Published 23 December 2022
Revised: 26 April 2023

Committees

MINUTES OF THE 192nd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 192nd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

1 December 2022

Secretary’s note: that A/Prof A Pomerleau was present at the 192nd meeting

The one hundredth and ninety-second meeting of the Medicines Adverse Reactions Committee (MARC) was held on 1 December 2022 in person at the Ministry of Health and via videoconference. The meeting commenced at 9am and closed at 1:40 pm.

MARC MEMBERS PRESENT

Dr C Cameron
Associate Professor L Parkin
L Carlyon
A Biggs-Hume
Dr A Romain
Dr C Kenedi
Honorary Associate Professor M Rademaker
Dr M Tatley

MARC SECRETARIAT PRESENT

T Coventry
N Zhong
L Collings

MEDSAFE STAFF IN ATTENDANCE

S Kenyon
V Cheer
J Prankerd
T Kim
S Tran
M Storey

INVITED GUESTS AND EXPERTS IN ATTENDANCE

W Woodhouse
Dr J Lee
Dr A Hynes

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from S Hanna, M Doogue, L McDermott and L Te Karu. The Chair welcomed the new nurse member, A Biggs-Hume.

1.2 Minutes of the 191st MARC Meeting

The minutes of the 191st 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 (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 raised a concern about the number of digoxin reports over time where the dose appeared to be very high.

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.

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

[Dr C Kenedi joined the meeting at this time]

3.2.1 Cephalosporins and neurotoxicity

Background

Medsafe was notified by a sponsor of a safety and effectiveness review initiated by Health Canada for the cephalosporin product class and the potential safety issue of seizures. The outcome of this review is not yet available.

The available information on cephalosporin-induced neurotoxicity was reviewed. Antibiotics, including cephalosporins have been associated with such adverse effects, however there is limited information in the NZ data sheets.

The Committee was asked to advise whether there is evidence for an association between the entire cephalosporin class and neurotoxicity, and whether section 4.4 and section 4.8 of cephalosporin data sheets should include this risk. The Committee was also asked to comment on whether inconsistencies in dose adjustment for renal impairment should be addressed.

Discussion

The Committee considered that although the available data is limited, an association between neurotoxicity and the cephalosporin class cannot be discounted.

The Committee discussed that the risk of neurotoxicity with cephalosporins appears to be associated with impaired renal function, older age and central nervous system disorders. Higher doses administered by intravenous injection, may also be a risk factor based on the characteristics of the case reports.

The Committee agreed that recognition of neurotoxicity in patients taking cephalosporins may be challenging, as there may be confounding by indication. Patients taking these medicines are acutely unwell and may have increased blood brain barrier permeability. It was discussed that physicians should consider cephalosporin-induced neurotoxicity in patients with risk factors and where the cause of new neurotoxic symptoms may be unclear.

The Committee recommended that all cephalosporin data sheets should include a consistent message regarding the risk of neurotoxicity in section 4.4. The warning should reflect that the evidence consists of case reports and include the risk factors identified . Information on management should also be included.

The Committee agreed that inconsistences in information on renal dose adjustment identified in some cephalosporin data sheets versus international product information should be reviewed by the relevant sponsor.

Recommendation 1

The Committee recommended that the data sheets for all cephalosporins should include consistent information in section 4.4 regarding the risk of neurotoxicity. The Committee recommended that the data sheets state that:

  • There have been reports of neurotoxicity associated with cephalosporin treatment, including encephalopathy, seizures and/or myoclonus
  • Risk factors include being elderly, renal impairment, central nervous system disorders and intravenous administration
  • Withdrawal of the medicine should be considered if there are signs of neurotoxicity.

Recommendation 2

The Committee recommended that inconsistences in renal dose adjustment information identified in some cephalosporin data sheets should be reviewed by the sponsor.

Recommendation 3

The Committee recommended that this safety issue be highlighted in Prescriber Update.

3.2.2 Pregabalin and risks in pregnancy

Background

In April 2022, the MHRA issued a drug safety update advising that pregabalin may slightly increase the risk of major congenital malformations (MCM) if used in the first trimester of pregnancy. The safety update cited a Nordic observational study of more than 2,700 pregnancies in Norway, Finland, Denmark and Sweden in people taking pregabalin in the first trimester. The UK Summary of Product Characteristics (SPC) for pregabalin was updated to provide information on the study findings. The European Medicines Agency (EMA) have also required similar updates.

The Committee was asked to advise whether the available information supports the need for the pregabalin data sheet to be updated to include information from the Nordic observational study on the risk of MCM.

Discussion

The Nordic study cited in the UK and European product information concluded that the risk of MCM among children exposed to pregabalin in the first trimester of pregnancy was slightly higher compared to unexposed children when number of events were directly compared. However, after adjustment for confounding factors, such as smoking and other diseases, this association was no longer statistically significant.

The data from the study also suggested a slightly higher risk of MCM among children exposed to pregabalin taken in pregnancy compared with children of mothers who took lamotrigine or duloxetine in pregnancy, which are two medicines with comparable therapeutic uses. The Committee noted that the study is currently unpublished and therefore has not been peer reviewed through the normal scientific process. It was considered that the small number of events and resultant low power meant that it was impossible to confirm, or rule out, an increased risk of MCM. It was also noted that there could be confounding by indication. However, it was also noted that the effect estimates were similar for the two active comparators, suggesting that confounding by indication may be minor.

The Committee noted that the data sheet already includes a strong warning in section 4.4 that pregabalin use in the first trimester of pregnancy may cause major birth defects in the unborn child and that pregabalin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus. The Committee discussed whether including the results of the study would change or strengthen this warning. The Committee considered that there was no need to update the data sheet information on use in pregnancy to include the results of the unpublished Nordic study at this time. The Committee considered that safety of pregabalin in pregnancy should continue to be monitored and reviewed again as new information becomes available.

[A Biggs-Hume left the meeting at this time]

3.2.3 Comirnaty RMP version 8

Background

The Comirnaty EU-Risk Management Plan (RMP) version 8 (with a final sign-off date 7 October 2022) is the latest version of the RMP submitted to Medsafe.

The Comirnaty EU-RMP v8 covers the following products:

  • Comirnaty Original (tozinameran all formulations, including the paediatric products)
  • Comirnaty Original/Omicron BA.1 (tozinameran and riltozinameran)
  • Comirnaty Original/Omicron BA.4-5 (tozinameran and famtozinameran).

This RMP evaluation primarily focuses on the Comirnaty Original/Omicron bivalent vaccines (especially the Original/Omicron BA.1 vaccine, and where data is available the Original/Omicron BA.4-5 vaccine). Where applicable, information on the product’s known and potential risks, missing information, pharmacovigilance activities and risk management activities are outlined.

The MARC was asked to consider whether the proposed RMP is considered appropriate for the Comirnaty Omicron bivalent vaccines as a booster in individuals 12 years of age and older.

Discussion

The Committee was satisfied with the RMP. There were no points of clarification or changes requested by the Committee.

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 43, Number 4, December 2022

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 Pharmacovigilance database update

W Woodfield gave an update on the progress of the strategic pharmacovigilance solution.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 1.40 pm.

Dr C Cameron Date

Chair, Medicines Adverse Reactions Committee

Secretary’s note: As a quorum was unable to be formed at the time of the meeting, the minutes and recommendations were ratified by the Committee via email after the meeting.

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