Published: 14 April 2022

Committees

MINUTES OF THE 189th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 189th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

10 March 2022

The one hundred and eighty-ninth meeting of the Medicines Adverse Reactions Committee (MARC) was held on Thursday 10 March 2022 at 133 Molesworth Street, Wellington, via video conference. The meeting commenced at 9am and closed at 2.18 pm.

MARC MEMBERS PRESENT

Dr C Cameron (Chair)
Associate Professor L Parkin
L Te Karu
Dr A Pomerleau
Associate Professor M Doogue
Honorary Associate Professor M Rademaker
Associate Professor M Tatley
L McDermott
Z Malik
Dr C Kenedi

MARC SECRETARIAT PRESENT

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

MEDSAFE STAFF IN ATTENDANCE

S Kenyon (Manager, Clinical Risk Management)
V Cheer (Senior Advisor, Pharmacovigilance)
M Storey (Senior Advisor, Pharmacovigilance)
J Prankerd (Senior Advisor, Pharmacovigilance)
T Kim (Advisor, Pharmacovigilance)
S Tran (Advisor, Pharmacovigilance)
R Javed (Medical Advisor, Clinical Assessment)
J Stanley (Medical Advisor, Clinical Assessment)

1.0 MATTERS OF ADMINISTRATION

1.1  Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Ms Carlyon  and Dr S Hanna.

1.2  Minutes of the 188th MARC Meeting

The minutes of the 188th 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 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 142360. This was a case of Stevens Johnson syndrome in a child aged 12 years who was taking lamotrigine. The Committee noted that there was a likely dosing error, and that the age bands of 2-12 years and 12-18 years in the dosing recommendations overlap, creating ambiguity around the correct dose for a 12-year-old. It was also noted that rapid dose titration, more than the absolute dose, is associated with increased risk of Stevens Johnson syndrome. The Committee considered that healthcare professionals should be reminded about the importance of appropriate lamotrigine dose titration in relation to Stevens Johnson syndrome.

Recommendation 1

The Committee recommended that case 142360 be highlighted in Prescriber Update to remind healthcare professionals about the importance of appropriate lamotrigine dose titration in mitigating the risk of skin reactions, including Stevens Johnson syndrome.

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 discussed case 142835. This was a case of cerebral infarction with Levlen ED. The Committee noted that a reminder about deep vein thrombosis as a risk of combined oral contraceptives had been recently published in Prescriber Update, but considered that this case should also be highlighted to prescribers.

Recommendation 2

The Committee recommended that case 142835 should be highlighted in Prescriber Update to remind prescribers about the risks of arterial thrombosis with combined oral contraceptives.

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  Glucagon like peptide-1 receptor agonists and drug induced liver injury

Background

In February 2021 the US Food & Drug Administration (FDA) initiated an evaluation into marketed products containing glucagon like peptide-1 receptor agonists (GLP1-RAs) and the signal of drug-induced liver injury (DILI). The FDA identified this safety signal through routine post-market pharmacovigilance activities. As a result of the evaluation, the FDA requested product information sheets for liraglutide (Saxenda, Victoza) to include information on hepatobiliary disorders. It is not yet known if DILI arises from other GLP1-RAs.

In New Zealand, dulaglutide is indicated for the management of type 2 diabetes mellitus (T2DM) and is the only funded GLP1-RA. T2DM affects many New Zealanders, therefore the expected use of this medicine is high. The three GLP1-RA products available in New Zealand (dulaglutide, exenatide, liraglutide) were discussed.

The Committee was asked to advise whether the current evidence supports an association between DILI and GLP1-RAs and whether any regulatory action is required.

Discussion

The Committee noted that the GLP1-RA class of medicines has been in use for a number of years and that non-alcoholic hepatitis is prevalent in the population using the medicine.

The Committee noted that the data sheet for liraglutide recommends monitoring of liver enzymes, while the data sheet for dulaglutide does not include this recommendation. It was thought that this may reflect the fact that liraglutide came to market earlier when there was more uncertainty around the risk of DILI. Consistency of data sheet information on liver enzyme monitoring across the class of GLP1-RAs was considered desirable.

Liver enzymes are often raised in this population at baseline and decrease on average while being treated with GLP1-RAs. It was considered that monitoring liver enzymes has limited utility for the purposes of detecting liver injury potentially related to GLP1-RA therapy. It was noted that liver enzymes are a useful marker of improvement in this population but this a separate issue to monitoring the safety of GLP1-RAs.  

The Committee noted that autoimmune hepatitis is a theoretical risk that has not emerged as a safety concern after use for a number of years. It was thought to be an occasional idiosyncratic reaction that is not occurring at a rate that is higher than expected.

It was noted that dulaglutide is newly funded in New Zealand, with Special Authority criteria making it available to Māori and Pacific peoples with type 2 diabetes. Therefore, there has been limited post-market experience in these New Zealand populations, but they are not expected to be at higher risk than the general population.

The Committee did not consider that the current evidence supports an association between GLP1-RAs and DILI. The Committee recommended that the liraglutide data sheet information on liver enzymes should be aligned with the dulaglutide data sheet.

Recommendation 3

The Committee recommended that the data sheet information on liver enzymes in the liraglutide data sheet is aligned with the dulaglutide data sheet (ie, the recommendation for liver enzyme monitoring can be removed).

3.2.2  Venlafaxine use in pregnancy

Background

A multicentre case-control study was published in August 2020 that assessed whether there were any associations between maternal antidepressant use and specific birth defects. The results of the study suggested some associations, with venlafaxine having the highest risk of being associated with congenital anomalies.

In addition to this, dose-related hypertension is a recognised adverse drug effect of venlafaxine and there is current evidence that suggests an association between antidepressant use during pregnancy and the risk of developing gestational hypertension. A retrospective cohort study showed potential associations between exposure to antidepressants and gestational hypertension.

The Committee was asked to advise whether the current evidence supports associations between venlafaxine use and increased risk of congenital malformations or gestational hypertension and whether any regulatory action is needed.

Discussion

The Committee noted that the number of pregnancies exposed to venlafaxine is small, making it difficult to draw conclusions on the risk of congenital malformations. It was noted that it was difficult to interpret the scientific literature as there was a lack of information on the background rate of the malformations.

The increasing use of venlafaxine during pregnancy in New Zealand was noted. The Committee requested that Medsafe continue to monitor usage to see if it continues to climb.

The risks associated with switching to a different antidepressant were considered alongside the limitations of the evidence of harm during pregnancy. The Committee noted that venlafaxine is not generally used as a first line medicine and that patients taking this medicine may have more a severe or unstable condition.

It was felt that the existing benefit risk statement in the data sheet regarding congenital effects covered the available evidence and was reasonable. The Committee considered that the Australian pregnancy category B2 statement should be removed from the venlafaxine data sheets as it is incongruent with the benefit-risk statement. The Australian classification system is no longer in use in clinical practice and is not required in New Zealand medicine data sheets.

The Committee considered that is it biologically plausible that venlafaxine could be associated with gestational hypertension. The evidence for increased risk of gestational hypertension with venlafaxine use suggested a possible association but was considered inconclusive. It was felt that the existing data sheet information regarding hypertension was sufficient.

Recommendation 4

The Committee recommended that the pregnancy category B2 statement be removed from venlafaxine data sheets.

3.2.3  Safety of non-steroidal anti-inflammatory drug exposure in 3rd trimester of       pregnancy

Background

Information in the New Zealand data sheets regarding the use of non-steroidal anti-inflammatory drugs (NSAIDs) in pregnancy is currently inconsistent. Medicines containing ibuprofen, diclofenac, ketoprofen or tenoxicam are contraindicated in the third trimester, medicines containing meloxicam or ketorolac are contraindicated throughout pregnancy, while naproxen and the COX-2 inhibitors (celecoxib, etoricoxib and parecoxib) are not contraindicated in pregnancy.

The Committee reviewed the association between second trimester use of NSAIDs and the risk of fetal renal impairment/oligohydramnios at the 187th meeting on 9 September 2021. The review highlighted inconsistencies across the NSAID data sheets in sections 4.3 Contraindications and 4.6 Fertility, pregnancy and lactation. The Committee considered that consistent pregnancy information is desirable to avoid giving the impression that certain NSAIDs are safer than others.

The Committee deferred their recommendation about updating the NSAID data sheet wording on second trimester use until they had reviewed the safety of NSAIDs in the third trimester. The available information on the safety of NSAIDs in the third trimester of pregnancy was reviewed in order to address the data sheet inconsistencies about use of these medicines in pregnancy.

The Committee was asked to advise whether all NSAIDs should be contraindicated in the third trimester of pregnancy, whether section 4.6 of the data sheets should be aligned, and whether any further action is needed.

Discussion

The Committee noted that the timeframe for the risk of oligohydramnios of beyond 20 weeks is an artefact of when oligohydramnios is generally detected. It was felt that oligohydramnios may occur earlier than this but may go undetected. It was noted that expressing the timeframe in weeks is in contrast to other risks, which are usually stated according to trimester. It is unknown if fetal renal injury has been observed in the context of NSAID-induced oligohydramnios.

The Committee noted that the literature describing risks of NSAID exposure during the third trimester was limited. Contraindications to use in the third trimester appear to be based on conventional wisdom and older data. The Committee noted that alignment of third trimester contraindications across all NSAIDs would be considered based on mechanism of action, rather than epidemiological data. The Committee considered that the similar affinity of cyclo-oxygenase-2 (COX-2) selective inhibitors and non-selective NSAIDs for COX-2 supports the idea that these two types of NSAIDs would have similar effects in pregnancy.

The Committee noted that the wide availability of over-the-counter NSAIDs in large pack sizes is often not considered and that usage in this context is difficult to measure. This ubiquity also contributes to public perception of NSAIDs as benign medicines.

The Committee concluded that all NSAIDs should be contraindicated in the third trimester of pregnancy and that the pregnancy information in the data sheets should be aligned. The Committee recommended that Medsafe consult with the Committee to develop text for all data sheets that appropriately encompasses the risks throughout pregnancy, including the risks of oligohydramnios and third trimester use.

Recommendation 5

The Committee recommended that Medsafe should consult with the Committee to develop suitable text for section 4.6 of all NSAID data sheets that encompasses the risks of use throughout pregnancy.

Recommendation 6

The Committee recommended that this topic be communicated in Prescriber Update.

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.

4.3  Prescriber Update Volume 43, Number 1, March 2022

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

4.4  Quarterly Summary of Medsafe Safety Communications

The Committee noted the quarterly summary of Medsafe safety communications.

5.0  OTHER BUSINESS

5.1  Oral updates on COVID-19 vaccine safety signals

The Committee was given an update on general reporting trends for COVID-19 vaccines.

5.2  Spikevax risk management plan

The Committee was given an overview of the proposed Spikevax risk management plan./p>

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2.18 pm.

Dr Chris Cameron 
Date: 4 April 2022
Chair, Medicines Adverse Reactions Committee 

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