Committees

Published: 20 December 2017

MINUTES OF THE 172nd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 172nd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

7 December 2017

The one hundred and seventy-second meeting of the Medicines Adverse Reactions Committee (MARC) was held on 7 December 2017 at Ministry of Health, 133 Molesworth Street, Thorndon, Wellington. The meeting commenced at 9am and closed at 2.30pm.

MARC MEMBERS PRESENT

Associate Professor D Reith (Chair)
Dr L Bryant
Dr N Cole
Dr K Eggleton
Professor C Frampton
Dr S Hanna
Dr S Jayathissa
Associate Professor D Menkes
C Ryan
J Tatler
Dr M Tatley

MARC SECRETARIAT PRESENT

L Chan (Senior Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE

S Kenyon (Manager, Clinical Risk Management)
A Taylor (Senior Advisor, Pharmacovigilance
M Storey (Senior Advisor, Pharmacovigilance
G Hill (Senior Medical Advisor, Pharmacovigilance)
A Kerridge (Advisor Science, Product Regulation)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

J Stenlund (Pharmacovigilance Officer, Uppsala Monitoring Centre)

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 171st MARC Meeting

The minutes of the 171st 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.

Associate Professor D Reith declared that he was the co-author for some reference papers of agenda item 3.2.2. The Committee discussed this potential conflict of interest and agreed Associate Professor D Reith should not Chair agenda item 3.2.2 and be excluded from voting on all recommendations. It was agreed that Dr S Jayathissa would Chair this 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.

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

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 cases 125172 and 125173 regarding the use of dabigatran and idarucizumab in the same patient. The patient was administered idarucizumab at a dose of 2.5 g and required a second 2.5 g dose later. The Committee noted the usual dose of idarucizumab is 5 g. The Committee noted there is information in the idarucizumab data sheet regarding the need for a second dose in a limited number of patients and considered that this information is important for prescribers.

The Committee discussed the wider use of antithrombotic medicines and considered that the prescribing and use of these medicines could be improved using a coordinated approach. The Committee also considered that using Cockroft-Gault instead of eGFR is more appropriate when calculating doses for patients with renal impairment.

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

Recommendation 1

The Committee recommended Medsafe communicates to the Minister of Health’s delegate and the Chief Medical Officer of the Ministry of Health the need for a coordinated approach on use of antithrombotic medicines.

Recommendation 2

The Committee recommended Medsafe includes information on the need for a second dose of idarucizumab in some patients in a future edition of Prescriber Update.

Recommendation 3

The Committee recommended Medsafe includes information on using Cockcroft-Gault rather than eGFR for calculating doses for patients with renal impairment 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.

Case 125469 highlighted that the risk categorisation for use in pregnancy can cause confusion for consumers and healthcare professionals. In particular, it was noted that the New Zealand Formulary (NZF) has recently adopted a new risk rating. The Committee asked Medsafe to highlight this issue to the NZF.

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

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 Causal and Serious Cases in 18 to 80 year age group

This is a new section of the CARM Quarterly Report. This section of the report highlighted that there have been a number of brand switch reactions reported with venlafaxine. On further discussion of these cases the Committee agreed that these reports appeared to be consistent with brand switch reactions reported with similar medicines such as fluoxetine.

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 Assessment of the potential risk of disabling and persistent musculoskeletal and nervous system adverse reactions from the use of fluoroquinolones

Background

The European Medicines Agency (EMA) is currently reviewing the safety of systemic and inhaled quinolone and fluoroquinolone antibiotics. The review will evaluate the persistence of serious side effects mainly affecting muscles, joints and the nervous system following reports of long-lasting side effects in the national safety databases and the published literature.

This review follows a US Food and Drug Administration (FDA) Drug Safety Communication published in July 2016. The FDA warned about the risk of disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient. A boxed warning (FDAs strongest warning) was revised to address these safety concerns. The Drug Safety Communication also highlighted that the indications for fluoroquinolone medicines will be restricted to those patients who have no other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections. This is because the FDA considers the risk of these serious side effects generally outweighs the benefits in these patients.

Health Canada published a summary of a safety review on the same subject in January 2017 and Australian Therapeutic Goods Administration (TGA) in September 2017. In both cases the conclusion was to recommend an update the product information (PI) to communicate that some well-known side effects of fluoroquinolones (e.g. tendonitis/tendinopathy, peripheral neuropathy and central nervous system disorders), although rare, may be persistent and/or disabling. In Australia it was also pointed out that more than one of these effects can happen in the same patient.

Considering the potential risk of serious, persistent effects and the use of fluoroquinolones in New Zealand, Medsafe considered that these safety concerns should be reviewed by the MARC.

Discussion

The Committee noted the available data on the potential risk of disabling and persistent musculoskeletal and nervous system adverse reactions from the use of fluoroquinolones is limited to case reports and case series. The Committee considered information on these risks should be included in fluoroquinolone data sheets and reflect the strength of the evidence.

The Committee discussed the availability of consumer information on these potential risks with fluoroquinolones. The Committee noted that unlike data sheets which are legally required for prescription medicines such as fluoroquinolones, consumer medicine information is voluntary. The Committee considered consumer medicine information for fluoroquinolones should also be updated to include information on these risks in-line with the data sheets.

The Committee discussed undesirable effects in general, including the chance of having an adverse reaction and the seriousness of the reaction. The discussion included the types of risks that healthcare professionals should discuss with their patients.

The Committee discussed antibiotic stewardship by prescribers to reduce antimicrobial resistance. The Committee noted the 2017 edition of the antibiotic guide produced by the Best Practice Advocacy Centre (BPAC) recommends fluoroquinolones are used second-line for urinary tract infections and are not listed as first choice or alternatives for respiratory indications. The Committee also discussed the use of fluoroquinolones in secondary care. The Committee considered this is a broader public health issue and there are awareness campaigns to ensure that antibiotics are prescribed and used appropriately. Indications as listed in fluoroquinolone data sheets are sufficient and do not require further restriction at this time.

Recommendation 4

The Committee recommended Medsafe requests sponsors of fluoroquinolones update their data sheets with information on the potential risk of disabling and persistent musculoskeletal and nervous system adverse reactions. Consumer medicine information (CMI) for fluoroquinolones should be updated in-line with data sheets.

Recommendation 5

The Committee considered indications as listed in fluoroquinolone data sheets are sufficient and do not require further restriction at this time.

Recommendation 6

The Committee recommended Medsafe includes information on this discussion 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

3.2.2 Modified-release paracetamol: Risk of overdose

Background

On 1 September 2017, the PRAC recommended that modified-release paracetamol be removed from the European market due to the complexity of managing overdose with these products.

The purpose of this paper was to:

Discussion

The Committee discussed the usage of these medicines and considered it would be helpful to obtain usage data from the sponsor(s) of modified-release paracetamol products to assess how widely used these medicines currently are. It is possible that usage patterns in New Zealand differ from other countries and this could change over time.

The Committee noted although the number of calls to the National Poisons Information Centre concerning modified-release paracetamol products is a small fraction of all calls regarding paracetamol (0.22% during the period 1 January 2008 to 8 October 2017), the majority (77.4%) were for therapeutic error. By comparison, less than a quarter (22.2%) of the calls regarding immediate-release paracetamol products were for therapeutic error. This data may indicate that consumers should receive counselling and advice on the dosing regimen of modified-release products which is different to immediate-release products. A review of the classification of modified-release paracetamol products should be conducted to consider upscheduling from pharmacy-only to pharmacist-only to ensure that a pharmacist is involved at the point of sale to provide advice to consumers.

The Committee discussed the population pharmacokinetic study by Salmonson et al, 2017. The Committee considered based on this study, the pharmacokinetics of modified-release paracetamol in overdose is predictable. Current guidelines on the management of paracetamol poisoning in Australia and New Zealand are based on a peak paracetamol dose at eight hours. The guidelines require updating because based on the recent population pharmacokinetic study, the peak dose of modified-release paracetamol can occur up to 24 hours after ingestion.

The Committee considered it necessary to raise awareness on the management of overdose from modified-release paracetamol products and how this differs to overdose from immediate-release products. This would be particularly helpful for emergency department doctors and toxicologists who are usually responsible for the management of paracetamol overdoses. Other healthcare professionals, including community pharmacists and general medicine doctors, and their patients could also benefit from this information.

Data sheets for modified-release paracetamol products are not mandatory as these are classified as pharmacy-only medicines. However, the Committee noted that data sheets are available for two products. The Committee considered that although the data sheets currently state that administration of N-acetylcysteine may be required, reference should be made to the N-acetylcysteine data sheet so this information can be easily located. Other updates in this section should also be made to reflect current information, provide helpful information for healthcare professionals and prompt them to refer to the guidelines for the management of paracetamol poisoning.

Recommendation 7

The Committee recommended Medsafe requests sponsor(s) of modified-release paracetamol products update the overdose section of their data sheets.

Recommendation 8

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

Recommendation 9

The Committee recommended Medsafe communicates with the National Poisons Information Centre to inform them of the Committee’s discussion on this topic.

Recommendation 10

The Committee recommended communication with authors of the guidelines on the management of paracetamol poisoning in Australia and New Zealand to inform them of the Committee’s discussion on this topic.

Recommendation 11

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

Recommendation 12

The Committee recommended Medsafe requests Periodic Benefit Risk Evaluation Reports from the sponsor(s) of modified-release paracetamol products. This report should include worldwide usage data and New Zealand usage data.

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

3.2.3 Influvac Tetra – Risk Management Plan

Background

Influenza infection is a significant cause of mortality and morbidity. Current strategies for mitigating the risk of infection includes vaccination with a seasonal influenza vaccine at the beginning of each influenza season. Vaccination is free for people meeting the PHARMAC funding criteria

There was a previous safety concern with seasonal influenza vaccine in 2010 when the CSL/Seqirus vaccine was found to cause an increase in the number of febrile convulsions in children.

Due to the previous concerns with influenza vaccine Medsafe considered it appropriate to request a Risk Management Plan (RMP) from the company. The purpose of this paper was to present the RMP and consider whether additional study of the safety of this vaccine is needed in New Zealand.

Discussion

The Committee noted the strains to be included in the trivalent and quadrivalent seasonal influenza vaccines for the New Zealand 2018 season. The Committee noted that there is one new A-strain to be included in both the trivalent and quadrivalent seasonal influenza vaccines.

The Committee discussed the Risk Management Plan (RMP) for Influvac Tetra. The Committee were pleased to see a proactive approach being taken to manage the safety of this medicine. The Committee noted population groups where there may be limited information and require enhanced monitoring by the sponsor. Overall, the Committee considered the RMP should include the following:

The Committee was supportive of additional monitoring proposed by the Centre for Adverse Reactions Monitoring (CARM) and Medsafe.

Recommendation 13

The Committee recommended Medsafe contact the sponsor of Influvac Tetra to request the Risk Management Plan (RMP) be updated to include the additional risks as detailed in the Committee’s discussion above.

Recommendation 14

The Committee supported the need for additional monitoring by Medsafe and CARM.

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

3.2.4 Gabapentin and the risk of respiratory depression without concomitant opioids

Background

The purpose of this paper was to review the risk of respiratory depression with gabapentin without the use of concomitant opioids following a Health Canada safety review. The review concluded that there is evidence to support a risk of serious breathing problems with the use of gabapentin alone and recommended updates to gabapentin product information.

In February 2017, Medsafe requested updates to the Neurontin (gabapentin) data sheet regarding the risk of respiratory depression when gabapentin is used without concomitant opioid use. The company provided their response to Medsafe in March 2017 and this has been reviewed and incorporated in the paper presented to the Committee.

Also in 2017, the Pharmacovigilance Risk Assessment Committee (PRAC) in the United Kingdom (UK) reviewed this topic and recommended that the product information of gabapentin-containing products be updated to state that gabapentin has been associated with severe respiratory depression.

Medicines containing gabapentin are available and funded in New Zealand. Medsafe considered the available information on the use of gabapentin without the concomitant use of opioids should be reviewed.

Discussion

The Committee discussed the strength of the evidence. It was noted available data on gabapentin and the risk of respiratory depression without concomitant opioids were limited to case reports and one retrospective study (Cavalcante et al, 2017). However, the strength of the evidence is unlikely to change significantly in future because the likelihood of conducting a randomised controlled trial to study this risk is low.

The Committee noted multivariate and propensity score-matched analyses in the retrospective study by Cavalcante et al, 2017 conducted in patients during phase-I post-anaesthesia recovery after major laparoscopic procedures. Multivariable analysis showed that gabapentin was associated with respiratory depression and these results were confirmed by propensity score-matched analysis among a subset of patients who did not have analgesia supplemented by intrathecal opioids. This was observed independent of comorbidities but it is not known how generalisable these results are. There was also a dose-response relationship observed. Overall, the Committee considered that there was a signal in this study and gabapentin could be associated with an increased risk of respiratory depression.

The Committee noted other regulatory agencies have required updates to their gabapentin data sheets. The Committee considered similar updates to the gabapentin New Zealand data sheets would be helpful for healthcare professionals when weighing up the benefits and risks of use in their patients. The data sheets should include information on patients who are at a higher risk of experiencing these adverse effects such as those with compromised respiratory function, respiratory or neurological disease, renal impairment and the elderly.

Recommendation 15

The Committee recommended Medsafe contact the sponsors of gabapentin to update their data sheets with information on the risk of respiratory depression without concomitant opioids.

Recommendation 16

The Committee recommended Medsafe communicates the Committee’s discussion on this topic to the Best Practice Advocacy Centre (BPAC) and Goodfellow Unit for consideration as part of their work on pain management.

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

3.2.5 Natalizumab (Tysabri) and haematological abnormalities in newborns whose mothers were treated with natalizumab during pregnancy

Background

In June 2017, Health Canada published a summary safety review on haematological abnormalities in newborns whose mothers were treated with natalizumab (Tysabri) during pregnancy following the publication of reports of newborns having anaemia, thrombocytopenic and leucocytosis. The review included reports provided by the manufacturer and from published literature.

Health Canada concluded there is a potential for haematological abnormalities in newborns whose mothers were treated with natalizumab during the third trimester and updated the Canadian product information to include this potential risk.

Discussion

The Committee noted that there were haematological abnormalities including increased white blood cell counts, anaemia, and thrombocyte abnormalities identified from cases in the literature, from the company’s post-marketing data and from animal studies. These effects are similar to those seen in patients treated with natalizumab. There may be varying effects depending on the timing of the dose in relation to the child’s birth.

The Committee noted that the haematologic abnormalities appear to be asymptomatic and reversible. However, this does not exclude the possibility of complications developing as the exposed newborn grows older.

The Committee considered there is a potential for blood count abnormalities to occur in newborns whose mothers were treated with natalizumab during pregnancy, particularly in the third trimester of pregnancy. Data sheets should be updated include information on this risk in both Section 4.6: Fertility, pregnancy and lactation and Section 4.8: Undesirable effects. The Committee also considered that healthcare professionals involved in the treatment of patients with multiple sclerosis, neonatologists and paediatricians should be informed of the Committee’s discussion.

Recommendation 17

The Committee recommended Medsafe contact the sponsor of natalizumab to update the data sheet with information on haematological abnormalities in newborns whose mothers were treated with natalizumab during pregnancy.

Recommendation 18

The Committee recommended Medsafe communicates the Committee’s discussion to the Multiple Sclerosis Treatment Assessment Committee (MSTAC) and the Perinatal Society of Australia and New Zealand (PSANZ).

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

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:

4.2 Medsafe Pharmacovigilance Activities

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

4.3 Prescriber Update Volume 38, Number 4, December 2017

The Committee noted the front cover listing titles of articles in the upcoming issue of Prescriber Update.

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 Therapeutic products regulation project – Update

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

6.0 ANNEXES

3.2.1 Assessment of the potential risk of disabling and persistent musculoskeletal and nervous system adverse reactions from the use of fluoroquinolones

  1. TGA report
  2. Bayer’s reviews [confidential]
  3. CARM report

3.2.2 Modified-release paracetamol: Risk of overdose

  1. Notification to the PRAC of a Referral under Article 31 of Directive 2001/83/EC. Medical Products Agency, Sweden. 30 June 2016
  2. PRAC recommends modified-release paracetamol be removed from market. EMA/562720/2017 Corr1. 01 September 2017
  3. Use of N-acetyl cysteine (NAC) in the management of paracetamol overdose. MARC Paper Sept 2013
  4. Panadol Osteo data sheet (Jan 2016)
  5. DBL Acetylcysteine data sheet (Apr 2017)

3.2.3 Influvac Tetra – Risk Management Plan

  1. Risk Management Plan for INFLUENZA VACCINE (SURFACE ANTIGEN, INACTIVATED) version 3.0
  2. Medsafe clinical evaluation report

3.2.4 Gabapentin and the risk of respiratory depression without concomitant opioids

  1. Pfizer review [confidential]
  2. Health Canada review [confidential]
  3. TGA review [confidential]
  4. PRAC Recommendations on Signals

3.2.5 Natalizumab (Tysabri) and haematological abnormalities in newborns whose mothers were treated with natalizumab during pregnancy

  1. Haghikia A, Langer-Gould A, Rellensmann G, et al. 2014. Natalizumab use during the third trimester of pregnancy. JAMA Neurology 71: 891-5.
  2. Biogen Inc. response to Medsafe’s request

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2.30pm.