Published: 21 August 2018

Committees

MINUTES OF THE 174TH MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 174th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
3 July 2018

The one hundred and seventy-fourth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 3 July 2018 at Ministry of Health, 133 Molesworth Street, Thorndon, Wellington. The meeting commenced at 9am and closed at 2:30pm.

MARC MEMBERS PRESENT
Dr S Jayathissa (Acting Chair)
Dr L Bryant
Professor C Frampton
Dr N Cole
Associate Professor D Menkes
Dr C Cameron
C Ryan
Dr K Eggleton
J Tatler
I Raiman
Dr M Tatley

MARC SECRETARIAT PRESENT
M Oldridge (Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE
S Kenyon (Manager, Clinical Risk Management)
G Hill (Senior Medical Advisor, Pharmacovigilance)
A Kerridge (Senior Advisor, Pharmacovigilance)
L Chan (Senior Advisor, Pharmacovigilance)
M Storey (Senior Advisor, Pharmacovigilance)
V Cheer (Senior Advisor, Pharmacovigilance)
J Solloway (Advisor, Pharmacovigilance)

INVITED GUESTS AND EXPERTS IN ATTENDANCE
Associate Professor R Braund (Centre for Adverse Reactions Monitoring)

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from D Reith and S Hanna.

1.2 Minutes of the 173rd MARC Meeting

The minutes of the 173rd 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 127096, which reported acute renal failure following a zoledronic acid infusion. The patient was not hydrated prior to administration. It was noted that a Prescriber Update article describing this risk was published in 2015.The Committee agreed that prescribers should be reminded to consider patient hydration prior to administration.

The Committee also noted a number of cases where patients were inappropriately co-prescribed aspirin with dabigatran or warfarin and had bleeding related adverse reactions. The Committee was informed that the Health Quality & Safety Commission are taking action on this issue.

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

Recommendation 1

The Committee recommended Medsafe includes an article about appropriate patient hydration measures with zoledronic acid in a future edition of Prescriber Update.

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 did not consider any of the reports required further action.

[Professor C Frampton joined the meeting at this time]

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 Special Populations: Serious Cases in Patients 18 to 80 years (Causal Cases Only)

The Committee noted a number of reports associated with venlafaxine. The Committee was informed that Medsafe had double-checked the bioequivalence and quality studies, which were found to meet international standards. In addition, the Committee was informed that the Mylan generic brand is also available in Australia, the United Kingdom, the United States and Canada. No quality issues have been identified in these countries with this product. Medsafe has notified PHARMAC of the reports and will continue monitoring.

The Committee noted cases related to Viekira Pak-RBV and psychosis. Medsafe is currently investigating this association.

The Committee also noted cases where a drug-drug interaction between atorvatstatin and ticagrelor was suspected. The Committee considered that Medsafe should further investigate this potential interaction.

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

Recommendation 2

The Committee recommended that Medsafe investigate the potential drug-drug interaction between atorvastatin and ticagrelor.

2.1.6 Special Reports: Seasonal Influenza Vaccine Report (March 2018 - April 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 Esmya (ulipristal acetate) under section 36 of the Medicines Act 1981

Background

At the 173rd meeting the Committee reviewed the available information on the possible risk of drug induced liver injury with Esmya (ulipristal acetate). The Committee recommended that Medsafe conduct a risk-benefit review of Esmya (ulipristal acetate) 5 mg under section 36 of the Medicines Act 1981.

The purpose of this paper was to review the information provided by the company in response to the section 36 notice.

The recommendations made in Europe by the Pharmacovigilance Risk Assessment Committee (PRAC) regarding Esmya (ulipristal acetate) were also presented in this paper.

Discussion

The Committee expressed concern about the serious potential for liver injury associated with Esmya (ulipristal acetate). In particular, the mechanism of liver injury remains unknown, making the time to onset difficult to determine.

The Committee considered the other options available in New Zealand for the treatment of uterine fibroids.

The Committee noted that leuprorelin, another pharmacological treatment option, does not appear to have the same potential for liver injury as Esmya (ulipristal acetate). However, the Committee accepted that some patients have difficulty tolerating the adverse effects associated with leuprorelin, such as hot flushes.

The Committee also discussed non-pharmacological treatment options. The Committee noted these are not always appropriate, particularly for those women with large uterine fibroids or with other co-morbidities, such as a high BMI.

The Committee discussed the importance of providing patients with options for treatment, provided they are fully informed.

The Committee commented that there is benefit from Esmya (ulipristal acetate) when compared to placebo. The Committee also noted that the Pharmacovigilance Risk Assessment Committee (PRAC) in Europe had recommended managing the risk of liver injury with Esmya (ulipristal acetate) with additional liver function monitoring. The Committee also noted the other risk minimisation activities recommended by the PRAC and that these may only apply in Europe.

The Committee considered that the risk of liver injury associated with Esmya (ulipristal acetate) could be managed with additional liver function monitoring, but determined that Esmya (ulipristal acetate) should only be used for treatment of uterine fibroids in those patients who are not eligible for surgery.

The Committee discussed the need for liver function to be monitored prior to treatment with Esmya (ulipristal acetate). The Committee considered that treatment should not be initiated if liver transaminase enzymes are above the upper limit of normal or if the patient has pre-existing liver problems.

The Committee considered that liver function monitoring should be more frequent in the early stages of treatment with Esmya (ulipristal acetate). The Committee suggested monitoring function after one week, then monthly for the first two courses of treatment. The Committee agreed that treatment should be stopped if liver transaminase enzyme levels are above the upper limit of normal. Liver function should be monitored two to four weeks after stopping treatment.

The Committee stated that patients should be provided with information about the need for liver enzyme monitoring and the symptoms of liver injury. It was suggested that an information card is included in the manufacturer's original pack.

The Committee also recommended that the risk of liver injury with Esmya (ulipristal acetate) and the recommendations made at this meeting are communicated to relevant prescribers.

The Committee were informed that an update on the risk of liver injury would be provided in the next Periodic Benefit-Risk Evaluation Report (PBRER) for Esmya (ulipristal acetate). The Committee requested an update on this issue after the next Periodic Benefit-Risk Evaluation Report (PBRER) is assessed.

Recommendation 3

The Committee recommended that Medsafe request the sponsor to change the indication for Esmya (ulipristal acetate) to 'For intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age who are not eligible for surgery', or words of a similar meaning.

Recommendation 4

The Committee recommended that Medsafe request the sponsor of Esmya (ulipristal acetate) to add a warning to the New Zealand data sheet stating that Esmya (ulipristal acetate) must not be used in women with known liver problems, or words of a similar meaning.

Recommendation 5

The Committee recommended that Medsafe request the sponsor of Esmya (ulipristal acetate) to add a precaution to the New Zealand data sheet stating that a liver function test should be performed before each treatment course and treatment must not be started if liver transaminase enzyme levels are above the upper limit of normal, or words of a similar meaning.

Recommendation 6

The Committee recommended that Medsafe request the sponsor of Esmya (ulipristal acetate) to add a precaution to the New Zealand data sheet stating that liver function tests should be performed after one week and then once a month during the first two treatment courses and two to four weeks after stopping treatment. If the test is abnormal (liver transaminase enzyme levels are above the upper limit of normal), the doctor should stop treatment and closely monitor the patient, or words of a similar meaning.

Recommendation 7

The Committee recommended that Medsafe request the sponsor of Esmya (ulipristal acetate) to include an information card in the manufacturer's original packaging that informs patients about the need for liver monitoring and to contact their doctor should they develop signs of liver injury.

Recommendation 8

The Committee recommended that Medsafe request the sponsor of Esmya (ulipristal acetate) to provide information to the Royal Australian and New Zealand College of Obstetricians and Gynaecologists so that their members can be educated regarding the risk of liver injury and new monitoring requirements.

Recommendation 9

The Committee recommended that the sponsor of Esmya (ulipristal acetate) is requested to provide Periodic Risk-Benefit Evaluation Reports (PBRERs) to Medsafe, including usage data for New Zealand.

Recommendation 10

Medsafe should provide an update to the Committee on this issue after reviewing the next Periodic Benefit-Risk Evaluation Report (PBRER) for (Esmya) ulipristal acetate.

3.2 Matters Referred to the MARC by Medsafe

3.2.1 Bexsero (recombinant Meningococcal group B vaccine) RMP

Background

Medsafe received a new medicine application from GlaxoSmithKline (GSK) for Bexsero (meningococcal B vaccine).

Due to previous interest with another meningococcal B vaccine product (MeNZB) when it was used during 2004 to 2008, Medsafe considered it appropriate to request a Risk Management Plan (RMP) for Bexsero from GSK.

The purpose of this paper was to seek the Committee's advice on whether any additional post-market activities are required in New Zealand should Bexsero be approved.

Discussion

The Committee considered each area of the RMP for completeness and appropriateness.

The Committee considered the important identified and potential risks, missing information and risk minimisation activities.

The Committee noted the risks identified in the Bexsero RMP were similar to the risks identified with MeNZB.

Members did not express any concerns with the RMP. The Committee unanimously endorsed this RMP. No changes to the RMP were recommended.

3.2.2 Atypical antipsychotics and sleepwalking/ sleep-related eating disorder

Background

Medsafe was notified of a Health Canada safety review which assessed the risk of sleepwalking (SW) and sleep-related eating disorder (SRED) with atypical antipsychotics.

As a result of their review, Health Canada recommended that the product information for all atypical antipsychotics should be updated to include these effects.

This paper reviewed the available evidence for these safety signals.

Medsafe sought the Committee's advice on whether the New Zealand data sheets for these products should include information on these adverse effects.

Discussion

The Committee commented that the term 'atypical' is generally unhelpful when describing antipsychotic activity. For example, atypical antipsychotics vary markedly in their ability to produce extrapyramidal and other adverse effects.

The Committee also commented on the difficulties in determining the overall incidence of these adverse reactions as patients may not be aware of them.

The Committee discussed the available evidence and considered the association possible for particular individual drugs.

The Committee reviewed the association measured by disproportionality in the WHO database for reporting of 'somnambulism' and 'sleep-related eating disorder' with individual atypical antipsychotics. The Committee noted that quetiapine showed the greatest disproportionality.

The Committee commented that inspection of classical antipsychotics would be warranted if this issue was to be pursued further.

The Committee noted that the association was only likely for quetiapine, olanzapine and ziprasidone and recommended all New Zealand data sheets for these medicines are updated. The Committee concluded that the New Zealand data sheets for aripiprazole, risperidone and paliperidone already contained sufficient information. The Committee concluded there was insufficient evidence of an association for other atypical antipsychotics.

The Committee also suggested including a future communication about quetiapine and sleep related disorders in Prescriber Update.

Recommendation 11

The Committee recommended that Medsafe request the sponsors of all olanzapine containing products to update the New Zealand data sheets to include sleepwalking and related sleep disorders as potential adverse reactions.

Recommendation 12

The Committee recommended that Medsafe request the sponsors of all ziprasidone containing products to update the New Zealand data sheets to include somnambulism and related sleep disorders as potential adverse reactions.

Recommendation 13

The Committee recommended that Medsafe request the sponsors of all quetiapine containing products to update the New Zealand data sheets to include somnambulism and related sleep disorders as potential adverse reactions.

Recommendation 14

The Committee recommended that Medsafe includes an article about parasomnias as adverse effects to medicines in a future edition of Prescriber Update.

3.2.3 Potential interaction between nefopam and tramadol

Background

Medsafe investigated the evidence that use of nefopam and tramadol concomitantly results in serotonin syndrome. This review was in response to a consumer query received by Medsafe.

Currently, there is no information related to this interaction in the New Zealand data sheets for either nefopam or tramadol.

The purpose of this paper was to seek the Committee's advice as to whether the New Zealand Acupan (nefopam) data sheet should include safety information related to this interaction.

Discussion

The Committee reviewed the available evidence regarding development of serotonin syndrome when nefopam and tramadol are used concomitantly.

Some members considered the available evidence was not strong enough and current usage of nefopam is not high enough to warrant a change to the New Zealand data sheet. However, the majority agreed this potential interaction should be described in the New Zealand Acupan (nefopam) data sheet as a general precaution.

The Committee agreed that the precaution should also describe other medicines known to increase serotonin availability such as selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs).

Recommendation 15

The Committee recommended that Medsafe request the sponsor of Acupan (nefopam) to add a precaution to the New Zealand data sheet stating that concomitant use of nefopam and another medicine that increases serotonin availability by any mechanism, such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs) or tramadol may cause serotonin toxicity, including serotonin syndrome, or words of a similar meaning.

3.2.4 Isotretinoin: review of (1) pregnancy prevention measures and (2) obsessive compulsive disorder

Background

This paper reviewed the current pregnancy prevention measures for patients taking isotretinoin in New Zealand. This review was precipitated by a review conducted by the Pharmacovigilance Risk Assessment Committee (PRAC), which resulted in changes to the Pregnancy Prevention Programme for oral retinoids, including isotretinoin.

This paper also reviewed the evidence for a possible association between oral retinoids and obsessive compulsive disorder (OCD), in response to a case report received by the Centre for Adverse Reactions Monitoring (CARM).

Discussion
Pregnancy Prevention Measures

The Committee noted the review of National Collections data performed by Medsafe that showed that some pregnancies had been exposed to isotretinoin.

The Committee discussed the current isotretinoin pregnancy prevention resources available to prescribers in New Zealand.

The Committee noted that a bestpractice isotretinoin module is available for prescribers. The module contains information about appropriate pregnancy prevention measures and contains a printable patient acknowledgement/consent form.

The Committee considered that greater visibility/accessibility of this module may support prescriber decision making and improve the safety information received by patients starting isotretinoin treatment.

The Committee also discussed the role of pharmacists in providing safety information about pregnancy prevention to female patients of childbearing age starting isotretinoin treatment.

The Committee recommended encouraging pharmacists to provide patients starting isotretinoin with a copy of the Consumer Medicines Information (CMI) leaflet and to counsel female patients of childbearing age on the need for appropriate contraceptive measures. In particular, the Committee highlighted the need for two forms of contraception.

The Committee also considered that a reminder to pharmacists to dispense isotretinoin in the manufacturer's original pack for female patients of childbearing age was appropriate. The packaging contains safety information, including information on pregnancy prevention.

The Committee discussed the special authority criteria for isotretinoin. The Committee noted that the current criteria no longer requires practitioners to undertake a prescriber course in acne/isotretinoin for isotretinoin treatment to be funded.

The Committee suggested writing to PHARMAC to request this criteria is reintroduced with the additional restriction that the practitioner is knowledgeable in contraception.

Obsessive-Compulsive Disorder (OCD)

The Committee discussed the case report of obsessive-compulsive disorder associated with oral isotretinoin submitted to CARM. In addition, the Committee considered international case reports reported in the WHO database.

The Committee reviewed the information in the New Zealand report and considered that the information was insufficient to determine whether or not isotretinoin was causally related to the onset of OCD.

The reports in the WHO database for isotretinoin and OCD did not provide sufficient information to assess the likelihood of a causal association.

The Committee considered that overall there was insufficient evidence of a causal association between isotretinoin and OCD to justify an update to the New Zealand isotretinoin data sheets at this time.

However, the Committee considered that additional monitoring through Medsafe's Medicines Monitoring (M²) system would be worthwhile, as information from further cases may provide further evidence of an association between isotretinoin and OCD.

[Professor C Frampton left the meeting at this time]

Recommendation 16

The Committee recommended that Medsafe contact the Best Practice Advocacy Centre (BPAC) about the possibility of making their bestpractice module on isotretinoin more visible to prescribers in New Zealand prescribing software.

Recommendation 17

The Committee recommended that Medsafe contact the Pharmaceutical Society of New Zealand (PSNZ) to remind pharmacists to dispense isotretinoin for women of childbearing age in the manufacturer's original pack.

Recommendation 18

The Committee recommended that Medsafe contact the Pharmaceutical Society of New Zealand (PSNZ) to encourage pharmacists to provide patient(s) starting isotretinoin treatment with a copy of the Consumer Medicines Information (CMI) leaflet at the first dispensing.

Recommendation 19

The Committee recommended that Medsafe contact the Pharmaceutical Society of New Zealand (PSNZ) to remind pharmacists to counsel female patients of childbearing age starting isotretinoin treatment about appropriate contraceptive measures.

Recommendation 20

The Committee recommended that Medsafe write to PHARMAC requesting that they restrict the isotretinoin special authority criteria to prescribers who have undertaken a relevant acne/isotretinoin course and are knowledgeable in the area of contraception.

Recommendation 21

The Committee recommended that the association between isotretinoin and obsessive-compulsive disorder is further investigated through Medsafe's Medicines Monitoring (M²) system.

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

4.1.1 Recommendation from Medicines Classification Committee to review the process for observers at Medsafe expert advisory committee meetings
September 2017 minute item 5.1

Recommendation 9

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

Outcome

The consultation closed on 15 January 2018:
www.medsafe.govt.nz/consultations/Observers/Observers%20at%20Ministerial%20Advisory%20Committee%20meetings.asp . The outcome of the consultation was referred back to the MARC for further advice.

Discussion

The Committee were briefed on the responses to the consultation. The Committee noted support for proposals six and eight from responders.

The Committee considered that individuals external to the Committee and the Ministry of Health could be invited to attend MARC meetings at the discretion of the Chair. The Committee agreed that it is beneficial to have the option to invite an expert if the current make-up of the Committee is not sufficient to make safe and accurate recommendations.

The Committee also commented on the need to define the scope of the invited individual's role. Invited individuals should only be present for agenda items within the scope of their invitation. The Committee agreed that the scope of participation in the meeting of the individual(s) should be determined by the Chair.

The Committee considered that invited experts should declare their conflicts of interest before participating in the agenda item(s) on which they have been invited to speak.

The Committee determined that industry representatives may be invited to answer questions that may arise for items under Section 36 of the Act. The representative must not be present for deliberation and voting. The representative must declare conflicts of interest; however, being an employee of the company they represent will not preclude them from providing information to the Committee.

The outcome of this consultation will be published on Medsafe's website when all other proposals have been considered.

Recommendation 22

The Committee requested that observers, experts and industry representatives can be invited to meetings at the discretion of the Chair within a defined scope.

There were no other 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.

The Committee was provided with an update on Arthrem (Artemisia annua) following publication of an alert communication on Medsafe's website.

4.3 Prescriber Update Volume 39, Number 2, June 2018

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

The Committee was informed that Medsafe is working to increase the number of electronic subscriptions. The Committee suggested that contacting Nurse Practitioners New Zealand and the Council of Medical Colleges might help increase subscription numbers.

Recommendation 23

The Committee recommended that Medsafe communicates with Nurse Practitioners New Zealand and the Council of Medical Colleges to promote Prescriber Update and enhance the safe use of medicines in New Zealand.

4.4 Quarterly Summary of Medsafe Early Warning System

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

5.0 ANNEXES

3.1.1 Consideration of Esmya (ulipristal acetate) under section 36 of the Medicines Act 1981

  1. Ulipristal acetate and drug induced liver. MARC paper March 2018
  2. Section 36 notice concerning Esmya (ulipristal acetate) 5mg tablets
  3. Vifor Pharma response to section 36 notice
  4. Esmya Periodic Safety Update Report 9
  5. European Risk Management Plan for Esmya - version 15.1
  6. Medsafe medical advisor report

3.2.1 Bexsero (recombinant Meningococcal group B vaccine) RMP

  1. Risk Management Plan for Bexsero - version 4.0
  2. Medsafe clinical assessment report

3.2.2 Atypical antipsychotics and sleepwalking/ sleep-related eating disorder

  1. Mylan review
  2. AstraZeneca review
  3. MSD review

3.2.3 Potential interaction between nefopam and tramadol

  1. 1. Teva review

3.2.4 Isotretinoin: review of (1) pregnancy prevention measures and (2) obsessive compulsive disorder

  1. Oratane acne treatment programme information and acknowledgement form
  2. Isotane acknowledgment form
  3. National collections data request summary

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2:30pm.

Dr S Jayathissa
Acting Chair, Medicines Adverse Reactions Committee
Date 16/08/2018

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