Published: 25 July 2019

Committees

MINUTES OF THE 178TH 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 178th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
    13 June 2019

    The one hundred and seventy-eighth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 13 June 2019 at the Ministry of Health, 133 Molesworth Street, Wellington. The meeting commenced at 9am and closed at 2pm.

    MARC MEMBERS PRESENT

    Associate Professor D Reith (Chair)
    Dr C Cameron
    Dr K Eggleton
    Dr S Jayathissa
    Associate Professor L Parkin
    Mrs C Ryan
    Professor L Stamp
    Dr M Tatley
    Ms L Te Karu

    MARC SECRETARIAT PRESENT

    M Oldridge (Advisor, Pharmacovigilance)

    MEDSAFE STAFF IN ATTENDANCE

    S Kenyon (Manager, Clinical Risk Management)
    L Chan (Senior Advisor, Pharmacovigilance)
    V Cheer (Senior Advisor, Pharmacovigilance)
    G Hill (Senior Medical Advisor, Pharmacovigilance)
    A Kerridge (Senior Advisor, Pharmacovigilance)
    J Prankerd (Senior Advisor, Pharmacovigilance)
    J Solloway (Advisor, Pharmacovigilance)
    M Spencer (Team Leader, Product Safety)
    L Stiles (Advisor, Regulatory Practice and Analysis)
    M Storey (Senior Advisor, Pharmacovigilance)

    1.0 MATTERS OF ADMINISTRATION

    1.1 Welcome and Apologies

    The Chair welcomed the attendees to the meeting. Apologies were received from S Hanna, D Menkes, I Raiman and J Tatler.

    1.2 Minutes of the 177th MARC Meeting

    The minutes of the 177th 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 discussed case 132344, which described a patient who experienced dysphagia following inadvertent administration of Botox (botulinum toxin type A) instead of Dysport (alternative brand). The two brands are not equivalent and subsequently an excessive dose of the toxin was administered. The Committee noted that 1000u of Dysport is similar to 400u of Botox. It was unclear from the report as to whether the adverse event (dysphagia) was the cause of death.

    The Committee noted that there is information in all of the botulinum toxin type A data sheets which states that units/unit doses of one brand are not interchangeable/equivalent with those of other brands.

    The Committee questioned whether the current credentialing of healthcare professionals who prescribe and administer botulinum toxin type A provides assurance that it will be given safely.

    The Committee was informed that CARM case 132344 is currently being reviewed by the Coroner and that once completed, the Coroner’s review would provide more insight into how this case arose. Additionally, it would contain decisions/recommendations based on the coroner’s findings. The Committee recommended that Medsafe communicates with the coroner to request that they provide an update on their decisions/recommendations regarding this case when they are available. The Committee also recommended that the coroner’s decisions/recommendations regarding CARM case 132344 are brought back to a future MARC meeting for further discussion.

    The Committee was informed that while Medsafe awaits the coroner’s review, an article highlighting the differences between brands of botulinum toxin type A will be included in the next edition of Prescriber Update.

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

    Recommendation 1

    The Committee recommended that Medsafe communicates with the coroner about CARM case 132344 and requests that they provide an update on their decisions/recommendations on this issue.

    Recommendation 2

    The Committee recommended that Medsafe brings this issue back to a future MARC meeting once the coroner has provided an update regarding their decisions/ recommendations about CARM case 132344.

    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 131862, which described a young patient who developed hyperphosphataemia following the use of Fleet enema.

    The Committee stated that although the use of Fleet enema has not been approved in children under the age of 12, it is standard clinical practice to use it in this group. The Committee considered that most paediatricians would be aware of the risk of hyperphosphataemia and would therefore use Fleet enema sparingly.

    The Committee reviewed the Fleet enema monograph presented in the New Zealand Formulary (NZF) and noted that currently there is little information regarding the risk of hyperphosphataemia. The Committee recommended that the Chair of the MARC writes to the NZF about improving the information on their website regarding this adverse reaction.

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

    Recommendation 3

    The Committee recommended that the Chair of the MARC writes to the New Zealand Formulary (NZF) about improving the information on their website regarding the risk of hyperphosphataemia with Fleet enema.

    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 events occurring in patients aged 18 years to 80 years were briefly outlined for the Committee.

    The Committee confirmed with the Director of the New Zealand Pharmacovigilance Centre that there were only four adverse drug reaction reports related to venlafaxine received during the last quarter (January 2019 – March 2019).

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

    2.1.6 Special Reports: Annual Review of Fatalities (January 2018 to 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

    No items

    3.2 Matters Referred to the MARC by Medsafe

    3.2.1 Use of Trimethoprim in the 65 Years or Older Population

    Background

    The British Medical Journal recently published a study (Crellin et al.) describing an association between trimethoprim and an increased risk of acute kidney injury and hyperkalaemia in patients aged 65 and older, compared with other antibiotics used to treat urinary tract infections (UTIs). The results were considered potentially significant by Medsafe, which triggered further investigation into the safety of trimethoprim in the elderly population.

    Trimethoprim is one of the most commonly used antibiotics as a treatment for UTIs, and has a high usage in the elderly population. The medicine has been previously associated with adverse effects such as hyperkalaemia, acute kidney injury (AKI) and sudden death, notably when used in combination with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Product information for trimethoprim products is limited on specific warnings for these outcomes, especially in the context of the elderly.

    The purpose of this paper was to review the results of Crellin et al. alongside previous studies, product information, and adverse drug reaction reports in order to assess whether there is a change in the risk of adverse outcomes (specific or as a whole) in the elderly population.

    Discussion

    The Committee reviewed the results of Crellin et al. and considered that the evidence for hyperkalaemia was strong while the evidence for AKI was weak. The Committee commented on the potential for trimethoprim to interfere with creatinine measurement/excretion, leading to false positives for AKI diagnosis. The Committee also questioned whether the methodology used allowed for accurate identification and coding of AKI.

    The Committee noted that previously published papers were not as valuable as Crellin et al. as the investigated product was trimethoprim in combination with sulfamethoxazole, rather than trimethoprim alone.

    The Committee reviewed the current warning in the trimethoprim data sheet regarding hyperkalaemia. The Committee noted that the warning states that older patients are at risk of hyperkalaemia and to monitor serum electrolytes closely. Additionally, the Committee reviewed the trimethoprim consumer medicines information (CMI) leaflet and noted that it contains a warning that mentions ‘patients over the age of 65 may be at an increased risk of side effects’. The Committee considered that these statements were sufficient and that no updates to the trimethoprim data sheet or CMI were required at the present time.

    However, the Committee considered that some health professionals may not be aware of medicines that can interfere with the measurement/excretion of creatinine, including trimethoprim. The Committee recommended that Medsafe includes an article about this topic in a future edition of Prescriber Update.

    Recommendation 4

    The Committee recommended that an article about medicines that interfere with creatinine measurement/excretion is published in a future edition of Prescriber Update.

    3.2.2 Carbimazole and Congenital Malformations

    Background

    In November 2018, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) concluded that data from epidemiological studies and case reports strengthens the evidence that carbimazole can cause congenital malformations when administered during pregnancy. The PRAC recommended amendments to the product information (ie, data sheets and consumer medicine information.

    The purpose of this paper was to review the risk of fetal harm when carbimazole is administered during pregnancy.

    Discussion

    The Committee considered the new evidence reviewed by the EMA PRAC and the additional information in the Medsafe report. The Committee agreed that the strengthened evidence was fairly convincing.

    The Committee agreed this issue was complicated. Hyperthyroidism during pregnancy should be treated because it can result in adverse maternal and neonatal outcomes. Antithyroid agents, such as carbimazole, have become the standard treatment for hyperthyroidism during pregnancy.

    The Committee discussed the need for stronger wording around contraception and the use of carbimazole during pregnancy, particularly in the first trimester and at high doses, in the carbimazole data sheet and CMI. The Committee agreed that the recommended amendments from the EMA PRAC’s update to the European carbimazole product information were sufficient. The Committee recommended that Medsafe requests the sponsor of carbimazole to update the data sheet and CMI in line with the EMA PRAC.

    Additionally, the Committee considered the need for further communication of this issue. The Committee recommended that the Chair of the MARC writes to the New Zealand Society of Endocrinology to draw their attention to the strengthened evidence regarding carbimazole and congenital malformations as well as the discussion had at this meeting.

    Recommendation 5

    The Committee recommended that Medsafe requests that the carbimazole data sheet and CMI is updated with additional information regarding contraception and congenital abnormalities in line with the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee’s (PRAC’s) recommended amendments.

    Recommendation 6

    The Committee recommended that the Chair of the MARC writes to the New Zealand Society of Endocrinology to draw their attention to the strengthened evidence regarding carbimazole and congenital malformations as well as the discussion had at this meeting.

    3.2.3 Fluoroquinolones and Aortic Aneurysm or Dissection

    Background

    Medsafe was alerted to a published study in 2018 about the potential risk of aortic aneurysm and dissection in association with use of fluoroquinolones. At the same time, the topic was under review by the FDA and PRAC, and their reviews are now complete. The conclusions of both FDA and PRAC were to recommend updates of the product information with a warning. Updates have also been requested in Singapore and Switzerland.

    The purpose of this paper was to review available information, focusing on oral and parenteral fluoroquinolone use. Considering the severity of the potential adverse reactions and the use of fluoroquinolones in New Zealand, Medsafe considered that these safety concerns should be referred to the MARC for advice as to whether data sheets and recommendations should be updated.

    This paper also provided an update on regulatory activities regarding the risk of disabling and persistent musculoskeletal and nervous system adverse reactions in relation to treatment with fluoroquinolones, which was previously discussed at the December 2017 MARC meeting.

    Following the safety concerns described above, some regulatory agencies have decided to restrict the indications for fluoroquinolones. Medsafe requested advice from the MARC as to whether the indications in NZ should be restricted.

    Discussion

    The Committee discussed the biological plausibility of aortic aneurysm/dissection with fluoroquinolone use. The Committee stated that ordinarily aortic aneurysms develop over time rather than acutely and questioned whether fluoroquinolone use could accelerate this process. The Committee then considered the relatively fast onset of Achilles tendon ruptures in the context of fluoroquinolone use and commented that therefore it could be biologically plausible. However, the Committee suggested that it would seem more biologically plausible in people with a pre-existing, undetected aortic aneurysm who have had their aneurysm rupture/dissect due to the acute effect of the quinolone.

    The Committee reviewed the presented evidence and noted that it indicated an increased risk of aortic aneurysm and dissection in patients taking systemic fluoroquinolones compared with patients taking no antibiotics or other antibiotics (amoxicillin). However, the absolute risk was still small.

    The Committee noted that the hazard ratio (HR) for aortic aneurysm reported in Pasternak et al was above one. The Committee commented that although the hazard ratio (HR) for aortic dissection was less than one, the confidence interval was very wide, suggesting small numbers of aortic dissection. The Committee stated that therefore an increased risk of dissection couldn’t necessarily be ruled out.

    The Committee considered that the presented evidence was insufficient to warrant additions to the fluoroquinolone contraindications at the present time. However, the Committee agreed that there was sufficient evidence to include a warning statement about the risk of aortic aneurysm/dissection in the fluoroquinolone data sheets. The Committee recommended that Medsafe requests the New Zealand sponsors of fluoroquinolones to update the data sheets accordingly.

    The Committee then considered the need for further communication of this issue. The Committee commented that few healthcare professionals would be aware of this newly identified risk. Therefore, the Committee recommended that Medsafe includes an article about fluoroquinolones and aortic aneurysm/dissection in a future edition of Prescriber Update.

    The Committee also discussed the possibility of communicating with cardiologists and vascular surgeons about this issue. The Committee commented that cardiologists typically provide information/advice to primary care following a patient echocardiogram. The Committee considered that it would be useful for cardiologists to provide information/advice to a patient’s general practitioner if screening has shown that a patient has the potential for developing an aneurysm or dissection. Then the GP can assess benefits and risks to determine the appropriateness of fluoroquinolone use.

    The Committee recommended that the Chair of the MARC writes to the Cardiac Society of Australia and New Zealand and the Australian and New Zealand Society for Vascular Surgery to inform them of the risk of aortic aneurysm/dissection with fluoroquinolone use and the discussion had at this meeting. Additionally, the letter should also recommend that cardiologists and vascular surgeons provide information/advice to a patient’s general practitioner if screening has shown that a patient has the potential for developing an aneurysm or dissection.

    The Committee considered that indications as listed in fluoroquinolone data sheets do not require further restriction at this time.

    Recommendation 7

    The Committee recommended that Medsafe requests the New Zealand sponsors of fluoroquinolones to include a warning statement about the risk of aortic aneurysm/ dissection in the data sheets.

    Recommendation 8

    The Committee recommended that Medsafe includes an article about the risk of aortic aneurysm/dissection with fluoroquinolone use in a future edition of Prescriber Update.

    Recommendation 9

    The Committee recommended that the Chair of the MARC writes to the Cardiac Society of Australia and New Zealand and the Australian and New Zealand Society for Vascular Surgery to inform them of the risk of aortic aneurysm/dissection with fluoroquinolone use and the discussion had at this meeting. The letter should also recommend that cardiologists and vascular surgeons provide information/advice to a patient’s general practitioner if screening has shown that a patient has the potential for developing an aneurysm or dissection.

    3.2.4 Sertraline and Nortriptyline: Potential Drug-Drug Interaction

    Background

    Medsafe reviewed an adverse drug reaction (ADR) report (ID: 125559) submitted to the Centre for Adverse Reactions Monitoring (CARM) as part of routine pharmacovigilance. The report described a suspected drug-drug interaction between sertraline and nortriptyline. During this time it was noted that there is currently no wording in the data sheets specifically describing a drug-drug interaction between nortriptyline and sertraline. As a result, Medsafe investigated the literature for evidence of such an interaction.

    The advice sought from the Committee was whether the presented evidence was sufficient to warrant inclusion of information regarding a drug-drug interaction in both the sertraline and nortriptyline data sheets.

    Discussion

    The Committee reviewed CARM case 125559, in addition to the company reports submitted to Medsafe. The Committee stated that although the reports did not appear to provide convincing evidence of a drug-drug interaction, there is well known risk of serotonin syndrome whenever a tricyclic antidepressant (TCA) and a selective serotonin reuptake inhibitor (SSRI) are taken concomitantly.

    The Committee noted that there is currently no information regarding this risk in the nortriptyline or sertraline data sheets. Therefore, the Committee recommended that these data sheets are updated with information about the risk of serotonin syndrome with the concomitant use of TCAs and SSRIs.

    The Committee also considered the need for other TCA and SSRI data sheets to include this information. The Committee recommended that as Medsafe revises other SSRI and TCA data sheets, consideration should be given to including information about the risk of serotonin syndrome with the concomitant use of TCAs and SSRIs, if it is not already mentioned.

    Recommendation 10

    The Committee recommended that Medsafe requests the New Zealand sponsors of nortriptyline and sertraline to update the data sheets to include information about the risk of serotonin syndrome with concomitant use of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).

    Recommendation 11

    The Committee recommended that as Medsafe reviews other SSRI and TCA data sheets, consideration should be given to including information about the risk of serotonin syndrome with the concomitant use of TCAs and SSRIs, if it is not already mentioned.

    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 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 40, Number 2, June 2019

    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 Early Warning System

    The Committee noted the quarterly summary of Medsafe early warning system communications.

    5.0 OTHER BUSINESS

    5.1 Survey on ADR reporting – Outcome Report for Survey of Healthcare Professionals

    The Committee was given a brief summary of the outcome of Medsafe’s recent healthcare professional survey on ADR reporting. The Committee provided Medsafe with suggestions for improving adverse reaction reporting and the uptake of Prescriber Update by healthcare professionals.

    6.0 ANNEXES

    3.2.1 Use of trimethoprim in the 65 years or older population

    1. Crelin et al.
    2. CARM data

    3.2.3 Fluoroquinolones and aortic aneurysm or dissection

    1. Report from Bayer
    2. Pasternak et al.
    3. Lee et al. (2018)
    4. Lee et al. (2015)
    5. Daneman et al.

    3.2.4 Sertraline and nortriptyline: potential drug-drug interaction

    1. CARM case 125559
    2. Pfizer company report
    3. Teva company report
    4. Vigibase reports

     

    The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2pm.

    Associate Professor David Reith
    Chair, Medicines Adverse Reactions Committee

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