Published: 27 January 2022

Committees

MINUTES OF THE 188th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 188th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

Thursday 2nd December

The one hundred and eighty-eighth meeting of the Medicines Adverse Reactions Committee (MARC) was held on Thursday 2nd December at 133 Molesworth Street, Wellington, via video conference. The meeting commenced at 9am and closed at 2.09pm.

MARC MEMBERS PRESENT

Dr C Cameron (Chair)
Associate Professor L Parkin
L Te Karu
L Carlyon
Dr A Pomerleau
Associate Professor M Doogue
Dr A Romain
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)

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.

1.2 Minutes of the 187th MARC Meeting

The minutes of the 187th 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 discussed case 142078. This was a case of pulmonary embolism with Levlen ED. The Committee noted concerns about the potential for patients not being informed about the signs and symptoms associated with deep vein thrombosis (DVT).

Recommendation 1

The Committee recommended that a Prescriber Update article be published about the signs and symptoms of DVT that patients who take combined hormonal contraceptives should be informed to monitor for, with reference made to consumer information leaflet available published by Medsafe (Hormonal Contraceptives and Blood Clots).

Recommendation 2

The Committee recommended to provide a letter to the Health Quality & Safety Commission to increase public awareness about the signs and symptoms of DVT to monitor for people who take combined hormonal contraceptives

The Committee discussed case 142282. This was a case of Bicalutamide and renal failure.

Recommendation 3

The Committee recommended that Medsafe review the signal of Bicalutamide and renal failure.

The Committee did not consider other 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

3.1.1 Dihydrocodeine: benefit-risk review

Background

At the MARC June 2021 meeting, the Committee queried the clinical benefits of dihydrocodeine (DHC) in pain management. The Committee noted that while the prescribing of DHC was low in New Zealand, the proportion of patients hospitalised from substance abuse and poisoning, associated with this medicine, was high compared to other weak opioids. The Committee expressed that the literature showed safety concerns with DHC use and the benefits in pain management were questionable. The Committee recommended Medsafe undertake a benefit-risk review of DHC.

On 12 July 2021, Medsafe issued a section 36(1) of the Medicines Act 1981 (the Act) notice to the sponsors of DHC products. Under this section of the Act, the Director – General of Health may request the sponsor to provide evidence that a product is safe and effective for the therapeutic purpose for which it is sold. If the sponsor is unable to satisfy the Director – General that the product is safe and effective for its therapeutic purpose, conditions on the use of the medicine may be imposed or the consent for distribution of the product may be revoked.

On 12 August 2021, Medsafe published a monitoring communication seeking feedback from consumers and healthcare professionals regarding the risks and benefits of DHC.

In this meeting, Medsafe presented a risk-benefit review of DHC and referred two DHC products to the Committee under section 36 (2) of the Act. The Committee was asked to advise whether the benefit-risk balance is favourable for the use of DHC for pain treatment and if any regulatory action is required to improve the balance of benefits and risks.

Discussion

The Committee commented initially on the hospitalisation data that had triggered this review. The Committee discussed potential confounding factors that may be present, rather than the drug itself, for the increased hospitalisations. The Committee highlighted that patient factors, such as the presence of other medicines (e.g., CNS depressants), may have the potential to exacerbate the side effects of DHC, and pre – dispose patients to harm.

The Committee agreed that it was difficult to review its net benefit versus other opioids.

The Committee discussed that it was difficult to review the harms associated with DHC. It was noted that the term ‘weak opioid’ may mean the DHC is seen as having less potential to cause harm.

The Committee considered that restricting access to DHC by revoking its consent would mean that there are fewer options for pain management.

The Committee noted that there are low numbers of patients in NZ currently using DHC, and that its use is not increasing. The Committee considered that there may be prescribers that may prefer prescribing DHC over other agents or who use it in certain clinical situations.

The Committee discussed the current inequities to access specialist pain services.

The Committee agreed that there was insufficient evidence to recommend revoking consent of the approved DHC products in New Zealand. However, they recommended that regulatory action was needed to improve information about DHC for prescribers and patients.

Recommendation 4

The Committee recommended that conditions be imposed on the indications of use of DHC to align with indications in the Australian Product Information for modified release opioid products:

[Product] is indicated for the management of severe pain where:

  • other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain, and
  • the pain is opioid-responsive, and
  • requires daily, continuous, long term treatment

[Product] is not indicated for use in chronic non-cancer pain other than in exceptional circumstances.

[Product] is not indicated as an as-needed (PRN) analgesia.

Recommendation 5

The Committee recommended that sponsors of DHC products in New Zealand supply a Consumer Medicines Information (CMI) sheet for publication on the Medsafe website.

Recommendation 6

The Committee recommended that the MARC write a letter to the Chief Medical Officer at the Ministry of Health to highlight inequities in access to pain services and of the need for leadership in the correct use of opioids.

3.2 Matters Referred to the MARC by Medsafe

3.2.1 Buccaline benefit-risk review

Background

Buccaline (Haemophilus influenzae, pneumococci (I, II, III), streptococci, staphylococci), is a restricted (pharmacist only) product that has been marketed in New Zealand for several decades. It is, indicated for the oral antibacterial prophylaxis of complications of colds and marketed with the claim ‘natural active oral vaccine’. Considering the limited evidence of efficacy or effectiveness of this product, a review of the benefits and risks of Buccaline was undertaken. The efficacy and safety of bacterial lystates for respiratory conditions, including Buccaline, was also recently reviewed by the European Medicines Agency (EMA) (27 June 2019).

The Committee was asked to advise whether the benefits of treatments outweigh the risks and advise on other potential issues associated with the medicine identified by Medsafe.

Discussion

The Committee noted that the use of the word ‘vaccine’ in association with Buccaline was concerning, and potentially misleading, as it can imply that Buccaline is comparable to other registered vaccines in terms of effectiveness and evidence base.

The Committee discussed concerns about the efficacy of the product and agreed there was lack of efficacy and safety data. It was acknowledged that the European Medicines Agency has required a randomised controlled trial for Buccaline, but the results will not be available until the year 2026. It was considered necessary to make any recommendations based on the currently available information.

The Committee agreed that public perception of the product may be incorrect. This could lead to harm if consumers delay or chose not to get the influenza vaccine and use Buccaline as an alternative.

The Committee discussed the implications associated with potential changes to the classification of Buccaline, including reclassification from a pharmacist only medicine to a prescription only medicine. The Committee did not see a benefit to reclassification of Buccaline as a prescription only medicine.

The Committee reinforced that approved medicines in New Zealand are endorsed by Medsafe as having a positive benefit risk balance. It was felt that if the product was to be evaluated against current requirements, there would be insufficient data to approve the product.

The Committee considered the harms that may be potentially associated with Buccaline use. These included using Buccaline as an alternative to well-studied vaccines or medicines, reduced uptake of the influenza vaccine, cost of product that may lack efficacy to the consumer, delay in seeking treatment and adverse reactions.

The Committee recommended that Medsafe undertakes a statutory risk-benefit review of Buccaline under section 36 of the Medicines Act 1981.

(L Te Karu left the meeting at this time.)

Recommendation 7

The Committee recommended that Medsafe request a review of the safety and efficacy of Buccaline under section 36 of the Medicines Act 1981.

3.2.2 Tocopherol and the risk of bleeding

Background

Medsafe were notified of a signal of tocopherol and intracranial haemorrhage at recommended doses of tocopherol.

Tocopherol (vitamin E) is a lipid-soluble antioxidant that reduces the state of oxidative stress. Alpha-tocopherol is the most biologically active form of tocopherol and the form known for its role in human health. The main oxidation product of alpha-tocopherol is tocopherylol quinone. Alpha-tocopherol is generally considered to have very modest anticlotting activity, however in contrast tocopherylol quinone is an anticoagulant.

This paper reviewed the potential safety concern of bleeding with tocopherol.

The Committee was asked to advise if the evidence presented supports there being an increased risk of bleeding with tocopherol, and if so, is further action required.

Discussion

The Committee discussed approved tocopherol-containing products that are currently available in New Zealand. It was noted that there are a range of general sale and pharmacy only products of which some are used in hospital.

The Committee discussed the evidence presented and noted that the information was more related to stroke, rather than all bleeding complications. It was noted that the information presented corresponded mostly to what is already known about topic.

The Committee discussed that it would be difficult to advise from the data presented about the risk of bleeding. It was also noted that there are different vitamin E compounds and the data presented talked about alpha-tocopherol specifically.

The Committee felt that possibly there is an association between tocopherol and the risk of bleeding, however there was insufficient evidence provided to support this and the clinical significance is not known.

The Committee agreed it may be helpful to check if there is an interaction with medicines that are known to cause bleeding such as oral anticoagulants.

Recommendation 8

The Committee recommended that Medsafe contact the sponsors of warfarin, dabigatran, rivaroxaban and apixaban, to ask them to review a possible interaction between vitamin E and their products regarding the risk of bleeding.

3.2.3 Update of Risk Management Plan for Comirnaty to include vaccination of children 5 - < 12 years of age

Background

This paper summarises an updated Risk Management Plan (version 3.0) for Comirnaty/Tozinameran/BNT162b2, a Covid-19 mRNA vaccine jointly developed by BioNTech and Pfizer. This RMP update was made in conjunction with the extension of the indication to children 5 to < 12 years.

The first Risk Management Plan was discussed at an out of session meeting on 20 January 2021.

The Committee was asked to advise whether any changes to the suggested questions on the RMP were required.

Discussion

The Committee discussed the proposed formulation, noting the change in formulation of the two new products (Paediatric and > 12 years). It was noted that the different products would have different cap and label colours to distinguish between the adult and children’s products. The Committee commented on the need for very clear information to be communicated by the company about these new products.

The Committee noted that within the New Zealand population, there are varying weights of children across the same age. It was noted that the development programme had examined several different doses and had selected the most appropriate for the age range.

The Committee suggested that the company could be asked about the appropriate dosing schedule for children who are 11 years old for their 1st dose, then subsequentially turn 12 before their 2nd dose.

The Committee agreed with the proposed requests for amendments to the Risk Management Plan and for confirmation that new safety information will be provided to Medsafe as it becomes available.

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

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.

4.3 Prescriber Update Volume 42, Number 4, December 2021

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.

(L Te Karu re-joined the meeting at 2pm)

5.0 OTHER BUSINESS

5.1 Oral updates on Covid – 19 vaccine signals

Discussion

Medsafe provided an update on Covid – 19 vaccine signals.

The Committee had no further comments.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2:09pm.

Dr Chris Cameron Date 14 January 2022
Chair, Medicines Adverse Reactions Committee

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