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Committees

Published: 29 September 2017

MINUTES OF THE 171st MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 171st MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

14 September 2017

The one hundred and seventy-first meeting of the Medicines Adverse Reactions Committee (MARC) was held on 14 September 2017 at Ministry of Health, 133 Molesworth Street, Thorndon, Wellington. The meeting commenced at 9am and closed at 3.30pm.

MARC MEMBERS PRESENT

Associate Professor D Reith (Chair)
Dr L Bryant
Dr K Eggleton
Professor C Frampton
Dr S Hanna
Dr S Jayathissa
Dr P Jones
Associate Professor D Menkes
I Raiman
C Ryan
J Tatler
Dr M Tatley

MARC SECRETARIAT PRESENT

L Chan (Senior Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE

S Kenyon (Acting Manager, Clinical Risk Management)
J Prankerd (Senior Advisor, Pharmacovigilance)
A Taylor (Senior Advisor, Pharmacovigilance
M Storey (Senior Advisor, Pharmacovigilance
G Hill (Senior Medical Advisor, Pharmacovigilance)
D Geddebo (Medical Advisor, Clinical Risk Management)
M Tagoc-Magtoto (Skilled Migrant Work Experience Intern, Clinical Risk Management)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

R Ferguson (Senior Clinical Editor, New Zealand Formulary)

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Dr N Cole.

1.2 Minutes of the 170th MARC Meeting

The minutes of the 170th 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 MEDSAFE PHARMACOVIGILANCE ACTIVITIES

2.1 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

2.1.1 Use of dexchlorpheniramine and other sedating antihistamines in children
June 2016 minute item 3.2.1

Recommendation 2

The Committee recommended that Medsafe updates the Label Statements Database to contraindicate the use of sedating antihistamines in children under 2 years for all indications and in children under 12 years for the treatment of insomnia. The contraindication in children under 6 years of age for the treatment of cough and colds is to remain.

Recommendation 3

The Committee recommended the Medicines Classification Committee consider reclassifying sedating antihistamines to prescription medicines when used in children under 6 years of age for the nausea and vomiting and travel sickness indications.

Recommendation 4

The Committee recommended an article be published in a future edition of Prescriber Update to advise healthcare professionals of any changes relating to the use of sedating antihistamines.

Outcome

A submission was made for the Medicines Classification Committee (MCC) meeting on 16 May 2017. Minutes from this meeting are available on the Medsafe website: www.medsafe.govt.nz/profs/class/Minutes/2016-2020/mccMin16May2017.htm

Medsafe is currently consulting on proposed updates to the Label Statements Database (LSD). The consultation period closes on 29 September 2017: www.medsafe.govt.nz/consultations/ChangesToLabelStatementsSedatingAntihistamines.asp

Following LSD consultation, an article will be included in Prescriber Update.

Discussion

The Committee noted that the MCC recommended that the sedating antihistamines brompheniramine, chlorpheniramine, cyclizine, dexchlorpheniramine, diphenhydramine, doxylamine, meclozine, promethazine and trimeprazine should not be amended and reclassified from non-prescription to prescription medicines when used in children under six years of age for the treatment of nausea and vomiting and travel sickness. The MCC felt that the proposed reclassification was not practical and that sedating antihistamines were well managed at pharmacy level. The Committee also noted that the MCC minutes included reference to anecdotal pharmacy experience and the Committee discussed whether this level of evidence was appropriate. 

It is likely that this topic will have to be revisited by the MCC as any changes to the Label Statements Database, which is currently being consulted on, will require input from the MCC. The Committee discussed that reclassifying the liquid formulations of these medicines could be a reasonable starting point. 

The Committee recognised the practical problems the MCC has raised but overall, the Committee agreed that public safety should be the primary concern when considering the reclassification of these medicines.

[Prof C Frampton joined the meeting at this time.]

2.2 Medsafe Pharmacovigilance Activities

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

The Committee noted that Medsafe recently published an alert communication on the use of tramadol during breastfeeding. The Committee considered that it may be helpful for midwives and general practitioners to be made aware of this alert communication. 

Recommendation 1

The Committee recommended Medsafe shares the alert communication on the use of tramadol during breastfeeding with midwives and general practitioners.

2.3 Prescriber Update Volume 38, Number 3, September 2017

The Committee noted the latest edition of Prescriber Update. The Committee noted they were impressed with the quality of the publication.

2.4 Quarterly Summary of Medsafe Early Warning System

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

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 sodium valproate in pregnancy

Background

The current indications of sodium valproate (Epilim):

Epilim IV is indicated in the treatment of patients with epilepsy or bipolar disorder, who would normally be maintained on oral sodium valproate and for whom oral therapy is temporarily not possible. 

Additionally, the use of sodium valproate is contraindicated in pregnancy and the Epilim data sheet contains extensive warnings relating to pregnancy and treatment advice.

Since Epilim (sodium valproate) was approved as a medicine in New Zealand, the Committee has reviewed many case reports of suspected adverse reactions including reports of teratogenic effects. 

The European Union (EU) is currently conducting an investigation into this issue. Therefore, it is timely to review the teratogenic and neurodevelopmental effects and investigate whether use in pregnancy has decreased since Medsafe issued reminders regarding this issue. 

The purpose of this paper was to review the use of sodium valproate (Epilim) in pregnancy. 

Discussion

The Committee considered it important to differentiate between the use of sodium valproate for epilepsy and the use for bipolar disorder. This is because there are factors that are different in the treatment of these conditions including the dose and duration of use of sodium valproate and possible differences in the risk of adverse pregnancy outcomes if these conditions are untreated. There are also other alternatives to sodium valproate for the treatment of mania, maintenance and prophylaxis of bipolar disorder. However, there are particular seizure disorders where sodium valproate may be the best option. 

The Committee were presented with studies that have been recently published on this topic. Despite the weak nature of observational studies, the Committee considered that the statistical analyses used in these studies were adequate and appropriate. 

The Committee noted the booklets on the benefits and risks of taking antiepileptic medicines for females produced by the Accident Compensation Corporation (ACC). The Committee commented that these booklets communicate risk in a way that people understand. In particular, the use of pictographs is helpful in illustrating the risks of malformations and learning and behavioural problems in unborn babies. The Committee were informed that there is an extensive distribution plan to ensure all stakeholders including healthcare professionals and consumers are aware of and have access to the booklet.

The Committee were also informed that the supplier of Epilim has developed a comprehensive package of risk management strategies including educational materials for consumers and healthcare professionals. 

The Committee discussed the importance of ensuring women of childbearing age who are taking sodium valproate are provided with advice regarding effective contraception. The Committee noted that the Epilim data sheet and the ACC booklets contain information on effective contraception. 

Overall, the Committee considered that it would be appropriate to restrict the indication for use of sodium valproate for the treatment of mania, maintenance and prophylaxis of bipolar disorder in women of childbearing age. Medsafe should contact the company to request this change.

Recommendation 2

The Committee recommended that Medsafe contact the company to request further restrictions on the use of sodium valproate in women of childbearing potential in the bipolar disorder indication.

Recommendation 3

The Committee recommended that any changes in the indication for sodium valproate be communicated to healthcare professionals and consumers.

The paper provided to the Committee on this topic can be found at www.medsafe.govt.nz/committees/MARC/Reports.asp

3.2.2 Review of immune checkpoint inhibitors in the New Zealand context

Background

Recently Medsafe was informed by the Centre for Adverse Reactions Monitoring (CARM) of two reports of the development of diabetes (Type 1) in patients who had received treatment with pembrolizumab.

Pembrolizumab, ipilimumab, nivolumab and atezolizumab are medicines called immune checkpoint inhibitors. Immune checkpoint inhibitors target proteins (‘checkpoints’) T-cells. By blocking these checkpoints, they allow the immune system to boost the immune response against cancer cells. There are two important immune-checkpoint receptors involved in the immune process of cancer cell growth: cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1). 

Given that these medicines are relatively new to New Zealand, their use is anticipated to increase and noting the severity of the recent reports of diabetes received, Medsafe considered a review of these medicines in the New Zealand context should be carried out. Therefore, the purpose of this paper was to present current data on the use of pembrolizumab, ipilimumab, nivolumab and atezolizumab.

Discussion

The Committee agreed that the use of immune checkpoint inhibitors is likely to increase over time. Currently, nivolumab and pembrolizumab are funded by PHARMAC and are likely to be more widely used than ipilimumab and atezolizumab. The Committee noted that immune checkpoint inhibitors are a growing area in oncology and have been shown to have benefits in patients including an increase in survival times. 

The Committee considered that although these medicines are known collectively as immune checkpoint inhibitors, their specific mechanism of action is slightly different from each other. Therefore, it is possible that adverse reactions to these medicines are specific for each medicine and cannot be considered class effects. However, the adverse reactions listed in the data sheets and those that are being reported to CARM, particularly those relating to immune-mediated effects, are biologically plausible.

The Committee noted that although patients will be initiated on these medicines in a hospital setting, general practitioners will also be involved in the longer-term management of these patients particularly if they have other chronic conditions. The Committee considered it was important that knowledge about immune-mediated effects with these medicines was widely disseminated to healthcare professionals likely to be involved in the care of these patients. This will help to ensure all healthcare providers involved in a patient’s care are aware of and thus able to continually monitor patients appropriately for adverse effects. 

Recommendation 4

The Committee recommended Medsafe includes an article on immune checkpoint inhibitors in a future edition of Prescriber Update.

Recommendation 5

The Committee recommended communication with relevant organisations to inform them of the Committee’s discussion on immune checkpoint inhibitors.

The paper provided to the Committee on this topic can be found at www.medsafe.govt.nz/committees/MARC/Reports.asp

3.2.3 Risks of severe depression, anxiety and suicidal ideation with hormonal contraceptives

Background

Historically, the use of combined hormonal contraceptives has been associated with depression and adverse mood effects in some women. High rates of psychological side effects have been described in reviews published before 1980. However the products and formulations available at that time were quite different to those available now. 

Medsafe recently reviewed information on the risk of suicidal ideation with the oral contraceptive containing cyproterone/ethinylestradiol. Although cyproterone/ethinylestradiol can be used as oral contraception, it is not recommended in women solely for contraception. It is possible that suicidal ideation occurs due to the conditions (eg, acne, polycystic ovary syndrome) that cyproterone/ethinylestradiol is used to treat rather than an adverse effect of treatment. 

Therefore, the scope of this review was widened to include the risks of severe depression, anxiety and suicidal ideation with hormonal contraceptives. Excluded from this review are emergency contraceptive pills, and postnatal depression. 

Discussion

The Committee noted that from puberty to menopause, women experience reduced 5-HT activity in the late luteal phase. This physiological cyclic nature of the menstrual cycle affects women differently and the effects are unpredictable. Those that are sensitive to these effects can experience adverse outcomes such as depressed mood independent of hormonal contraceptive use. The Committee acknowledged that changes in mood (both improvement in mood and worsening of mood) are commonly reported in women using combined hormonal contraceptives.

The Committee was presented with published literature on this topic. The Committee considered that many studies used different definitions of depression and anxiety. No reliable pattern could be ascertained from studies investigating hormonal contraceptives and their depressive or anxiolytic effects. Although completed suicide, suicidal ideation and related terms are more easily defined, these are much rarer and therefore more difficult to study. No studies could be identified that specifically assessed the risk of suicidal ideation with hormonal contraceptives.

Hormonal contraceptives are widely prescribed by general practitioners and access was recently widened to allow selected oral contraceptives to be sold over the counter after a consultation with a pharmacist if they have completed a Pharmacy Council and Pharmaceutical Society of New Zealand approved training programme. It is important that all healthcare professionals providing hormonal contraception to women are aware of changes in mood so that an alternative method of contraception can be provided if necessary and women are linked with mental health service providers for support.

Overall, the Committee considered that the available information on the risks of severe depression, anxiety and suicidal ideation with the use of hormonal contraceptives was conflicting. Data sheets for these medicines contain sufficient information on what is currently known about these effects. 

Recommendation 6

The Committee recommended Medsafe includes information on this discussion of risks of severe depression, anxiety and suicidal ideation with hormonal contraceptives in the MARC’s Remarks section of Prescriber Update for this meeting.

The paper provided to the Committee on this topic can be found at www.medsafe.govt.nz/committees/MARC/Reports.asp

4.0 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

4.1.1 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 124588 regarding increased hepatic enzymes and jaundice suspected to be caused by the use of aspirin in chloroform applied to the skin and oral flucloxacillin in a 72-year-old female patient. While both flucloxacillin and chloroform could have contributed to the hepatic adverse effects in this patient, the liver enzyme test results were unusual for flucloxacillin-induced hepatotoxicity. The Committee noted that aspirin in chloroform is extemporaneously compounded by a pharmacist (not an approved product) and is funded by PHARMAC. The Committee considered that the details of this case and concerns about the suitability of using chloroform topically should be communicated to PHARMAC.

The Committee discussed case 122072 regarding interstitial lung disease and respiratory failure suspected to be caused by the use of methotrexate, adalimumab and leflunomide in a 67-year-old female patient. She had stable and mild interstitial lung disease up until adalimumab was added to her treatment regime. The reporter had questioned whether it was acceptable to use adalimumab in patients with interstitial lung disease as there was no guidance in the data sheet. The Committee considered that further investigation by Medsafe would be helpful in assessing the association of interstitial lung disease with these medicines.

Recommendation 7

The Committee recommended communicating its concerns of using chloroform topically and details of case 124588 with PHARMAC.

Recommendation 8

The Committee recommended Medsafe further investigates the use of combinations and sequencing of conventional and biologic disease-modifying anti-rheumatic drugs (DMARDs) and the risk of interstitial lung disease.

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

4.1.2 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 of the reports required further action.

4.1.3 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.

4.1.4 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.

5.0 OTHER BUSINESS

5.1 Recommendation from Medicines Classification Committee to review the process for observers at Medsafe expert advisory committee meetings

The Committee was provided with the proposed consultation document on the process for observers at Ministerial Advisory Committees. Further information on the background and reasons for undertaking this review is available in the minutes of the 58th meeting of the Medicines Classification Committee: www.medsafe.govt.nz/profs/class/Minutes/2016-2020/mccMin16May2017.htm

The Committee discussed the contents of the proposed consultation document and agreed that the current process for observers for this Committee does not require any changes. The Committee considered that Medsafe’s consultation regarding observers at Ministerial Advisory Committees should proceed.

Recommendation 9

The Committee considered that the Medsafe consultation regarding observers at Ministerial Advisory Committees should proceed.

5.2 New Zealand Formulary (NZF) discussion on risk communication

The Committee was given a summary of the sources of information used and process followed to compile the information included in the product monographs and chapter summaries of the New Zealand Formulary. The Committee had the opportunity to discuss and comment on some of these aspects. 

5.3 Vaccine Safety Expert Advisory Group – Formalising the group and potential to act as an advisory group to MARC

The Committee was given some background information on the Vaccine Safety Expert Advisory Group and what its current functions are as well as the proposed future capacity to expand. The Committee was informed that there are currently a number of groups that are involved in delivering the immunisation programme. However, there is no formal process for the sharing of information between these groups. 

The Committee considered that a detailed business case is required with information on how the Vaccine Safety Expert Advisory Group and the Committee could potentially work together in promoting vaccines safety.

5.4 Therapeutic products regulation project – Update

The Committee was given an update on the therapeutic products regulation project.

6.0 ANNEXES

3.2.1 Use of sodium valproate in pregnancy

  1. Full company report
  2. CARM data
  3. ACC booklets

3.2.2 Review of immune checkpoint inhibitors in the New Zealand context

  1. Pardoll 2012
  2. CARM data

3.2.3 Risks of severe depression, anxiety and suicidal ideation with hormonal contraceptives

  1. Bayer’s review
  2. Pfizer’s review
  3. MSD’s review
  4. CARM data

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 3.30pm.

Associate Professor David Reith
Chair, Medicines Adverse Reactions Committee

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