approved on some labels will be consistently considered equivalent by the TGA.

One respondent suggested that the wording 'excessive and prolonged' would be difficult for consumers at minimal literacy levels to understand. This respondent suggested a number of alternative options, including changing the word order, deleting the word 'excessive' and using more consumer-focused wording. Two respondents also suggested clearly specifying the time period which is intended by the term 'a few days'.

Some respondents requested that the TGA allow industry an 18 month implementation timeframe for the changeover, given that some companies have only just completed the labelling update of these products to comply with Schedule 2 of the Medicines Advisory Statement Specification 2014.

TGA response

Hepatotoxicity statement

The TGA endorses the proposal that the label warning about liver damage should also be required for the other OTC NSAIDs.

The recommendations of the TGA safety review of diclofenac included advice that, while the risk of liver damage with excessive or long term use of oral diclofenac is already appropriately conveyed in the existing Australian Product Information (PI) for prescription diclofenac medicines, the labels of OTC oral diclofenac medicines should be amended to include a statement that conveys this known risk of hepatic injury to the consumer.

Liver damage is identified as a known potential side effect, not just in the PI for diclofenac, but also in the PI documents for the innovator products containing ibuprofen ("Brufen"), naproxen ("Naprosyn"), ketoprofen ("Orudis") and mefenamic acid ("Ponstan").

Liver damage is also identified as a potential side effect for ibuprofen, naproxen, mefenamic acid and flurbiprofen in the entries for these NSAIDs in Martindale's The Complete Drug Reference, as well as in the United States Food and Drug Administration's Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).

Therefore, in relation to the labels of these other OTC NSAID medicines, the stakeholder submission is justified in proposing these medicine labels should also be amended to include the same statement proposed for diclofenac, which conveys the risk of hepatic injury to the consumer.

Consequently, the TGA will require the additional words "...or liver damage" for all of the OTC oral NSAID labels.

Appropriateness for children under 12 years of age

The TGA does not agree that paediatric-specific products should be exempted from the requirements.

Although the prevalence of cardiovascular risk factors may be less likely in children under 12 years of age, the review of the cardiovascular safety of non-steroidal anti-inflammatory drugs concluded that the risk applied to all users, even those without pre-disposing risk factors.

Many children suffer repeatedly and/or over long periods from the conditions that NSAID medicines are marketed for, such as teething, cold, flu, earaches, sore throats, headache, sprains and strains, 'minor aches' etc. Some pain-relief medicines are intensively advertised to parents for use whenever their child suffers from any pain or fever. Other children may use these medicines long-term and/or at higher doses for relief of pain of conditions such as juvenile arthritis; and some adults (such as elderly patients who have difficulty swallowing) may use the products as well. It is therefore not clear that the users of paediatric-specific medicines will be substantially less likely than the users of the adult formulations to take these medicines for long periods or at higher doses than recommended. Users of these medicines should be provided with the same safety advice that will be provided to the users of the adult medicines.

Alternative wording

The wording 'excessive or prolonged use' that was originally proposed in this consultation (in place of the current wording 'excessive use') will not now be required, provided the medicine label includes the full three-sentence 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 and increase the risk of heart attack, stroke or liver damage". The word 'excessive' is generally taken to mean that something has gone beyond its usual or proper limits; and can apply to a recommended period of time as well as to a recommended dose. In this case 'excessive' is expected to be understood in the context of the two immediately preceding sentences to apply to both 'more than a few days at a time' and 'more than the recommended dose'.

The TGA notes the concerns raised by one of the respondents regarding potential consumer comprehension issues with the word 'excessive'. However, it is expected that the overall wording of the set of three sentences will make the meaning clear - as discussed above.

The TGA appreciates the respondents' suggestions for specific alternative wording for the RASML. However, in this case the TGA still considers that the currently proposed wording is the most appropriate.

The RASML allows for alternative wording to be used on medicine labels as long as the meaning is unchanged. However, any alternative wording that is proposed by a sponsor must still convey the advice that the risks apply to both prolonged use and high doses.

In relation to the time period which is intended by the term 'a few days', it is not possible to specify an exact maximum time period that will apply to all of these multiple NSAIDs and multiple patient groups. Patients who need to use the medicines for more than 'a few days' should consult a doctor for specific advice.

Timeframe

The TGA notes the submission requests in relation to the implementation timeframe. However, the TGA has on 11 May 2015 imposed a new condition of registration on all currently supplied oral OTC medicines containing these NSAIDs, requiring the statement "Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage" (or words to that effect) to be present on the affected labels by 1 July 2016.

Outcome

The updated RASML will require the advisory 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 and increase the risk of heart attack, stroke and liver damage" on the labelling of all oral OTC medicines containing diclofenac, flurbiprofen, ibuprofen, ketoprofen, mefenamic acid or naproxen.

The RASML implementation timeframe for the changeover will be aligned with the implementation timeframe of July 2016 that has been required by a recent condition of registration applied to the currently supplied medicines.

2. Other issues

i. Concerns regarding the total number of statements that are now required

Two respondents expressed concern over the number of statements that are required for the labels of NSAID medicines, and one questioned whether the scheduling was still appropriate. The respondents were concerned about the increasing possibility for important advice to be overlooked, as well as a potential risk of "warning label fatigue", and a potential health risk from perception that NSAIDs are nonetheless 'safe' because they are available in a general retail setting.

TGA response

The TGA notes these concerns, and will continue to review the wording of all statements in the RASML as part of the ongoing review process, with the concerns of the respondents in mind.

In the case of the specific new statement "Excessive use can be harmful and increase the risk of heart attack, stroke and liver damage" that is required as a result of the current consultation, the statement was worded as an extension to an existing statement with the specific intent of being as concise as possible without sacrificing meaning.

It should also be noted that sponsors are currently permitted to combine individual statements into fewer, more concise statements where possible, provided the intent is not changed.

The option for OTC NSAIDs to be considered for rescheduling was put forward in the TGA Consultation: Review of cardiovascular safety of non-steroidal anti-inflammatory drugs and Safety review of diclofenac (closed 6 November 2014). The TGA response to submissions for this separate consultation will be published shortly.

ii. Prominence and placement

To further promote the safe and effective use of medicines, one respondent emphasised that the print size of medicine label warnings needs to be adequate to ensure all consumers can read the warning. Additionally, these warnings should be displayed prominently such that it is intuitive for the consumer to read.

TGA response

Appropriate print size and placement of medicine label warnings are two of a number of issues that are being considered as part of the ongoing TGA review of submissions to the Consultation: Medicine labelling (closed 6 November 2014).

iii. Education and pharmacovigilance

Some respondents were concerned that consumers may be unnecessarily frightened by label warning changes if the communication is handled poorly. The respondents commented on the critical importance of optimum communication and education to health practitioners, retailers and consumers. They recommended provision of further information for consumers at the point of supply in order to improve the safety and quality use of these medicines. The respondents indicated their interest in assisting with the education aspects of implementation of these labelling changes, when finalised and as appropriate.

Submissions also noted the need for further pharmacovigilance to monitor associated adverse effects and any impact of the new NSAID warnings on use of other pain relievers.

TGA response

The TGA will collaborate with relevant stakeholders in the education aspects of implementation of these labelling changes. Further information will be published shortly as part of the TGA response to the Consultation: Review of cardiovascular safety of non-steroidal anti-inflammatory drugs and Safety review of diclofenac (closed 6 November 2014).

iv. OTC PI and CMI documents

A respondent recommended that these advisory statements should be included in the Product Information (PI) and Consumer Medicines Information (CMI) for these medicines, and that all medicine boxes should contain a CMI leaflet.

TGA response

It is a general expectation that existing PI and CMI documents for these OTC medicines are updated as necessary to include relevant new safety advice. However, the specific issues raised by this respondent fall within the scope of the TGA Consultation: Review of cardiovascular safety of non-steroidal anti-inflammatory drugs and Safety review of diclofenac (closed 6 November 2014). The TGA response to submissions for this earlier consultation will be published shortly.

v. Additional statement

One respondent proposed addition of a statement that use of multiple NSAIDs should be avoided due to the increased risk of adverse effects.

TGA response

The RASML No. 2 will require the statement "Unless advised by your doctor or pharmacist, do not use [this product / insert name of product] with other products containing [NSAID name], aspirin or other anti-inflammatory medicines or with medicines that you are taking regularly". The wording of this statement was adopted following public consultation (the 'RASML Update 6' consultation) in 2011.

vi. Wording of the 'Conditions' - Terminology

A respondent noted that the terms 'oral medicines' and 'oral preparations' in the 'conditions' for the affected entries have no definition in the Medicines Advisory Statements Specification or in the Poisons Standard. The respondent suggested that the terminology should be changed to 'medicines for internal use', as 'internal use' is defined in these instruments (as meaning '...administration: (a) orally, except for topical effect in the mouth; or (b) for absorption and the production of a systemic effect; (i) by way of a body orifice other than the mouth; or (ii) parenterally, other than by application to unbroken skin)'.

In general the TGA agrees that the use of more consistently applied and defined terminology in the RASML is desirable. The TGA will consider this as part of the ongoing RASML revision process. However, a term such as 'oral medicine' is necessary to capture medicines such as flurbiprofen lozenges which are administered orally for a topical rather than systemic effect, but which are ultimately swallowed, with the associated safety concerns.

3. Final proposal

Amended advisory statement for diclofenac, flurbiprofen, ibuprofen, ketoprofen, mefenamic acid and naproxen in preparations for oral use

The labels of oral medicines containing diclofenac, flurbiprofen, ibuprofen, ketoprofen, mefenamic acid or naproxen will require an additional advisory statement to the effect that excessive or prolonged use can increase the risk of heart attack, stroke or liver damage.

To minimise the total number of required statements for these medicine labels in the RASML, the TGA proposes that the new statement will be included in the RASML as an extension to the currently required 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'; as follows.

  • 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.

The RASML implementation timeframe for the changeover will be aligned with the implementation timeframe of July 2016 that has been required by a recent condition of registration applied to the currently supplied medicines.

Outcomes

Labelling

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 the warning statement: "Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage." (or words to that effect)

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.

Scheduling

The TGA concluded that the current scheduling and availability of OTC NSAIDs was appropriate and that the addition of stronger warnings about the risks associated with excessive use would be sufficient. Thus no changes to scheduling are proposed at this time.

Health professional and consumer awareness

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 amend their Product Information (PI) documents 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 those 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.