Published: 4 March 2024

Committees

MINUTES OF THE 196th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

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

    MINUTES OF THE 196th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

    7 December 2023

    The one hundred and ninety-sixth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 7 December 2023 at the Ministry of Health. The meeting commenced at 9am and closed at 1.40pm.

    MARC MEMBERS PRESENT

    A/Prof M Doogue (chair)
    Dr C Kenedi
    Dr M Rademaker
    Dr L Te Karu
    Prof L Parkin
    Prof M Tatley
    Ms L McDermott
    Ms L Carlyon
    Ms A Biggs-Hume
    A/Prof A Pomerleau
    Dr S Leitch
    Dr H Wilson

    MARC SECRETARIAT PRESENT

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

    MEDSAFE STAFF IN ATTENDANCE

    S Kenyon (Manager, Clinical Risk Management)
    M Storey (Team Leader, Pharmacovigilance)
    L Chan (Principal Technical Specialist, Pharmacovigilance)
    V Cheer (Senior Advisor, Pharmacovigilance)
    J Prankerd (Senior Advisor, Pharmacovigilance)
    S Tran (Senior Advisor, Pharmacovigilance)
    K Van Bart (Medical Advisor, Clinical Risk Management)
    J Park (Advisor, Pharmacovigilance)
    T O’Flynn (Medical Advisor, Clinical Risk Management)

    INVITED GUESTS AND EXPERTS IN ATTENDANCE

    Dr J Lee (CARM)
    Dr A Hynes (CARM)
    Dr D Hughes (Pharmac)

    1.0 MATTERS OF ADMINISTRATION

    1.1 Welcome and Apologies

    The Committee and Medsafe welcomed A/Prof M Doogue as the new chair.

    The Chair welcomed the attendees to the meeting. No apologies were received.

    1.2 Minutes of the 195th MARC Meeting

    The minutes of the 195th 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 noted a high number of reports for empagliflozin in this category, including cases of Fournier’s gangrene.

    The Committee highlighted the importance of patient education, particularly awareness of the signs/symptoms and maintaining perineal hygiene.

    The Committee noted that because Fournier’s gangrene is rare, healthcare professionals may not be aware of this potential adverse reaction with empagliflozin.

    The Committee noted existing communication activities by Medsafe, including previous Prescriber Update articles and a patient information leaflet. The Committee considered that further communication from bpacnz and the New Zealand Formulary could raise awareness among healthcare professionals, particularly general practitioners.

    Recommendation 1

    The Committee recommended that cases of Fournier’s gangrene with empagliflozin are highlighted to bpacnz and the New Zealand Formulary. Further communications should be considered by these organisations to raise healthcare professional awareness.

    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 Direct-acting oral anticoagulants (DOACs) and anticoagulant-related nephropathy (ARN)

    Background

    Oral anticoagulants include warfarin, dabigatran etexilate, rivaroxaban and apixaban.

    Anticoagulant-related nephropathy (ARN), a form of acute kidney injury (AKI), has been identified as an adverse reaction associated with warfarin, and prescribing information in New Zealand and internationally reflects this risk. More recently, international regulators have reviewed the potential association of ARN with the newer oral anticoagulants. The European Medicines Agency reviewed the risk with dabigatran and rivaroxaban (separate reviews) and requested updates to the prescribing information. The Australian Therapeutic Goods Administration (TGA) identified a class effect for all oral anticoagulants and requested updates to the prescribing information. The United States Food and Drug Administration is currently reviewing the risk of acute kidney injury with DOACs.

    In New Zealand, the Xarelto (rivaroxaban) data sheet was updated in May 2023 to include ARN. The current dabigatran and apixaban data sheets do not include this risk. Therefore, the Committee was asked to consider whether ARN is a class effect for DOACs or for specific DOACs, and whether the data sheets should be updated.

    Discussion

    Some Committee members noted the term ARN combines pathology with aetiology (anticoagulants) and the preferred terminology is AKI with haemorrhagic nephropathy. Both terms will be used interchangeably in this discussion.

    Although this initial review was limited to currently approved oral anticoagulants, the Committee discussed the risk of ARN for all oral anticoagulants. The Committee noted that this paper did not review the risk for anticoagulants given parenterally.

    The Committee commented that the reported prevalence of ARN in patients being treated with warfarin in a retrospective study was improbably high and likely biased and hence unlikely to represent population values. The Committee noted that risk should be represented by incidence given AKI is an acute condition.

    The Committee noted that the risk of haemorrhage from oral anticoagulants is well-known, and that AKI is a consequence of glomerular haemorrhage. The Committee noted that data sheets for some oral anticoagulants mention urogenital bleeding as an adverse reaction, however the kidneys may not be a common organ associated with this term.

    The Committee noted that cases were in over-anticoagulated patients and that, like other haemorrhagic complications, the risk was proportional to degree of anticoagulation.

    The Committee agreed that there was evidence for an association between acute kidney injury with haemorrhagic nephropathy and oral anticoagulants as a drug class. For consistency, and to avoid giving the impression that certain anticoagulants do not carry this risk, the Committee recommended that all oral anticoagulant data sheets should be updated to include ARN/AKI.

    The committee noted differences between the data sheets with respect to monitoring renal function. This may be appropriate given the differences in elimination pathways between anticoagulants and their respective dosing guidelines.

    Recommendation 2

    The Committee recommended that all data sheets for oral anticoagulants be updated with the risk of ARN/AKI.

    3.2.2 Potential drug interaction between estrogen-based hormone replacement therapy and lamotrigine

    Background

    In May 2023, the European Medicines Agency (EMA) agreed that the Summary of Product Characteristics (SmPCs) of oral hormonal replacement therapy (HRT) products be updated to include information about a drug interaction with lamotrigine.

    Information on a drug interaction between lamotrigine and hormonal contraception is currently included in the lamotrigine and combined oral contraceptive (COC) data sheets. However, there is no information about this interaction in the data sheets of products indicated for HRT.

    The Committee was asked to review the information on a drug interaction between HRT and lamotrigine, and to consider if updates to the data sheets of HRT products are required.

    Discussion

    The Committee noted that therapeutic drug monitoring of lamotrigine is available in New Zealand.

    The Committee noted that HRT is generally used at the lowest effective dose, however higher doses may be used, particularly when used off-label.

    The Committee noted that the lamotrigine data sheet contains information on an interaction with COC products. There is also mention that the effect of HRT has not been studied but a similar interaction could occur. The Committee noted that a pharmacokinetic study on ethinylestradiol/levonorgestrel (a combined oral contraceptive) has been demonstrated to increase the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels.

    The Committee agreed that, despite the limited evidence, there was reasonable evidence to support this interaction. Considering the potential serious outcomes that may arise from a reduction in lamotrigine levels, for example changes in seizure frequency and mood stability, the Committee recommended that the data sheets for estrogen-based HRTs are updated to include information on this drug interaction

    The Committee considered that this interaction applied to systemic administration of estrogens. Systemic absorption from vaginal-based HRTs is considered low and therefore updates to the data sheet of these products to include a drug interaction with lamotrigine is not warranted for products that are only for vaginal use.

    Recommendation 3

    The Committee recommended that all estrogen-based HRT data sheets (excluding vaginal preparations) are updated to include information on a drug interaction with lamotrigine.

    3.2.3 Third generation aromatase inhibitors and tendon disorders

    Background

    Medsafe was notified by a sponsor about a safety review conducted by Health Canada on third generation aromatase inhibitors (AIs; anastrozole, exemestane, letrozole) and the potential risk of tendon disorders.

    The Committee was asked to review the available information on this issue and consider whether further action is required in New Zealand.

    Discussion

    The Committee noted that AIs are primarily used in post-menopausal women who already have lower estrogen levels and an increased risk of tendonitis, and that AIs further lower oestrogen levels.

    The Committee queried the applicability of a study that suggested switching to a specific AI could reduce the risk of tendonitis. As AIs share the same mechanism, a switch to a medicine of the same drug class was unlikely to minimise the risk.

    The Committee noted that trigger finger (a form of tenosynovitis) is listed as an adverse reaction across all third generation AIs. The Committee commented on the crossover between tenosynovitis and carpal tunnel syndrome which is also listed as an adverse reaction. 

    The Committee noted the limited evidence for tendon rupture, but commented that tendonitis is a risk factor for tendon rupture.

    Overall, the Committee considered there was sufficient evidence to support a class effect of third generation AI and the risk of tendon disorders (including tendonitis, tendosynovitis, and tendon rupture). There was insufficient evidence to support that tendon disorders with this drug class are confined to a specific location.

    Recommendation 4

    The Committee recommended that all third generation aromatase inhibitor data sheets are updated to include tendon disorders as a warning and adverse event.

    Recommendation 5

    The Committee recommended that third generation aromatase inhibitors and the risk of tendon disorders is highlighted in Prescriber Update.

    3.2.4 Tumour lysis syndrome with tyrosine kinase inhibitors and monoclonal antibodies when used in cancer treatment

    Background

    Tumour lysis syndrome is an oncologic emergency that is the result of massive tumour cell lysis releasing potassium, phosphate and nucleic acids into the systemic circulation. This could lead to potentially life-threatening acute kidney injury (AKI) and cardiac arrhythmias. Tumour lysis syndrome most commonly occurs after the initiation of cytotoxic therapy in patients with high-grade haematological malignancies, but it can also occur with other tumour types.

    Tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) are commonly indicated to treat various types of cancer, including haematological cancers and solid tumours. Because tumour lysis syndrome commonly occurs soon after initiation of cytotoxic treatment, TKIs and mAbs have been discussed as possible causes of tumour lysis syndrome when used to treat cancer. The Committee was asked to advise on information on tumour lysis syndrome that should be included in the data sheets for these medicines.

    Discussion

    The Committee noted that any medicine used to treat malignancies carries the risk of tumour lysis syndrome, however this risk is related to factors such as the type of malignancy (eg, higher for haematological malignancies) and how aggressive the malignancy is being treated rather than the medicine itself. The Committee noted that tumour lysis syndrome occurring after cancer treatment is well known amongst oncologists.

    The Committee considered that updating a medicine data sheet with information on tumour lysis syndrome based on whether it was a TKI or mAb was not appropriate as these are broad groups of medicines, rather than particular classes. Most use of these is not associated with risk and only a few of these are used in circumstances where tumour lysis syndrome occurs.

    The Committee noted that nivolumab, pembrolizumab and midostaurin are indicated for haematological malignancies but tumour lysis syndrome is not listed in the data sheet. Given that haematological malignancies generally carry a higher risk of tumour lysis syndrome when treated with a cancer therapy, the Committee recommended that the data sheets for these medicines are updated.

    Recommendation 6

    The Committee recommended that the nivolumab, pembrolizumab and midostaurin data sheets are updated with information on tumour lysis syndrome.

    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 4, December 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 Updates from the Pharmacovigilance Guideline consultation

    The Committee was given an update on the Pharmacovigilance Guideline consultation. The Committee noted the audience for this consultation will be for the pharmaceutical industry.

    5.2 Updates on the #MedSafetyWeek 2023 campaign

    The Committee was given an overview of the 2023 #MedSafetyWeek campaign.

    5.3 Potential Prescriber Update articles

    The Committee suggested adverse reactions with dexamethasone and a spotlight article on lisdexamfetamine as topics for future Prescriber Update articles.

    The Chair and the Committee noted that this was Prof M Tatley’s last meeting and thanked him for his long and outstanding service to the Committee.

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

    Associate Professor Matt Doogue
    Chair, Medicines Adverse Reactions Committee
    Date:  27 February 2024 

Hide menus
Show menus
0 1 2 4 5 6 7 9 [ /