Published: 4 December 2024

Committees

MINUTES OF THE 199th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 199th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

18 November 2024

Secretariat note regarding the recommendation for agenda item 3.2.2: Medsafe has not currently accepted the recommendation to update the zopiclone data sheet as no evidence for this medicine was presented at the meeting. Medsafe will review the available information on zopiclone before considering this recommendation.

12 September 2024

The one hundred ninety-nine meeting of the Medicines Adverse Reactions Committee (MARC) was held on 12 September 2024 at the Ministry of Health, Wellington. The meeting commenced at 9am and closed at 2pm.

MARC MEMBERS PRESENT

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

MARC SECRETARIAT PRESENT

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

MEDSAFE STAFF IN ATTENDANCE

S Kenyon (Manager, Clinical Risk Management)
M Storey (Team Leader, Pharmacovigilance)
L Chan (Principal Technical Specialist, Pharmacovigilance)
V Cheer (Senior Advisor, Pharmacovigilance)
S Tran (Senior Advisor, Pharmacovigilance)
J Park (Advisor, Pharmacovigilance)
Dr K Van Bart (Medical Advisor)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

Dr J Lee (Medical Assessor, Centre for Adverse Reactions Monitoring)
Dr A Hynes (Medical Assessor, Centre for Adverse Reactions Monitoring)
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 Dr A Barrett as a new specialist clinician member of the Committee and announced the appointment of Prof L Parkin as the Director of the New Zealand Pharmacovigilance Centre. A/Prof A Pomerleau was reappointed for a further term.

1.2 Minutes of the 198th MARC Meeting

The minutes of the 198th 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. 

There were no 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

Members were given a brief description of fatal reports received in the last quarter.

The Committee noted report 157198 involving a non-specified lung injury with methotrexate. Given the recent attention on drug-induced pneumonitis, the Committee recommended that Medsafe write a Prescriber Update article on pneumonitis, its aetiology and medicines known to increase the risk of pneumonitis.

2.1.2 Serious cases associated with medicines

Reports of serious cases associated with medicines, allergy reports and brand switches, were briefly outlined for the Committee.

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

2.1.3 Serious cases associated with vaccines

Reports of serious cases associated with vaccines were briefly outlined for the Committee.

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

Recommendation 1

The Committee recommended that Medsafe highlight pneumonitis, and medicines known to cause pneumonitis in Prescriber Update.

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 Review of clozapine safety and monitoring requirements: clozapine-induced neutropenia and agranulocytosis

Background

Clozapine is a second generation (also called atypical) antipsychotic medicine indicated for treatment resistant schizophrenia and those intolerant of other antipsychotic medicines.

While many people experience significant benefits from clozapine, treatment can also cause significant adverse effects. There are haematological monitoring requirements for clozapine to manage the risk of neutropenia (including agranulocytosis) which were put in place when the medicine was reintroduced to the market.

Regular monitoring of blood cell counts is mandatory throughout clozapine treatment in New Zealand due to the risk of clozapine-induced neutropenia, agranulocytosis and consequent infection.

The purpose of this paper was to provide information about (1) the haematological adverse effects of clozapine (focus on neutropenia and agranulocytosis) and (2) the required haematological monitoring as part of a review of clozapine safety and monitoring requirements. 

Discussion

The Committee noted the international regulatory history of clozapine which is different to many other medicines. Clozapine was withdrawn from the market during the 1970s due to deaths from sepsis consequent to neutropenia (including agranulocytosis). Clozapine was later reintroduced and approved by regulatory authorities following clinical trials showing efficacy in schizophrenia. In order to manage the safety risk, blood monitoring for all patients was mandated in countries who approved clozapine use. The Committee stated that they considered that the mandatory blood monitoring requirement has created barriers for people to start or continue clozapine treatment.

The Committee noted how the current requirement for mandatory blood monitoring for clozapine in New Zealand is a condition of the approval under the Medicines Act 1981.

The Committee highlighted the efficacy of clozapine. The Committee commented that they considered clozapine to be the most effective of the currently available antipsychotics. The Committee observed that in their opinion despite the patient group who take clozapine having more severe illness, patients who start on clozapine have comparable or better outcomes than other patients treated with other antipsychotics. The Committee also considered that for patients with ‘negative symptoms’ clozapine is regarded by psychiatrists as the most effective antipsychotic. The Committee commented that in their view in New Zealand, people start on clozapine later than in some other countries.

The Committee noted Medsafe’s Clozapine Consultation 2023, which gathered information about peoples’ experiences with clozapine use in New Zealand. This included some respondents who take clozapine stating that they would not make any changes to the blood monitoring requirements. The Committee noted that people who take clozapine may appreciate the reassurance that regular blood monitoring provides and regular interaction with the health system that comes with it.

The Committee noted that patients treated with clozapine, or who are not treated and might benefit, are a particularly vulnerable population. The committee also noted that many patients with schizophrenia are successfully treated and are living full lives.

The Committee commented on difficulties the health system has relating to the blood monitoring requirements. People living in more remote areas may find it hard to access blood monitoring services. The committee noted several respondents to the clozapine consultation had commented that clozapine cannot be supplied until the blood test results are loaded into the patient monitoring system which can cause difficulties. It was also acknowledged that the current very strict requirements can cause problems for both patients and pharmacists.

The Committee discussed that there was a need to recognise that there are also risks of not starting patients on clozapine and using a different antipsychotic as the alternative treatment may not provide the same level of benefit. The committee discussed that management needs of individuals’ risk of side effects vary by circumstance. The Committee discussed experiences with managing the risk of side effects for patients in a wide range of settings.

The Committee noted that other medicines which can cause neutropenia/agranulocytosis do not have mandated monitoring requirements. The Committee commented on the need for mandated requirements versus clinical guideline. A question was raised as to the legal situation of the mandated requirements.

The Committee discussed the evidence that the risk of neutropenia leading to infection is highest early in treatment and decreases over time. In the current monitoring requirements, weekly blood monitoring for the first 18 weeks is mandated. The optimal duration and frequency of monitoring for safety is unclear. The Committee decided that if changes to the existing monitoring schedule are proposed, further expert advice should be sought from relevant specialists, including haematologists and psychiatrists.

The Committee speculated on whether monitoring could include other methods, for example reactive testing to patient symptoms such as fever, sore throat. The committee noted the importance of managing the risks of other clozapine adverse effects, such as constipation and myocarditis, rather than blood tests.

The Committee also wondered whether any changes should take place over a period of time, or all at once.

The Committee noted that the FDA are having an upcoming meeting about clozapine monitoring and the outcome of this meeting should be considered in New Zealand before any changes are made as it may provide additional information.

The Committee agreed that Medsafe should seek further expert advice on blood monitoring requirements for clozapine before any changes could be proposed.

3.2.2 Use of benzodiazepines for non-epilepsy indications during pregnancy and the risk of miscarriage

[Dr M Rademaker was absent for agenda items 3.2.2 and 3.2.4]

Background

An article on the use of benzodiazepines during pregnancy and risk of miscarriage was recently published in JAMA Psychiatry by Meng et al. This was a nationwide, population-based, case-time-control study conducted in Taiwan. Considering the complexity of the data, Medsafe decided to seek expert advice from the Committee.

Benzodiazepines have been available in New Zealand for many years. Benzodiazepines are used in the treatment of severe anxiety, severe insomnia, as a pre-medicant, and in epilepsy.

This review focuses on the use of benzodiazepines during pregnancy for the treatment of non-epilepsy indications and the risk of miscarriage.

The Committee was asked to comment on the strength of the evidence for an association between benzodiazepines included in the review and the risk of miscarriage.

Discussion

The Committee noted that the findings from Meng et al showed an increased risk of miscarriage from benzodiazepine exposure in pregnancy. The strengths of the study included:

  • The case-time-control series was an appropriate study design to address the study question.
  • More than one source was used to minimise the misclassification of cases and exposure.
  • The findings were consistent across their primary and sensitivity analyses.
  • Use of a negative control period.
  • Confounders were appropriately controlled.

The committee noted that the results are consistent with other studies.

The Committee noted the lack of local spontaneous case reports of miscarriage from benzodiazepine exposure in pregnancy. This under-reporting is most often seen when a medicine is risk factor rather than ‘causal’. That is one contributor to overall risk rather than a sole cause of an event. Miscarriage is common and there are many factors that can contribute to risk in an individual.

The Committee commented that zopiclone, although structurally different to benzodiazepines, has similar pharmacological properties. Further review is needed to determine if there is a similar risk of miscarriage.

Overall, the Committee considered the findings from Meng et al to be sufficient to require action and recommended benzodiazepine and zopiclone data sheets should include information on the risk of miscarriage when used during pregnancy. In addition, the Committee considered it important that the data sheet also highlights that the risk of miscarriage is also communicated to women who are planning pregnancy.

Recommendation 2

The Committee recommended that the benzodiazepine and zopiclone data sheets are updated with information on the risk of miscarriage.

3.2.3 Anti-CD20 antibodies and pyoderma gangrenosum

Background

In 2023, Medsafe was made aware of requests from international regulators to update product information for anti-CD20 antibodies to include pyoderma gangrenosum (PG). Approved anti-CD20 antibodies in New Zealand are obinutuzumab, ocrelizumab, ofatumumab and rituximab.

The Committee was asked to review the information on PG and the potential association with anti-CD20 antibodies.

Discussion

The Committee noted that PG is a rare disease that can be difficult to diagnose, potentially leading to inappropriate treatment and/or treatment delays.

The Committee discussed the PG cases reported in the literature and in pharmacovigilance databases. Rituximab and ocrelizumab were the most frequently reported anti-CD20 medicines. Reporting rates across the class appear proportionate to use. Cases were predominately in females in their fifth decade, involving the vulvovaginal area. There were insufficient information to identify other relevant risk factors.

The median time to onset of symptoms was approximately 3 years after the start of treatment with an anti-CD20 antibody. The Committee commented that this long onset time may contribute to under-reporting of suspected cases. They noted that only a small number of PG cases have been reported worldwide, relative to the amount of use of these medicines such that even after accounting for under-reporting the risk is low.

Given the small number of cases reported and potential confounding by the nature of the patient population, the Committee considered that the current evidence of a causal link between anti-C20 antibodies and PG is weak.

The Committee questioned whether updating the data sheet with information about PG would have an impact on a shorter time to diagnose PG or on decisions to use anti-CD20 medicines. However, they considered that it is important to raise awareness of this possible adverse reaction amongst gynaecologists, as they will likely be seeing patients presenting for a diagnosis. The Committee suggested that a monitoring communication would inform healthcare professionals about PG and encourage reporting of suspected cases.

Recommendation 3

The Committee recommended that Medsafe publish a monitoring communication to gather more information on a possible association between anti-CD20 antibodies and pyoderma gangrenosum.

3.2.4 Empagliflozin and risk factors for ketoacidosis

Background

Ketoacidosis is a known safety concern for empagliflozin and other sodium-glucose cotransporter-2 (SLGT2) inhibitor medicines.

The Centre for Adverse Reaction Monitoring (CARM) and Medsafe have continued to receive several serious case reports of ketoacidosis and diabetic ketoacidosis (DKA) associated with empagliflozin treatment.

On review of these cases, a number present with risk factors that increase the risk of ketoacidosis. In some cases, empagliflozin was continued when risk factors for ketoacidosis were present, and the person developed ketoacidosis.

This review summarises case reports of ketoacidosis and empagliflozin that have been reported to CARM and Medsafe and highlight action to be taken by Medsafe on review of these reports.

Discussion

The Committee noted Medsafe’s review and the proposed actions, including a Prescriber Update article about the topic.

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 45, Number 3, September 2024

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.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2pm.

Associate Professor M Doogue
Chair, Medicines Adverse Reactions Committee
Date:  27 November 2024

Hide menus
Show menus
0 1 2 4 5 6 7 9 [ /