Published: 13 April 2021

Committees

MINUTES OF THE 185^th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

• 1.0 MATTERS OF ADMINISTRATION
  • 1.1 Welcome and Apologies
  • 1.2 Minutes of the 184^th MARC Meeting
  • 1.3 Potential Conflicts of Interest
• 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) 
    • 2.1.2 Special Populations: Serious Cases Associated with Medicines in Children under 18 years (Causal Cases Only)
    • 2.1.3 Special Populations: Serious Cases Reporting Adverse Events Following Immunisation Terms with Vaccines in Children under 18 years
    • 2.1.4 Special Populations: Serious Non-Fatal Cases Causally Associated with Critical Terms in Patients Over 80 Years
    • 2.1.5 Causal and Serious Cases in Patients Aged 18 to 80 Years
    • 2.1.6 COVID-19 vaccine safety monitoring
• 3.0 PHARMACOVIGILANCE ISSUES
  • 3.1 Matters Referred to the MARC under Section 36 of the Medicines Act 1981
  • 3.2 Matters Referred to the MARC by Medsafe
    • 3.2.1 SSRI/SNRI antidepressants and the risk of postpartum haemorrhage
    • 3.2.2 Clozapine monitoring frequency and duration
• 4.0 MEDSAFE PHARMACOVIGILANCE ACTIVTIES
  • 4.1 Report on Standing Agenda Items from Previous Meetings of the MARC
  • 4.2 Medsafe Pharmacovigilance Activities
  • 4.3 Prescriber Update Volume 42, Number 1, March 2021
  • 4.4 Quarterly Summary of Early Warning System
• 5.0 OTHER BUSINESS
  • 5.1 Discussion on AESI with demonstration
  • 5.2 Ad26.COV2-S - Risk Management Plan
  • 5.3 End of terms for C Ryan, J Tatler, I Raiman and Dr K Eggleton

MINUTES OF THE 185^th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
11 MARCH 2021

The one hundred and eighty fifth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 11 March 2021 via Microsoft Teams videoconference. The meeting commenced at 9am and closed at 1.35pm.

MARC MEMBERS PRESENT

• Dr C Cameron (Chair)
• Dr K Eggleton
• Dr C Kenedi
• Associate Prof L Parkin
• Hon. Associate Professor M Rademaker
• I Raiman
• C Ryan
• J Tatler
• Associate Professor M Tatley
• L Te Karu

MARC SECRETARIAT PRESENT

• T Coventry (Advisor, Pharmacovigilance)
• N Zhong (Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE

• S Kenyon (Manager, Clinical Risk Management)
• G Hill (Senior Medical Advisor, Pharmacovigilance)
• V Cheer (Senior Advisor, Pharmacovigilance)
• A Kerridge (Senior Advisor, Pharmacovigilance)
• M Storey (Senior Advisor, Pharmacovigilance)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

• No invited guests.

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Prof L Stamp, who has resigned from the Committee. The Chair expressed thanks to Prof Stamp for her contributions. Dr S Hanna was also unable to attend the meeting.

1.2 Minutes of the 184^th MARC Meeting

The minutes of the 184^th meeting were accepted as a true and accurate record of the meeting.

1.3 Potential Conflicts of Interest

Committee members submitted their Conflicts of Interest Declaration forms to the Secretary. The Chair reminded the MARC members that in addition to conflicts disclosed in the declaration forms, members should declare conflicts of interest at the commencement of discussion of any relevant agenda item.

There were no potential conflicts of interest 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 case ID 138728, where a patient administered adalimumab developed metastatic colon cancer and passed away four months after diagnosis. The Committee noted that colon cancer can be a complication of the one of the conditions indicated for adalimumab treatment. The diagnosis of colon cancer can also be delayed in patients with this condition. The Committee noted that some studies have found an increased risk of malignancies with immunomodulators.

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 discussed case ID 139011, where a preterm neonate was given paracetamol and developed deranged liver function tests, raised international normalised ratio (INR), deranged thyroid function tests and acute onset liver failure. The Committee noted that the paracetamol dose and dose interval differed from that recommended for a preterm neonate, and this may have contributed to the adverse reactions. The Centre for Adverse Reactions Monitoring (CARM) has attempted to follow up on details of the circumstances of this case.

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 causal and serious events occurring 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 2.1.6 COVID-19 vaccine safety monitoring

The Committee was given a brief update on the safety monitoring of the Comirnaty vaccine. It was noted that the reports received were consistent with the known safety profile. The overview included processes for reviewing individual reports.

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 SSRI/SNRI antidepressants and the risk of postpartum haemorrhage

Background

On 28 September 2020, the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) reviewed the evidence on the risk of postpartum haemorrhage (PPH) with the use of selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), and other antidepressants. The review of spontaneous data and the literature concluded there is a slightly increased risk of PPH with SSRIs, SNRIs and vortioxetine during the month before delivery. Subsequently, the PRAC recommended that the product information for SSRIs, SNRIs and vortioxetine be updated to include the risk of PPH, particularly when exposed within the month prior to delivery.

This report reviewed the available evidence of postpartum haemorrhage (PPH) with the use of antidepressants, with a focus on SSRI/SNRI and vortioxetine. This report also reviewed the New Zealand data sheet for SSRIs, SNRIs, and vortioxetine to see if the risk of PPH is already stated or will be included in the next data sheet update as indicated by the sponsors.

The Committee was asked to advise whether the current evidence supports an association of postpartum haemorrhage when SSRIs and SNRIs are used within the month prior/or close to delivery. The Committee was also asked to advise whether all data sheets for SSRIs, SNRIs and vortioxetine should be updated to include this risk.

Discussion

The Committee noted that this safety issue is known to the obstetrician-gynaecologist profession and maternal mental health psychiatrists and is considered to have biological plausibility. It was noted that the risk of bleeding is also slightly increased in surgical patients taking SSRIs.

It was considered that the scientific evidence supports a small increased risk of PPH when SSRIs or SNRIs are used prior to delivery. The Committee acknowledged that it is difficult to compare the results of the studies due to the use of differing study designs, definitions of PPH and exposure periods. Severity of depression was noted to be a potential confounding factor. It was also noted that it is unknown whether the definitions of PPH used correlate to clinically significant bleeding or whether the increased risk corresponds with worse outcomes.

The Committee acknowledged that the increase in absolute risk of PPH is small, and needs to be balanced with the benefits of continuing treatment close to delivery.

The Committee considered that given the safety concerns around use of antidepressants in pregnancy, they are unlikely to be continued unless there is an important clinical reason. The use of antidepressants during pregnancy for mild depression was expected to be uncommon.

The Committee acknowledged that stopping an antidepressant close to delivery and restarting after delivery poses a risk of harm to the mother, as the medicine takes four to six weeks to take effect. This may leave the mother more vulnerable to postpartum blues, depression or psychosis during a higher risk period. The significant burden associated with these conditions was acknowledged. The risk of relapse can be life threatening to the mother and/or child. It can also interrupt breastfeeding and distort maternal-child bonding, leading to downstream consequences for the child’s neurodevelopment.

The Committee considered that it is important to notify lead maternity carers and primary care physicians of this risk. This was considered to be particularly important for rural practitioners and their patients, as access to dedicated maternal mental health services and emergency treatment may be limited. When communicating about this risk to patients, the use of absolute risk was considered to be preferable to relative risk.

The Committee advocated for the use of benefit-risk statements in data sheets and other communications to healthcare professionals that balance the risk of PPH with the risks associated with discontinuing treatment in the presence of postpartum stressors. While use of SSRIs, SNRIs or vortioxetine before delivery should be considered a risk factor for PPH, the Committee noted that care should be taken not to imply that practice should be changed as this is not reflected in international guidelines.

The Committee considered that the current evidence supports an association of postpartum haemorrhage when SSRIs and SNRIs are used within the month prior/or close to delivery. The Committee advised that this risk should be communicated in a Prescriber Update article and should be notified to the relevant professional bodies.

Recommendation 1

The Committee recommended that all data sheets for SSRIs, SNRIs and vortioxetine should be updated to include the risk of postpartum haemorrhage when used within the month prior/or close to delivery.

Recommendation 2

The Committee recommended that this topic is communicated in a Prescriber Update article and that the relevant professional bodies are notified, including the Royal Australia New Zealand College of Psychiatrists, the New Zealand College of Midwives, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists and the Royal New Zealand College of General Practitioners.

3.2.2 Clozapine monitoring frequency and duration

Background

During treatment with clozapine, white blood cell count (WBC) and absolute neutrophil count (ANC) are routinely monitored due to the risk of agranulocytosis. Blood levels are measured every week during the first 18 weeks of treatment, then at least every four weeks throughout treatment and for four weeks after discontinuation of clozapine. To this end the companies supplying the medicine are required by Medsafe to provide a database to enable tracking of blood test results.

In New Zealand, during the COVID-19 level 4 lockdown period in 2020, guidelines were issued by groups without reference to regulatory requirements stating that monitoring requirements for clozapine could be relaxed. The need to return to the regular monitoring schedule (concerning frequency and duration) has been questioned by some clinicians.

Arguments in favour of a change have been, for example, that haematological adverse reactions are uncommon after the first year of clozapine treatment, that regular blood testing is an additional burden, and that the current monitoring requirements may exclude some patients from treatment. Reasons against a change is that the risk of adverse reactions, such as neutropenia and agranulocytosis, may be fatal.

The report presented to the Committee by Medsafe discussed the haematological monitoring requirements for patients taking clozapine, and examined the frequency, severity and timing of neutropenia adverse events during treatment.

The Committee was asked to advise whether there is sufficient evidence that a change to the frequency and/or duration of haematological monitoring for patients taking clozapine would continue to mitigate the risks to patients, and if so, what change is supported by the evidence. The Committee was also asked whether this topic requires further communication other than MARC’s Remarks in Prescriber Update.

Discussion

The Committee noted that the evidence around haematological monitoring is incomplete. There are no studies available to demonstrate the comparative safety of different monitoring regimens. The current testing regimen is not based on scientific evidence.

The superior efficacy of clozapine in treatment resistant schizophrenia was acknowledged, as was the significant burden of the condition. It was considered important to balance the relatively small risk of harm from agranulocytosis against the benefits of treatment. It was noted that most issues with agranulocytosis appear within the first year of treatment.

It was highlighted that the literature states that mandatory haematological monitoring may be a significant barrier to treatment and may contribute to underutilisation of clozapine. There was a lack of consensus on whether altering the monthly testing frequency would reduce the barrier to starting treatment. It was volunteered that perhaps the testing system should be made easier to navigate and more efficient, rather the reducing the frequency of testing.

It was also suggested that barriers to treatment could be reduced by giving clinicians the opportunity to reduce the frequency of testing to three-monthly after one year of treatment, subject to a documented informed consent discussion about the risks and benefits of less frequent testing.

It was considered that regular contact with clinicians should be maintained. It was considered important to educate patients about reporting symptoms of infection, as transient agranulocytosis can occur between blood tests.

The Committee noted the trend of moving management of patients who are stable on clozapine into primary care. It was considered important that adequate support and resources are provided to primary care physicians.

The Committee expressed concern about reducing frequency of testing in the absence of evidence of safety. The lack of appetite for funding research on this topic was noted.

It was also noted that Māori are overrepresented in the population of patients taking clozapine. It was considered important to consult with Māori healthcare professionals on this topic.

Given the limited evidence and the fact that agranulocytosis is just one concern in a multifaceted issue, the Committee considered that a cross-organisational group should be convened to assess the risks and benefits, barriers to prescribing, haematological testing requirements and propose next steps.

Recommendation 3

The Committee recommended that a cross-organisational group is convened to holistically review the benefits and risks of clozapine, barriers to treatment, haematological testing requirements and to propose next steps.

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

There were no standing agenda items for which the MARC made further recommendations.

4.2 Medsafe Pharmacovigilance Activities

The Committee noted the report detailing Medsafe’s recent pharmacovigilance activities.

The Committee noted that Medsafe has facilitated a cross-organisation discussion on colchicine poisoning. This group considered that a recent fatal overdose and number of other poisonings indicated a need to consider strategies for improving safety of colchicine in the community. The relevant organisations have been contacted to promote safe prescribing and dispensing. It was noted that research is underway to assess the efficacy of prophylactic colchicine when initiating allopurinol.

4.3 Prescriber Update Volume 42, Number 1, March 2021

The Committee noted the latest edition of Prescriber Update.

4.4 Quarterly Summary of Medsafe Early Warning System

The Committee noted the quarterly summary of Medsafe early warning system communications.

5.0 OTHER BUSINESS

5.1 Discussion on AESI with demonstration

The Committee was given a demonstration of the Qlik application developed to estimate background rates of Adverse Effects of Special Interest (AESI).

5.2 Ad26.COV2-S - Risk Management Plan

The Committee was provided with a report summarising the Medsafe assessment of the Risk Management Plan (RMP) for Ad26.COV2.S, a COVID-19 vaccine currently under evaluation by Medsafe.

The Committee was asked to provide feedback on whether the proposed questions and amendments were suitable, and whether additional questions and/or amendments to the RMP were required. The Committee considered that the proposed questions and requested amendments were suitable.

5.3 End of terms for C Ryan, J Tatler, I Raiman and Dr K Eggleton

The Committee thanked Catherine Ryan, Jo Tatler, Isabel Raiman and Dr Kyle Eggleton for their outstanding contributions to the Committee.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 1.35pm.

Dr C Cameron
Chair, Medicines Adverse Reactions Committee
Date:31 March 2021