Published: 17 April 2025
Committees
MINUTES OF THE 201th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
- 1.0 MATTERS OF ADMINISTRATION
- 2.0 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE 3.0 PHARMACOVIGILANCE ISSUES
- 4.0 MEDSAFE PHARMACOVIGILANCE ACTIVTIES
- 5.0 OTHER BUSINESS
MINUTES OF THE 201st MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
13 March 2025
The two hundredth and first meeting of the Medicines Adverse Reactions Committee (MARC) was held on 13 March 2025 at the Ministry of Health. The meeting commenced at 9am and closed at 12.40pm.
A/Prof M Doogue (Chair)
Dr A Barrett
Ms A Biggs-Hume
A/Prof A Pomerleau
Dr C Kenedi
Dr H Wilson
Ms L Carlyon
Ms L McDermott
Prof L Parkin
Dr M Rademaker
Dr S Leitch
Prof T Lumley
T Coventry (Senior Advisor, Pharmacovigilance)
N Zhong (Senior Advisor, Pharmacovigilance)
L Collings (Senior Advisor, Pharmacovigilance)
S Kenyon (Manager, Clinical Risk Management)
M Storey (Team Leader, Pharmacovigilance)
L Chan (Principal Technical Specialist, Pharmacovigilance)
V Cheer (Senior Advisor, Pharmacovigilance)
S Tran (Senior Advisor, Pharmacovigilance)
J Park (Advisor, Pharmacovigilance)
Dr K Van Bart (Senior Medical Advisor)
H Wilson (Advisor Science)
K Fu (Advisor Science)
INVITED GUESTS AND EXPERTS IN ATTENDANCE
Dr D Hughes (Chief Medical Officer, PHARMAC)
Dr J Lee (Medical Assessor, Centre for Adverse Reactions Monitoring)
Dr J Gordon (Medical Assessor, Centre for Adverse Reactions Monitoring)
Dr J Sanson (Medical Assessor, Centre for Adverse Reactions Monitoring)
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 200th MARC Meeting
The minutes of the 200th 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
Members were provided a summary of serious reports received in the last quarter. 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 Systemic fluoroquinolones: update on regulatory actions and review of safety concerns
Background
Fluoroquinolone antibiotics have been associated with prolonged, disabling and potentially persistent and/or irreversible adverse reactions that may affect multiple body systems. These reactions have been reported in patients irrespective of their age and potential risk factors, and there are no proven treatments available. The frequency of persisting reactions is usually considered to be rare or unknown.
This Committee was updated on regulatory actions regarding the risk of disabling and persistent adverse drug reactions in relation to treatment with fluoroquinolones. The safety of fluoroquinolones was previously discussed in the December 2017 and June 2019 MARC meetings.
In January 2024, the MHRA recommended that fluoroquinolones must only be used when other antibiotics that are commonly recommended for the infection are inappropriate, an addition to the 2019 restrictions where fluoroquinolones should not be prescribed for non-severe, self-limiting, or non-bacterial infections.
The European Medicine Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) have also requested the product information for fluoroquinolone antibiotics be updated with information on DRESS syndrome. Currently the majority of fluoroquinolone data sheets do not list DRESS as an adverse drug reaction.
Following the safety concerns described above and recent actions taken by international regulatory agencies, Medsafe requested advice from the MARC on whether the restrictions to the indications for use of fluoroquinolone antibiotics are needed, and if any updates to the data sheet are required.
Discussion
The Committee noted that there has been a 25 percent decrease in community usage of fluoroquinolones since 2019. Factors may include antimicrobial stewardship activities and guideline changes making fluoroquinolones second-line antibiotics. The Committee also noted in many other countries there is wide use of moxifloxacin for respiratory tract infections and this is not the case in New Zealand.
Internationally, drug utilisation studies suggest that regulatory actions including communication of safety issues do not appear to have made a large impact on usage patterns. However, usage has trended downwards over time.
The Committee noted that the MHRA has required that the indications for fluoroquinolones state that regardless of the infection/indication for use, fluoroquinolones should only be prescribed when other commonly recommended antibiotics are inappropriate. Including information within the indications section of the product information on types of conditions that fluoroquinolones should not be used to treat, as has been done in other jurisdictions. The Committee discussed that adding conditions NOT to be treated in the indications was a departure from standard data sheet conventions.
The effect of restricting the New Zealand data sheet indications for fluroquinolones to infections where other antibiotics are inappropriate was discussed. It was noted that a risk of making indications more restrictive is that the medicines may not be prescribed to some patients who need them. It was noted that care should be taken not to imply that fluoroquinolones have a worse benefit-risk profile relative to other classes of antibiotics, as all antibiotics have adverse effects and benefit-risk differs between patients. The Committee noted that other antibiotics may be inappropriate when there was bacterial resistance, the patient had a contraindication to treatment with that antibiotic, the patient had adverse effects with a first line antibiotic, or there had been a treatment failure.
The current indications for ciprofloxacin include that it can be used to treat ‘complicated and uncomplicated’ infections. Therefore, the Committee discussed whether it was appropriate for the indications to include uncomplicated infections. It was noted that there are serious, uncomplicated infections where fluoroquinolones may be the most appropriate antibacterial treatment. It was considered that the phrase ‘complicated and uncomplicated’ should be removed from the indication, as it was redundant if the indication was changed to make ciprofloxacin a second line treatment option.
The Committee agreed that the data sheet indications for fluoroquinolones should be updated to include a statement around when the benefits of using fluoroquinolones are most likely to outweigh the risks.
Disabling and potentially persistent adverse reactions that have been reported with fluoroquinolones, include tendinopathy, peripheral neuropathy and neuropsychiatric effects. The product information in other jurisdictions describes these reactions as potentially irreversible. The Committee discussed whether the description of severe, persisting adverse reactions in fluoroquinolone data sheets should include that they may be irreversible, rather than just persistent.
It was noted that the current term, ‘persistent’ is weaker than the term irreversible. It was noted that the term ‘irreversible’ may not be applicable to all adverse reactions covered by this warning. For example, the Committee considered that tendinopathies usually resolve over time, while peripheral neuropathy may be prolonged. There is limited data on whether these adverse reactions may be irreversible or how long they may persist for. The Committee agreed that the data sheets should state that these reactions may be potentially irreversible.
The Committee noted that there were differences in the safety information in data sheets between products in New Zealand and compared to overseas product information. The Committee agreed that several aspects of the safety information in fluoroquinolone data sheets be updated to align with international Product Information. The Committee recommended that where possible the Australian Product Information should be used.
It was noted that some prescribers are not aware that severe, persisting adverse reactions have been reported with fluoroquinolones. The committee agreed that a Prescriber Update article on fluoroquinolones would help to raise awareness.
Recommendation 1
The Committee recommended that the indications for fluoroquinolone medicines should be updated.
Recommendation 2
The Committee recommended that the warning in all fluoroquinolone medicine data sheets regarding disabling and potentially persistent adverse reactions should be updated to include that they may be potentially irreversible.
Recommendation 3
The Committee recommended that several aspects of the safety information in fluoroquinolone data sheets be updated to reflect current knowledge of the medicine safety profile.
Recommendation 4
The Committee recommended a Prescriber Update article is published on fluroquinolone antibiotics.
3.2.2 Topical steroid withdrawal reactions
Background
Topical corticosteroid withdrawal (TSW) reaction is a rare reaction occurring after stopping long-term use of topical corticosteroids (TCS) products, typically of moderate to high potency and may represent a rebound-type reaction.
Published literature describing TSW mainly consists of reviews and case series, however the quality of evidence at the current time is low. TSW is not a well-defined diagnosis although there appears to be some distinct symptoms that are different from a flare up of the person’s original skin disease. There is currently no standard treatment for TSW.
In 2021, the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) reviewed the risk of TSW and implemented risk minimisation measures. These included communicating the risk to healthcare professionals and consumers through updates to summary of product characteristics (SmPC) and patient information leaflets, and publishing an article on TSW reactions in Drug Safety Update. More recently, the MHRA announced that TCS products will be labelled with their potency. This is to help patients with correct selection and simplify the advice to patients requiring multiple steroid products of different potencies.
Other regulators such as the Health Sciences Authority and Health Canada have issued communications on TSW reactions.
In 2013, Medsafe published a Prescriber Update article highlighting a case of steroid rebound reaction and in 2021 Medsafe requested all TCS sponsors to include rebound effect in TCS data sheets. However, the term rebound effect refers to recurrence of the underlying disease, which is relatively common, not TSW reactions.
In New Zealand, 16 suspected cases of TSW reactions and/or rebound effect have been reported. Two-thirds of those were reported in 2021 or after, coinciding with MHRA’s review.
The MARC was asked to consider the risk of TSW from TCS, and whether regulatory action is required to manage the risk.
Discussion
The Committee discussed that inappropriate overuse of topical corticosteroids is common and a withdrawal syndrome is one consequent risk. The Committee noted that topical steroid withdrawal differs from red skin syndrome, steroid addiction and rebound flares. Topical corticosteroids induce vasoconstriction which can be followed by rebound vasodilation and erythema when the topical corticosteroid is stopped, resulting in continued steroid application and use of increasingly potent corticosteroids. Another overuse risk is adrenal suppression. With prolonged use of high doses topical steroids there can be sufficient systemic exposure to suppress ACTH and cortisol production and sometimes Cushing’s syndrome. As with systemic steroids secondary adrenal insufficiency can develop and sudden withdrawal can precipitate symptomatic adrenal insufficiency. The risk of topical corticosteroid steroid withdrawal is highest with overuse of potent and very potent steroids.
The Committee noted that topical steroid withdrawal reactions typically result from long-term inappropriate use, that is for longer than advised in the data sheets for topical steroids. TSW is dose and duration related and the risk greatest with potent and very potent corticosteroids. The committee noted the evidence suggests it is unlikely with moderate or mild corticosteroids. The Committee recommended that the data sheets for potent and very potent topical corticosteroids should be updated to describe the risk of topical steroid withdrawal in section 4.9 Overdose. The Committee considered that the classification of steroid potency should used by the New Zealand Formulary and DermNet was valid and useful to clinicians and patients. The potent and very potent corticosteroids are:
- Potent corticosteroids: betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone butyrate, mometasone furoate, methylprednisolone aceponate
- Very potent corticosteroids: clobetasol propionate and betamethasone dipropionate. (in an optimised vehicle).
The Committee agreed that potency information on the package labelling of topical corticosteroids would be helpful for consumers. It was noted that there is a risk that some consumers could misconstrue topical corticosteroids labelled as being mild potency as being ineffective while others may perceive potent topical corticosteroids as being unsafe. It was also noted that absorption of topical corticosteroids is influenced by the area of skin that they are applied to. The importance of patient education to explain steroid potency and appropriate use was emphasised. The Committee recommended that all topical medicines containing a steroid should be labelled with their potency as mild, moderate, potent or very potent as described in New Zealand Formulary guidance.
It was noted that the duration of use of topical corticosteroids is an important factor in the risk of topical corticosteroid withdrawal. It was noted that the recommended duration of use varies by body-site as this influences the amount absorbed. The Committee noted that most data sheets for potent and very potent topical corticosteroids state that in most cases, continuous use up to four weeks should be considered the maximum (ie, topical corticosteroid should not be used long-term continuously). The Committee considered that a maximum recommended duration of use of up to four weeks should be listed in the data sheets for all potent and very potent topical corticosteroids.
The Committee recommended that a Prescriber Update article be published on topical corticosteroids.
Recommendation 5
The Committee recommended that the data sheets for potent and very potent topical corticosteroids should be updated to describe the risk of topical steroid withdrawal in section 4.9 Overdose.
Recommendation 6
The Committee recommended that the data sheets for potent and very potent topical corticosteroids be updated to state that they are indicated for short-term use (up to four continuous weeks).
Recommendation 7
The Committee recommended that that the package labelling of topical corticosteroids should be labelled with their potency for example mild, moderate, potent or very potent.
Recommendation 8
The Committee recommended that an article is published in Prescriber Update on appropriate use of topical corticosteroids and the risks of excessive or prolonged use.
3.2.3 Stimulant medicines used for attention deficit hyperactivity disorder (ADHD) and the risk of Parkinson’s disease
Background
The available information on a possible association between central nervous system (CNS) stimulant medicines used in (ADHD) and Parkinson’s disease was reviewed.
The biological plausibility of a relationship between stimulant treatment as used for ADHD and later development of Parkinson’s disease is unclear. It has been hypothesised that stimulant medicines may have a neurotoxic effect. Animal studies have shown that amphetamines are toxic to mesencephalic dopaminergic neurons at high doses. Prolonged abuse of methamphetamines/amphetamines with high cumulative exposure has been linked with parkinsonism and increased risk of Parkinson's disease, including younger onset of disease. Conversely, there is limited evidence of methylphenidate neurotoxicity in animal studies.
The Committee is asked to advise whether regulatory action is needed at this time in relation to a possible risk of Parkinson’s disease with stimulant medicines used for ADHD.
Discussion
The Committee considered the literature articles examining a possible relationship between stimulant medicines and Parkinson’s disease.
A cohort study by Curtin et al found a substantially increased risk of cerebellar and basal ganglia disorders in people with ADHD who were treated with stimulants, compared to people without ADHD. The outcome of ‘cerebellar and basal ganglia diseases’ was broad and included conditions such as secondary parkinsonism and essential tremor. The subanalysis of people with Parkinson’s disease found an increased risk in both ADHD patients overall and ADHD patients treated with stimulants. However, the confidence intervals were overlapping for the exposed and unexposed groups.
There was possible misclassification bias is this study. Unmeasured confounders include traumatic head injury and exposure to environmental toxins. A limitation of studies using health claims databases is that confounding exposures (eg, illicit drugs, tobacco, antipsychotics) may not be accurately characterised. Stimulant exposure was not quantified and a dose-response relationship was not examined. It was noted that the extent of exposure to stimulants is likely vary widely and may be intermittent.
The Committee noted that: the study included participants born from 1950; ADHD was first included in the Diagnostic and Statistical Manual of Mental Disorders (DSM) in 1968; and electronic health records used were first available from 1996. The data was considered to be incomplete.
Another study by Kindt et al found that people aged 50 years and older with a diagnosis of ADHD who were treated with prescription stimulants had a reduced risk for development of Parkinson’s disease when compared with those who were not prescribed stimulant medicines. The reasons for this finding are not clear. Unmeasured confounders include tobacco use, antipsychotic use and illicit drug use. It is possible that there were unmeasured differences in the characteristics of those who received stimulant treatment compared to those who did not.
The Committee noted that examination of an epidemiological link between stimulant medicines and Parkinson’s disease is complicated by a long latency between exposure and outcome and difficulties in quantifying exposure. The possibility of confounding by the underlying condition of ADHD was acknowledged.
The Committee considered that while there may be possible biological plausibility, the available evidence is insufficient to support an association between prescription stimulant treatment and Parkinson’s disease. The Committee did not consider that any regulatory action is needed 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 noted a Medsafe safety review of GLP-1 receptor agonist medicines.
4.3 Prescriber Update Volume 46, Number 1, March 2025
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 Committee training session
The Chair will provide a pharmacology training session at an upcoming meeting.
The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 12.40 pm.
A/Prof M Doogue
Chair, Medicines Adverse Reactions Committee
Date: 31 March 2025
