Published: 13 October 2022

Committees

MINUTES OF THE 191st MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 191st MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

8 September 2022

The one hundred and ninety-first meeting of the Medicines Adverse Reactions Committee (MARC) was held on 8 September 2022 by teleconference. The meeting commenced at 9am and closed at 1.45pm.

MARC MEMBERS PRESENT

Dr, C, Cameron (chair)
Associate Professor L, Parkin
L, Te Karu
L, Carlyon
Associate Professor M, Doogue
Dr, A, Romain
L, McDermott
Z, Malik
Dr, C, Kenedi
Honorary Associate Professor, M, Rademaker
Dr, M, Tatley

MARC SECRETARIAT PRESENT

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

MEDSAFE STAFF IN ATTENDANCE

S, Kenyon (Manager, Clinical Risk Management)
G, Hill (Senior Medical Advisor, Pharmacovigilance)
V, Cheer (Senior Advisor, Pharmacovigilance)
M, Storey (Principal Technical Specialist – Pharmacovigilance)
J, Prankerd (Senior Advisor, Pharmacovigilance)
T, Kim (Advisor, Pharmacovigilance)
S, Tran (Advisor, Pharmacovigilance)
J, Crockett (Advisor Science, Product Regulation)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

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

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting.

Apologies were received from Dr A Pomerleau and Dr S Hanna.

1.2 Minutes of the 190th MARC Meeting

The minutes of the 190th 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. 

Honorary Associate Prof M Rademaker declared competing interest relating to agenda item 3.2.1. Honorary Associate Pro M Rademaker was excluded from making recommendations for this agenda item.

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 discussed case #143872 that reported DRESS syndrome with allopurinol. The Committee explored possible factors that may have led to the development of DRESS in the case.

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

Recommendation 1:

The Committee recommended that the Centre for Adverse Reaction Monitoring (CARM) presents the cases of DRESS reported with allopurinol at the next Medicines Adverse Reaction Committee.

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.

3.0 PHARMACOVIGILANCE ISSUES

3.1 Matters Referred to the MARC under Section 36 of the Medicines Act 1981

3.1.1 None

3.2 Matters Referred to the MARC by Medsafe

3.2.1 Recent safety signals related to use of Janus kinase inhibitors

Background

In a recent large post-authorisation safety study (ORAL Surveillance), participants taking tofacitinib for rheumatoid arthritis, who were aged 50 years and older with at least one cardiovascular risk factor had a higher risk of major adverse cardiovascular events (MACE), malignancies (excluding non-melanoma skin cancer), serious infections, thromboembolic events and mortality compared to participants taking tumour necrosis factor inhibitors (TNFi).

The results from the study triggered international regulatory action to improve the overall risk-benefit balance of tofacitinib and other Janus kinase (JAK) inhibitors indicated for inflammatory diseases.

The United States Food and Drug Administration (FDA) considered that although other JAK inhibitors approved for inflammatory diseases have not been studied to the same extent as tofacitinib, these medicines share the same mechanism of action and therefore may have similar risks. The FDA has subsequently updated the product labelling for all JAK inhibitors approved for the treatment of inflammatory diseases.

Approved JAK inhibitors indicated for the treatment of inflammatory conditions are tofacitinib and upadacitinib. Ruxolitinib is a JAK inhibitor indicated for the treatment of myeloproliferative neoplasms.

The Committee was asked to review the information presented and whether regulatory action is required to improve the risk-benefit balance of approved oral JAK inhibitors in New Zealand. Such actions may include restricting the therapeutic indication for use and/or strengthening the warnings and precautions section of the data sheet.

Discussion

The Committee reviewed the information presented on the risk of MACE, malignancies, and thromboembolic events with JAK inhibitors. The risks were considered separately.

The Committee discussed that the risk of MACE, malignancies and thromboembolic events in a patient taking a JAK inhibitor would be influenced by underlying risk factors for each of these conditions present in the patient. These need to be considered when reviewing the benefit risk for each patient by the clinician.

The Committee highlighted the current funding criteria for upadacitinib in New Zealand. It is likely that JAK inhibitors would be prescribed by specialised clinicians, who would have expert knowledge in their field.

The Committee noted that there is currently insufficient data to distinguish whether the safety concerns differ between medicines of the same class. The Committee considered that the risks should be treated as a class effect until further research and evidence is available. The Committee therefore recommended that the data sheet warning of these adverse effects be strengthened to improve the risk benefit balance of tofacitinib. The same warning statements should be adopted for all JAK inhibitors approved for the treatment of inflammatory diseases.

The Committee noted that ruxolitinib is indicated for the treatment of myeloproliferative neoplasm, however the same warning and precaution statements should also be applied.

The Committee agreed that restricting the use of upadacitinib and tofacitinib through changes to the indication for inflammatory diseases may impact the benefit-risk for use in patients who may have disabling disease. The use of JAK inhibitors should be based on the risk benefit balance of the individual.

[M Rademaker left the meeting prior to the recommendations]

Recommendation 2

The Committee recommended that the warning statements for MACE, malignancies and thrombotic events be strengthened in the data sheet for tofacitinib and upadacitinib.

Recommendation 3

The Committee recommended that a warning statement for MACE, secondary malignancies and thromboembolic events be added to the ruxolitinib data sheet.

[M Rademaker returned to the meeting following the recommendations]

3.2.2 Cannabidiol, potential drug interaction with systemic mTOR and calcineurin inhibitors

Background

In March 2022, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) reviewed a potential drug-drug interaction relating to cannabidiol (CBD) with systemic mammalian target of rapamycin (mTOR) and calcineurin inhibitors.

A drug interaction with cannabidiol may result in increased serum levels and toxicity of mTOR and calcineurin inhibitors.

The PRAC review arose from a phase 1 open-label pharmacokinetic drug-drug interaction trial to investigate the effect of cannabidiol on the pharmacokinetics of other medicines including everolimus.

The Committee was asked to review the information on drug-drug interaction from CBD and mTOR and calcineurin inhibitors.

Discussion

The Committee discussed how cannabidiol likely has a wide effect on cytochrome P450 (CYP) enzymes and transporters, however, this is not yet fully understood. A review of available pharmacokinetic studies may provide further insight.

The Committee considered that the available evidence on the interaction between cannabidiol and mTOR/calcineurin inhibitors is limited. The Committee discussed how these medicines are metabolised differently, and therefore the information on a possible interaction would be specific to each medicine.

The Committee noted that mTOR and calcineurin inhibitors have a narrow therapeutic index. Use of these medicines in clinical practice include post-transplant treatment. Interactions that have the potential to alter the therapeutic levels of these medicines may lead to harm, and therefore need to be communicated.

The Committee agreed that the evidence showed a clinically significant drug interaction with cannabidiol and mTOR. The interaction with calcineurin inhibitors was less certain, and further evidence is needed.

The Committee considered that interactions between cannabidiol (including recreational cannabis) and other medicines needs to be further explored.

Recommendation 4

The Committee recommended that the data sheet for sirolimus be updated to include information on a drug-drug interaction with cannabidiol.

3.2.3 Quetiapine and gestational diabetes mellitus

Background

On 22 January 2021, Medsafe was notified of a safety signal for the risk of gestational diabetes mellitus (GDM) associated with the use of quetiapine.

The signal had been identified by the EMA, who requested that the sponsor provide a cumulative review of post-marketing, clinical trial and literature data. On review of the information, the signal was closed by the EMA and no further action required.

This paper seeks the Committee’s advice on whether quetiapine is associated with gestational diabetes mellitus, and if so, if any regulatory activity is required.

Discussion

The Committee considered that due to their metabolic adverse effects, quetiapine and some other atypical antipsychotics can increase the risk of GDM. The Committee recommended updates to the pregnancy section of the quetiapine data sheet.

The Committee discussed screening for GDM and noted that access to screening may be a barrier for some women. The Committee also noted the increasing prevalence of GDM in New Zealand. The Committee recommended that these concerns be further communicated.

The Committee discussed the results from Huthwaite et all 2018 study, which suggested that quetiapine is widely prescribed in primary care in New Zealand for unapproved indications, including sleep and anxiety. The Committee noted the increasing amount of quetiapine dispensings and was concerned that this may reflect increasing unapproved use. Use of quetiapine for an unapproved indication, in an absence of data and risk of adverse effects, impacts the risk-benefit balance, including in pregnant women. The Committee agreed these issues should be raised further.

The Committee recommended that Medsafe contact the Best Practice Advocacy Centre New Zealand (bpacnz) about the possibility of writing an article on the metabolic adverse effects of atypical antipsychotics, including effects in pregnancy. The article could also discuss concerns around the use of quetiapine for unapproved indications.

Recommendation 5

The Committee recommended that section 4.6 of the quetiapine data sheet is updated with risk of metabolic adverse effects, including diabetes, during pregnancy.

Recommendation 6

The Committee recommended that a letter is written to Te Whatu Ora and Te Aka Whai Ora that outlines concerns about unapproved use of quetiapine. The letter should also include the Committee’s concerns around access to gestational diabetes screening and the increasing prevalence of gestational diabetes in New Zealand.

Recommendation 7

The Committee recommended that Medsafe contact the Best Practice Advocacy Centre New Zealand (bpacnz) about the possibility of writing an article on the metabolic effects of atypical antipsychotics and concerns around unapproved use of quetiapine.

3.2.4 Risk Management Plan for Zolgensma (omasemnogene abeparvovec)

Background

The Committee was presented with the Risk Management Plan (version 0.1) for Zolgensma (onasemnogene abeparvovec), a gene replacement therapy for treatment of patients with spinal muscle atrophy (SMA).

The Committee was asked whether the Risk Management Plan, proposed studies, pharmacovigilance, and risk minimisation activities are sufficient.

Discussion

The Committee found the Risk Management Plan appropriate, and no further action was required.

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 3, September 2022

The Committee noted the latest edition of Prescriber Update. The Committee noted they were very impressed with the quality of the publication.

4.4 Quarterly Summary of Medsafe Safety Communications

The Committee noted the quarterly summary of Medsafe safety communications.

5.0 OTHER BUSINESS

5.1 Covid-19 vaccine update

The Committee were informed about a safety alert published by Medsafe for Nuvaxovid (Novavax Covid-19 Vaccine) and myocarditis and pericarditis.

5.2 Resignation of Z Malik

The Committee noted that Z Malik has resigned from the Committee, and this would be his last meeting.

The Committee thanked Z Malik for his outstanding contribution and commitment to the Committee as the nurse member.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 1:45 pm.

Dr Chris Cameron
Chair, Medicines Adverse Reactions Committee
Date 23 September 2022

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