Published: 25 October 2018

Committees

MINUTES OF THE 175TH MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 175th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

13 September 2018

The one hundred and seventy fifth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 13 September 2018 at the Ministry of Health. The meeting commenced at 9am and closed at 2pm.

MARC MEMBERS PRESENT

Associate Professor D Reith (Chair)
Dr S Hanna
Associate Professor D Menkes
Dr L Bryant
Dr S Jayathissa
Dr R Savage
C Ryan
Dr K Eggleton
Dr N Cole
J Tatler
Dr C Cameron

MARC SECRETARIAT PRESENT

J Solloway (Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE

S Kenyon (Manager, Clinical Risk Management)
M Storey (Senior Advisor, Pharmacovigilance)
Dr G Hill (Senior Medical Advisor)
A Kerridge (Senior Advisor, Pharmacovigilance)
V Cheer (Senior Advisor, Pharmacovigilance)
M Oldridge (Advisor, Pharmacovigilance)
J Lagan (Advisor, Product Safety), present for item 5.3
J Campbell (Senior Advisor, Medical Devices), present for item 5.3

INVITED GUESTS AND OBSERVERS IN ATTENDANCE

Associate Professor R Braund (Centre for Adverse Reactions Monitoring, University of Otago)

1.0  MATTERS OF ADMINISTRATION

1.1  Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from I Raiman.

1.2  Minutes of the 174th MARC Meeting

The minutes of the 174th 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 128906 where gastrointestinal haemorrhage, congestive heart failure and bradycardia were suspected to be caused by dabigatran and digoxin in a patient with impaired renal function. The Committee discussed the availability of clinical decision making tools in regards to appropriate dosing of dabigatran and noted that these prompts appear with the first prescription of dabigatran and not on repeat prescribing. The Committee determined that there was sufficient information and education on dabigatran available. However, the Committee noted the increasing use of rivaroxaban and considered if further education on appropriate prescribing of this medicine.

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

Recommendation 1

The Committee recommended Medsafe includes an article on rivaroxaban 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 discussed case 128224 where ventricular fibrillation and cardiac arrest were suspected to be caused by droperidol. The Committee discussed the usage of this medicine is and noted that it is commonly used in a hospital setting as an anti-emetic. It was noted that QT prolongation is an established risk of droperidol and CARM has received other cases of a similar nature in the past. The Committee determined that relevant organisations should be made aware of this case to ensure that prescribers are aware of the potentially fatal risk of QT prolongation associated with droperidol use.

The Committee discussed case 129102 where a neonate suffered feeding, respiratory and weight issues, and somnolence while the breastfeeding mother took tramadol. The Committee noted there are conflicting recommendations on the use of tramadol in breastfeeding, varying between organisations. The current New Zealand data sheet states tramadol is not recommended in breast feeding, because its safety in infants and newborns has not been studied. The Committee considered that increased monitoring for the use of tramadol during breastfeeding is warranted to gather more information.

The Committee discussed case 128073 which described an inflammatory mass, suspected to be due to therapy with adalimumab and methotrexate. It was noted that CARM is receiving a high number of reports for biologic medicines. The Committee noted that patients with possible adverse reactions to biologic medicines are often presenting in primary care. Additionally, specialists are having less input into patients who are well-controlled and adverse effects are often managed in primary care. They considered that education on undesirable effects and monitoring for these medicines is required.

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

Recommendation 2

The Committee recommended that Medsafe writes to the Australian and New Zealand College of Anaesthetists, the Australasian College for Emergency Medicine, and the New Zealand Hospital Pharmacists Association to highlight case 128224.

Recommendation 3

The Committee recommended that Medsafe highlights case 128224 in a future edition of Prescriber Update.

Recommendation 4

The Committee recommended that Medsafe monitors opioid adverse and withdrawal effects from tramadol in breastfeeding babies on the M2 monitoring scheme.

Recommendation 5

The Committee recommended that Medsafe writes to organisations, such as the Goodfellow Unit, to request they consider creating educational material on biologic medicines.

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 Associated with Critical Terms in Patients Over 80 Years (Causal Cases Only)

Reports of events occurring in patients over 80 years were briefly outlined for the Committee.

The Committee discussed case 128048 where a patient developed hepatic cirrhosis, suspected to be due to Arthrem, a natural health supplement. The Committee noted Medsafe had previously issued an alert communication from their early warning system on hepatic effects associated with Arthrem use. However, none of the previous cases reported hepatic cirrhosis. Since the Medsafe communication was published in February 2018, other additional reports of adverse hepatic reactions have been received. The Committee considered that the communication should be updated to include all new cases received by CARM. The Committee also recommended that the updated alert should be republished for visibility and the relevant societies should be notified.

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

Recommendation 6

The Committee recommended that Medsafe updates and republishes the alert communication on Arthrem and potential risk of harm to the liver. The updated communication should also be sent to the Pharmaceutical Society of New Zealand.

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

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  Brand switches in New Zealand

Background

Over the past two decades, generic medicines have become an established part of the New Zealand healthcare system. Due to the operations of PHARMAC, generally only one brand of a medicine is subsidised and readily available. The funded brands may change as a cheaper generic medicine becomes available, and patients must undergo a “brand switch”. Although the new brand is an approved generic that meets New Zealand bioequivalence standards, there have been instances where a number of patients have experienced adverse reactions when switching brand, culminating in reports to the Centre for Adverse Reactions Monitoring (CARM).

This paper reviews the trends in brand switches that attracted higher than expected reporting and seeks to identify how Medsafe can act to enhance public trust in the healthcare system, as well as ensure patient safety is assured when a brand switch occurs.

Discussion

The Committee discussed the quality of modern bioequivalence studies. It was agreed that for most medicines, the generic medicine is very close to the innovator in pharmacokinetic parameters. A wider variance can sometimes be observed for modified-release formulations. However, so long as these formulations fall within accepted regulatory pharmacokinetic parameters, they are considered clinically equivalent. The Committee considered that publication of bioequivalence studies would help health professionals better understand the benefit of generics. This could then be passed onto patients.

The Committee discussed the generalisability of bioequivalence studies to the whole population. It was noted that bioequivalent studies typically only include healthy volunteers. Using patients is not considered viable. The Committee considered that a small number of patients may require a second option if changes in disease control or adverse effects are experienced subsequent to a change in medicine brand.

The Committee discussed the reasons why patients experience adverse reactions after a change in their brand in medicine. The nocebo effect was noted to be a major factor, however some reactions may be physiological. The Committee also questioned how many of the adverse reaction reports were perceived harm and how many were actual harm. When brand switches produce media attention, it becomes very easy to misattribute symptoms of the condition as adverse effects to the medicine. Behavioural contagion was considered another potential causative mechanism.

The Committee discussed the loss of placebo effect as a potential cause of therapeutic failure with generic medicines. It was noted that in many conditions, such as psychiatry, the placebo effect is often a contributing factor to therapeutic success. When patients lose faith that their medicine works, the placebo effect is lost.

The Committee discussed brand loyalty after noting increased ADR reporting following a change from innovator to generic. The Committee considered that introducing special funding for a particular brand of medicine may increase brand loyalty and this may lead to further negative outcomes.

The Committee considered that additional expert opinion will be helpful in formulating a strategy to convey information on brand switches to the public.

The Committee stated they are confident in the way Medsafe approves generic medicines, which is consistent with international best practice and they are supportive of the regulators’ processes for auditing generic medicine manufacturers to the international standards for Good Manufacturing Practice (GMP).

Recommendation 7

The Committee recommended that Medsafe discusses strategies for managing brand switches and communicating to the public with other experts.

3.2.2  Granulocyte-colony stimulating factors and pulmonary haemorrhage/haemoptysis

Background

At the 14-17 May 2018 Pharmacovigilance Risk Assessment Committee (PRAC) meeting, the PRAC recommended that the Marketing Authorisation Holders (MAHs) for lenograstim, pegfilgrastim and lipegfilgrastim products should update the Summary of Product Characteristics’ (SmPCs) to list haemoptysis and pulmonary haemorrhage as potential adverse reactions. This recommendation was made on the basis of evidence from the EudraVigilance database, the possibility of a class effect and the responses from MAHs.

Currently, no New Zealand granulocyte-colony stimulating factor (G-CSF) data sheet lists pulmonary haemorrhage as an adverse effect. However, some of the data sheets list haemoptysis as a potential adverse reaction.

This paper sought the Committee’s expert opinion on whether a class effect is plausible and if all New Zealand G-CSF data sheets should be updated to list haemoptysis and pulmonary haemorrhage as potential adverse reactions.

Discussion

The Committee considered the recommendation made by the PRAC, in addition to international published case reports. The Committee agreed that a class effect is plausible and that pulmonary haemorrhage and haemoptysis are rare adverse reactions.

The Committee noted that pulmonary/lung infiltrate is listed as an adverse reaction in the G-CSF data sheets. The Committee were asked whether this term adequately describes pulmonary haemorrhage and haemoptysis. The Committee did not consider pulmonary/lung infiltrate a sufficient term as it is broad and relates to an x-ray finding.

The Committee agreed that haemoptysis and pulmonary haemorrhage should be listed as potential adverse reactions in all G-CSF data sheets, in accordance with international regulatory action.

The Committee noted that G-CSFs are used in a niche population and therefore communication in the MARC’s Remarks section of Prescriber Update is sufficient to communicate this change.

Recommendation 8

The Committee recommended that Medsafe requests all sponsors of G-CSFs to update their data sheets to include pulmonary haemorrhage and haemoptysis as potential adverse effects.

3.2.3  Dabigatran and gout, gout aggravation and gout-like symptoms

Background

In September 2017 a report of gout aggravation in association with dabigatran treatment was received by the Centre for Adverse Reactions Monitoring (CARM). The patient experienced a marked increase in episodes of gout after starting dabigatran and improved after treatment with dabigatran had been stopped, without other interventions.

A review of the World Health Organization (WHO) database Vigibase showed that 70 cases of gout or gout-like symptoms suspected to be associated with dabigatran use had been reported worldwide. This was a higher number than expected, making the association a safety signal.

To obtain more information, the safety concern was added to the medicines monitoring (M2) scheme on 31 January 2018. The monitoring finished 31 July 2018. During the reporting period, eight more cases of gout, gout aggravation or gout-like symptoms were reported to CARM.

The purpose of this paper is to review the available information on the possible risk of drug induced gout, gout aggravation or gout-like symptoms with dabigatran.

Discussion

The Committee discussed the cases reported to CARM while the drug-reaction pair was listed on M2 and international reports. The Committee considered that in some cases, there was a possibility the gout or gout-like reaction was caused by dabigatran but the cases were often confounded. The Committee considered that the short time to onset may be an indication of temporal association. However, there is no clear biological plausibility. The Committee also noted that co-occurrence of conditions requiring therapy with dabigatran (such as atrial fibrillation) and gout have been shown in clinical studies. Additionally, deteriorating renal function (present in some cases) has been associated with gout in clinical studies. These indicate a potential degree of confounding by indication.

The Committee noted a recent report provided to Medsafe that discusses recent pharmacoepidemiogical studies examining this association. The Committee stated that case-control studies are speculative and cannot provide sufficient evidence for causation. However, the studies do show that further research into the association could be warranted. Additionally, the Committee concluded that the studies showed the risk of gout occurring after dabigatran initiation to be similar to that occurring after warfarin initiation. The current data therefore suggests that patients with atrial fibrillation are at higher risk of gout and the association between dabigatran use and gout onset is confounded.

The Committee concluded that there was insufficient evidence to suggest an association between dabigatran and gout, gout aggravation or gout-like symptoms. The safety concern remains as a signal and should still be monitored as part of regular pharmacovigilance. The Committee did not recommend any actions to be taken by Medsafe at this time.

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

172nd MARC Meeting: 3.2.2 Modified-release paracetamol: Risk of overdose

Recommendation 8

The Committee recommended the Medicines Classification Committee considers reclassifying modified-release paracetamol from pharmacy-only to pharmacist-only medicines.

Discussion

The Committee noted that the Medicines Classification Committee (MCC) recommended that modified release paracetamol be reclassified from a pharmacy-only medicine to a restricted medicine at the 60th meeting on 26 April 2018. However, an objection had been received from GlaxoSmithKline and the item is being re-reviewed at the next meeting of the MCC on 2 November 2018. The Committee expressed their continued support of the MCC’s original decision.

Recommendation 9

The Committee recommended the MARC Chair writes a letter to the MCC Chair, expressing the MARC’s support of the original MCC decision to reclassify modified-release paracetamol from a pharmacy-only medicine to a restricted medicine.

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.

4.3  Prescriber Update Volume 39, Number 3, September 2018

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  Regulatory system strengthening in the Western Pacific region

The Committee was briefed on the actions of national regulatory authorities to strengthen medicines regulatory systems in the Western Pacific region.

5.2  Methods for signal prioritisation

The Committee was briefed on Medsafe’s methods for signal prioritisation. The Committee supported Medsafe’s current practices.

5.3  Strategy for promoting reporting of adverse reactions to medicines and medical device incidents

The Committee was briefed on Medsafe’s strategy for promoting the reporting of adverse reactions to medicines and medical devices. The Committee supported Medsafe’s strategy.

6.0  ANNEXES

2.1  Additional CARM Reports

  1. Seasonal Flu Vaccine Report July 2018
  2. Varicella shingles vaccine report

3.2.1  Brand switches in New Zealand

  1. Signal detection and evaluation in New Zealand, Report for MARC June 2009
  2. Guideline on the Regulation of Therapeutic Products in New Zealand, Part 6 – Bioequivalence
  3. EMA Guideline on the investigation of bioequivalence
  4. EMA Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms

3.2.2  Granulocyte-colony stimulating factors and pulmonary haemorrhage/haemoptysis

  1. Amgen review [confidential]
  2. PBRER#12 for Zarzio [confidential]
  3. WHO case reports (all ISCRs)
  4. WHO case reports (G-CSF sole suspect)

3.2.3  Dabigatran and gout, gout aggrevation or gout-like symptoms

  1. Boehringer Ingelheim review [confidential]
  2. CARM report.

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
Date 13 September 2018

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