Published: 19 July 2021

Committees

MINUTES OF THE 186th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 186th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
10 June 2021

The one hundred and eighty-sixth meeting of the Medicines Adverse Reactions Committee (MARC) convened via Teams videoconference on 10 June 2021. The meeting commenced at 9am and closed at 2.30pm.

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
L Te Karu
Dr S Hanna

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)

INVITED GUESTS/OBSERVERS

J Duncan

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 A Romain, L McDermott, Z Malik, and L Carlyon as new members of the Committee.

No apologies were received.

1.2 Minutes of the 185th MARC Meeting

The minutes of the 185th 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 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 discussed case 139546. This was a case of meningioma with cyproterone acetate. The Committee noted that this risk was highlighted to healthcare professionals in the September 2020 edition of Prescriber Update.

The Committee discussed case 139444. This was a case of diabetic ketoacidosis (DKA) in a patient with type 2 diabetes on empagliflozin. The Committee noted that healthcare professionals may not associate DKA in patients with type 2 diabetes as this condition is more commonly associated with patients with type 1 diabetes. With the recent funding access to empagliflozin, the Committee thought it was important to highlight the risk of DKA in patients taking empagliflozin.

The Committee did not consider any other reports required further action.

Recommendation 1

The Committee recommended highlighting that diabetic ketoacidosis can occur in patients with type 2 diabetes on empagliflozin in a future edition of Prescriber Update.

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 Consideration of bufexamac medicines under section 36 of the Medicines Act 1981

Background

Serious skin reactions have been reported overseas following the use of topical bufexamac-containing products. The Therapeutic Goods Administration (Australia) determined that the benefit-risk balance of bufexamac-containing products was unacceptable and removed bufexamac-containing products from the Australian Register of Therapeutic Goods on 18 September 2020.

On 10 December 2020, Medsafe on behalf of the Director-General of Health issued a notice under section 36(1) of the Medicines Act 1981 (the Act), requesting the sponsor to provide evidence of the safety and efficacy of Antiseptic Soothing Cream within 60 days. As the sponsor did not provide evidence to support favourable safety and efficacy in response to the section 36 notice, Medsafe on behalf of the Director-General of Health decided to refer the matter to the MARC under section 36(2) of the Act.

On notification of the proposed referral to the MARC, the sponsor requested Medsafe to change the status of the medicine to ‘approval lapsed’.

Medsafe is seeking advice from the MARC on whether, under section 36(3) of the Act, to:

  1. prohibit the sale or supply of the medicine or
  2. impose conditions on the sale or supply of the medicine.

Topical medicines containing bufexamac 5% or less are classified as ‘general sale’ so they can easily be imported into New Zealand. Given the risk of dermatological reactions associated with the use of bufexamac, Medsafe asked the Committee to advise whether additional actions are needed, such as referring bufexamac to the Medicines Classification Committee (MCC) to review its classification.

Discussion

The Committee noted that all of the active ingredients in Antiseptic Soothing Cream (bufexamac, chlorhexidine and lidocaine) are potent sensitisers that may cause skin reactions.

The Committee noted that the MARC reviewed the safety of medicines containing bufexamac and indicated for dermatitis, hives and rash in 2011. At the time, the MARC concluded that the benefit-risk balance was unfavourable and recommended that the consent be revoked. The MARC considered that Paraderm Plus (a topical preparation containing bufexamac, chlorhexidine and lidocaine) could remain on the market with a revised indication so that consumers had an alternative option to treat dermatological complaints without the need to use topical steroid or antibiotic preparations unnecessarily.

The Committee commented that in the past two decades a surge in availability of natural and healthcare products for the skin meant that many topical steroid-free alternatives were available to alleviate dermatological complaints.

The Committee considered the risk-benefit profile of medicines containing bufexamac was unfavourable given that bufexamac is a potent sensitiser associated with skin reactions with limited, if any, benefits. The Committee recommended that the consent to distribute medicines containing bufexamac be revoked.

In addition, the Committee recommended that Medsafe requests the MCC to review the classification of bufexamac.

Recommendation 2

The Committee recommended to the Minister’s delegate that the sale and supply of medicines containing bufexamac be prohibited (ie, that the consent to distribute should be revoked).

Recommendation 3

The Committee recommended Medsafe to submit an application to the Medicines Classification Committee to reclassify preparations containing bufexamac to a prescription medicine.

Recommendation 4

The Committee recommended that Medsafe issue an alert communication on this issue.

3.2 Matters Referred to the MARC by Medsafe

3.2.1 Boron-containing excipients and fertility concerns

Background

In 2017, the European Medicines Agency (EMA) added boric acid and borates to its guidance on excipients and requirements for patient information leaflets. The guidance requires a contraindication and warning about fertility concerns for children under 2 years of age for medicines where the indicated dose would result in administration of boron in excess of the threshold of 1 mg boron per day.

In April 2021, the Royal College of Ophthalmologists (UK) released a safety alert regarding the above EMA guidance. The statement noted that some manufacturers have added contraindications to their chloramphenicol eye drop products for children under two years of age due to the boric acid content. The College considered that when used appropriately, the benefits of chloramphenicol eyedrops in paediatric ophthalmic practice outweigh the possible risks posed by boron ingestion.

Following the statement from the Royal College of Ophthalmologists, Medsafe has received several queries from healthcare professionals regarding this potential safety concern. Some queries concerned whether chloramphenicol eye drops should continue to be used in children under two, or whether a boron-free alternative such as chloramphenicol eye ointment should be used instead.

As a result, a review of all medicines containing boric acid and borax has been carried out. The medicines with the highest daily boron dose at the maximum dose in the data sheet were presented to the Committee. This includes antibiotic eye drops containing tobramycin and chloramphenicol as they may be dosed frequently in severe superficial eye infections.

The Committee was asked to advise whether the data sheets for any of these medicines should be changed to reflect fertility concerns due to boron-containing excipients or whether these should be changed in any other respect to mitigate this concern.

Discussion

The Committee noted that the evidence relating to boron and fertility concerns was based on animal studies and appeared to be dose related. The relevance to humans was uncertain.

The Committee commented that the human studies looked at environmental boron exposure in areas high in natural boron. These studies did not find a correlation between environmental boron exposure and fertility issues. However, it was noted that the numbers of people in the exposed groups were small, and the range of estimated daily boron exposures varied. The Committee noted that in general, it is difficult to undertake human studies to determine whether boron exposure in early life increases the risk of later infertility. The Committee emphasised that although these human studies did not show a concern of fertility and developmental issues, there were no sufficiently robust studies to rule this out. The Committee agreed that the data sheets for all boron containing medicines should be updated to reflect what is known from the animal and human studies.

The Committee noted that a statement issued by the Royal College of Ophthalmologists (“chloramphenicol eye preparations have been widely used in children of all ages for many years with no documented adverse effects on fertility”) was not meaningful as documented cases would not be expected given the length of time between exposure and outcome.

The Committee considered the following medicines that could exceed the threshold of 1 mg of boron per day when used at the maximum dose outlined in the data sheet or package labelling for under 2 years of age. The Committee made the following recommendations:

Chloramphenicol eye drops – the Committee agreed that the sponsors for chloramphenicol should adopt a paediatric dosing in their data sheets that aligns with the Starship Guidelines (one drop into the affected eye(s) four times a day) for bacterial conjunctivitis. This dose would not result in the child being exposed to high levels of boron.

Clear Eyes (naphazoline) 0.01% eye drops – the Committee noted that the Clear Eyes packaging has no lower age limit. This was concerning as the Committee considered this product should not be used in children. The New Zealand Formulary for Children states an age limit of 12 years of age. The Committee expressed concerns that because Clear Eyes is a pharmacy-only medicine, it could be used in children under the age of 12 years inappropriately without further investigation or adequate input from a healthcare professional. The Committee recommended the package labelling be updated to reflect the age recommendation in the New Zealand Formulary for Children through a Label Statements Database consultation.

Isopto Carpine (pilocarpine) eye drops – the Committee noted that the 4% strength of this product exceeds the daily boron threshold when used in children under 2 years of age. The Committee further noted that ophthalmological use of pilocarpine is rare in this age group and that lower strength Isopto Carpine available should be used instead where the daily boron exposure would not be exceeded.

Tobrex (tobramycin) eye drops – the Committee noted that ophthalmological use of tobramycin is not featured in clinical guidelines and the dispensing data show very low usage in children under 2 years of age. As tobramycin can be instilled hourly for severe superficial eye infections, the Committee recommended the data sheet be updated to include the maximum number of drops per day that does not exceed the maximum daily boron exposure.

Lastly, the Committee commented that the issue of boron and fertility issues may not be well known in primary care and recommended that this issue is communicated to the relevant professional bodies.

Recommendation 5

The Committee recommended that all data sheets for medicines with boron-containing excipients include a statement that reflects what is known from animal and human studies such as, ‘excipients containing boron have been shown to cause reduced fertility and effects on embryofoetal development in animal studies and this appears to be dose related. The relevance of this to humans is uncertain’.

Recommendation 6

The Committee recommended that the sponsors for chloramphenicol eye drops adopt a paediatric dosing (under 2 years of age) in their data sheets that follow the New Zealand Starship Guidelines for bacterial conjunctivitis.

Recommendation 7

The Committee recommend that the packaging for Clear Eyes include an age limit for use in people 12 years and over through a Label Statements Database consultation.

Recommendation 8

The Committee recommended an update to the Tobrex eye drop data sheet to state a maximum number of drops per day for children under 2 years of age so that the maximum daily exposure of boron is not exceeded.

Recommendation 9

The Committee recommended that this issue is highlighted to the Pharmaceutical Society of New Zealand, and the Royal New Zealand College of General Practitioners.

3.2.2 Misuse of stimulant laxatives

Background

In August 2020, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom published their benefit-risk review of over-the-counter (OTC) stimulant laxatives (orally and rectally administered). Following this review, the MHRA introduced pack size restrictions, revised recommended ages for use, and new safety warnings

The Committee was asked to review the information on the misuse of stimulant laxatives in New Zealand and to advise whether the evidence of the misuse warrants taking further action.

Suggested options for further action included applying to the Medicines Classification Committee (MCC) to reclassify stimulant laxatives, updating the Label Statements Database to include warnings for stimulant laxatives and communicating this topic to healthcare professionals (eg, an article in Prescriber Update).

Discussion

The Committee noted that although there was no literature documenting misuse of stimulant laxatives in New Zealand, members of the Committee have seen the misuse of laxatives anecdotally through their various practice settings. However, the extent of the misuse is difficult to quantify.

The Committee considered the implications of reclassifying stimulant laxatives so that they are:

  1. available for general sale (eg, glycerol suppositories) for use only in adults (ie, 18 years of age and older)
  2. classified as pharmacy-only medicines (ie, bisacodyl, sennosides and sodium picosulfate) for use only in patients aged 12 years of age and above
  3. otherwise classified as restricted medicines.

The Committee also considered whether pack size restrictions could be included in the proposed classification statements to reflect that these medicines should only be used for short-term, occasional constipation.

The Committee noted that any reclassification could disadvantage patients who may have a medical need to purchase stimulant laxatives conveniently OTC. The Committee also noted that if an age restriction is decided this would need to be evidence-based. From the available data it is unclear which age group is misusing laxatives.

The Committee was advised that when an application to reclassify a medicine is made to the MCC, there is an open consultation where affected stakeholders and consumers are able to comment.

The Committee considered whether introducing pack size restrictions for stimulant laxatives would reduce the issue of misuse. It was noted that if pack sizes were reduced to smaller quantities it would not prevent buyers from ‘shopping’ around. The Committee noted that restricting pack size is unlikely to reduce the misuse of laxatives among patients with eating disorders as laxative misuse in this group is not an impulsive act, but the misuse occurs over a long period of time.

The Committee noted that reclassifying large pack sizes could raise public awareness of the dangers of stimulant laxatives and allow early engagement with a health professional. This would be particularly beneficial for elderly patients with unresolved constipation due to an undiagnosed medical condition, and individuals who may be considering misusing laxatives for weight loss.

The Committee considered that the above options were unlikely to reduce the misuse of laxatives. The Committee recommended Medsafe undertake a Label Statements Database consultation to include warning and advisory statements to the manufacturer’s original pack for all stimulant laxatives (eg, ‘does not help with weight loss’ and ‘prolonged or excessive use can be harmful’).

The Committee noted that the effectiveness of the recent MHRA regulation activities around stimulant laxatives have not yet been evaluated but would be interested to learn about the effectiveness of these interventions.

The Committee was advised that there were guidelines and recommendations from the Pharmaceutical Society of New Zealand to assist pharmacists around the supply and storage of OTC medicines associated with misuse which included stimulant laxatives. The Committee considered that to the Society be contacted so the Committee could endorse the guidelines.

Recommendation 10

The Committee recommended adding warning and advisory statements to the manufacturer’s original pack for all stimulant laxatives through a Label Statements Database consultation.

Recommendation 11

The Committee recommended that Medsafe write to the Pharmaceutical Society of New Zealand to endorse their practice and guidelines on the supply and storage of medicines that could be misused over the counter.

3.2.3 Options for minimising opioid abuse, misuse and dependence

Background

In December 2020, Medsafe presented a paper to the Committee regarding opioid abuse, misuse and dependence. This paper reviewed the available data on opioid use to try and ascertain if there was a problem in New Zealand, or a recent increase in problems as seen in other countries. At the time, the Committee noted that from the global data, New Zealand was doing comparatively well with the issue of opioid abuse, misuse and dependence.

A recommendation the Committee made was for Medsafe to 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.

In this meeting, the Committee was presented an options paper for minimising opioid abuse, misuse and dependence in New Zealand. The Committee was asked to consider which regulatory activities would be appropriate to implement.

Discussion

The Committee queried the clinical benefits of dihydrocodeine in pain management. The Committee noted that while the prescribing of dihydrocodeine was low in New Zealand, the proportion of patients hospitalised from substance abuse and poisoning, associated with this medicine, was high. The Committee expressed that the literature showed safety concerns with dihydrocodeine use and the benefits in pain management were questionable. The Committee recommended Medsafe undertake a risk benefit review of dihydrocodeine.

The Committee considered the addition of warning and advisory statements to the original manufacturer’s packaging for all opioids through a Label Statements Database consultation. The Committee noted that most medicines are repackaged down in community and hospital pharmacies so the statements on the original manufacture’s packaging are unlikely to reach out to patients. The Committee still considered it helpful to have these statements in cases where they are dispensed to patients.

The Committee discussed the advantages of a Cautionary and Advisory Label (CAL) for opioids. Since CALs are placed on the final dispensed product the patient receives, it would promote further engagement and discussions between the patient and their primary healthcare professional. The engagement would likely be from individuals who may not be aware of the addiction and misuse opioids can have. The Committee advocated Medsafe to discuss the feasibility of developing a CAL label for opioids with the Pharmaceutical Society of New Zealand.

The Committee recommended the New Zealand opioid product data sheets align with the safety warnings seen in the Australian product information.

The Committee considered that a consumer information leaflet would be useful to highlight the risks of opioid use.

The Committee agreed that a Risk Management Plan should be submitted as part of new medicine applications for opioids. The Committee noted that for this policy to occur, an update to Medsafe’s ‘Guidelines on the Regulation of Therapeutic Products in New Zealand’ is required.

The Committee considered the possibility of utilising the New Zealand ePrescription Service (NZePS) as a platform for a prescription drug monitoring programme for opioids. The Committee acknowledged that this may not be a feasible option as the NZePS may not be designed to capture or collect this data. The Committee recommended Medsafe to contact the NZePS to learn more about its capability.

Recommendation 12

The Committee recommended Medsafe undertake a risk benefit review of dihydrocodeine.

Recommendation 13

The Committee recommended addition of warning and advisory statements for all opioids through a Label Statements Database consultation.

Recommendation 14

The Committee recommended Medsafe discuss the feasibility of developing a Cautionary and Advisory Label for opioids with the Pharmaceutical Society of New Zealand.

Recommendation 15

The Committee recommended the New Zealand opioid product data sheets align with the safety warnings seen in the Australian product information.

Recommendation 16

The Committee recommended Medsafe develop a consumer information leaflet that highlights the risks of opioid use.

Recommendation 17

The Committee recommended that Risk Management Plans are submitted as part of a new medicine application for opioids.

Recommendation 18

The Committee recommended Medsafe to contact the New Zealand ePrescription Service to learn more about its capability.

[Dr S Hanna left the meeting at this time]

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.

The Committee was given a brief presentation on the work Medsafe has done around myocarditis with the Comirnaty vaccine and vaccine-induced thrombotic thrombocytopenia with COVID-19 vaccines.

4.3 Prescriber Update Volume 42, Number 2, June 2021

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 Vaxzevria (ChAdOx1-S AZD1222) Risk Management Plan

The Committee was provided with a report summarising Medsafe’s assessment of the Risk Management Plan (RMP) for Vaxzevria.

The Committee was asked to provide feedback on whether the proposed questions and amendments were suitable, and whether additional questions and/or amendments to the RMP were required. The Committee considered that the proposed questions and requested amendments were suitable.

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

Dr C Cameron
Date: 6 July 2021
Chair, Medicines Adverse Reactions Committee

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