Published: 4 August 2022

Committees

MINUTES OF THE 190th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 190th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

9 June 2022

The one hundred and ninetieth meeting of the Medicines Adverse Reactions Committee (MARC) was held on Thursday 9 June 2022 at 133 Molesworth Street, Wellington and via video conference. The meeting commenced at 9am and closed at 2.13 pm.

MARC MEMBERS PRESENT

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

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)
G Hill (Senior Medical 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)
A Weil (Advisor Science, Product Regulation)
A Corkill (Advisor Science, Product Regulation)

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. No apologies were received.

1.2 Minutes of the 189th MARC Meeting

The minutes of the 189th 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 commented on case 143028 involving DRESS syndrome following initiation of allopurinol. The Committee considered it was important to remind prescribers that certain medicines require to be initiated and titrated differently to reduce the risk of DRESS.

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

Recommendation 1

The Committee recommended that a Prescriber Update article is written on the importance that certain medicines require to be initiated and titrated differently to reduce the risk of DRESS.

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 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

Reports of causal and serious events occurring in patients aged 18 to 80 years were briefly outlined for the Committee.

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 Buccaline: referral to the Committee under section 36(2) of the Medicines Act 1981

[This section is still in preparation.]

3.2 Matters Referred to the MARC by Medsafe

[Dr C Kenedi joined the meeting at this time.]

3.2.1 Opioids and serotonin syndrome

Background

In June 2020 the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (EMA’s PRAC) reviewed the evidence of the interaction between buprenorphine-containing medicinal products with serotonergic medicines leading to serotonin syndrome.

The PRAC recommended that the Summary of Product Characteristics (SmPC) and patient information leaflet (PIL) of buprenorphine-containing products should be updated, based on their review. The PRAC also recommended that the sponsors of serotonergic medicines should ensure that this possible interaction with buprenorphine is reflected in their SmPC.

The Committee was asked to review the information on serotonin syndrome caused by an interaction between opioids and serotonergic medicines.

Discussion

The Committee discussed that serotonin syndrome is a clinical diagnosis with a spectrum of presentations. The Committee considered how other factors may be influential in the development of serotonin syndrome, in addition to a pharmacodynamic interaction between serotonergic medicines.

The Committee agreed that the risk of developing serotonin syndrome from taking an opioid in combination with another serotonergic medicine differed between different opioids. This different level of risk was highlighted in an article by Perananthan and Buckley 2021. The Committee recommended that opioids listed as high risk (tramadol, pethidine, dextromethorphan) and medium risk (fentanyl and methadone) should contain a standardised warning statement in the data sheet on the risk of serotonin syndrome when taken with serotonergic medicines.

The Committee highlighted that higher doses of fentanyl used in anaesthesia and acute pain, and higher doses of methadone used in opioid substation therapy, are more likely to be involved in serotonergic interactions, compared to when these medicines are used at lower doses. 

The Committee considered that opioids with a low risk of serotonin syndrome, for example morphine and oxycodone, did not require a warning statement, and that current statements in these data sheets could be removed as the available information on the interaction did not demonstrate clinical significance. 

The Committee recommended that the data sheets of serotonergic medicines should also be updated with an interaction warning for opioids that are considered at high and medium risk of serotonin syndrome and that examples are provided. 

The Committee recommended that healthcare professionals are made aware that the risk of serotonin syndrome can differ among different opioids, and that serotonin syndrome can also occur with illicit drug use and over-the-counter products.

Recommendation 3

The Committee recommended that a standardised warning on the risk of developing serotonin syndrome with serotonergic medicines is added to the data sheet for opioids considered to be at high and medium risk of causing serotonin syndrome. In addition, the fentanyl and methadone data sheet should include that higher doses of these medicines are more likely to be of a concern.

Recommendation 4

The Committee recommended that the data sheets of serotonergic medicines be updated with an interaction warning for opioids that are considered high and medium risk of serotonin syndrome and examples are listed.

Recommendation 5

The Committee recommended a Prescriber Update article to highlight that the risk of serotonin syndrome can differ among different opioids, and that serotonin syndrome can occur with illicit drug use and over-the-counter products.

3.2.2 Methylphenidate and the risk of birth defects

Background

In 2019, the Pharmacovigilance Risk Assessment Committee (PRAC) recommended that the Summary of Product Characteristics (SmPC) for methylphenidate-containing products be updated with information on birth defects.

In July 2021, the Therapeutic Goods Administration (TGA) changed their pregnancy category for methylphenidate products and updated their Product Information to reflect this change.

The Committee has been asked to review the information on methylphenidate-containing products and the risk of birth defects when used in pregnant women.

Discussion

The Committee reviewed the recent available studies on first trimester exposure of methylphenidate and risk of birth defects. The Committee commented that methylphenidate use in pregnancy is generally low and therefore there is a great level of uncertainty on the risk of congenital malformations.

The Committee noted that recent observational studies did not suggest an overall increased risk of birth defects with first trimester exposure to methylphenidate. However, one study showed a small increased risk of cardiac malformations, corresponding to 3 additional infants born with congenital cardiac malformations for every 1,000 women who received methylphenidate during the first trimester of pregnancy compared with non-exposed pregnancies. This association could not be ruled out however, the Committee emphasised that the evidence at the current time is not definitive.

Despite the weak association, the Committee agreed that prescribers and patients should be made aware of the results from the recent observational study so that women of childbearing age are informed. The current data sheets did not reflect the current available evidence from the recent observational study.

The Committee recommended the data sheet be updated with results from the recent observational study. There should also be an emphasis for prescribers to discuss and weigh the benefits and risks with the individual requiring methylphenidate treatment.

Recommendation 6:

The Committee recommended that the methylphenidate data sheets be updated regarding fetal exposure in first trimester of pregnancy and risk of overall birth defects and cardiac malformations. There should also be emphasis for prescribers to discuss and weigh the benefits and risks with the individual requiring treatment.

3.2.3 Prostaglandin associated periorbitopathy

Background

The European Medicines Agency Pharmacovigilance Risk Assessment Committee recommended, that the product information for bimatoprost should be updated to add the adverse reaction of prostaglandin associated periorbitopathy (PAP) in November 2021.

Advice was sought from the Committee was on whether PAP is considered a class effect, and if yes, whether the risk differed between different medicine in the class.

The other approved ocular prostaglandin analogues are latanoprost and travoprost.

Discussion

The Committee reviewed the current evidence for the risk of PAP across the three ocular prostaglandin analogues. The Committee considered the evidence showed a class effect, with the risk being different among prostaglandin analogues. Bimatoprost appeared to have the highest risk.

The Committee noted that PAP may be more common than people are aware of, however it may be difficult to separate this drug effect from the ageing process.

The Committee questioned whether the clinical features of PAP are already widely accepted in ophthalmology practice. It was considered that education to healthcare professionals was important so that patients are informed of possible ocular effects prior to starting treatment.

The Committee recommended that the data sheets for prostaglandin analogues should be updated to include information on PAP. Currently, only the clinical characteristics of PAP are listed.

Recommendation 7

The Committee recommended a Prescriber Update article to highlight the topic of prostaglandin associated periorbitopathy with prostaglandin analogues.

Recommendation 8

The Committee recommended that the data sheets for prostaglandin analogues should be updated to include information on prostaglandin associated periorbitopathy.

3.2.4 Methenamine benefit-risk review

Background

Methenamine hippurate (also known as hexamine hippurate) is a urinary antibacterial agent intended for ‘suppression or elimination of urinary tract bacteria’.

Methenamine hippurate is a ‘grandfathered’ medicine that was available in New Zealand before the 1969 Food and Drug Act and subsequent Medicines Act 1981 came into force. Medicines that were already on the market prior to 1969 were accepted without evaluation. Methenamine hippurate has therefore not undergone a rigorous benefit-risk evaluation consistent with today’s standards.

There is renewed interest in the use of methenamine hippurate as an alternative to low-dose daily antibiotic prophylaxis for the prevention of recurrent urinary tract infection (UTI) in women.

Medsafe therefore considers it timely to review the efficacy and safety of methenamine hippurate to ensure that the benefit-risk balance of this historically approved medicine is favourable.

Methenamine hippurate is a general sale medicine. As such there is no requirement for the sponsor to supply a data sheet or Consumer Medicine Information (CMI) leaflet.

Discussion

The Committee noted that methenamine hippurate is a prodrug that converts to formaldehyde in an acidic environment. Formaldehyde is the active substance that exerts bactericidal activity in the urine.

Formaldehyde is classified as a Group 1 carcinogen by the International Agency for Research of Cancer (IARC). Information on the safety of long-term exposure to formaldehyde in the bladder is lacking. However, the Committee noted that methenamine hippurate has been used by a large number of patients in New Zealand over many years with little apparent evidence of serious harm or concerns of carcinogenicity.

The Committee considered that, although the mechanism of action is plausible, the current evidence supporting the efficacy of methenamine hippurate for the suppression or elimination of urinary tract bacteria is weak. Methenamine hippurate may have a role in antimicrobial stewardship by providing an alternative to antibiotics for preventing urinary tract infection. On balance, the Committee considered methenamine hippurate to have a favourable benefit-risk profile.

The Committee expressed concern about the lack of information for healthcare professionals and consumers to ensure methenamine hippurate is used appropriately. The Committee also expressed concern about the lack of transparency in the promotional information for consumers that the active substance is formaldehyde (referred to only as the ‘bactericidal agent’). The Committee recommended that the sponsor provide a data sheet and CMI leaflet to be published on the Medsafe website. These documents should clearly state that methenamine is converted into formaldehyde in the body.

The Committee noted that in 2019, in response to feedback on the proposal to fully fund methenamine hippurate, PHARMAC was going to consider providing guidance for prescribers on the appropriate use of the medicine. The Committee expressed interest to know whether PHARMAC has since developed this guidance. The Committee also expressed interest to know what safety and efficacy data PHARMAC considered in their decision to increase subsidy for methenamine hippurate.

The Committee expressed concern that the general sale classification may not be appropriate for methenamine hippurate. Consultation with a healthcare professional is advisable for patients with symptoms of recurrent urinary tract infection to ensure accurate diagnosis and appropriate treatment. The Committee recommended that Medsafe should ask the Medicines Classification Committee to review the classification of methenamine hippurate.

Recommendation 9

The Committee recommend that Medsafe requests the sponsor for methenamine hippurate to provide a data sheet and CMI. These documents should state that the active substance is formaldehyde.

Recommendation 10

The Committee recommended that Medsafe asks PHARMAC whether they have provided guidance for prescribers about the appropriate use of methenamine hippurate, and what safety and efficacy information they considered in their decision to increase the subsidy.

Recommendation 11

The Committee recommended that Medsafe submits an application to the Medicines Classifications Committee to review the classification of methenamine hippurate.

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 43, Number 2, June 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 COVID-19 vaccine safety signals.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2.13 pm.

Dr Chris Cameron Date: 6 July 2022
Chair, Medicines Adverse Reactions Committee

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