Published: 5 September 2023

Committees

MINUTES OF THE 194th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 194th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

8 June 2023

The one hundred and ninety fourth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 8 June 2023 in person at the Ministry of Health, 133 Molesworth Street, Wellington, and via videoconference. The meeting commenced at 9am and closed at 12:30 pm.

MARC MEMBERS PRESENT

Dr, C, Cameron (Chair)
Prof, L, Parkin
A/Prof, M, Doogue
A/Prof, A, Pomerleau
L, Carlyon
Dr, L, Te Karu
L, McDermott
A Biggs-Hume
Prof, M, Tatley
Dr M, Rademaker
Dr, C, Kenedi

MARC SECRETARIAT PRESENT

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

MEDSAFE STAFF IN ATTENDANCE

Dr, S Kenyon, PhD, Manger Clinical Risk Management
M, Storey, Team Leader Pharmacovigilance
V, Cheer, Senior Advisor (Pharmacovigilance)
J, Prankerd, Senior Advisor (Pharmacovigilance)
S, Tran, Advisor (Pharmacovigilance)
K, Van Bart, Medical Advisor, Clinical Risk Management
T, O’Flynn, Medical Advisor, Clinical Risk Management
T, Keats, Advisor (science), Product Regulation Branch
A, Weil, Senior Advisor, Compliance Management Branch

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Dr S Hanna.

1.2 Minutes of the 193rd MARC Meeting

The minutes of the 193rd 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.

Dr, M, Rademaker declared a potential competing interest to item 3.2.1. The competing interest did not impact Dr, M, Rademaker from discussions or voting on the 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 (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

Reports of events occurring in patients aged 18 to 80 years were briefly outline for the Committee.

The Committee were concerned to note two reports of Fournier’s gangrene associated with empagliflozin, particularly as other cases have been presented at previous meetings. The Committee were provided an update about Fournier’s gangrene cases reported with empagliflozin to CARM.

The Committee commented on two reports of anaphylaxis with ferric carboxymaltose, CARM ID 146600, 146821. The Committee discussed whether the rate of infusion was a factor in these cases. The Committee considered that rate related infusion reactions can also occur with other medicines, in particular antibiotics and chemotherapy. The Committee recommended that Medsafe write a Prescriber Update article about infusion related reactions.

Recommendation 1

The Committee recommended that Medsafe write a Prescriber Update article about infusion related reactions.

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.

2.2 Centre for Adverse Reactions Monitoring (CARM) Annual Fatality Report

The Annual Fatality Reports for 2021 and 2022 were briefly outlined for the Committee.

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

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 Molnupiravir: review of efficacy information

Background

In February 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency recommended the refusal of the marketing authorisation for molnupiravir (Lagevrio).

The CHMP concluded that the clinical benefit of molnupiravir in the treatment of adults with coronavirus disease (COVID-19) who are not receiving supplemental oxygen, and who are at increased risk of developing severe COVID-19, could not be demonstrated.

The Committee was asked to advise whether the evidence for efficacy is strong enough to support the current approved indication of molnupiravir.

Discussion

The Committee discussed the information presented for molnupiravir efficacy. The Committee discussed the outcome of the PANORAMIC trial and results subsequent from observational studies included in the report. The Committee highlighted that while the PANORAMIC trial did not suggest that molnupiravir is efficacious in preventing hospitalisation and/or death from COVID-19, it may be beneficial in reducing symptom severity, reducing viral load, and accelerating recovery time.

The Committee commented on the lack of information available in Māori and Pacific peoples, and individuals with multiple comorbidities.

The Committee considered that overall, molnupiravir may have some benefit in reducing symptom severity, reducing viral load, and accelerating recovery time. This was consistent across the studies. The Committee agreed that molnupiravir appears to be less effective than nirmatrelvir/ritonavir (Paxlovid) for the treatment of the current variants of concern (VOC) of COVID-19.

The Committee acknowledged that some individuals may not be able to safely take Paxlovid or have access to remdesivir, other treatment options for COVID-19. Molnupiravir may be a treatment option in these circumstances. The Committee discussed the safety profile of molnupiravir, and that it is generally well tolerated.

The Committee considered the ever-changing COVID-19 environment, including variant strains, and how new evidence on treatments is emerging rapidly.

The Committee agreed that the available evidence on the efficacy of molnupiravir supports its current indication for the treatment of mild-to-moderate COVID-19 disease in adults aged 18 years and over who are at increased risk of progressing to severe COVID-19, hospitalisation, or death.

No further action is needed at this time.

3.2.2 Safety and efficacy of pholcodine

Background

In December 2019, the Committee reviewed the risks and benefits of pholcodine. At that time, the Committee considered that the risk-benefit balance of pholcodine was marginal but there was insufficient evidence to indicate an unfavourable risk-benefit balance. The available evidence on the association between prior pholcodine exposure and an increased risk of anaphylaxis with neuromuscular blocking agents (NMBA) was included in this review.

In 2022, the results of this case-control study (ALPHO study) became available. The results of the ALPHO study together with a more recent observational study by Sadleir et al (2021) prompted regulators in Europe, United Kingdom, Australia and Malaysia to withdraw pholcodine-containing medicines from the market.

Considering the latest information, the Committee was asked to review the safety and efficacy of pholcodine under Section 35 of the Medicines Act 1981

Discussion

The Committee noted actions taken by other regulators regarding pholcodine. The Committee noted there is large use of pholcodine in New Zealand.

The Committee discussed the safety profile of pholcodine, in particular the updated safety information on prior pholcodine exposure and an increased risk of anaphylaxis with NMBAs. The Committee noted the evidence of an ecological association, where the number of reports of NMBA-related hypersensitivity declined following the withdrawal of pholcodine in Norway.

The Committee commented that identifying potential cases of NMBA-related anaphylaxis from prior pholcodine use is difficult in spontaneous reports. Details about previous pholcodine consumption might not have been included. The Committee discussed how individuals who experience an anaphylaxis reaction during surgery are generally sent for immunological testing to identify the potential medicine, of which the results are usually reported to CARM. Pholcodine immunoglobulin E levels may be tested. However, it might not be clear if NMBA has sensitised the patient to pholcodine or the other way round.

The Committee acknowledged that cross-sensitisation from pholcodine was of particular concern for anaesthetists. Establishing prior pholcodine consumption in patients needing acute unplanned surgery would be difficult. The Committee also acknowledged patients may not recall previous pholcodine consumption.

The Committee noted that no new efficacy information was available since the previous discussion by the Committee in 2019. The Committee noted that a dry cough is self-limiting, and likely improves regardless of pholcodine use, and that other non-pharmacological options may also be used. The Committee agreed that the available efficacy data was limited.

The Committee considered other treatment options for dry cough such as dextromethorphan and non-pharmacological options. The Committee acknowledged general practice feedback that a severe dry cough, especially at night, can be extremely unpleasant, especially in those with comorbidities. The Committee commented on potential concerns with dextromethorphan use, and the importance of pharmacist consultation to reduce known risks. Non-pharmacological treatments may be an option for a mild transient cough, however, may represent an equity issue. The Committee recommended that Medsafe contact Best Practice Advocacy Centre (Bpacnz) to write an article about the management of dry cough.

Overall, the Committee considered there was evidence of an association between pholcodine use and an increased risk of anaphylaxis from NMBA administration. Whilst the risk of anaphylaxis may be small, it can be a serious and life-threatening event. Risk minimisation measures proposed by the company were not considered to manage this risk.

The Committee recommended to the Minister’s delegate that the consent for pholcodine be revoked due to safety concerns under Section 35 of the Medicines Act 1981.

The Committee recommended that Medsafe communicate any regulatory action, in particular to consumers.

The Committee did not consider this issue required a medicine recall.

Recommendation 2

The Committee recommended to the Minister’s delegate that the consent for pholcodine is revoked under Section 35 of the Medicines Act 1981.

Recommendation 3

The Committee recommended that Medsafe communicate any regulatory action, in particular to consumers.

Recommendation 4

The Committee recommended that Medsafe contact Best Practice Advocacy Centre (Bpacnz) to write an article about management of dry cough in primary care.

3.2.3 Epidyolex (cannabidiol) Risk Management Plan

Background

The Committee were presented the Risk Management Plan (EU, version 0.1) for Epidyolex.

Epidyolex is an approved medicine indicated for use as adjunctive therapy of seizures associated with Lennox-Gastraut syndrome (LGS) or Dravet syndrome (DS) in individuals 2 years of age and older.

The Committee was asked whether the Risk Management Plan, pharmacovigilance, and risk minimisation activities are sufficient, if any elements require clarification, and if there are further questions that Medsafe should ask the sponsor relating to Epidyolex.

Discussion

The Committee commented on the ethanol content in Epidyolex, and whether the company had explored possible alternative formulations.

Ethanol content in medicines may pose risks to young children. The Committee discussed that alcohol consumption in children may result in hypoglycaemia and that this should be included in a warning relating to ethanol content in the data sheet.

The Committee noted the risk of hepatotoxicity with this medicine, but considered that the ongoing monitoring and risk minimisation measures were appropriate.

The Committee were concerned that the potential risk of urinary retention was not included in the data sheet.

The Committee agreed that Medsafe should refer the Risk Management Plan back to the Committee if there any changes relating to the approved indication.

Overall, the Committee were satisfied with the Epidyolex Risk Management Plan and Medsafe’s questions to the sponsor.

3.2.4 Pericarditis following mpox vaccination

Background

Medsafe were alerted to two suspected adverse drug reaction (ADR) reports of pericarditis following vaccination against monkeypox (mpox). In March 2023, Medsafe published a monitoring communication to encourage reporting of any ADRs following mpox vaccination.

The purpose of this paper is to provide the MARC with an update on the signal investigation.

Discussion

The Committee noted the signal investigation report and agreed with Medsafe’s plan to continue monitoring this safety concern.

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 2, June 2023

The Committee noted the latest edition of Prescriber Update.

The Committee were provided an update on a new section of Prescriber Update, ‘recent data sheet updates: important new safety information’.

4.4 Quarterly Summary of Medsafe Safety Communications

The Committee noted the quarterly summary of Medsafe safety communications.

5.0 OTHER BUSINESS

5.1 End of term for Dr S Hanna

The Committee were informed that Dr, S, Hanna term on the Committee is near completion.

The Committee thanked Dr, S, Hanna for his contribution and commitment to the Committee as an urban general practitioner member.

5.2 Therapeutics Products Bill

The Committee discussed the progress of the Therapeutics Products Bill and requested an update at the next meeting from the ministry policy team.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 12:30 pm.

Dr Chris Cameron
Chair, Medicines Adverse Reactions Committee
Date 28 June 2023

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