Published: 19 April 2016

Committees

MINUTES OF THE 165th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING - 10 MARCH 2016

MINUTES OF THE 165th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
10 March 2016

 

The one hundred and sixty fifth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 10 March 2016 at The Rydges, 75 Featherston Street, Pipitea, Wellington, New Zealand. The meeting commenced at 9.15am and closed at 2.40pm.

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

MARC SECRETARIAT PRESENT
J Prankerd (Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE
R Pollock (Acting Manager, Clinical Risk Management)
S Kenyon (Principal Technical Specialist, Pharmacovigilance)
R Perry (Advisor, Pharmacovigilance)
G Hill (Senior Medical Assessor)
A Kerridge (Advisor, Pharmacovigilance)
S Stubbs (Advisor, Pharmacovigilance)
H Hoang (Advisor, Science (MAAC and MCC Secretary))

L Holding (Team Leader, Committee and Support Services)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

Dr R Savage (Senior Medical Assessor, Centre for Adverse Reactions Monitoring)

1. MATTERS OF ADMINISTRATION

1.1. Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Dr N Cole and Associate Professor D Menkes.

1.2. Minutes of the 164th MARC Meeting

The minutes of the 164th 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. 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. Consumer reporting of adverse drug reactions

At the 162nd meeting held on 11 June 2015, the Committee recommended that a pilot of consumer reporting of adverse drug reactions is carried out and that promotion of adverse drug reaction reporting to healthcare professionals should continue including the value of consumer reporting.

Outcome

Medsafe has drafted a consumer-specific reporting form and consumer information leaflet for the pilot. Medsafe is in the process of establishing requirements for the pilot programme.

Discussion

An update on the project was given and the Committee noted that this was an ongoing issue. The reporting forms are expected to be ready in two weeks.

Recommendation 1

The Committee recommended for the progress of the project to be reported back at a future meeting.

2.1.2. Misuse of quetiapine

At the 164th meeting held on 3 December 2015, the Committee recommended that Medsafe obtains further information regarding the use of quetiapine in New Zealand.

Outcome

The Director of the National Addiction Centre at the University of Otago provided Medsafe with further information. Medsafe was advised that there is no evidence that quetiapine is addictive but may be used to help with post intoxication symptoms.

Discussion

The Committee discussed anecdotal evidence has indicated that quetiapine may be being used off-label for insomnia. The Committee was concerned about use in certain populations. The Committee considered that further investigation would be helpful.

Recommendation 2

The Committee recommended Medsafe investigate this further and based on the results of the investigation considers an article around the use of quetiapine in New Zealand in a future edition of Prescriber Update.

2.1.3. Hormone replacement therapy and risk of ovarian cancer

At the 164th meeting held on 3 December 2015, the Committee recommended that Medsafe considers requesting companies to update the data sheet with a class warning such as that used in Europe.

Outcome

Medsafe provided the European wording to the Committee for their comments on the suitability for the New Zealand data sheets.

Discussion

The Committee discussed the suitability of the wording for the New Zealand data sheets. The Committee considered the wording to be suitable for the New Zealand environment.

Recommendation 3

The Committee recommended that Medsafe request sponsors to update the data sheets with the European wording. The Committee additionally recommended the sponsor updates the Consumer Medicine Information in line with the data sheet updates.

There were no other standing agenda items for which the MARC made further recommendations.

2.2. Medsafe Pharmacovigilance Activities

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

A discussion was had around Medsafe’s consultation on the data sheet format consultation and noted the opportunity for the Committee to comment and feedback.

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

The Committee noted the project to update the online index of Prescriber Update articles is now complete.

The Committee discussed the Prescriber Update survey. The Committee considered Prescriber Update to be a valuable publication. The Committee had a discussion around the format of the publication and communicating information to healthcare professionals and patients. Ways of communicating and quantifying benefits and risks were noted. The Committee were encouraged to participate in the survey. The Committee noted that the results of the survey will be published in Prescriber Update.

Recommendation 4

The Committee recommended that Medsafe includes an article on the communication of benefits and risks in a future edition of Prescriber Update.

2.3. Prescriber Update Volume 37, Number 1, March 2015

The Committee noted the latest edition of Prescriber Update.

2.4. Quarterly Summary of Medsafe Early Warning System

The Committee noted the quarterly summary of Medsafe early warning system communications. The Committee were advised of a change in the format. This quarterly summary now covers a wider range of Medsafe’s communications. Dear Healthcare Professional Letters and Consumer Education Materials that have been published in the last quarter additionally appear in this summary.

3. 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. Risk of pulmonary arterial hypertension with interferons alfa and beta

Background

In July 2014, a signal of pulmonary arterial hypertension with interferons alfa and beta was raised by France with the Pharmacovigilance Risk Assessment Committee (PRAC). The results of the PRAC review were announced in April 2015. The PRAC considered that pulmonary arterial hypertension was an adverse reaction for all interferons and the Summary of Product Characteristics (SPCs) should be updated accordingly.

Interferons alfa and beta are used for a number of indications in New Zealand including multiple sclerosis, hepatitis, carcinoma, lymphoma, leukaemia and myeloma.

Pulmonary arterial hypertension is not currently an adverse reaction in New Zealand data sheets. Hypertension is present in New Zealand data sheets.

The purpose of the report is to present the available information regarding this safety concern for the Committee’s advice.

Discussion

The Committee discussed the information presented to them. The Committee noted that pulmonary arterial hypertension is a serious but rare disease.

The Committee discussed the prevalence of pulmonary arterial hypertension and the use of interferons in New Zealand. The Committee noted that the use of these medicines seems to be decreasing as alternative medicines become available.

The Committee considered that the available evidence was weak and based on case reports only. The Committee considered that many of the case reports were confounded by the patient’s medical history, current conditions or other medicines they were taking. However the Committee noted cases where the patient recovered after stopping interferon treatment (positive dechallenge).

The Committee also discussed whether the risk of pulmonary arterial hypertension was associated with both alfa and beta interferons or only alfa or beta. The Committee considered that it would be helpful to prescribers to include pulmonary hypertension as an adverse event in the data sheets for both interferon alfa and beta.

Recommendation 5

The Committee recommended Medsafe requests the sponsors of interferon alfa and beta containing medicines to update the adverse events section of the data sheet to include pulmonary hypertension as an adverse event. 

3.2.2. Contraception with levonorgestrel subcutaneous implants (Jadelle) and weight-based efficacy

Background

Medsafe was informed by the Centre of Adverse Reactions Monitoring (CARM) of a report of unintended pregnancy (ie, contraceptive failure) in an obese patient using a levonorgestrel subcutaneous implant (Jadelle). The patient became pregnant just before the end of four years following implant of Jadelle.

The New Zealand data sheet for Jadelle states that the implants are effective for five years in those up to 60 kg and that the implants should be removed after four years in those that are heavier.

The purpose of this paper is to present the current data on weight-based efficacy of levonorgestrel subcutaneous implants so that the Committee can recommend whether any regulatory action is required. Specifically, whether an additional caution or warning be added to the data sheet for the overweight or obese.

Discussion

The Committee discussed the available evidence presented to them and noted the view of Family Planning which had been obtained by Medsafe.

The Committee considered the evidence suggests a reduction in efficacy with increasing weight. The Committee considered there is good data on what the median drug level is over time but not on what the lowest drug levels may be.

The Committee discussed the risks associated with this issue and it was considered clear from the available information that contraceptive levels drop with increasing weight and increasing time.

A discussion was had around the current data sheet wording and the Committee considered that appropriate advice is already present in the data sheet and updates are not required. However the advice to remove Jadelle after four years in women heavier than 60 kg may not be widely known amongst healthcare professionals. Consequently, the Committee discussed the importance of communicating this information to patients.

The Committee agreed conversations should occur between physicians and patients. Patients over 60 kg should be informed of their option to replace the implant after four years rather than five due to the evidence suggesting reducing levonorgestrel concentrations with increasing weight and time.

The Committee recommended communication on this risk should be published for prescribers. Additionally, the Committee considered further information would be useful such as the weight of patients at the time of Jadelle insertion and the nearest recorded weight at the time of pregnancy.

The Committee noted that evidence to date suggests that levonorgestrel implants are a very effective form of contraception.

Recommendation 6

The Committee recommended that Medsafe includes an article in a future edition of Prescriber Update to remind healthcare professionals that levonorgestrel concentration is lower at the end of implant use and it is inversely related to body weight.

Recommendation 7

The Committee recommended that Medsafe informs Family Planning of the Committee’s discussion and suggest the following information should be recorded and included in all future adverse reaction reports:

  • patients’ weight at time of Jadelle insertion
  • patients’ weight at the time of pregnancy
  • time since Jadelle insertion to pregnancy.

3.2.3. Risk of adverse cardiovascular events in patients taking sulfonylureas

Background

The cardiovascular safety of anti-diabetic medication has been of concern for many years and is now required to be demonstrated for new antidiabetic agents. A number of studies have recently been published which investigated the cardiovascular safety of the sulfonylureas.

There are three oral anti-diabetic medications for type 2 diabetes mellitus in New Zealand: metformin, sulfonylureas and pioglitazone. Of the sulfonylureas, at this time gliclazide is the most commonly used and glibenclamide is the least commonly used. The third funded sulfonylurea in New Zealand is glipizide.

Sulfonylureas work by increasing insulin release from the beta cells in the pancreas. Sulfonylureas bind to potassium channels on membranes of the beta cells. There are similar potassium channels in the heart.

This paper summarised recent information on the association between treatment with sulfonylureas and adverse cardiovascular events.

Discussion

The Committee discussed the studies and the information presented to them. It was noted that there is very little information available from randomised controlled trials as cardiovascular events were not generally monitored outcomes. A number of different observational studies have been published. These are difficult to interpret as sometimes sulfonylureas were treated as a class or different sulfonylureas were compared. In addition there appeared to be significant difference between patients treated with different sulfonylureas and those treated with metformin. Many studies had no information on potential confounders such as smoking. In studies comparing sulfonylureas with metformin, patients taking metformin experienced fewer cardiovascular events. However it is not clear if metformin is protective and sulfonylurea treatment neutral or metformin treatment is neutral and sulfonylureas cause an increase in adverse cardiovascular effects.

The Committee discussed plausible pharmacological explanations and mechanisms with regards to a class effect. The Committee concluded there is insufficient evidence to conclude there is a class effect, this is consistent with differential effects of different sulfonylureas on potassium channels of the heart. The Committee considered that the available evidence indicated an increased risk of cardiovascular effects with glibenclamide compared to gliclazide.

The Committee also noted that hypoglycaemic episodes were also more likely with glibenclamide.

The Committee also discussed whether communication was needed and agreed a publication is needed. The Committee noted a recent article about diabetes has been published by the Best Practice Advocacy Centre which discusses preferred sulfonylureas. The Committee recommended that a Prescriber Update article informing prescribers of the cardiovascular risk with sulfonylureas is published.

Recommendation 8

The Committee recommended that Medsafe includes an article in a future edition of Prescriber Update about cardiovascular risk with sulfonylureas.

Recommendation 9

The Committee recommended that the data sheet for glibenclamide should be updated to include adverse cardiovascular events.

4. 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.

There was a discussion around giving the influenza vaccine to immunosuppressed patients. There was a discussion around suicidality and anti-epileptic medications and the Committee noted an article on this topic was published in the March edition of Prescriber Update.

There were also discussion on the role medicines may play in the development of interstitial lung disease and pancreatitis.

Recommendation 10

The Committee recommended that Medsafe considers an article on interstitial lung disease from the perspective of encouraging healthcare professionals to consider interstitial lung disease earlier as a possible adverse effect.

The Committee did not consider any 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 noted a group of reports associated with anti-epileptic medication.

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.

A discussion was had regarding an interaction between roxithromycin and warfarin. There was a discussion around drug-induced hyponatraemia.

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

Recommendation 11

The Committee recommended the interaction between roxithromycin and warfarin be discussed at the June 2016 meeting.

Recommendation 12

The Committee recommended that Medsafe includes an article on hyponatraemia in a future edition of Prescriber Update.

4.1.5. Special Reports: Annual Report ACC Cases (January 2015 – December 2015)

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

5. OTHER BUSINESS

5.1. Deputy Chair

The Committee had a discussion around the value of having a Deputy Chair for this Committee.

5.2. Therapeutic products regulation project – Update

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

6. ANNEXES

3.2.1 Risk of pulmonary arterial hypertension with interferons alfa and beta

  1. MSD Response
  2. Roche Response
  3. Bayer Response
  4. Biogen Response

3.2.2 Contraception with levonorgestrel subcutaneous implants (Jadelle) and weight-based efficacy

  1. Centre for Adverse Reactions Monitoring. 2015. Case Report 117740. Dunedin: New Zealand Pharmacovigilance Centre, University of Otago.
  2. Bayer New Zealand Limited. 2015. Data sheet – Jadelle. URL: http://www.medsafe.govt.nz/profs/datasheet/j/Jadelleimplant.pdf (accessed 15 February 2016).
  3. 2014. Medicines Adverse Reactions Committee report – Levonorgestrel emergency contraception and weight-based efficacy. Wellington: Ministry of Health.
  4. 2014. Minutes of the 158th Medicines Adverse Reactions Committee Meeting – 12 June 2014. URL: http://www.medsafe.govt.nz/profs/adverse/Minutes158.htm#3.2.4 (accessed 15 February 2015).
  5. Roke C. 2015. Query regarding levonorgestrel implant (Jadelle). Auckland: Family Planning New Zealand.
  6. Lam F. Response to CARM report of contraceptive failure. Sydney, Australia: Bayer Australia Ltd.
  7. Centre for Adverse Reactions Monitoring. 2015. Jadelle and Pregnancy – CARM cases as at 31 December 2015. Dunedin: New Zealand Pharmacovigilance Centre, University of Otago.
  8. Centre for Adverse Reactions Monitoring. 2015. Jadelle and Pregnancy – WHO cases as at 31 December 2015. Dunedin: New Zealand Pharmacovigilance Centre, University of Otago.

3.2.3 Risk of adverse cardiovascular events in patients taking sulfonylureas

  1. Hong J, Zhang Y, Lai S et al 2013 ‘Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease’ Diabetes Care 36: 10304-1311.
  2. Schramm TK, Hilmar Gislason GH, Vaag A et al 2011 ‘Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study’ European Heart Journal 32:1900-1908.
  3. Huang Y, Abdelmoneim AS, Light P 2015 ‘Comparative cardiovascular safety of insulin secretagogues following hospitalisation for ischaemic heart disease among type 2 diabetes patients: a cohort study’ Journal of diabetes and its complications 29: 196-202.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2.40pm.

Associate Professor D Reith
Chair, Medicines Adverse Reactions Committee

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