Published: 23 January 2020





    5 December 2019

    The one hundred and eightieth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 5 December 2019 at the Ministry of Health, 133 Molesworth Street, Wellington. The meeting commenced at 9am and closed at 2.30pm.


    Associate Professor D Reith (Chair)
    Dr C Cameron
    Dr S Hanna
    Associate Professor D Menkes
    L Te Karu
    Associate Professor L Parkin
    Dr R Savage
    Professor L Stamp
    C Ryan
    J Tatler
    I Raiman
    Dr C Gresham


    J Prankerd (Senior Advisor, Pharmacovigilance)


    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)
    A Kerridge (Senior Advisor, Pharmacovigilance)



    1.1 Welcome and Apologies

    The Chair welcomed the attendees to the meeting. Apologies were received from Dr K Eggleton.

    1.2 Minutes of the 179th MARC Meeting

    The minutes of the 179th 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.

    Mrs I Raiman declared that she had financial interests in Johnson and Johnson. It was agreed that Mrs I Raiman should be excluded from the discussion on item 3.2.1 and excluded from voting on all recommendations relating to that item.

    There were no other potential conflicts of interest which were considered likely to influence the discussions or decisions of the MARC at this meeting.


    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.

    [Dr C Gresham and C Ryan joined the meeting at this time.]

    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 133836 where a young patient developed hyponatraemia and tonic/clonic convulsions after taking desmopressin. The Committee discussed the need for concomitant reduction of fluid intake with this medicine and noted convulsions may be caused in some people without a reduction in fluid intake. The Committee recommended further communication of this risk.

    Recommendation 1

    The Committee recommended that this case is highlighted in a future edition of Prescriber Update in the ‘Gathering knowledge from adverse reaction reports’ section.

    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.

    The Committee had a discussion regarding differences in life expectancy between people of different ethnicities, particularly Māori in New Zealand. The Committee considered it would be useful to investigate what additional information could be provided in future CARM quarterly reports to examine any discrepancies or trends between ethnicities.

    Recommendation 2

    The Committee recommended Medsafe and CARM discuss what additional information could be provided regarding ethnicity.  

    2.1.5 Causal and Serious Cases in Patients Aged 18 to 80 Years

    Reports of events occurring in patients 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 Reports: Serious Paediatric Adverse Drug Reactions (January 2018 – December 2018)

    The Committee did not consider any of the reports required further action.

    2.1.7 Supplementary information: Lamotrigine

    CARM gave a summary of all cases reported to CARM from 1 May 2019 to 15 November 2019 describing a reaction to a lamotrigine-containing product following the decision by PHARMAC to move to one funded brand of lamotrigine.

    The Committee expressed concern at the problems reported by patients and reviewed all information currently available.

    The Committee began by discussing the information provided to CARM on cases reporting a fatal outcome. The Committee did not consider that any urgent regulatory action was identified as a result of these discussions. These cases are currently under coronial investigation and the Committee awaits the coronial findings.

    The Committee then discussed the remaining case reports received by CARM. CARM’s analysis of the reports indicates many cases coded as “therapeutic response decreased”, reflecting an increased number of such cases compared to before the brand switch. There was also a proportion of cases with apparent difficult to treat epilepsy (with or without other health conditions) because they were prescribed more than one antiepileptic or there was evidence in the reports that it had taken a long time to stabilise the condition.

    The Committee was presented with results from the bioequivalence study for Logem. The Committee noted Logem has been through the same approval process as for all medicines in New Zealand and the data supported that it is bioequivalent to Lamictal.

    The Committee considered that if a patient is stable on a certain brand they should ideally remain on that brand, especially those with difficult to treat epilepsy. However, the Committee also noted that in some situations, such as restricted or withdrawn supply, patients may need to change brands. In these cases, patients should have input from specialists and additional clinical monitoring, which could include therapeutic drug monitoring. The Committee considered that all lamotrigine products had met the standards needed for approval and the problem was much more likely to be related to the switch rather than the standard of the products. The Committee does not advise changing brands in people with controlled epilepsy, particularly difficult to treat epilepsy. The Committee was concerned that anyone who had switched and were stable on the new brand should not switch again. The Committee also encouraged better communication between general practitioners and pharmacists about brand switches.

    The Committee asked CARM and Medsafe to keep this issue under close review. The Committee will keep a watching brief and await the coronial findings.


    3.1 Matters Referred to the MARC under Section 36 of the Medicines Act 1981

    No items

    [I Raiman left the meeting at this time.]

    3.2 Matters Referred to the MARC by Medsafe

    3.2.1 Pholcodine: benefit-risk review


    The Medicines Classification Committee (MCC) reviewed the classification for pholcodine at their 61st meeting in November 2018. The MCC didn’t recommend any changes to the classification of pholcodine however they requested Medsafe perform a review of the benefits and risks of harm of pholcodine.

    The purpose of this paper was to review the balance of benefits and risks of harm of pholcodine. In particular, the paper examined the evidence for an association between pholcodine and an increased risk of anaphylaxis with neuromuscular blocking agents (NMBAs).


    [J Tatler joined the meeting at this time.]

    The Committee considered the available efficacy and safety data for pholcodine to be limited. The Committee noted pholcodine is an old medicine. Pholcodine has been used in New Zealand since the 1960s and has not been subjected to the same scrutiny as medicines that are approved today. The Committee noted pholcodine is used for a self-limiting cough.

    The Committee discussed the available evidence around pholcodine and NMBA-induced anaphylaxis. The Committee considered that although there is no clear causal association there is some data on an ecological association between pholcodine and NMBA-induced anaphylaxis. The Committee discussed the available studies investigating the possible association between pholcodine exposure and antibody sensitisation. The Committee acknowledged concerns from the sector that widespread availability of pholcodine may be responsible for sensitisation to NMBAs. Anaphylaxis could be a very serious, sometimes fatal, reaction.

    The Committee also discussed what alternative medicines people will take if pholcodine was unavailable and any possible flow on effects, for example in primary care. The Committee discussed the option of restricting the use of pholcodine noting the absence of efficacy data and the possibility of occasional serious adverse reactions. The Committee additionally noted that reclassifying pholcodine to a higher classification would require data sheets to be provided for all pholcodine-containing medicines. This would provide information to healthcare professionals and patients on the use and possible side effects of the medicine.

    The Committee noted the European Medicines Agency (EMA) reviewed the evidence for a link between pholcodine and NMBA-induced anaphylaxis in 2011. The EMA requested Marketing Authorisation Holders to submit a protocol for a case-control study. The Committee considered this would provide useful information however at this time there is no information to indicate that the study has been completed.

    The Committee considered that the benefit-risk balance is marginal, but there is currently insufficient evidence to indicate an unfavourable benefit-risk balance. The Committee also had concerns that patients are not receiving adequate information about the medicine at the point of sale. The majority of the Committee agreed that the MCC should consider reclassifying this medicine to a more restricted classification and pharmacists should primarily inform patients of the risk of harms, including the risk of anaphylaxis. The need to raise awareness with healthcare professionals around this issue was also discussed.

    Recommendation 3

    The Committee recommended that the Medicines Classification Committee considers reclassifying pholcodine to a more restricted classification.

    [I Raiman joined the meeting at this time.]

    3.2.2 Direct acting oral anticoagulants and risk of recurrent thrombotic events


    In March 2019 at the 177th meeting, the Committee discussed a case (CARM ID: 130309) where a patient suffered a thromboembolic stroke following cessation of dabigatran treatment two weeks prior. The Committee considered a potential rebound effect may occur upon stopping dabigatran. The Committee requested that Medsafe further investigates this safety concern.

    The minutes of the 177th MARC meeting are available on the Medsafe website.


    The Committee discussed difficulties in differentiating between the possible reasons for recurring thromboembolic events. The Committee noted possible reasons including predisposing risk, under dosing and nonadherence which may contribute to the thromboembolic events seen. The Committee considered the available information around a rebound effect with direct oral anticoagulants is very weak. The Committee also noted no mechanism has been proposed.

    The Committee determined that there is insufficient evidence of a rebound effect. The Committee unanimously determined no data sheet updates, communication or regulatory action was required.

    3.2.3 Cyproterone acetate and the risk of hepatic toxicity


    The Centre for Adverse Reactions Monitoring (CARM) received a case report regarding a 44-year-old woman who was treated with cyproterone for about 4 months in preparation for hysterectomy due to endometriosis. The patient developed severe hepatitis.

    The data sheets for cyproterone includes information about direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, but states that it has been reported in patients treated with 200 – 300 mg cyproterone acetate and mostly in men with prostatic cancer.

    Considering that cyproterone is also indicated for women and there is a potential risk of hepatic reactions also for women and with lower doses, the wording in the data sheets may not be accurate. Therefore, Medsafe considered that this safety concern should be reviewed by the MARC. Note that this review was not relevant to contraceptives use as these medicines contain far less cyproterone.


    The Committee discussed the information and considered that although hepatic toxicity may be more common at higher doses, it has been seen at lower doses. The Committee considered the data sheet wording is inadequate and should incorporate the concept that hepatic toxicity is not gender specific and can happen at lower doses.

    The Committee noted international product information for cyproterone refers to a wider dose range regarding the risk of hepatic toxicity, with some starting at 100 mg. The Committee considered the wording in the Swedish product information to be clear and in agreement with the Committee’s view that hepatic toxicity may occur at any dose achievable with the cyproterone only medicines (excluding the cyproterone/ethinylestradiol combination tablet).

    The Committee also noted that the Procur data sheet needs an additional update as the dose is not clarified adequately.

    The Committee unanimously agreed the New Zealand data sheet for cyproterone should be updated.

    Recommendation 4

    The Committee recommended Medsafe requests sponsors to update the data sheets.

    3.2.4 Potential drug-drug interaction between capecitabine and proton pump inhibitors


    Capecitabine is an oral prodrug of 5-fluorouracil used in the treatment of the following cancers: breast, colon, oesophagogastric and colorectal.

    Proton pump inhibitors (PPIs) inhibit gastric acid secretion by blocking the proton pump of the gastric parietal cell. Their uses include treatment of gastric and duodenal ulcers, in combination for the eradication of Helicobacter pylori, and the treatment of dyspepsia and gastro-oesophageal reflux disease. PHARMAC’s 2018 year in review shows omeprazole was widely used (the second top prescription medicine by volume).

    The potential interaction between capecitabine and PPIs has been described by Chu et al (2017) and Sun et al (2016). Both studies report this potential interaction could result in reduced efficacy of capecitabine. The proposed mechanism of the interaction is that PPIs increase gastric pH which may reduce the dissolution and absorption of capecitabine.

    Information on this potential interaction in clinical texts is varied. The purpose of this paper is to review the potential interaction between capecitabine and PPIs.


    The Committee considered that although the available evidence is weak, an interaction between capecitabine and PPIs is plausible and cannot be ruled out.

    The Committee discussed the number of people this is likely to affect and considered it is likely to be high because PPIs are widely prescribed. The Committee also discussed alternative medicines for gastric acid suppression.

    The Committee did note there is a potential knowledge gap about this interaction amongst prescribers of capecitabine. The Committee considered that communication would be valuable to highlight this possible interaction although the clinical significance is not known. The Committee also considered that communication would be useful for prescribers to reconsider their patients’ need for a PPI, especially with long term use.

    The Committee discussed appropriate communication methods and agreed communicating with the New Zealand Society for Oncology would be the most appropriate.

    The Committee considered that this potential interaction cannot be excluded at this time and unanimously agreed that this should be stated in the data sheet.

    Recommendation 5

    The Committee recommended Medsafe requests sponsors to update the data sheets.

    Recommendation 6

    The Committee recommended communication with oncologists to inform them of the Committee’s discussion on this topic.


    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:

    4.2 Medsafe Pharmacovigilance Activities

    The Committee noted the report detailing Medsafe’s recent pharmacovigilance activities.

    4.3 Prescriber Update Volume 40, Number 4, December 2019

    The Committee noted the latest edition of Prescriber Update. The Committee stated 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.


    The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 230 pm.

    Associate Professor D Reith
    Date:  13 January 2020
    Chair, Medicines Adverse Reactions Committee

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