Published: 6 October 2020

Committees

MINUTES OF THE 183rd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

  • 1.0 MATTERS OF ADMINISTRATION
  • 2.0 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

    MINUTES OF THE 183rd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
    10 September 2020

    The one hundred and eighty-third meeting of the Medicines Adverse Reactions Committee (MARC) was held on 10 September 2020 via Zoom videoconference. The meeting commenced at 9am and closed at 12pm.

    MARC MEMBERS PRESENT

    Associate Professor D Reith (Chair)
    Dr C Cameron
    Dr K Eggleton
    Associate Professor D Menkes
    Associate Professor L Parkin
    Mrs I Raiman
    Mrs C Ryan
    Professor L Stamp
    Ms J Tatler
    Associate Professor M Tatley
    Mrs 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)
    L Chan (Principal Technical Specialist, 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 Dr S Hanna.

    The Committee paid tribute to the passing of Dr Chip Gresham. The Committee was shocked and saddened by his loss and remembered fondly his passion for the outdoors and his contribution to his community and profession. Despite only being on the Committee for a short time Dr Gresham had made some important contributions to the Committees discussions and the members had valued his input.

    1.2 Minutes of the 182nd MARC Meeting

    The minutes of the 182nd 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.

    Mrs I Raiman declared that she had financial interest in Johnson & Johnson, with Jansen being a subsidiary. It was therefore considered there was a conflict of interest for agenda item 3.2.2. It was agreed that Mrs I Raiman be excluded from the discussion and decisions for this agenda item.

    There were no other 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 136929 where a patient used ocular chloramphenicol and died months later from aplastic anaemia. The Committee noted that aplastic anaemia from the use of ocular chloramphenicol is a very rare adverse event. It was also discussed that the narrative given had limited background information. Nevertheless, the use of ocular chloramphenicol is commonly prescribed in primary care and also supplied by pharmacists over the counter as a restricted medicine therefore the Committee recommended highlighting this case.

    Recommendation 1

    The Committee recommended that this case of aplastic anaemia with ocular chloramphenicol is highlighted in the Gathering Knowledge section of Prescriber Update.

    The Committee did not consider any other 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 136848 where a child experienced symptoms similar to viral gastroenteritis (vomiting, diarrhoea and dehydration). Although the reporter suspected the child may have been exposed to sodium chlorite (marketed as Miracle Mineral Solution), follow up failed to confirm this suspicion. The Committee noted that Medsafe had already issued an Alert Communication on this topic.

    The Committee did not consider any other 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 (causal and serious cases) were briefly outlined for the Committee.

    The Committee noted that for Case ID 136652, described a drug-drug interaction with allopurinol and azathioprine that resulted in pancytopenia. The Committee noted that the information in the data sheet on this interaction was not optimal and should be reviewed. Medsafe advised the Committee this issue has been investigated and updates to the data sheet are being requested.

    The Committee did not consider any other 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

    No items.

    3.2 Matters Referred to the MARC by Medsafe

    3.2.1 Macrolides in pregnancy

    Background

    Macrolide antibiotics such as erythromycin, azithromycin, clarithromycin and roxithromycin are frequently used medicines in New Zealand. A UK population-based cohort study was recently published (Fan et al. 2020). The results of the study suggested some risks associated with the use of macrolides in pregnancy. Medsafe reviewed the available information on macrolides and their use in pregnancy

    The results by Fan et al. showed that macrolide prescribing in the first trimester was associated with a small but increased risk of any malformation, and specifically cardiovascular malformation. In addition, macrolide prescribing in any trimester was associated with increased risk of genital malformations.

    Published studies are mostly observational and overall the Medsafe review found studies with conflicting conclusions. Another recent study where more patients were exposed to macrolides compared to the Fan study did not find an increased risk of birth defects. Older studies also showed conflicting results regarding the risks of macrolide use during pregnancy.

    The review by Medsafe also found some inconsistencies in the information about pregnancy risks between the New Zealand Formulary (NZF) pregnancy summary and the data sheets for the medicines.

    Discussion

    The Committee discussed both the limitations and strengths of the study by Fan et al. The Committee highlighted the issue of the potential confounding by indication of the two antibiotic groups, and the concept of treatment failure bias. It was noted that the authors tried to minimise bias through a variety of methods such as propensity scoring and using negative control cohorts.

    The Committee decided overall that no action needed to be taken at this time in regard to use of macrolide antibiotics in pregnancy.

    The Committee considered the inconsistency of the information presented across different sources in regards the use of macrolides in pregnancy. The Committee considered that it would be difficult to suggest changes to make these sources consistent due to the high level of uncertainty of the evidence.

    [Mrs I Raiman left the meeting at this time]

    3.2.2 Domperidone – benefit-risk review of use in children under 12 years old

    Background

    In 2014 the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) completed a benefit-risk review of domperidone. It concluded that the benefit-risk balance remained favourable in the management of nausea and vomiting but the available data did not support the use of domperidone for other indications. The PRAC also noted that there were limited data to support paediatric use and therefore requested that the sponsor undertake a Post Authorisation Efficacy Study (PAES) for the use of domperidone for this age group.

    Following the completion of the PAES, the UK Medicines and Healthcare products Regulatory Agency (MHRA) removed the paediatric indication. Therefore Medsafe considered that this issue should be reviewed by the MARC.

    In addition, the Committee was asked whether the weight restriction should be increased from 35 kg to 40 kg given that at the specified dose of 0.25 mg/kg/dose, the approved formulation cannot deliver a dose below 10 mg.

    Discussion

    The Committee agreed that the PAES demonstrated a lack of efficacy for domperidone in children and that this outcome was supported by other evidence from the scientific literature.

    It was highlighted to the Committee that currently the data sheet states that domperidone is indicated in the use in adult and children weighing over 35 kg but has no age restrictions. Therefore, a child under the age of 12 years who weighs more than 35 kg could take domperidone. The Committee agreed that based on the outcome of the PAES, the indication should be revised to specify its use only in adults and adolescents aged 12 years and over weighing 35 kg or more.

    The Committee noted that a standardised formula for domperidone oral suspension is approved by the Medication Safety Expert Advisory Group of the Health Quality and Safety Commission NZ. This formula may be used quite widely for both adults and children to achieve accurate dosing. Although the recommended dose (0.25 mg/kg three to four times per day up to a maximum daily dose of 1 mg/kg) cannot be achieved with the 10 mg tablet in patients weighing less than 40 kg, the Committee did not consider it necessary to increase the weight restriction for domperidone from 35 kg to 40 kg to reflect the dose form of the currently approved products.

    The Committee noted that in Europe and in the UK the use of domperidone is only indicated for nausea and vomiting whereas the NZ data sheet has additional indications. The Committee agreed that Medsafe should perform an internal review of the indications for domperidone use in adults.

    Recommendation 2

    The Committee recommended that the indication in the data sheet should be revised to specify the use of domperidone in adults and children aged 12 years and over.

    Recommendation 3

    The Committee recommended that Medsafe performs an internal review of the indications for domperidone use in adults.

    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.

    There were no other 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 commented that they were pleased to see Medsafe maintaining good communication with other regulatory agencies from other countries.

    [Mrs I Raiman re-joined the meeting at this time.]

    4.3 Prescriber Update Volume 41, Number 3, September 2020

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

    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 Survey on reporting side effects to medicines: outcome report for survey of consumer

    The Committee was given a brief summary of the outcome of Medsafe’s recent consumer survey on reporting side effects to medicines.

    5.2 End of terms for Associate Prof D Reith and Associate Prof D Menkes

    The Committee thanked both Associate Professor David Reith and Associate Professor David Menkes for their outstanding contribution to the Committee.

    6.0 ANNEXES

    6.1.1 Macrolides in pregnancy

    1. Studies included in the meta-analysis by Fan H et al.
    2. NZPhvC number of reports involving a macrolide up to 30 June 2020

    6.1.2 Domperidone – benefit-risk review of use in children under 12 years old

    1. Domperidone benefit-risk review 2014, 158th MARC meeting
    2. Comparison of paediatric information in domperidone data sheets

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

    Associate Professor David Reith
    Chair, Medicines Adverse Reactions Committee

    Date: 28 September 2020

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