Published: 10 February 2021

Committees

MINUTES OF THE 184th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 184th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
3 December 2020

The one hundred and eighty-fourth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 3 December 2020 via Zoom videoconference. The meeting commenced at 9am and closed at 2.30pm.

MARC MEMBERS PRESENT

Dr C Cameron (Chair
Dr K Eggleton
Dr S Hanna
Dr C Kenedi
Associate Professor L Parkin
Hon. Associate Professor M Rademaker
I Raiman
C Ryan
Professor L Stamp
J Tatler
Associate Professor M Tatley
L Te Karu

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)
L Chan (Principal Technical Specialist, Pharmacovigilance)
V Cheer (Senior Advisor, Pharmacovigilance)
A Kerridge (Senior Advisor, Pharmacovigilance)
J Patel (Advisor Science, Product Regulation Branch)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

No invited guests.

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair opened with a karakia and welcomed the attendees to the meeting. The Chair extended a warm welcome to Dr Chris Kenedi as a new member of the Committee and welcomed back Hon. Associate Professor Marius Rademaker to the Committee.

No apologies were received.

1.2 Minutes of the 183rd MARC Meeting

The minutes of the 183rd meeting were accepted as a true and accurate record of the meeting.

1.3 Potential Conflicts of Interest

Committee members submitted their Conflicts of Interest Declaration forms to the Secretary. The Chair reminded the MARC members that in addition to conflicts disclosed in the declaration forms, members should declare conflicts of interest at the commencement of discussion of any relevant agenda item.

There were no potential conflicts of interest 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 discussed case ID 138422. This was a report of facial application site dermatitis and scarring with the use of Sukin Face Wash. The Committee noted that there are many herbal and organic oil ingredients listed in the product and would be difficult to ascertain the causative agent(s). The Committee also considered the reaction may have been due to the batch of the product itself, rather than the ingredients listed in the Sukin product

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.

2.1.8 Seasonal Influenza Vaccine Report

Summary of adverse events following immunisation following administration of the 2020 seasonal influenza vaccine 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 Gabapentin and pregabalin safety review

Background

Gabapentin and pregabalin (also collectively referred to as gabapentinoids) are antiepileptics that are also indicated for the treatment of neuropathic pain. Guidelines generally recommend tricyclic antidepressants, gabapentin and pregabalin as first-line medicines for neuropathic pain.

PHARMAC funding for gabapentin and pregabalin was widened in mid-2018. This led to some concerns that the use of gabapentin and pregabalin would increase leading to a higher likelihood of misuse, abuse and/or dependence. There was also some concern about the use of gabapentin and pregabalin in the elderly and whether reduced doses are needed.

During 2019, actions on the use of gabapentin and pregabalin were taken in other countries. For example, the United Kingdom classified both gabapentin and pregabalin as controlled drugs due to the rising number of deaths linked to the medicines. Gabapentinoids and risk of harmful and hazardous use was reviewed in Australia. The United States and Canada also published safety communications on the risk of respiratory depression when used with other central nervous system (CNS) depressants, including opioids.

The Committee was asked to consider three potential safety concerns with gabapentin and pregabalin: misuse, abuse and dependence; opioid-related death and respiratory depression; and use in elderly patients.

Discussion

The Committee discussed the prescribing of gabapentin and pregabalin for pain management. The Committee noted there may be prescribing of gabapentin and pregabalin for unapproved indications such as chronic non-neuropathic pain (eg, lower back pain) and chronic itch despite the low quality of evidence for their use in these situations. The Committee acknowledged the complexity of treating pain. Prescribers are often faced with limited pharmacological treatment options leading to the inappropriate prescribing of medicines to manage pain, including gabapentin and pregabalin.

To reduce the amount of inappropriate prescribing, the Committee agreed there is a need for primary healthcare provider education on the low quality of evidence for using gabapentinoids to treat chronic non-neuropathic pain. There is evidence for a multidisciplinary and biopsychosocial approach in treating pain, including treating the emotional distress as well as the pain. There is also encouraging evidence to show “authentic engagement” with the patient can be more effective in reducing their distress.

The Committee also discussed that there may be a lack of awareness among primary healthcare providers on the potential for patients to misuse gabapentinoids, and the potential for gabapentin to augment the effects of opioids.

Lastly, the Committee discussed the current gabapentin and pregabalin data sheets. The Committee suggested strengthening the pregabalin data sheet statement on respiratory depression when used concomitantly with CNS depressants (eg, opioids) so it is more aligned with the gabapentin data sheets. In addition, the Committee agreed information on using a reduced dose in the elderly should be strengthened in the gabapentin and pregabalin data sheets. The current pregabalin data sheet states no dose adjustment is necessary for elderly patients unless their renal function is compromised. Although age-related renal impairment is an important factor to consider for dose adjustment in the elderly, it is also important to consider that the elderly (particularly in frail patients) are more prone to adverse effects of medicines such as increased CNS adverse effects. Therefore, the Committee agreed that dose adjustments may be required in the elderly, irrespective of their renal function.

Recommendation 1

The Committee recommended that Medsafe liaise with appropriate bodies to request additional educational materials are made to increase the awareness to primary care providers that gabapentinoids should not be prescribed for chronic non-neuropathic pain, the potential for gabapentinoids to be misused, and their potential interaction with opioids.

Recommendation 2

The Committee recommended Medsafe requests the pregabalin data sheet be revised to strengthen the statement on respiratory depression with the use of CNS depressants (eg, opioids), and the gabapentin and pregabalin data sheets be updated to include information that dose adjustments may be required in the elderly, irrespective of renal function.

3.2.2 Opioids and abuse, misuse and dependence

Background

Opioids are used for pain treatment. They are generally indicated for moderate to severe acute pain and for cancer pain. They are not recommended for chronic non-cancer pain due to concerns over the long-term efficacy and safety of treatment, including the risk of abuse, misuse and dependence.

There has been international concern over increases in opioid prescribing, mainly attributed to prescribing for chronic non-cancer pain. The opioid epidemics in the USA and Canada coincided with sharp increases in prescription opioid-related deaths and overdoses. National governments and their respective medicines regulators have implemented various legislative changes and regulatory actions with the aim of limiting opioid harm in their jurisdictions.

The Committee was asked to review the available data on opioid use and to ascertain if there is a problem of abuse, misuse and dependence in New Zealand or a recent increase in this problem as seen elsewhere.

Discussion

The Committee acknowledged that there is a balance between regulating these medicines to prevent harm while still allowing patients safe and appropriate access to opioids to manage pain.

The Committee noted that from the global data, New Zealand is doing comparatively well with the issue of opioid abuse, misuse and dependence.

There have been concerted efforts across New Zealand in both primary and secondary care to minimise the use of strong opioids. For example, in secondary care, some hospitals have developed policies on the appropriate amount of opioids to prescribe to patients on discharge from hospital and educating junior doctors on these policies.

The Committee discussed that strong opioids in New Zealand are tightly regulated in terms of dispensing and the re-supply of repeats.

Nevertheless, the Committee agreed that there is evidence of abuse, misuse and dependence in New Zealand. The Committee was asked whether any regulatory actions for particular areas of opioid abuse, misuse and dependence were needed. It was suggested that given the relative success of control of strong opioids and their comparative greater use, the focus should be on weak opioids. Suggestions were to investigate updating the data sheets to include or strengthen the statement of harm so it is consistent with international product information, and developing a consumer leaflet that highlights the risk of opioid use. The Committee also highlighted that it was important to remind prescribers that the World Health Organization (WHO) Analgesic Ladder is a tool intended to manage chronic cancer pain and not chronic non-cancer pain. The Committee also wished to highlight the issue of hyperalgesia with the use of opioids.

Recommendation 3

The Committee recommended that Medsafe bring back an options paper concentrating on actions for weak opioids but also considering appropriate changes to data sheets, other regulatory options, education of prescribers and consumers and working with other agencies if appropriate.

Recommendation 4

The Committee recommended Medsafe to develop a consumer leaflet that highlights the risk of opioid use.

Recommendation 5

The Committee recommended raising awareness to prescribers that the WHO Analgesic Ladder is a tool intended to manage chronic cancer pain, and to highlight the issue of hyperalgesia with the use of opioids in a future edition of Prescriber Update.

[Dr C Kenedi was not present for this agenda item]

3.2.3 HER2- and CD receptor-targeted monoclonal antibodies and the risk of interstitial lung disease

Background

Medsafe was informed by CARM of a report of severe, life-threatening interstitial pneumonitis in a patient who received treatment for metastatic melanoma with pembrolizumab (Keytruda). Reports of interstitial lung disease (ILD) relating to rituximab and trastuzumab have also been received.

There is a plausible biological mechanism for a link between ILD and other monoclonal antibodies such as pertuzumab, obinutuzumab and daratumumab, which also use an immune-mediated pathway for their action. However, a relationship between pertuzumab, obinutuzumab and daratumumab and ILD does not currently appear to be documented in the literature.

The data sheets for atezolizumab, ipilimumab, nivolumab, cetuximab, trastuzumab, trastuzumab emtansine and rituximab contain information on the risk of pneumonitis. Currently the New Zealand pertuzumab data sheet does not list ILD as an adverse reaction, despite ILD being listed in international prescribing information.

The Committee was asked to consider whether the risk of ILD should be evaluated as part of the Sponsor’s Periodic Benefit Risk Evaluation Report (PBRER) submissions for pertuzumab, daratumumab and obinutuzumab, and whether any data sheet updates should be requested.

Discussion

The Committee noted that the link between HER2- and CD receptor-targeted monoclonal antibodies and the risk of ILD is difficult to establish. Some of the monoclonal antibodies discussed can be used to treat ILD and rheumatic diseases that are associated with ILD. They are often used concomitantly with other medicines that have a known association with ILD. The small number of New Zealand case reports was noted.

Because of the potential confounding from the underlying disease and concomitant medicines and limited information available, the Committee reflected that Medsafe could request the sponsors to gather information on the risk of ILD as part of their PBRER submissions. This would be limited to the medicines that currently do not have ILD listed in their data sheet.

Recommendation 6

The Committee recommended that the pertuzumab data sheet be updated to list interstitial lung disease to harmonise with international product information.

Recommendation 7

The Committee recommended that the risk of interstitial lung disease be assessed in the PBRERs for pertuzumab, daratumumab and obinutuzumab.

[Dr C Kenedi left the meeting at this time]

3.2.4 Tricyclic antidepressants and the risk of congenital malformation

Background

The current New Zealand data sheets for tricyclic antidepressant (TCA) medicines contain conflicting information about the risk to the fetus if used in pregnancy. It is important that the information in the data sheets reflect the current evidence about the risk to the fetus as the information may influence women’s decisions about pregnancy.

The Committee was asked to consider the available evidence on the risk of congenital malformation with the use of TCAs in the first trimester of pregnancy, and whether there is a need to update the data sheets for TCAs about the risk to the fetus.

Discussion

The Committee noted that there are conflicting statements in some TCA data sheets regarding the risk of congenital malformation to the fetus when taken in pregnancy. Some data sheets contain the Therapeutic Goods Administration Australia (TGA) pregnancy category C statement (“drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects in the human fetus or neonate without causing malformations”) while containing a statement that “epidemiological studies have suggested an increased risk of congenital abnormalities associated with the use of tricyclic antidepressants in pregnancy”. The Committee was reminded that the TGA pregnancy category system is not mandated in New Zealand, however, some sponsors chose to include this in the New Zealand data sheet to harmonise with Australia.

The Committee discussed the level of uncertainty of the risk of congenital malformation when TCAs are taken in the first trimester of pregnancy. The Committee also discussed that maternal depression without pharmacological treatment has been associated with adverse outcomes for the baby. After considering the evidence presented, the Committee concluded it was difficult to say that there is no risk, but at the same time difficult to say there is a risk and agreed that the current level of evidence is inconclusive. Therefore, it is essential that prescribers discuss the benefits and the level of evidence on risk of harm with women who take TCAs to enable them to make informed decisions.

Recommendation 8

The Committee recommended that the data sheets for TCAs be revised to remove the TGA Pregnancy category and for Medsafe to write to the sponsors of TCAs with a suggested wording that reflects the inconclusive information on TCAs use in the first trimester of pregnancy and the risk of congenital malformations in the fetus.

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 41, Number 4, December 2020

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 Early Warning System

The Committee noted the quarterly summary of Medsafe early warning system communications.

5.0 OTHER BUSINESS

5.1 COVID-19 vaccine safety monitoring

The Committee was given a summary of COVID-19 vaccine safety monitoring strategy in development by CARM and Medsafe.

6.0 ANNEXES

3.2.1 Gabapentin and pregabalin safety review

  1. CARM data

3.2.2 Opioid and abuse, misuse and dependence

  1. Opioid products approved in New Zealand
  2. Opioid usage information
  3. Australian boxed warning and class statements
  4. Explanation of the linked national collections data
  5. National Poisons Centre data
  6. Line listing of NZ tramadol cases for Drug abuse and Drug diversion

3.2.3 HER2- and CD receptor-targeted monoclonal antibodies and the risk of interstitial lung disease

  1. CARM data

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2.30pm.

Dr C Cameron
Chair, Medicines Adverse Reactions Committee
Date: 1 February 2021

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