Published: 5 May 2024
Committees
MINUTES OF THE 197th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
- 1.0 MATTERS OF ADMINISTRATION
- 2.0 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE
CENTRE
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
- 4.0 MEDSAFE PHARMACOVIGILANCE ACTIVTIES
- 5.0 OTHER BUSINESS
MINUTES OF THE 197th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
14 March 2024
The one hundred and ninety-seventh meeting of the Medicines Adverse Reactions Committee (MARC) was held on 14 March 2024 at Ministry of Health building, Wellington. The meeting commenced at 9am and closed at 1 pm.
MARC MEMBERS PRESENT
A/Prof, M, Doogue (chair)
Dr, C, Kenedi
Dr, M, Rademaker
Dr, L Te Karu
Prof L Parkin
Dr, R, Savage
Ms, L, McDermott
Ms, L, Carylon
Ms, A, Biggs-Hume
A/Prof, A, Pomerleau
Dr, S, Leitch
Dr, H, WilsonMARC SECRETARIAT PRESENT
L, Collings (Senior Advisor, Pharmacovigilance)
N, Zhong (Senior Advisor, Pharmacovigilance)
T, Coventry (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)
J, Park (Advisor, Pharmacovigilance)
K, Van Bart (Medical Advisor, Clinical Risk Management)
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)
Dr, M, Wang (Clinical pharmacology trainee)1.0 MATTERS OF ADMINISTRATION
1.1 Welcome and Apologies
The Chair welcomed the attendees to the meeting.
1.2 Minutes of the 196th MARC Meeting
The minutes of the 196th 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
Members were given a brief description of the fatal reports.
The Committee discussed a drug reaction with eosinophilia and systemic symptoms (DRESS) with allopurinol. The Committed noted that it was reported allopurinol was started at 300mg a day. The Committee considered the importance of starting allopurinol at low doses and slowly titrating the dose.
The Committee commented on an overdose. The Committee questioned why the medicine was prescribed despite previous issues. The Committee discussed some of the available measures to restrict access/supply for high-risk patients.
The Committee did not consider any of the reports required further action.
2.1.2 Serious cases associated with vaccines
Reports of serious cases associated with vaccines were briefly outlined for the Committee.
The Committee did not consider any of the reports required further action.
2.1.3 Serious cases associated with medicines
Reports of serious cases associated with medicines were briefly outlined for the Committee.
The Committee commented on hydrocortisone/natamycin/neomycin ointment use on genitalia. The Committee considered that this ointment is not suitable for sensitive areas, such as under the foreskin. The Committee also discussed how prescribing the ointment may lead to antimicrobial resistance and that sensitisation may occur from the neomycin component.
The Committee was presented with a review by CARM on CARM reports of liver injury occurring after nitrofurantoin exposure for ≤7 days.
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 Ibuprofen and renal tubular acidosis
Background
In 2022, the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (EMA’s PRAC) requested that the product information for all ibuprofen with codeine combination products be updated with warnings on renal tubular acidosis (RTA) and severe hypokalaemia. It was considered that the risk was higher with prolonged use at higher than recommended doses and particularly in combination with codeine.
In the United Kingdom (UK), the product information for all systemic ibuprofen containing medicines has been updated to say the risk may occur following acute overdose and in patients taking ibuprofen products over long periods at high doses, including doses exceeding the recommended daily dose.
In New Zealand, there is one approved product containing ibuprofen with codeine. The company has already updated the data sheet with warnings that RTA and hypokalaemia have been reported when taking ibuprofen with codeine at higher than recommended doses.
The Committee was asked to consider whether the data sheets should be updated regarding this new information and if the updates should align with the EMA or UK actions.
Discussion
The Committee discussed that the risk of hypokalemic RTA with ibuprofen is dose dependent. The Committee considered that longer treatment durations may also increase the risk, however, agreed there is not enough information to understand risks of different treatment durations to define a threshold of risk.
The Committee noted that there have been case reports where RTA occurred at therapeutic doses. The Committee considered possible risk factors such as genetic dispositions and variations in carbonic anhydrase, that may increase the risk of ibuprofen-induced RTA in certain individuals, but these have not yet been defined.
The Committee noted that there is a plausible mechanism for ibuprofen-induced RTA to occur. It was also highlighted that metabolic acidosis can occur with ibuprofen in two other ways. In overdose, ibuprofen is acidic and at high doses this lowers pH. Hyperkalemic RTA has been seen as a class effect of non-steroidal anti-inflammatory medicines (NSAIDs), this is a different mechanism to hypokalemic RTA, which appears to be specific to ibuprofen.
The Committee noted that the scientific literature discussing potential mechanisms suggested that ibuprofen inhibits carbonic anhydrase, and this is not reported with other NSAIDs. Therefore, the Committee did not consider a class effect for all NSAIDs to be needed at this time.
The Committee considered that ibuprofen is a widely used medicine, where the renal adverse effects of acute tubular necrosis are known and is more common than hypokalemic RTA.
Overall, the Committee agreed that RTA and hypokalaemia may occur following ibuprofen ingestion and recommended that all ibuprofen-containing products taken systemically should be updated with this information. The Committee recommended that the data sheets should include that the risk is increased with higher doses of ibuprofen and following acute overdose, however, may also occur within the recommended dose range.
The Committee also recommended that signs and symptoms of RTA be included in the data sheets to prompt healthcare professionals to consider this diagnosis in patients with unexplained hypokalaemia.
Recommendation 1
The Committee recommended the data sheets for all ibuprofen-containing products taken systemically should be updated to include information about risk of RTA and hypokalaemia.
3.2.2 SSRIs, SNRIs with alcohol in overdose and suicide
Background
In 2022, EMA’s PRAC committee recommended updating sections 4.4 (warnings and precautions), 4.5 (interactions) and 4.9 (overdose) of the venlafaxine prescribing information (SmPCs) to reflect data regarding suicidal/suicide events, severe intoxication with venlafaxine, and combined poisoning involving alcohol and/or other medicines or other substances.
Venlafaxine is a serotonin and noradrenaline re-uptake inhibitor (SNRI). The scope of this review was widened to also include selective serotonin re-uptake inhibitors (SSRIs).
The purpose of the paper was to review information on co-ingestion of SSRIs/SNRIs with alcohol in overdose and suicide.
Discussion
The Committee noted that in the Medicines Regulations 1984, anti-depressant medicines are required to be packaged in a safety container and are packaged in blister strips.
The Committee noted that the venlafaxine data sheet has been recently updated in line with the EU SmPCs. The Committee agreed that venlafaxine toxicity is different to that of SSRIs due to venlafaxine’s potential for cardiac complications or seizures when taken in overdose.
Venlafaxine is the only SNRI currently approved for use in New Zealand and the Committee agreed that it was likely a class effect of SNRIs.
The Committee agreed there is a pharmacodynamic synergistic mechanism between alcohol and medicines that cause CNS depression. The Committee particularly noted that the anti-depressant medicine mirtazapine is sedating, and that additive sedation may have secondary impacts on activities such as driving and operating machinery.
The Committee noted the increasing use of the SSRI, sertraline, from community dispensing data from 2018 to 2022.
The Committee highlighted that cases of overdose and suicide are complex and multifactorial, and commented that alcohol and depression are major risk factors. The contribution of exposures, including medicines, to these outcomes may not be quantifiable as contributing factors.
The Committee discussed the use of alcohol with anti-depressant medicines, and that in clinical practice, the combination is not advisable. The Committee recommended that all SSRI data sheets should contain consistent information about ingestion of alcohol.
The Committee considered that local guidelines in New Zealand sufficiently acknowledge that venlafaxine is a second-line treatment option for depression. The Committee agreed that no changes are required to the venlafaxine data sheet relating to indications for use or relating to ingestion of alcohol.
The Committee suggested that the information in section 4.9 on doses of concern be removed from data sheets as per clinical guidance and risk to patients. This information is readily available to healthcare professionals through the National Poisons Centre.
Recommendation 2
The Committee recommended that all SSRI data sheets should contain consistent information about ingestion of alcohol.
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 45, Number 1, March 2024
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 Clozapine Survey 2023
The Committee was presented with a preliminary draft report of responses from the Clozapine Survey 2023.
The Committee provided feedback and comments on the format and structure of the report for Medsafe to review before publication.
The Committee discussed that the haematological monitoring requirements of clozapine was an area of initial focus and recommended this topic to be further discussed at a future meeting.
5.2 Buccaline
The Committee noted the minutes from the meeting of 9 June 2022 have not yet been published. The Committee asked for the minutes to be published.
5.3 Health Sector Changes
The Chair updated the Committee about the disestablishment of the National Medicines Safety Expert Advisory Group of Health Quality and Safety Commission (HQSC) and the establishment of the National Medicines Steering Group in the Ministry of Health and the Medication Digital Ecosystem Oversight Group.
5.4 Unapproved Medicines Use
The Committee expressed concern at the continued high use of unapproved medicines with supply shortages.
The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 1 pm.
Associate Professor Matt Doogue
Chair, Medicines Adverse Reactions Committee
Date 18 April 2024
