Published: 27 March 2015

Committees

Minutes of the 161st Medicines Adverse Reactions Committee Meeting - 12 March 2015

MINUTES OF THE 161st MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

12 March 2015

The one hundred and sixty first meeting of the Medicines Adverse Reactions Committee (MARC) was held on 12 March 2015 in Room G01, Freyberg Building, 20 Aitken Street, Wellington, New Zealand. The meeting commenced at 9 am and closed at 3 pm.

MARC MEMBERS PRESENT

Associate Professor D Reith (Chair)
Dr L Bryant
Dr N Cole
Professor C Frampton
Dr S Jessamine
Associate Professor D Menkes
C Ryan
Dr M Tatley
Dr K Wallis

MARC SECRETARIAT PRESENT

L Chan (MARC Secretary, Medsafe)

MEDSAFE STAFF IN ATTENDANCE

A Govender (Advisor, Pharmacovigilance)
R Jaine (Principal Clinical Advisor)
C James (Manager, Clinical Risk Management)
S Kenyon (Principal Technical Specialist, Pharmacovigilance)
R Pollock (Senior Advisor, Pharmacovigilance)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

Dr R Savage (Senior Medical Assessor, 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 Dr S Jayathissa and Dr P Jones.

1.2 Minutes of the 160th MARC Meeting

The minutes of the 160th 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 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.

Dr N Cole declared that she has received sponsorship from one pharmaceutical company to attend a conference. This pharmaceutical company is a sponsor of a factor VIII replacement product.

Professor C Frampton declared that he provides ongoing statistical consulting to AFT Pharmaceuticals who are sponsors of some ibuprofen-containing medicines.

The Committee referred to the European Medicines Agency (EMA) policy on handling of declarations of interests of scientific committees' members. The Committee agreed that Dr Cole was able to participate and vote in agenda item 3.2.1. The Committee agreed that Professor Frampton should have no participation or voting for agenda item 3.2.3 and should not be present for the discussions.

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

2.0 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

2.2 Medsafe Pharmacovigilance Activities

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

The Committee discussed the annex on the use of sodium valproate in pregnancy. The Committee noted that the use of sodium valproate is contraindicated in New Zealand in pregnant women with epilepsy which differs from Europe. In addition, the use of sodium valproate should be avoided in pregnancy unless there are no effective alternatives.

2.3 Prescriber Update Volume 36, Number 1, March 2015

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

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 Inhibitors to factor VIII treatments

[Dr S Jessamine joined the meeting at this time.]

Background

Factor VIII replacement products are used to treat patients with haemophilia A. The main side effect of concern is the development of antibodies that prevent the clotting action of factor VIII (inhibitors).

In 2013, Gouw et al published the results of the RODIN study. One of the outcomes of this study was a comparison of the effect of different factor VIII replacement products. In this study there was a higher risk of patients developing inhibitors when treated with Kogenate (Kogenate FS in New Zealand) compared to Advate. These results prompted a review in Europe by the Pharmacovigilance Risk Assessment Committee (PRAC). The PRAC considered that the data did not support a conclusion that Kogenate Bayer (or Nexilate NexGen) were associated with an increased risk of developing factor VIII inhibitors compared to other products.

The publication of the RODIN study prompted further analyses using different data sets, which have recently been published. Concerns have been raised by the NZ haemophilia treaters group regarding the results of these studies. Therefore the purpose of this paper was to review both the RODIN study and the additional analyses.

Discussion

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

The Committee discussed the development of inhibitors to factor VIII treatments. It was noted that there may be different factors which potentially contribute to the development of inhibitors. The Committee noted that some inhibitors are transient and the incidence of inhibitor formation is therefore partly influenced by the frequency of testing. Transient inhibitors are not clinically significant. In contrast, the high responding inhibitors are clinically significant and they persist unless the patient is successfully tolerised.

The Committee considered that it would be very difficult to account for all these factors in an observational study. The choice of which factor VIII product is used is dependent on the physician, patient factors such as ease of use of the product, what factor VIII products are available and over time is also related to funding.

The Committee discussed the RODIN study and the additional four observational studies utilising different cohorts and registries that have been conducted to further investigate this issue.

The Committee noted the limitations of these studies. These studies are observational. Factor VIII treatments that were used were site specific. No centralised laboratory testing was used in these studies. There was an imbalance between comparison groups in the studies for genetic risk factors for developing factor VIII inhibitors. It was unclear if there were significant differences between centres in choice of product and if this may have influenced the results. The results may also have been influenced by changes in the use of products over time. It seemed likely that most studies were not powered to detect differences between different products, however power calculations were not presented for all the studies.

Given the low number of events and the potential for residual confounding, the Committee concluded that there is no clear evidence of any differences between recombinant factor VIII products. However the Committee considered that the data were sufficient to show that there was no difference in risk of inhibitor development between recombinant factor VIII products and plasma derived factor VIII products.

Recommendation 1

The Committee recommended that there is insufficient evidence to support a difference in the risk of inhibitor development when patients are treated with different factor VIII products.

Recommendation 2

The Committee recommended that haemophilia treaters and patients should continue to use the product which best suits the needs of the patient.

[Dr S Jessamine left the meeting at this time.]

3.2.2 Macrolides and risk of cardiac arrhythmias

Background

Recently, several journal articles have suggested an increased risk of developing abnormal heart rhythms or cardiovascular death with the use of macrolides. The availability of data and strength of association varies between the different macrolides. There are currently four macrolides that are approved for use in New Zealand (azithromycin, clarithromycin, erythromycin, roxithromycin).

The purpose of this report was to evaluate the available data and determine whether any further advice or action is required regarding the cardiovascular risks associated with macrolides. This includes people already at risk of cardiovascular adverse effects as well as those without any known risk factors.

Discussion

The Committee was given an explanation of propensity scores and how these are used in observational studies to adjust for certain covariates. Propensity scores reduce bias due to these confounding variables so that outcomes in the treatment group and the no treatment or control group can be compared in a simplified statistical model.

The Committee discussed the various published studies. It was noted that the large prospective cohorts used macrolides for different indications. Confounding by indication could therefore partially explain why there were diverse results obtained from the various studies. In addition, the studies had different designs, different duration and episodes of treatment and different extent of monitoring of the various outcomes.

It was also discussed by the Committee whether macrolides should be considered as individual medicines or together as a class. The available data does not provide strong evidence for differentiation of the individual medicines. The Committee therefore agreed that macrolides should be considered together as a class.

The Committee noted that information on QT interval prolongation in the various data sheets for macrolides is not consistent. In addition, information on the medicines that can interact with macrolides requires modernising to reflect medicines that are currently available on the New Zealand market with a consideration made for pharmacodynamic interactions. The Committee noted that the clarithromycin data sheets are the only macrolide data sheets that contain a contraindication for use in patients with a history of QT prolongation or ventricular arrhythmia and patients with hypokalaemia.

The Committee agreed that the macrolide data sheets should be harmonised so that information in the precautions section on QT interval prolongation is consistent and information on interacting medicines is more current. The contraindication for use in patients with a history of QT prolongation or ventricular arrhythmia and patients with hypokalaemia should be removed.

Recommendation 3

The Committee recommended that Medsafe request the sponsors of azithromycin, clarithromycin, erythromycin and roxithromycin to update the precautions, interactions and contraindications sections of the data sheets so that the information is consistent across all macrolide data sheets.

Recommendation 4

The Committee recommended that Medsafe includes an article in a future edition of Prescriber Update to remind healthcare professionals on the risk of QT interval prolongation with the use of macrolides.

3.2.3 Ibuprofen and cardiovascular disorders

[Dr S Jessamine joined the meeting via teleconference at this time. Professor C Frampton left the meeting at this time.]

Background

In June 2014 the European Medicines Agency’s (EMA’s) Pharmacovigilance Risk Assessment Committee (PRAC) began a review of systemic ibuprofen to evaluate cardiovascular risks when high doses (2400 mg daily) are taken over long time periods.

The PRAC will also review the interaction between ibuprofen and low-dose aspirin.

The cardiovascular risks of concern in this report are primarily focused on the incidences of myocardial infarction (MI) and stroke. The purpose of this paper was to review the available information on cardiovascular risks with ibuprofen.

Discussion

The Committee noted that the published studies on the risk of cardiovascular disorders with the use of ibuprofen were mostly observational, underpowered and highly confounded.

The Committee discussed that there is a hint of a dose-response curve but there was insufficient evidence to confidently identify this. The data suggests that there is no increased risk of myocardial infarction in doses less than or equal to 1200 mg daily, there is insufficient data between the doses of 1200 mg and 2400 mg daily and there is evidence that there is an increased risk in long-term treatment at a dose of 2400 mg daily.

The Committee clarified that the maximum recommended dose for ibuprofen tablets purchased as a general sale medicine or a pharmacy only medicine is 1200 mg daily. Higher doses are available on prescription only.

The Committee noted that the information on cardiovascular risks is not consistent between the various ibuprofen data sheets. It was noted that some data sheets include information on using doses of 2400 mg until the acute phase of the condition being treated is under control; some data sheets suggest that the lowest effective dose for the shortest possible duration should be used. In addition, information on there being no consistent evidence that concurrent use of aspirin mitigates the possible increased risk of serious cardiovascular thrombotic events associated with non-steroidal anti-inflammatory drugs (NSAIDs) should be included in all data sheets.

The Committee agreed that the ibuprofen data sheets should be harmonised so that information on cardiovascular risks is clear and consistent across all data sheets.

The Committee discussed how the results of this review should be communicated to healthcare professionals and consumers. The Committee agreed that Medsafe can use the method(s) that communicates this best.

Recommendation 5

The Committee recommended that Medsafe request the sponsors of ibuprofen to update the information on cardiovascular risks in data sheets so that this is consistent across all data sheets.

Recommendation 6

The Committee recommended that Medsafe communicates the results of this review to healthcare professionals and consumers.

[Dr S Jessamine left the meeting via teleconference at this time. Professor C Frampton re-joined the meeting at this time.]

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 did not consider any of the 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 discussed case 113855 involving a patient who experienced myocarditis following use of clozapine. Although this is a well-known risk, the Committee considered that it is serious and further communication is required.

The Committee noted case 114400 involving a medication dosing error with paracetamol occurring within a healthcare professional context.

Recommendation 7

The Committee recommended that Medsafe include an article on the risk of myocarditis with clozapine in a future edition of Prescriber Update.

The Committee did not consider any of the other 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 discussed case 113981 which was a report of acute renal failure following zoledronate infusion. It was noted that a Prescriber Update article on this risk was published in 2010.

Recommendation 8

The Committee recommended that Medsafe include an article on the risks following zoledronate infusion in a future edition of Prescriber Update.

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

4.1.5 Special Reports: Annual Report ACC Cases (January 2014 – December 2014)

The Committee discussed case 112020 which was a report of various ocular reactions following the use of atropine eye drops.

Recommendation 9

The Committee recommended that Medsafe include a general article on ocular reactions in a future edition of Prescriber Update.

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

5.0 OTHER BUSINESS

5.1 New regulator regime project

The Committee was given an update on the new regulator regime project to date.

6.0 ANNEXES

3.2.1 Inhibitors to factor VIII treatments

  1. Gouw SC, van der Bom JG, Ljung R, et al. 2013. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 368: 231–239.
  2. Kessler CM, Iorio A. 2013. The Rodin (Research of Determinants of INhibitor Development among PUPs with haemophilia) study: the clinical conundrum from the perspective of haemophilia treaters. Haemophilia 19: 351–354.
  3. Bayer’s comments on recent publications on FVIII inhibitor development in previously untreated patients (PUPs) [confidential].
  4. Calvez T, Chambost H, Claeyssens-Donadel S, et al. 2014. Recombinant factor VIII products and inhibitor development in previous untreated boys with severe hemophilia A. Blood 124(23): 3398–3408.
  5. Collins PW, Palmer BP, Chalmers EA, et al. 2014. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe haemophilia A, 2000-2011. Blood 124(23): 3389–3397.
  6. Vézina C, Carcao M, Infante-Rivard C, et al. 2014. Incidence and risk factors for inhibitor development in previously untreated severe haemophilia A patients born between 2005 and 2010. Haemophilia 20: 771–776.
  7. Fischer K, Lassila R, Peyvandi F, et al. 2015. Inhibitor development in haemophilia according to concentrate. Four-year results from the EUropean Haemophilia Safety Surveillance (EUHASS) project. Thromb Haemost 113(4).
  8. Centre for Adverse Reactions Monitoring. 2015. Factor VIII products. Summary of reports on CARM database to 31 December 2014 [confidential]. 4 February 2015.

3.2.2 Macrolides and risk of cardiac arrhythmias

  1. 1. US Food and Drug Administration. 2013. Azithromycin (Zithromax and Zmax) and the risk of potentially fatal heart rhythms. Drug Safety Communications. 12 March 2013.

3.2.3 Ibuprofen and cardiovascular disorders

  1. List of products in New Zealand that contain ibuprofen.
  2. European Medicines Agency. 2014. European Medicines Agency starts review of ibuprofen medicines. 13 June 2014.
  3. Ibucode Plus data sheet (1 July 2013).
  4. Nurofen Plus data sheet (18 March 2011).
  5. Panafen Plus data sheet (January 2014).
  6. Brufen data sheet (3 December 2014).
  7. Brufen Sustained Release (SR) data sheet (3 December 2014).
  8. Fenpaed Oral Suspension data sheet (4 July 2007).
  9.  Ibuprofen (Arrowcare) data sheet (1 July 2013).
  10. Ibuprofen (Ethics) data sheet (25 November 2010).
  11. Maxigesic data sheet (April 2011).
  12. Ibugesic data sheet (19 May 2014).
  13. Centre for Adverse Reactions Monitoring. 2015. Ibuprofen and cardiovascular reactions [confidential]. 4 February 2015.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 3 pm.

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