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Published: 7 July 2015

Committees

Minutes of the 162^nd Medicines Adverse Reactions Committee Meeting - 11 JUNE 2015

1.0 MATTERS OF ADMINISTRATION
2.0 MEDSAFE PHARMACOVIGILANCE ACTIVTIES
3.0 PHARMACOVIGILANCE ISSUES
- 3.1 Matters Referred to the MARC under Section 36 of the Medicines Act 1981.
- 3.2 Matters Referred to the MARC by Medsafe.
4.0 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE
- 4.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports.
5.0 OTHER BUSINESS
- 5.1 Therapeutic products regulatory regime project
6.0 ANNEXES

MINUTES OF THE 162^ND MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

11 June 2015

The one hundred and sixty-second meeting of the Medicines Adverse Reactions Committee (MARC) was held on 11 June 2015 at The Rydges, 75 Featherston Street, Pipitea, Wellington, New Zealand. The meeting commenced at 9 am and closed at 2.30 pm.

MARC MEMBERS PRESENT

Dr P Jones (Chair)
Dr L Bryant
Dr N Cole
Professor C Frampton
Dr S Jayathissa
Associate Professor D Menkes
I Raiman
C Ryan
J Tatler
Dr M Tatley
Dr K Wallis

MARC SECRETARIAT PRESENT

L Chan (MARC Secretary, Medsafe)

MEDSAFE STAFF IN ATTENDANCE

R Jaine (Principal Clinical Advisor)
C James (Manager, Clinical Risk Management)
S Kenyon (Principal Technical Specialist, Pharmacovigilance)
R Pollock (Senior Advisor, Pharmacovigilance)
J Prankerd (Advisor, Pharmacovigilance)
S Stubbs (Advisor, Pharmacovigilance)

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Associate Professor D Reith and Dr K Eggleton.

1.2 Minutes of the 161^st MARC Meeting

The minutes of the 161^st meeting were accepted as a true and accurate record of the meeting.

1.3 Potential Conflicts of Interest

Committee members submitted their Conflicts of Interest Declaration forms to the Secretary. The Chair reminded the MARC members that in addition to conflicts disclosed in the declaration forms, members should declare conflicts of interest at the commencement of discussion of any relevant agenda item.

There were no potential conflicts of interest which were considered likely to influence the discussions or decisions of the MARC at this meeting.

2.0 MEDSAFE PHARMACOVIGILANCE ACTIVITIES

2.1 Report on Standing Agenda Items from Previous Meetings of the MARC

The Committee reviewed the list of outstanding recommendations made by the MARC at previous meetings. Background information on these issues can be found in the minutes of previous MARC meetings on the Medsafe website: www.medsafe.govt.nz/profs/MARC/Minutes.asp

[Professor C Frampton and I Raiman joined the meeting at this time.]

2.2 Medsafe Pharmacovigilance Activities

The Committee noted the report detailing Medsafe's recent pharmacovigilance activities.

2.3 Prescriber Update Volume 36, Number 2, June 2015

The Committee noted the titles of the articles in the latest edition of Prescriber Update.

2.4 Quarterly Summary of Medsafe Early Warning System

The Committee noted the quarterly summary of Medsafe early warning system communications.

3.0 PHARMACOVIGILANCE ISSUES

3.1 Matters Referred to the MARC under Section 36 of the Medicines Act 1981

No items

3.2 Matters Referred to the MARC by Medsafe

3.2.1 Pioglitazone and bladder cancer

Background

The potential for pioglitazone to cause bladder cancer was identified in pre-clinical studies prior to approval and closely monitored post-marketing. In 2011 the MARC reviewed the available data worldwide and considered that the data sheets should be updated to include further information on this risk.

A substantial number of new studies have been published since the last MARC review. The manufacturer Takeda also announced the conclusion of the Kaiser-Permanente study, stating that the 10 year results showed no association.

Therefore, this issue was re-presented to the MARC for further advice.

Discussion

The Committee discussed the available studies investigating this risk. The available studies include observational studies, meta-analyses and randomised controlled trials.

It was noted that ascribing a causal effect from observational studies is challenging due to confounding by indication (diabetes could be associated with bladder cancer), and other confounders including age, gender and smoking status. The majority of these studies obtain data on the use of pioglitazone through prescription databases where doses and actual intake are not available. There are long latency periods both for the development of cancer and the initiation of treatment for diabetes with pioglitazone (normally initiated third-line).

Studies included in each meta-analysis were consistent between different meta-analyses but the lack of consistent results made it difficult to draw a conclusion. The randomised-controlled trials did not necessarily include cancer as an outcome of interest and it was unclear whether these outcomes were actively sought in the trials. In addition, these trials were small and lacked power to make conclusions on this outcome measure.

The Committee concluded that these studies showed evidence of an association between pioglitazone and bladder cancer. However, there was insufficient evidence to conclude that this is a causal effect. The Committee agreed that the data suggested it was unlikely that pioglitazone was a cancer inducer.

The Committee discussed if any additional monitoring of bladder cancer should be undertaken during treatment with pioglitazone and concluded that there was insufficient evidence to provide any specific advice on monitoring for this risk.

The Committee considered that the current information on bladder cancer in the warnings and precautions section of the pioglitazone data sheet is sufficient. The Committee considered that as there is no change to the information on this risk, no further communication is required at this stage.

Recommendation

The Committee recommended that no further action or advice is required regarding the risk of bladder cancer with use of pioglitazone.

3.2.2 Consumer reporting of adverse drug reactions

Background

Traditionally, spontaneous reporting of adverse drug reactions (ADRs) has been the domain of healthcare professionals. However, more countries are encouraging consumers to directly report ADRs. While consumers can report ADRs in New Zealand, there is no specific reporting scheme and consumers are not specifically encouraged to report ADRs.

The purpose of this paper was to seek input and advice from the Committee about direct reporting of ADRs by consumers. This includes input about what should be included in the consumer reporting form, how this reporting scheme should be communicated to consumers and what other information may be needed such as a consumer survey investigating the awareness of ADR reporting.

Discussion

The Committee agreed that consumer reporting of adverse drug reactions (ADRs) is important and complements reports received from healthcare professionals. It was noted that internationally consumer ADR reporting is growing and New Zealand should further engage with this movement.

Consumers tend to provide more subjective information which helps to understand the impact an ADR has on daily life and quality of life. Other positive benefits of direct ADR reporting by consumers include the earlier accumulation of reports covering a wider spectrum of suspected reactions. The Committee noted that consumers have multiple motivations for reporting ADRs and it is important that these are considered when interpreting the reports.

The Committee considered that the structure of the system is important. An online reporting form would be useful for consumers and could assist with the processing of a report. It was noted that consumer action groups have used the reporting system in the past.

The Committee discussed the importance of not excluding consumers with poor health literacy. Ensuring multiple methods of reporting are available (online, written, phone etc.) and encouraging assistance from a healthcare professional in completing a form may manage these concerns.

Consumers need to have a clear understanding of the impact that their reports can have and the range of action that may be taken. This will help to manage expectations and could be achieved through regular feedback (eg, yearly) on the value and contribution of consumer reports. In addition, it is important that consumers are directed to other sources of information such as online health forums (eg, healthtalk.org) and that further medical advice should be sought from their healthcare professional.

The Committee discussed patient portals - where patients are able to access their health records online - and how this could improve the quality and level of detail of reports. The ability for a consumer to access a pre-populated electronic reporting form through the portal was considered useful and could be investigated further.

Reports received from consumers to date have indicated that consumers are agreeable for contact to be made with their healthcare professional for further information to be obtained if required.

The Committee noted that the current service and response provided to each reporter is personalised and this interaction is valuable. However, the Committee discussed if the level of response currently provided would be feasible long-term. The Committee considered that any duplicate reports (ie, from both the healthcare professional and the consumer) could be easily identified and matched.

The Committee was given an explanation of how the increase in the number of reports may impact on the current reporting system and the available resource for this. It was noted that reporting was likely to have an incremental rather than a sudden increase.

The promotion of consumer reporting should be focussed on the positives and the potential benefits for the healthcare system. This includes promotion to both consumers and healthcare professionals to emphasise that this is a collaborative approach and ultimately enhances medicines safety and public health. The Committee considered that reports of ADRs to over the counter and complementary medicines should be encouraged as reports to these medicines are currently lacking.

The Committee considered that a pilot should be undertaken. This pilot can be broken down into different stages with each stage focussing on particular aspects of reporting. For example, the form can be tested in one stage to test if it is readable and understandable, then a second stage can test promotional activity. Focus groups with various consumer groups could also be valuable.

Recommendation

The Committee recommended that a pilot is undertaken for the various steps involved in consumer reporting of adverse drug reactions.

Recommendation

The Committee recommended that promotion of adverse drug reaction reporting to healthcare professionals should continue and include the value of consumer reporting.

3.2.3 Statin-associated autoimmune myopathy

Background

Statins have been associated with myalgia, myopathy, myositis and rhabdomyolysis. These musculoskeletal effects are usually self-limiting and mostly resolve when the statin is stopped. In contrast, there are a small number of patients who develop an autoimmune myopathy characterised by progressive muscle weakness, elevated muscle enzymes, specific antibodies against the target of statins, and progression of signs and symptoms even when the statin is stopped.

The purpose of this paper was to review the available information on statin-associated autoimmune myopathy.

Discussion

The Committee noted that polymyositis, which is a well-recognised type of autoimmune myopathy, would present very similarly to statin-associated autoimmune myopathy. While many autoantibodies have been reported to be associated with polymyositis, only anti-Jo-1 is routinely available. The committee was uncertain if testing for antibodies to HMG-CoA reductase is easily available. The treatment for polymyositis with glucocorticoids and immunosuppressive medicines is also very similar to the treatment for statin-associated autoimmune myopathy. These clinical, diagnostic and therapeutic factors taken together indicate a possibility that statin-associated autoimmune myopathy is under-recognised.

The Committee discussed statin-associated autoimmune myopathy in the context of general myalgia symptoms that are well known to occur with statin treatment. Elderly patients who are prescribed statins may experience profound muscle weakness resulting in falls. It was noted that any complaint of muscle problems from a patient treated with statins would involve stopping the statin. Further investigation including checking creatine kinase (CK) levels, would occur if symptoms did not resolve with stopping the statin alone.

The Committee noted that information on statin-associated autoimmune myopathy in the various data sheets for statins are not consistent. The Committee considered that although statin-associated autoimmune myopathy is very rare, information on this risk should be communicated within the context of general myalgia symptoms with statin treatment.

Recommendation

The Committee recommended that Medsafe request the sponsors of atorvastatin, simvastatin, and pravastatin to update their data sheets so that information on statin-associated autoimmune myopathy is consistent across all statin data sheets.

Recommendation

The Committee recommended that Medsafe includes an article on muscle effects with statin treatment in a future edition of Prescriber Update.

4.0 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

4.1.1 Fatal Cases (Causal Cases Only)

Members were given a brief description of the fatal reports for which CARM had assessed the causality to be at least possible.

The Committee discussed case 114877 regarding gentamicin and the aggravation of renal failure in an elderly patient. The Committee noted that the Health Quality and Safety Commission (HQSC) is following up on this case.