Published: 3 November 2021

Committees

MINUTES OF THE 187th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 187th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
9 September 2021

The one hundredth and eighty seventh meeting of the Medicines Adverse Reactions Committee (MARC) was held on 9 September 2021 via videoconference. The meeting commenced at 9am and closed at 2.20pm.

MARC MEMBERS PRESENT

Dr C Cameron (Chair)
Dr A Romain
Dr C Kenedi
Associate Professor L Parkin
Hon. Associate Professor M Rademaker
Z Malik
L Carlyon
L McDermott
Associate Professor M Tatley
Dr S Hanna
Dr A Pomerleau
Associate Professor M Doogue

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)
J Prankerd (Senior Advisor, Pharmacovigilance)
R Javed (Medical Advisor, Clinical Assessment)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

T Teunissen (Advisor, Pharmacovigilance, COVID-19 Vaccine and Immunisation Programme)
M Walton (Advisor, Pharmacovigilance, COVID-19 Vaccine and Immunisation Programme)
J Duncan (Principal Advisor, Pharmacovigilance, COVID-19 Vaccine and Immunisation Programme)

1.0 MATTERS OF ADMINISTRATION

1.1  Welcome and Apologies

The Chair welcomed the attendees to the meeting. The Chair extended a warm welcome to Dr A Pomerleau and Associate Professor M Doogue as new members of the Committee. Apologies were received from L Te Karu.

1.2  Minutes of the 186th MARC Meeting

The minutes of the 186th meeting were accepted as a true and accurate record of the meeting.

1.3  Potential Competing Interests

Committee members submitted their Competing Interests 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 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

No items.

3.2  Matters Referred to the MARC by Medsafe

3.2.1  Phentermine risk benefit review

Background

In December 2020, the Centre for Adverse Reactions Monitoring (CARM) received a report of stroke where phentermine was listed as the suspect medicine (CARM ID 139240). This case was reviewed by the Medsafe pharmacovigilance team. Medsafe was concerned about the safety of phentermine relative to the clinical benefits as cerebrovascular and cardiovascular events have been reported to CARM in the past. It was decided a risk-benefit review should be undertaken and that this review be presented to the Medicine Adverse Reactions Committee (MARC) for advice.

In addition, a review of the New Zealand data sheet for Duromine (the approved product for phentermine) contains a statement in the therapeutic indications that treatment with phentermine may be continued beyond 12 weeks, however longer-term use has not been approved in other countries. Medsafe would like to seek the advice of the MARC as to whether this statement should be revised, subject to the Committee’s overall view on the benefit risk balance for this medicine.

Discussion

As phentermine is a grandfathered product, the Committee noted that there is limited evidence regarding safety and efficacy. While studies show a clinically significant weight loss, this was noted to persist only while taking the medicine, with weight returning to baseline after cessation of phentermine.

The available literature was largely published prior to the year 2000. The randomised controlled trials consisted of small numbers of participants, with possible differential loss to follow up. A meta-analysis was noted to have an unclear methodology and a lack of assessment of bias in the included studies. From an epidemiological perspective, the evidence was considered uncertain.

It was also noted that the index case report lacks detail. Patients taking phentermine are inherently at increased risk of cerebrovascular and cardiovascular events due to elevated body mass index. The New Zealand pharmacovigilance database includes thirty-eight reports for phentermine, dating back to 1970. It was acknowledged that there may be under-reporting, although use is unknown as this is not a funded medicine.

It was noted that there is also limited data available around efficacy and safety when phentermine is used for longer than twelve weeks. From anecdotal experience, the Committee considered that phentermine is usually prescribed for a period of twelve weeks only. However, there are situations where phentermine may be prescribed for a longer period, including by specialists. This longer-term use is currently included in the data sheet.

It is known that phentermine and topiramate combinations are used longer-term in overseas jurisdictions with an acceptable safety profile. It was considered that this experience can inform the safety profile of phentermine when used beyond twelve weeks. Apart from one clinical trial conducted in 1968, not much is known about the efficacy and safety profile of the medicine when used intermittently rather than continuously.

The Committee considered that the evidence for a problem with phentermine addiction and misuse in New Zealand is limited to anecdotes. The relatively high price of phentermine products is likely to limit illicit use. The available abrupt cessation study was considered reassuring.

Anecdotally, it was noted that any calls to the National Poisons Centre or emergency department presentations would more likely be related to child exploratory exposures rather than misuse of phentermine. The lack of affordable alternative treatments for weight loss was noted. It was considered that phentermine has a role in bariatric medicine.

The Committee considered that the benefits of treatment with phentermine outweigh the risks of harm, and that a statutory benefit-risk review is unnecessary. It was considered that there is no need to make any changes to the data sheet or communicate further on this topic at this time.

3.2.2  Non-steroidal anti-inflammatory drug exposure in the second trimester and the risk of fetal renal impairment and oligohydramnios

[S Hanna left the meeting during this agenda item]

Background

On 15 October 2020, the US FDA issued a Drug Safety Communication warning that the use of non-steroidal anti-inflammatory drugs (NSAIDs) at around 20 weeks or later in pregnancy may cause rare but serious kidney problems in an unborn baby, leading to oligohydramnios and related pregnancy complications. The advice was based on the findings of a literature review and cases reported to the FDA Adverse Event Reporting System (FAERS) database.

The FDA required the NSAID product labels (prescribing information) to be updated with information about the risk of oligohydramnios and advice to avoid NSAID use in pregnant women from 20 weeks of pregnancy.

Other international regulators such as Health Canada have also taken actions regarding this safety concern.

The Committee was asked to advise whether the pregnancy advice in NSAID data sheets should be aligned to state that use of the medicine from 20 weeks gestation may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. The Committee was also asked to advise whether all NSAID data sheets should be aligned to state that use in the third trimester is contraindicated, and whether further communication on the risk of fetal renal impairment associated with NSAID exposure in pregnancy is required.

Discussion

The Committee noted that many of the cases of oligohydramnios associated with NSAID use in the literature describe use of indomethacin for tocolysis, although other NSAIDs were also implicated. These individuals may be monitored more closely, leading to possible detection bias.

Some case reports describe reversible oligohydramnios detected after short-term NSAID use. In some cases, the duration of use was unknown. It was considered that the risk of oligohydramnios is likely to increase with prolonged use.

It was noted that oligohydramnios might occur earlier in pregnancy, and the greater risk from 20 weeks gestation may reflect easier detection in the latter part of the second trimester. The Committee expressed concern that stating that oligohydramnios can occur from 20 weeks may be arbitrary and could provide false reassurance regarding treatment earlier in pregnancy. The Committee considered that any warnings in the data sheet should reflect this uncertainty.

The Committee noted that oligohydramnios is generally an effect of an underlying pregnancy-related condition, and is not a diagnosis in itself. However, depending on severity, gestational age and duration, oligohydramnios can lead to harmful complications. The lack of information on the harms arising from NSAID-induced oligohydramnios was noted.

The Committee considered that any required data sheet text relating to ultrasound monitoring of amniotic fluid when NSAIDs are used during pregnancy should reflect what is achievable in the New Zealand health system. The Committee commented that there is a lack of suitable alternative treatments for analgesia in pregnancy. It was considered that an alternative to paracetamol is necessary. There were concerns that discouraging short-term use of NSAIDs may increase the use of opioids. The Committee considered that the wording of any warnings should take into account the benefits of short-term use.

The Committee agreed that the review highlighted a number of inconsistencies across NSAID data sheets that need to be addressed. Consistent pregnancy information is desirable to avoid giving the impression that certain NSAIDs are safer than others.

Among the inconsistencies is a disagreement across data sheets about use in the third trimester. Many, but not all, data sheets state that NSAID use is contraindicated in the third trimester. The meloxicam and ketorolac data sheets contraindicate use across all trimesters, but in other jurisdictions are contraindicated only in the third trimester.

The Committee previously considered the risk of spontaneous abortion when NSAIDs are taken during pregnancy at the 170th meeting on 8 June 2017. The evidence was considered uncertain. However, it was recommended that NSAID data sheets be updated with information on this risk.

The Committee considered that the safety of NSAID use in the third trimester should be reviewed at a future meeting. The recommended wording about the risk of oligohydramnios will also be agreed at this time and incorporated into the recommended pregnancy warnings for NSAIDs.

Recommendation 1

The Committee recommended that the safety of NSAID use in the third trimester should be reviewed at a future meeting.

Recommendation 2

The Committee recommended that the pregnancy advice should be aligned across all NSAID data sheets and should include a warning about the risk of oligohydramnios in the second trimester. The wording should be agreed upon at a future meeting when use in the third trimester is reviewed.

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

TThere 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./p>

TThe Committee was given a demonstration of the Qlik apps for COVID-19 adverse events following immunisation and hospitalisation data.

4.3  Update on myocarditis and pericarditis with Comirnaty

The Committee was given an overview of the case reports of myocarditis in New Zealand and the possible mechanisms for COVID-19 vaccine-induced myocarditis that are described in the literature. The Committee was satisfied with the regulatory actions taken to date.

4.4  Prescriber Update Volume 42, Number 3, September 2021

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

4.5  Quarterly Summary of Medsafe Safety Communications

The Committee noted the quarterly summary of Medsafe safety communications.

5.0 OTHER BUSINESS

No items./p>

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2.20pm.

Dr C Cameron
Chair, Medicines Adverse Reactions Committee

Date: 9 October 2021

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