Consultation: Review of Cardiovascular Safety of Non-Steroidal Anti-Inflammatory Drugs

Therapeutic Goods Administration

Therapeutic Goods Administration

About the Therapeutic Goods Administration (TGA)

• The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health, and isresponsible for regulating medicines and medical devices.
• The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk managementapproach designed to ensure therapeutic goods supplied in Australia meet acceptable standardsof quality, safety and efficacy (performance), when necessary.
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Copyright

© Commonwealth of Australia 2014
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Version history

Contents

1. Background

2. Cardiovascular risk review

2.1 The review

2.2 Request for advice from the Advisory Committee on the Safety of Medicines

2.3 Consideration of report by innovator sponsors

3. Safety review of diclofenac

3.1 The review

3.2 Request for advice from the Advisory Committee on the Safety of Medicines

3.3 Consideration of report by innovator sponsors

4. Conclusions

5. Recommendations

Option 1 – Status quo

Option 2 – Non-regulatory

Option 3 – Regulatory

Label changes

Re-scheduling OTC NSAIDs

Option 4 – Combination of regulatory and non-regulatory activities

6. Next steps

Making submissions

Content of submissions

What will happen?

Enquiries

1. Background

The eight non-steroidal anti-inflammatory drugs (NSAIDs)celecoxib, etoricoxib, indomethacin, meloxicam, piroxicam, diclofenac, ibuprofen and naproxen are available in Australia as prescription medicines. Three of these NSAIDs, diclofenac, naproxen and ibuprofen, are also available in lower dose forms without a prescription as either pharmacist-only or pharmacy only medicines. Low-dose oral ibuprofenand topical piroxicam are unscheduled, available not only in pharmacies but also in supermarkets and other retail outlets, and are widely used as analgesics. Pharmacist-only, pharmacy only and unscheduled medicines are collectively known as over-the-counter (OTC) medicines.

The use of NSAIDs at prescription-only dosages is known to increase the risk of hypertension, heart failure, myocardial infarction and stroke. Following a TGA review of the safety of these medicinesin 2005-2006, their Australian Product Information (PI) documents are now required to include appropriate warnings regarding these risks under the heading ‘Precautions’. These cardiovascular risks are also reflected in the Consumer Medicine Information (CMI) documents.Diclofenac is also known to carry a risk of hepatotoxicity (liver damage).

There are several mandatory warnings and other advisory statements that must be included on the labels of OTC products containing diclofenac, ibuprofen or naproxen. All products must include the following warning statements relating to duration of use and concomitant use of multiple pain relievers:

“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

“Unless a doctor has told you to, do not use this product with other products containing [diclofenac/ibuprofen/naproxen], aspirin or other anti-inflammatory medicines or other medicines you are taking regularly.”

However, the required statements currently do not warn of the risk of cardiovascular events andOTC diclofenac products are not currently required to carry a warning statement regarding the risk of liver damage.

To address this, the TGA undertook two reviews - a Review of cardiovascular safety of non-steroidal anti-inflammatory drugs and a Safety review of diclofenac. This summary document provides an overview of the conclusions from these reviews and provides four alternative options to address the risks identified in the reviews. The options put forward focus specifically on strategies to mitigate the risks associated with OTC NSAIDs.

Copies of the Review of cardiovascular safety of non-steroidal anti-inflammatory drugs and Safety review of diclofenac can be found on the TGA website.

2. Cardiovascularrisk review

2.1The review

In early 2012, the TGA commenced an update to its 2005-2006 safety review of NSAIDs. A search of the medical literature published from 2005 onwards was carried out and approximately 200 papers that appeared relevant to the review were identified.

The 49 Australian sponsors of these medicineswere provided with a list of the literature references and invited to provide comment and any additional information that might be of relevance to the Review. Submissions were received from the following:

1.Australian Self-Medication Industry Inc (ASMI)

2.Abbott Australasia Pty Ltd

3.Alphapharm Pty Ltd

4.Boehringer Ingelheim Pty Ltd

5.Novartis Consumer Health Australasia Pty Ltd

6.Novartis Pharmaceuticals Australia Pty Ltd

7.Pfizer Australia Pty Ltd

8.Reckitt Benckiser Pty Ltd

A review of the literature identified through the TGA’s search, other relevant information (such as PI and CMI documents and adverse event reports), and the material submitted by the companies and organisations listed above was undertaken. The reviewers:

1.carried out a literature-based review of the cardiovascular safety of diclofenac, naproxen and ibuprofen and provide a comparative risk-benefitanalysis of these medicineswhen used at the dosages available with and without prescription

2.compared the cardiovascular safety ofdiclofenac, naproxen and ibuprofen with that of the five NSAIDs available only on prescription

3.reviewed the current warnings in the PI and CMI documentsfor all eightNSAIDsand provide advice on the appropriateness, consistency and adequacy of these warnings and any changes that might need to be made

4.provided advice on any changes that might need to be made to the warnings on the labels for OTC products containing diclofenac, naproxen and ibuprofen.

The reviewincluded a number of recommendations for changes to the PI documents and labels of the different medicines reviewed. Specifically that:

1.all eight NSAIDs reviewed are associated with significantly increased risks of stroke, heart attack or other cardiovascular events and they should be used with caution in patients with predisposing cardiovascular risk factors

2.there is a need for more awareness amongst health professionalsand patients regarding the cardiovascularrisks associated with all NSAIDs

3.the cardiovascularrisks and necessary precautions are described in the current PIs, but there is a need for greater consistency in the wording used and for prescribers to be made more aware of the importance of assessment of risks in each individual patient, the increased risk of cardiovascular events (especially in patients with prior cardiovascular disease or cardiovascular risk factors) and the need for periodic assessment to detect any signs or symptoms indicating cardiovascular events associated with NSAID treatment

4.nomajor changes to the availability of OTC NSAIDs (diclofenac, ibuprofen and naproxen) are needed. These medicinesprovide effective pain relief when used according to the label at recommended doses for short durations

5.the risk of gastrointestinal bleeding is well covered in thelabels for OTC products

6.there is a need to increase consumer awareness about the cardiovascular risks associated with these medicinesthrough additional and stronger label warnings about those risks via amendments to the Required Advisory Statements for Medicine Labels (RASML). The addition of the following information and warnings to the labels of OTC NSAIDs would help to ensure safer use.

1. ‘NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.’ [or words to that effect]
2. Stronger reminders that patients with cardiovascular disease and/or cardiovascular risk factors should seek the advice of a health professional before using these NSAIDs. Health professionals and patients should remain alert for cardiovascular events even in absence of previous cardiovascular symptoms. Patients should be informed about signs and/ or symptoms of serious cardiovascular toxicity and the steps to take if they occur.
3. Stronger reminders about limiting the dose and duration of treatment in accordance with the package instructions unless otherwise advised by a health professional.

2.2Request for advice from the Advisory Committee on the Safety of Medicines

Advice on the review was sought fromthe Advisory Committee on the Safety of Medicines (ACSOM) at its meeting on 9 November 2012. The Committee was asked to provide advice on whether the changes to the PI,CMI and product labelling would be sufficient to mitigate the cardiovascular risks identified inthe review.

ACSOM advised that while changes to the PI, CMI and product labelling would be important, labelling changes alone were insufficient to mitigate the risk of adverse cardiovascular events associated with the use of the OTC NSAIDs ibuprofen, naproxen and diclofenac.

The Committee advised that taken in totality, the evidence regarding cardiovascular risks associated with NSAIDs was sufficiently compelling that the TGA should give consideration to other measures to mitigate the risks associated with the use of NSAIDs.Given the safety concerns, the committee supported the need for additional risk mitigation activities to limit OTC NSAID use and raise awareness of the risks associated with the use of these medicines.

With regard to any proposed label changes, ACSOM advised that that any warnings on the labels need to be clear and be understood by consumers who will not be consulting a health professional prior to purchasing these medicines OTC.

ACSOM was particularly concerned that the cardiovascular safety profile of diclofenac appears to be similar to that of other cyclooxygenase-2 (COX-2) inhibitors[1] which are only available on prescription. This, coupled with the additional risks of hepatotoxicity, warrants further consideration. ACSOM advised that the TGA give consideration to undertaking a full risk-benefit review of diclofenac.

2.3Consideration of report by innovator sponsors

In May 2014,following redaction of information identified as commercially confidential, a copy of theReview of cardiovascular safety of NSAIDswas provided to the sponsors responsible for the innovator products for their comment prior to wider consultation with other stakeholders.Several of the sponsors provided comment and, following consideration of those comments, small editorial amendments were made to the review to improve accuracy and clarity. The conclusions and recommendations in the review have not been affectedby those amendments.

3. Safety review of diclofenac

3.1The review

Following consideration of theadvice from ACSOM that the TGA should give consideration to undertaking a further review of diclofenac, aliterature-based review of the safety of diclofenac was commenced. The review included the following conclusions and recommendations.

1.There is no emerging safety information regarding gastrointestinal or hepatic effects. The risk/benefit remains favourable and the PI conveys appropriate warnings/precautions.There is consistent evidence that there is an increased risk of serious cardiovascular events with the use of diclofenac. The overall risk/benefit remains favourable however the PI needs to updated to more appropriately convey the risks. It is recommended that:

–post coronary artery bypass graft pain relief and treatment of severe heart failure be added to the list of contraindications.

–stronger warnings about the cardiovascular risk be added to the precautions together with the need to carefully consider the risks and benefits of treatment in individuals at higher risk of cardiovascular disease.

2.The use of diclofenac as an OTC product for short term use at a low dose remains appropriate. The current RASML for OTC products contain sufficient warnings regarding the potential for gastrointestinal side effects. However they do not contain adequatewarnings about the potential risk of cardiovascular side effects or serious hepatic side effects. The RASML statement‘do not use if you have heart failure’ does not adequately cover the risk to those with heart disease who have not developed heart failure and those at high risk of heart disease. The addition of warnings to convey the risk to those people with heart disease and the risk of serious hepatic side effects is warranted.

3.Based on the available information the risk/benefit profile for topical diclofenac remains favourable. There is a paucity of evidence of serious systemic side effects with topical diclofenac. Despite this relative lack of evidence it is recommended that the CMI or package insert (as appropriate) for topical diclofenac include warnings that systemic absorption is likely and that adverse cardiovascular events have been associated with oral diclofenac.

4.All of the above changes should be communicated via a TGA web statement, a Medicines Safety Update article and liaison with NPS MedicineWise.

3.2Request for advice fromthe Advisory Committee on the Safety of Medicines

Advice was sought from ACSOM on the Safety review of diclofenac at its meeting on 7 March 2014.Specifically, the Committee was asked to provide advice on whether on whether the inclusion of additional warnings on the labels of diclofenac-containing medicines regarding the potential risk of cardiovascular and liver side effects was an appropriate risk minimisation activity, whether ACSOM considered any additional risk minimisation activities should be implemented and the strength of the evidence to support the safety of topical diclofenac products.

The Committeesupported the conclusions and recommendations in the reviewregarding the cardiovascular and hepatotoxicity risks associated with diclofenac. ACSOM agreed that COX-2 inhibitors have a well-established increased risk of adverse cardiovascular events. The committee also agreedthat the elevated risk of cardiovascular events with diclofenac was more comparable to the highly COX-2 selective agents, which are prescription-only medicines.

The committee discussed the results from observational studieswhich showed that the increased cardiovascular risk for diclofenac was not limited to patients with a pre-existing history of heart disease. Patients at risk of heart disease, such as patients with vascular disease risk factors or diabetes, also had an increased risk of cardiovascular events with the use of diclofenac. ACSOM noted that a large proportion of the population has a low to moderate risk of heart disease and as many people at risk of heart disease are undiagnosed or are unaware that they have risk factors, the cardiovascular risks associated with oral diclofenac should be communicated widely to encompass these individuals.

ACSOM advised that the inclusion of additional RASML statements on OTC oral diclofenac products would be an appropriate risk minimisation measure. The committee advised that new statements should convey that the risk applies more broadly than just for those with pre-existing heart disease, and that those at risk of heart disease are also at increased risk.

ACSOM considered that there was a lack of awareness in the general community as to the cardiovascular risk of OTC NSAIDs and in particular, diclofenac. ACSOM advised that the use of publications such as those from NPS MedicineWise and the Medicines Safety Update may increase awareness and correct undue perceptions of safety for these products among health professionals.

With regard to adverse effects on the liver, ACSOM noted that there were no genetic risk factors for liver injury. The committee discussed the putative mechanism by which diclofenac causes adverse liver effects. ACSOM noted that an increased risk of a rise in liver enzymes was observed with diclofenac in comparison with most NSAIDs, however the absolute risk of serious adverse events was low. ACSOM considered that, as diclofenac can be purchased OTC, there is the potential for no, or only limited, monitoring of patients using these products and therefore early signs of hepatotoxicity may be missed.

ACSOM noted that there was a perception that the level of access to the consumer is a direct measure of safety and that the availability of oral diclofenac as an OTC medicine may give a false perception of safety to the general public.