Published: 25 October 2019

Committees

MINUTES OF THE 179TH MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

  • 1.0 MATTERS OF ADMINISTRATION
  • 2.0 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE
  • 3.0 PHARMACOVIGILANCE ISSUES

    MINUTES OF THE 179th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

    12 September 2019

    The one hundred and seventy-ninth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 12 September 2019 at the Ministry of Health, 133 Molesworth Street, Wellington. The meeting commenced at 9am and closed at 1.45pm.

    MARC MEMBERS PRESENT

    Associate Professor D Reith (Chair)
    Dr K Eggleton
    Associate Professor L Parkin
    C Ryan
    Professor L Stamp
    Dr M Tatley
    L Te Karu
    Dr S Hanna
    Associate Professor D Menkes
    J Tatler
    I Raiman
    Dr C Gresham

    MARC SECRETARIAT PRESENT

    J Prankerd (Senior Advisor, Pharmacovigilance)

    MEDSAFE STAFF IN ATTENDANCE

    S Kenyon (Manager, Clinical Risk Management)
    G Hill (Senior Medical Advisor, Pharmacovigilance)
    L Chan (Principal Technical Specialist, Pharmacovigilance)
    M Storey (Senior Advisor, Pharmacovigilance)
    V Cheer (Senior Advisor, Pharmacovigilance)

    INVITED GUESTS AND EXPERTS IN ATTENDANCE

    Dr Richard McNeil, Clinical Pharmacologist

    1.0 MATTERS OF ADMINISTRATION

    1.1 Welcome and Apologies

    The Chair welcomed the attendees to the meeting. Apologies were received from Dr C Cameron.

    1.2 Minutes of the 178th MARC Meeting

    The minutes of the 178th 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 132801 where a patient developed respiratory distress, tachypnoea and metabolic acidosis after an overdose of Bonjela (choline salicylate) teething gel. The Committee discussed whether the current availability of Bonjela or the current instructions for use are possible issues. The Committee noted that the usage instructions and warning statements are on the package and the current classification of Bonjela. The Committee considered that there is likely to be some benefit from Bonjela being classified as a pharmacy medicine to enable some instruction around its use.

    Recommendation 1

    The Committee recommended that a submission is made to the Medicines Classification Committee to review the classification of Bonjela (choline salicylate).

    [Associate Professor D Menkes joined the meeting at this time.]

    The Committee did not consider any of the other 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.

    The Committee noted that there were no cases in this section of the report describing adverse reactions to venlafaxine.

    2.1.6 Special Reports: ACC Cases (January 2018 – December 2018)

    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 Cafergot (ergotamine tartrate + caffeine) under section 36 of the Medicines Act 1981.

    Background

    At the 14 March 2019 MARC meeting, the Committee discussed the potential risk of pancreatitis in association with Cafergot treatment. The Committee recommended that Medsafe conduct a benefit-risk review of Cafergot under section 36 of the Medicines Act 1981.

    The purpose of this paper is to review the available information on benefits and risks with Cafergot according to section 36 of the Act.

    Discussion

    The Committee discussed the type of patients taking Cafergot. Although it is not possible to confirm, it does not seem likely that many new people are starting treatment with Cafergot as the average age of patients is increasing over time. Noting the likely use of Cafergot in an ageing population, the Committee considered the importance of considering the increasing risk of cardiovascular reactions in this group for whom treatment is not recommended in the data sheet. The Committee agreed it is not appropriate for new patients to be started on this medicine.

    The Committee noted that the available data on the efficacy of Cafergot are limited and dated and that Cafergot is no longer available in many countries.

    The Committee considered that adverse drug reactions associated with the use of Cafergot are concerning especially in higher risk groups such as the children (for whom this medicine is contraindicated) and elderly (for whom this medicine is not recommended). However it is possible that a small group of patients respond well to Cafergot and find this medicine effective. Some individuals may also find it difficult to change treatments. The Committee discussed the impact of Cafergot being unavailable on patients gaining benefit from Cafergot and agreed that although it could be upsetting for these patients to change there are other treatment options with a better benefit risk profile.

    The Committee discussed various regulatory activities and alternatives for treatment of migraine. The Committee considered that there are more modern treatment options available and prescribers should be discussing medicine changes with their patients.

    The Committee considered that there are concerns with the use of Cafergot and the benefits of use no longer outweigh the risks of harm. The Committee therefore recommended that consent to distribute Cafergot in New Zealand be revoked.

    The Committee emphasised the importance of a transition period to enable patients to find alternative treatment options in a safe manner. The Committee also considered it is important for advice to be given to prescribers and additional support to patients that may be needed to ensure a smooth transition. The Committee recommended a 6 month transition period and various organisations and groups contacted to inform them of the Committee’s recommendations and discussion.

    Recommendation 2

    The Committee recommended that consent to distribute Cafergot in New Zealand be revoked by the Minister’s delegate.

    Recommendation 3

    The Committee recommended that Medsafe communicates the outcome of this discussion and the subsequent decision of the Minister’s delegate to health care professionals, consumers and PHARMAC.

    3.2 Matters Referred to the MARC by Medsafe

    3.2.1 The use of topiramate during pregnancy for migraine prevention

    Background

    Migraine is a common condition with a higher prevalence in women than men. It is also most common in those aged 30 to 39 years. Migraine does not appear to increase the risk of death but it is a major cause of morbidity. During pregnancy most women (60–70%) with a history of migraine report improvement over their pregnancy course, while about 5% describe worsening, and the remainder report no change. This is thought to be due to the changes in estrogen levels.

    Topiramate is an antiepileptic medicine used in the treatment of epilepsy and prevention of migraines. The use of topiramate for migraine prevention in pregnant women is contraindicated in the United Kingdom (UK). However, in New Zealand there is no such contraindication, and topiramate can be used for migraine prophylaxis during pregnancy if the potential benefit justifies the potential risk to the fetus.

    The purpose of this paper is to review information on the use of topiramate for the prophylaxis of migraine in pregnant women to determine the best course of action for New Zealand patients. Note that the use of topiramate in pregnant women for the treatment of epilepsy is not included in this review and is considered to be a risk benefit discussion for the woman and her doctor.

    Discussion

    The Committee considered the paper presented to them and noted the risks involved (eg, oral clefts) can affect the quality of life of the affected individual.

    The Committee discussed the guidelines for migraine prevention and other alternative medicines to topiramate. Some guidelines do not include topiramate as first-line for migraine prevention. Overall, the Committee considered that topiramate for migraine prevention appears to be efficacious but there are other alternatives.

    The risk of congenital malformations reported in various sources such as the literature, pregnancy registries and the topiramate data sheet was also discussed. The Committee considered there are significant risks with using topiramate during pregnancy and noted the importance of effective birth control in women of child bearing potential.

    The Committee also noted the higher background incidence rate of oral clefts in Māori compared to the overall New Zealand population reported in a study. The Committee determined it was appropriate to include a specific statement about this in the topiramate data sheets.

    The Committee considered the United Kingdom safety information for topiramate and the relevance this has in New Zealand. The Committee determined that it was appropriate to contraindicate the use of topiramate for migraine prevention in pregnancy and in women of childbearing potential if not using a highly effective method of contraception.

    Recommendation 4

    The Committee recommended that Medsafe writes to the sponsors of topiramate products requesting updates to New Zealand data sheets.

    3.2.2 Serotonin reuptake inhibitors and persistent sexual dysfunction

    Background

    In May 2018, Medsafe received a communication highlighting a recently published paper in the International Journal of Risk and Safety in Medicine on the risk of persistent sexual dysfunction after treatment with antidepressants, 5α-reductase inhibitors and isotretinoin.

    The purpose of this paper is to review the risk of persistent sexual dysfunction after discontinued treatment with serotonin reuptake inhibitors (SRIs).

    Discussion

    The Committee considered the strength of the evidence to be low and it is difficult to draw conclusions from the available data. The Committee considered the sensitive nature of the issue and the possibility of confounding by indication. The Committee noted that anxiety as well as depression are indications for antidepressants. The Committee considered anxiety and sexual dysfunction have been associated in the past, and before serotonin reuptake inhibitors were available. However, the Committee also noted that case reports have been reported around the world in different settings and in different cultures. There is also some plausibility of a mechanism but no strong evidence of causality to date.

    The Committee considered the European product information on this issue and determined, based on their review of the available information, that updates to the data sheets regarding the risk of persistent sexual dysfunction are necessary.

    Recommendation 5

    The Committee recommended that Medsafe writes to the sponsors of serotonin reuptake inhibitors requesting updates to New Zealand data sheets.

    3.2.3 Dextromethorphan – benefit-risk review

    Background

    At the 61st Medicines Classification Committee (MCC) meeting on 2 November 2018, Medsafe presented a submission proposing the reclassification of cough medicines containing the active ingredients dextromethorphan, opium tincture, squill oxymel and pholcodine from general sale and pharmacy-only medicines to restricted medicines.

    At the meeting, the MCC recommended that dextromethorphan should be reclassified from a general sale and pharmacy-only medicine to a restricted medicine. The MCC also suggested that Medsafe should review the benefit-risk profile and efficacy of dextromethorphan. The dextromethorphan re-classification notice was published in the New Zealand Gazette on 25 February 2019.

    Further information can be found in the minutes of this meeting.

    The purpose of this paper is to present a benefit-risk review of dextromethorphan.

    Discussion

    The Committee discussed the available information on the benefits and risks of dextromethorphan.

    The Committee discussed the risk for abuse and adverse drug reactions. The Committee considered that the recent classification change of dextromethorphan has been a valuable step in mitigating the risks of abuse in New Zealand and fully support the MCC decision.

    The Committee noted that there is evidence of risk of harm and abuse from the use of dextromethorphan and that there are important risks such as serotonin syndrome to be aware of. The risk of potential harm and the risk of experiencing untoward outcomes was also discussed. The Committee considered that the risks of harm from use of dextromethorphan should be communicated to highlight the risk of abuse and as a reminder for health care professionals to consider whether use in each individual is appropriate. The Committee also noted that the possibility of interactions is a potential risk. The Committee considered that, although limited, there is some evidence of efficacy.

    The Committee discussed possible unexpected consequences of removing dextromethorphan as a treatment option for cough. The Committee considered that this may increase usage of antimicrobials because of the absence of treatments for cough.

    The Committee also discussed the current data sheet for dextromethorphan and considered that updates regarding the risks of dependence, serotonin syndrome and overdose would better inform patients and prescribers.

    The Committee considered that the benefit-risk balance from the use of dextromethorphan was marginally favourable. The Committee considered that the actions taken by the MCC to reclassify dextromethorphan were sufficient at this time to ensure public safety.

    Recommendation 6

    The Committee recommended that Medsafe writes to the sponsors of dextromethorphan products requesting updates to data sheets regarding the risks of dependence, serotonin syndrome and overdose.

    Recommendation 7

    The Committee recommended the Chair writes to the Medicines Classification Committee to acknowledge the Committee’s opinion that they fully support the decision to reclassify dextromethorphan.

    3.2.4 Shingrix (recombinant varicella zoster virus vaccine) Risk Management Plan

    Background

    Medsafe has received a new medicine application (NMA) from GlaxoSmithKline (GSK) for Shingrix (recombinant varicella zoster virus vaccine). As part of their application, GSK provided a Risk Management Plan (RMP) to Medsafe.

    The purpose of this paper is to seek the Committee’s advice on the RMP for Shingrix, including whether any additional post-market activities are required in New Zealand should Shingrix be approved.

    Discussion

    The Committee noted the Shingrix Risk Management Plan and considered it to be a good Risk Management Plan. The Committee noted the vaccine contains a new plant based adjuvant.

    The Committee had a discussion on susceptibility in different ethnicities. The Committee noted there is no data on Māori/Pasifika at the moment and considered it to be useful for the company to collect and record ethnicity data from reporters.

    The Committee had no further requests from the company if the vaccine is made available and/or funded New Zealand.

    Recommendation 8

    The Committee recommended Medsafe requests that the sponsor of Shingrix collects ethnicity information as part of their documentation of adverse event reporting.

    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 40, Number 3, September 2019

    The Committee noted the latest edition of Prescriber Update. The Committee noted they were very impressed with the quality of the publication and enjoy the quirky titles. The Committee also considered value in communicating with various organisations to promote Prescriber Update.

    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

    The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 1.45pm.

    Associate Professor D Reith
    Chair, Medicines Adverse Reactions Committee
    Date: 14 October 2019

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