Published: 26 April 2023

Committees

MINUTES OF THE 193rd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 193rd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

9 March 2023

The one hundredth and ninety-third meeting of the Medicines Adverse Reactions Committee (MARC) was held on 9 March 2023 in person at the Ministry of Health and via videoconference. The meeting commenced at 9am and closed at 12.38pm.

MARC MEMBERS PRESENT

Dr C Cameron
A/Prof M Doogue
A/Prof A Pomerleau
L Carlyon
L Te Karu
L McDermott
A Biggs-Hume
Dr A Romain
Honorary A/Prof M Rademaker
Prof M Tatley

MARC SECRETARIAT PRESENT

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

MEDSAFE STAFF IN ATTENDANCE

S Kenyon, Manager Clinical Risk Management
V Cheer, Senior Advisor (Pharmacovigilance)
J Prankerd, Senior Advisor (Pharmacovigilance)
S Tran, Advisor (Pharmacovigilance)
M Storey, Team Leader Pharmacovigilance
K Van Bart, Medical Advisor, Clinical Risk Management
T O’Flynn, Medical Advisor, Clinical Risk Management
A Lynch, Advisor (Science), Product Regulation
N Khalajiassadi, Advisor (Science), Product Regulation

INVITED GUESTS AND EXPERTS IN ATTENDANCE

Dr J Lee

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, Prof L Parkin and Dr C Kenedi.

1.2 Minutes of the 192nd MARC Meeting

Correction that: A/Prof A Pomerleau was present at the 192nd meeting. This was not stated in the minutes.

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 discussed CARM ID 145567 involving lisinopril and angioedema. The Committee highlighted that this case was unusual as angioedema does not normally progress to a fatal outcome.

The Committee recommended that the risk of angioedema with ACE inhibitors and how to manage the risk is highlighted in Prescriber Update.

The Committee did not consider any other reports required further action.

Recommendation 1:

The Committee recommended that the risk of angioedema with ACE inhibitors and how to manage the risk is highlighted in Prescriber Update.

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 casual and serious cases in patients aged 18 to 80 years were briefly outlined for the Committee.

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 Serious cases – mpox vaccine

The Committee was provided an overview of two case reports of pericarditis suspected to be related to vaccination against mpox (monkeypox).

Noting the clinical investigations and time to onset of both cases, the Committee considered it not possible to exclude an effect of the vaccine. The Committee agreed that the causality was ‘possible’ in both cases.

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 Interleukin inhibitors and the risk of pancreatitis

Background

A signal of pancreatitis in association with tocilizumab (an interleukin-6 inhibitor (IL-6)) was detected on analysis of individual case safety reports, in the World Health Organization (WHO) database, and information on this signal published in the WHO Pharmaceuticals Newsletter.

Pancreatitis is not currently listed as an adverse reaction with tocilizumab in the New Zealand, however, it is listed in some international product information, including in Australia.

Medsafe reviewed the available information related to this potential signal and in doing so, widened the review to include the interleukin inhibitor (IL) class and the risk of pancreatitis.

The Committee was asked whether there is evidence for an association between tocilizumab and the risk of pancreatitis. In addition, whether there is information to support a possible class effect of pancreatitis with interleukin inhibitors as a drug class effect.

Discussion

The Committee discussed the association between pancreatitis and tocilizumab. The Committee acknowledged that causal association may be difficult to establish in most cases due to confounding. However, the Committee agreed the available evidence suggests an association between pancreatitis and tocilizumab, and recommended that the data sheet be updated.

The Committee considered that there may be biological plausibility for other IL-6 inhibitors such as siltuximab to also cause pancreatitis. The Committee considered that because siltuximab is indicated for a rare disease and therefore having low usage, a signal would be difficult to detect. The Committee noted that it would be important for health professionals to be aware when prescribing other IL-6 inhibitor medicines, that cases of pancreatitis have been reported with tocilizumab. The Committee recommended that Section 4.4 of the siltuximab data sheet should be updated stating that cases of pancreatitis have been reported with other interlukein-6 inhibitors.

The Committee did not find an association between the IL inhibitor class and pancreatitis at the present time. The Committee discussed that each IL inhibitor has different actions in the body, and therefore the signal of pancreatitis with tocilizumab, cannot be extrapolated. The Committee also noted a signal for ustekinumab detected in the Japanese adverse event reporting database. The Committee recommended that Medsafe issues a monitoring communication to collect more information on the possible risk of pancreatitis with the interleukin inhibitor drug class.

Recommendation 2:

The Committee recommended that the tocilizumab data sheet be updated to include pancreatitis in Section 4.8.

Recommendation 3:

The Committee recommended that data sheets of other interleukin-6 inhibitors (ie, siltuximab) be updated in Section 4.4, stating that cases of pancreatitis have been reported with other interlukein-6 inhibitors.

Recommendation 4:

The Committee recommended that Medsafe issues a monitoring communication on the possible risk of pancreatitis with the interleukin inhibitor drug class.

3.2.2 Probiotics and pre-eclampsia

Background

Probiotics are widely available in New Zealand as dietary supplements to support gut health. There are a number of products that are marketed specifically for use in pregnancy and breastfeeding.

A recent Cochrane review analysed the use of probiotic supplements for the prevention of gestational diabetes mellitus and related outcomes. The review did not find evidence of a reduced risk of gestational diabetes with probiotics compared to placebo. However, the review did find evidence of an increased risk of pre-eclampsia with the use of probiotics.

The Committee was asked to review whether the current available evidence supports a plausible causal relationship between probiotic supplementation and increased risk of pre-eclampsia, noting that the available information is for overweight or obese pregnant people only.

Discussion

The Committee expressed concerns about the number of probiotics being marketed for use in pregnancy with claims unsupported by scientific evidence.

The Committee noted probiotics are not regulated by Medsafe and therefore any regulatory action would be limited to risk communication to affected stakeholders and liaising with other agencies.

The Committee noted that the probiotics studied and included in the Cochrane review differed across the studies and included a range of bacterial species and strains. It was therefore difficult to ascertain whether any adverse treatment effects could be attributed to the presence of certain constituents in the formulation. Overall, the Committee considered the current evidence did not suggest a plausible causal relationship between probiotic supplementation and an increased risk of pre-eclampsia. No action was recommended at this time.

3.2.3 Risk of thromboembolism from vaping- caution with combined oral contraceptives

Background

A recent Coroners report was released investigating the tragic death of a 17-year old female. She died from a pulmonary thromboembolism and at the time of her death was taking the combined oral contraceptive Levlen. During the investigation, she was found to have heterozygous Factor V Leiden mutation. The coroner determined that the use of Levlen in conjunction with her inherited thrombophilia disorder, contributed to the development of the pulmonary embolism.

During the investigation it was noted that she had started vaping and the coroner sought further expert advice from a physician who specialises in both obstetrics and haematology. The physician provided an overview on Factor V Leiden mutation and risk of thromboembolism with combined oral contraceptive use. The expert then referenced two articles which showed an association between vaping and the development of thromboembolism. However, it was noted that data from large cohort studies investigating this association is not yet available. One of the coroner’s recommendations was that medical practitioners and people at risk of thromboembolism be alert to this information.

Venous and arterial thromboembolism are known adverse events linked to combined hormonal oral contraceptives, of which smoking is considered to be a factor that further increases this risk. It is unknown whether vaping/use of electronic cigarettes also carries a risk of thromboembolism either alone or in combination with oral contraceptive use. Given the widespread use of combined oral contraceptives and the number of individuals who vape, the potential risk of harm should be investigated.

The MARC reviewed the current information relating to vaping and risk of thromboembolism, particularly in women that take combined oral contraceptives.

Discussion

The Committee noted that the use of hormone replacement therapy is associated with an increased risk of thromboembolism and this should also be included in the scope of the discussion.

The Committee commented that the variability of the vaping device and product ingredients adds complexity in defining what mechanisms might potentially increase the risk of thromboembolism.

The Committee agreed that the effects of vaping in people on hormonal therapy is unknown. At the present time, there is a lack of evidence to show that vaping increases the risk of thromboembolism. However, given that data on the long term health risk from vaping is still in its infancy, a better understanding of this will become clearer with time as more research and long term studies emerge.

The Committee noted that there is a vaping monitoring programme whereby side effects from vaping can be reported to the New Zealand Pharmacovigilance Centre. These reports are collected on behalf of the Vaping Regulatory Authority.

To capture potential interaction between vaping and associated adverse reactions with medicines, the Committee considered that it is important for healthcare professionals to state the vaping status of the patient when submitting adverse drug reaction reports to CARM.

The Committee considered it would be useful to review case reports of adverse reactions associated with vaping and medicines.

Recommendation 5:

The Committee recommended to highlight in Prescriber Update that healthcare professionals should include the vaping status of the patient when an adverse drug reaction is reported to CARM.

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 1, March 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 Outcome of MHRA’s consultation on identifying, declaring and managing interests of members of expert advisory committees

An overview was provided on the recent outcome of the MHRA’s consultation on the new Code of Practice for Expert Advisory Committees.

5.2 Demo of the pharmacovigilance database

The Committee was given a demo of the updated pharmacovigilance database.

5.3 Resignation of Dr A Romain

The Committee noted that Dr A Romain has resigned from the Committee, and this would be his last meeting.

The Committee thanked Dr A Romain for his outstanding contribution and commitment to the Committee as a rural general practitioner member.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 12.38pm.

Dr C Cameron
Chair, Medicines Adverse Reactions Committee
Date: 12 April 2023

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