Published: 24 October 2023

Committees

MINUTES OF THE 195th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 195th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

14 September 2023

The one hundred and ninety-fifth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 14 September 2023 at the Ministry of Health. The meeting commenced at 9am and closed at 2.30pm.

MARC MEMBERS PRESENT

Dr C Cameron (Chair)
Ms A Biggs-Hume
Dr C Kenedi
Dr H Wilson
Ms L Carlyon
Dr L Te Karu
Dr M Rademaker
A/Prof M Doogue
Dr R Savage
Dr S Leitch

MARC SECRETARIAT PRESENT

T Coventry (Senior Advisor, Pharmacovigilance)
N Zhong (Senior Advisor, Pharmacovigilance)
L Collings (Senior Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE

S Kenyon (Manager, Clinical Risk Management)
M Storey (Team Leader, Pharmacovigilance)
V Cheer (Senior Advisor, Pharmacovigilance)
J Prankerd (Senior Advisor, Pharmacovigilance)
K Van Bart (Medical Advisor, Clinical Risk Management)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

Dr J Lee (Medical Assessor, CARM)
Dr D Hughes (Chief Medical Officer, PHARMAC)

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. The Chair welcomed H Wilson and S Leitch as new members of the Committee. Apologies were received from L Parkin, A Pomerleau and L McDermott.

1.2 Minutes of the 194th MARC Meeting

The minutes of the 194th meeting were accepted as a true and accurate record of the meeting.

1.3 Potential Competing Interests

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

M Rademaker declared that he has a competing interest and would not take part in discussion or voting for item 3.2.4.

There were no other potential competing interests which were considered likely to influence the discussions or decisions of the MARC at this meeting.

2.0 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

2.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

2.1.1 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 did not consider any of the reports required further action.

2.1.2 Special Populations: Serious Cases Associated with Medicines in Children under 18 years (Causal Cases Only)

Reports of serious cases associated with medicines in children under 18 years were briefly outlined for the Committee.

The Committee did not consider any of the reports required further action.

2.1.3 Special Populations: Serious Cases Reporting Adverse Events Following Immunisation Terms with Vaccines in Children under 18 years

Reports of events occurring in children under 18 years were briefly outlined for the Committee.

The Committee did not consider any of the reports required further action.

2.1.4 Special Populations: Serious Non-Fatal Cases Causally Associated with Critical Terms in Patients Over 80 Years

Reports of events occurring in patients over 80 years were briefly outlined for the Committee.

The Committee did not consider any of the reports required further action.

2.1.5 Causal and Serious Cases in Patients Aged 18 to 80 Years

The Committee did not consider any of the reports required further action.

2.1.6 Special Populations: Cases in patients aged 65 years and over – Ethnicity Māori

Reports of events occurring in patients aged 65 years and over (ethnicity Māori) were briefly outlined for the Committee.

The Committee did not consider any of the reports required further action.

2.1.7 Special Populations: Cases in patients aged 65 years and over – Ethnicity Pacific Peoples

Reports of events occurring in patients aged 65 years and over (ethnicity Pacific Peoples) were briefly outlined for the Committee.

The Committee did not consider any of the reports required further action.

2.1.8 Review of ethnicity as a risk factor for severe cutaneous adverse reactions (SCARs) associated with allopurinol

The Committee noted an analysis of reports of severe cutaneous adverse reactions (SCARs) associated with allopurinol in New Zealand.

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 Oral lidocaine containing products and risks of toxicity in younger children and infants

Background

Previous international regulatory authority safety communications have highlighted reports of serious adverse reactions with use of oromucosal lidocaine-containing products in younger children and infants. In most cases, the product was used incorrectly, or accidental ingestion occurred.

In New Zealand, oromucosal lidocaine-containing products are available over the counter for topical anaesthesia of the mouth and may be used for treatment in younger children and infants.

The available information on the risk of toxicity in younger children and infants with oromucosal lidocaine-containing products was reviewed. The Committee was asked to advise whether any regulatory action is needed to mitigate these risks.

Discussion

The Committee discussed the oromucosal lidocaine-containing products reviewed in the report, including a product for infant teething. The Committee considered that the effectiveness of oromucosal lidocaine products for the management of teething is uncertain. The Committee also considered other products available in New Zealand for infant teething. It was noted that teething causes upset for some children more than a few days at a time and treatment may continue for months.

The Committee agreed that the risk of toxicity from oromucosal lidocaine products in younger children and infants was dose related. The Committee commented on the different strengths of oromucosal lidocaine products available as non-prescription medicines. The Committee considered that the greatest risk of toxicity was due to accidental overdose or when package label instructions where not followed correctly.

The Committee highlighted a need for review of the labelling of these products, including warning statements and maximum doses to ensure these products are used appropriately. The Committee also noted a different analgesic product indicated for teething was recently upscheduled to a pharmacist only classification to mitigate the risks associated with overdose. The Committee also questioned the appropriateness of the current classification for 10% oromucosal lidocaine products. The Committee agreed a review of the classification of oromucosal lidocaine products should be undertaken.

The Committee noted that mandatory warning statements on the label and classification changes is within the remit of the Medicines Classification Committee (MCC), and recommended referral of this issue to this Committee.

Recommendation 1

The Committee recommended that oromucosal lidocaine products be referred to the Medicines Classification Committee (MCC) to review the classification of oromucosal lidocaine products and consider whether mandatory label statements are needed.

3.2.2 DPP-4 inhibitors and GLP-1 receptor agonists and the risk of intestinal obstruction

Background

The available information describing a possible class association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors and intestinal obstruction was reviewed.

The review was triggered by an FDA Newly Identified Safety Signal (NISS) with DPP-4 inhibitors. The scope of this report also considers GLP-1 RAs due to a possible common mechanism.. The Committee was asked to advise whether the data sheets for these medicines should be updated to include this risk and whether any other regulatory action is required.

Discussion

The Committee considered that the effects of GLP-1 receptor agonists on gastrointestinal motility are well understood and that ileus could represent an extreme end of the spectrum of pharmacological effect.

It was considered surprising that the cohort study by Faillie et al found a higher risk of intestinal obstruction with DPP-4 inhibitors than GLP-1 RAs. Given the hypothesised mechanism, it would be expected that the effect would be greater with GLP-1 RAs. It was considered that the study suggests an association but the limitations of the study mean that it should be interpreted with caution.

The Committee noted that terms such as intestinal obstruction and/or ileus are listed in the exenatide product information in New Zealand and in international product information for other GLP-1 RAs. The Committee considered that there is a reasonable likelihood of a class effect and that the New Zealand data sheets for GLP-1 RAs should be aligned with respect to this risk.

The Committee considered that the term ileus is a more specific term that describes the risk more clearly than intestinal obstruction.

The Committee considered that an M2 monitoring communication would be useful to gather further information on whether cases of intestinal obstruction including ileus are occurring in patients treated with DPP-4 inhibitors in New Zealand.

Recommendation 2

The Committee recommended that sponsors be requested to update the data sheets for GLP-1 receptor agonists to list gastrointestinal obstruction including ileus as a class adverse reaction.

Recommendation 3

The Committee recommended that Medsafe publish a monitoring communication to gather more information on a possible association between DPP-4 inhibitors and intestinal obstruction including ileus.

3.2.3 Acetylcholinesterase inhibitors and the risk QT prolongation and Torsades de Pointes

Background

Donepezil, rivastigmine and galantamine are acetylcholinesterase inhibitors (AChEIs) indicated for the treatment of Alzheimer’s disease (AD).

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (EMA’s PRAC) reviewed the risk of QT prolongation and Torsades de Pointes (TdP) with galantamine and donepezil. The European product information for these products were updated with information on QT prolongation and TdP.

The New Zealand rivastigmine (Exelon) data sheet contains information on the risk of QT prolongation and TdP. The current donepezil and galantamine data sheets do not have this information. The Committee was asked to advise whether the risk of QT prolongation and TdP can be considered a class effect for AChEIs and if the data sheets for all remaining AChEI medicinal products should be updated.

Discussion

The Committee agreed that the available evidence supports a relationship between AChEIs as a class and QT prolongation and Torsade de Pointes. It was considered that the data sheets should be updated to include this risk.

Recommendation 4

The Committee recommended that sections 4.4 and 4.5 the data sheets for AChEIs should be updated to describe the risks of QT prolongation and Torsade de Pointes.

3.2.4 Isotretinoin – psychiatric disorders and sexual dysfunction

[M Rademaker left the meeting for the duration of this item.]

Background

 A report on the risk of psychiatric and sexual adverse effects of isotretinoin was recently produced by the Commission on Human Medicines (CHM) who provided independent expert advice to the Medicines and Healthcare products Regulatory Agency (MHRA)recommending the introduction of new safety measures in the United Kingdom (UK).

The available information on oral isotretinoin and the risk of psychiatric disorders and sexual dysfunction was reviewed. The Committee was asked to advise whether further regulatory action is required.

Discussion

The Committee considered that the concerns around psychiatric disorders have arisen mostly as a result of surveys rather than scientific studies. It was noted that psychiatric conditions such as depression are common and will occur coincidentally in people taking isotretinoin. The association between isotretinoin and psychiatric disorders has been well-studied and a drug-attributable effect has not been established. It was also noted that the doses used in New Zealand are different to those used overseas and which may mean the risk is different in the New Zealand context.

It was considered important to assess mood where this is indicated, but this was not considered to be more important in patients taking isotretinoin than the many other medicines that may impact mood.

There was concern that the data sheet warning was strong and not justified by the weak evidence. The possibility of undue emphasis on this potential risk detracting from important safety concerns such as risks in pregnancy was acknowledged. The Committee considered that the wording of the warnings in the data sheet should be modified to replace the term ‘psychotic symptoms’ with ‘behavioural disorders and irritability’ and the term ‘suicide’ should be replaced with ‘suicidality’.

The Committee considered that the characterisation of psychiatric risks in the Consumer Medicines Information could be improved but extensive editing of this information is out of the remit of the Committee and the responsibility for this lies with the sponsor.

With regard to sexual dysfunction, the Committee also noted that the evidence is not strong. It is difficult to routinely screen for sexual dysfunction in the younger population that is treated with isotretinoin.

The Committee stated that the mucocutaneous effects of isotretinoin are well known and that vulvovaginal dryness should be listed as an adverse effect in the data sheet and Consumer Medicines Information. The Committee did not consider that the evidence was sufficient to include other adverse sexual disorders or additional warnings in the data sheet.

The Committee noted that the dosage information in the data sheet is different to clinical practice in New Zealand. The Committee considered that the sponsor should be asked to review the dosing information in the data sheet with respect to local guidelines.

Recommendation 5

The Committee recommended removing the term ‘psychotic symptoms’ from the warning in section 4.4 of the data sheet and replacing it with ‘behavioural disorders and irritability’. The Committee recommended removing the term ‘suicide’ from the warning in section 4.4 and replacing it with ‘suicidality’. The language in section 4.8 should be aligned with section 4.4.

Recommendation 6

The Committee recommended adding vulvovaginal dryness as an adverse reaction to section 4.8 of the data sheet and the Consumer Medicines Information.

Recommendation 7

The Committee recommended that the sponsor be asked to review the dosing information in the data sheet with respect to local guidelines.

4.0 MEDSAFE PHARMACOVIGILANCE ACTIVITIES

4.1 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

4.2 Medsafe Pharmacovigilance Activities

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

4.3 Prescriber Update Volume 44, Number 3, September 2023

The Committee noted the latest edition of Prescriber Update.

4.4 Quarterly Summary of Medsafe Safety Communications

The Committee noted the quarterly summary of Medsafe safety communications.

5.0 OTHER BUSINESS

5.1 Clozapine survey

The Committee was updated on the progress of the survey being conducted by Medsafe on clozapine use in New Zealand.

5.2 Pharmacovigilance database

The Committee was updated on the implementation of the new pharmacovigilance database.

5.3 Therapeutics legislation

The Committee was updated on the process for developing secondary legislation after the Therapeutics Act was passed.

The Committee thanked the Chair for her excellent contributions to the Committee. The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2.30 pm.

Dr Chris Cameron
Chair, Medicines Adverse Reactions Committee
Date 11 October 2023

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