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Published: 13 April 2017

MINUTES OF THE 169th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING 9 March 2017


MINUTES OF THE 169th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING 9 MARCH 2017

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

MARC SECRETARIAT PRESENT
L Chan (Senior Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE
R Pollock (Manager, Clinical Risk Management)
S Kenyon (Principal Technical Specialist, Pharmacovigilance)
G Hill (Senior Medical Advisor, Pharmacovigilance)
J Prankerd (Advisor, Pharmacovigilance)
M Zhan (Advisor, Pharmacovigilance)

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Professor C Frampton.

1.2 Minutes of the 168th MARC Meeting

The minutes of the 168th meeting were accepted as a true and accurate record of the meeting.

The Committee discussed the quality of papers presented by Medsafe, particularly those from the 168th meeting, and how these could be made more readily available to the public.

Recommendation 1

The Committee recommended Medsafe explore the possibility of publishing papers presented by Medsafe so that these are more readily available to the public.

1.3 Potential Conflicts of Interest

[J Tatler joined the meeting at this time.]

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.

Dr P Jones declared that he holds shares with Johnson & Johnson. This relates to annex 1 of agenda item 2.1 on submissions received by Medsafe on the consultation to remove the label warning statement on sedation for loratadine/desloratadine-containing products. The Committee agreed Dr Jones should have no participation or voting for annex 1 of agenda item 2.1 and should not be present for the discussion.

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

[Dr P Jones left the meeting at this time.]

2.1.1 Loratadine and desloratadine: Review of sedation warning
166th meeting 29 June 2016 minute item 3.2.2

Recommendation 5

The Committee recommended that the current warning statement should be amended in the Label Statements Database for loratadine and desloratadine.

Outcome

Medsafe consulted on amending the current warning statement on sedation in the Label Statements Database (www.medsafe.govt.nz/consultations/WarningStatementsOTCLoratadineAndDesloratadine.asp). Consultation closed on 11 November 2016. Responses from the consultation were presented as annex 1 of this report and presented to the Committee for discussion.

Discussion

The Committee was reminded that the current warning statement on sedation is:

Although this medicine is unlikely to affect your ability to drive or operate machinery, a few people may be impaired and care should be taken.

At the 166th meeting, the Committee recommended that the warning statement on sedation be updated to:

Very rarely, people get drowsy on this medicine. You should make sure you are not affected before doing activities that require full attention.

The Committee was provided with the submissions received. These submissions will be published on the Medsafe website (www.medsafe.govt.nz/consultations/outcome.asp). The Committee was asked to provide advice to Medsafe on whether the proposed label statement from the 166th meeting should be revised or removed from the package label.

The Committee discussed the best way of communicating risks and frequencies of risks to consumers. The Committee considered information to consumers should be transparent, specific and easy to understand.

The Committee agreed on the alternative warning statement suggested by Johnson & Johnson.

Recommendation 2

The Committee recommended Medsafe adopts the warning statement on sedation suggested by Johnson & Johnson:

Some people might get drowsy on this medicine. You should make sure you are not affected before doing activities that require full attention, such as driving or operating machinery.

[Dr P Jones re-joined the meeting at this time.]

2.1.2 Use of tramadol in children
166th meeting 29 June 2016 minute item 3.2.3

Recommendation 6

The Committee recommended that Medsafe request the sponsors of tramadol-containing products to add a contraindication in children under 2 years of age and update the warnings and precautions section of the data sheets.

Outcome

Medsafe has requested the sponsors of tramadol-containing products to update the data sheets.

Discussion

The Committee noted the injection formulation of tramadol listed in the New Zealand Formulary for Children has dosing instructions for children from the age of 1 year. Therefore, this is not aligned with the recommendation from the Committee that the use of tramadol in children is contraindicated in children under 2 years of age.

Recommendation 3

The Committee recommended Medsafe communicates the contraindication of tramadol in children under 2 years of age with the New Zealand Formulary for Children.

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.

The Committee noted the revised dosing recommendations for use of etoricoxib for rheumatoid arthritis and ankylosing spondylitis. The recommended dose listed in the data sheet for these indications is now 60 mg or 90 mg once daily. The minimum effective daily dose is 60 mg once daily. In some patients, 90 mg once daily may provide increased therapeutic benefit. However, dose escalation from 60 mg to 90 mg should be considered on individual patient basis. The Committee considered that this information should be communicated to healthcare professionals.

Recommendation 4

The Committee recommended the revised dosing recommendations for use of etoricoxib for rheumatoid arthritis and ankylosing spondylitis be highlighted in the MARC's Remarks section of Prescriber Update for this meeting.

2.3 Prescriber Update Volume 38, Number 1, March 2017

The Committee noted the latest edition of Prescriber Update.

The Committee were advised of a new section titled 'Gathering Knowledge from Adverse Reactions Reports' to highlight interesting cases reported to the Centre for Adverse Reactions Monitoring (CARM).

The Committee noted it was another excellent 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.

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 Concomitant use of opioids, benzodiazepines and other CNS depressants and the risk of serious side effects

Background

In August 2016, the United States Food and Drug Administration (FDA) issued a drug safety communication on the risks of concomitant opioid and benzodiazepine use. The FDA stated that they had conducted and reviewed several studies which showed serious risks (including death) are associated with the combined use of opioids and benzodiazepines and other medicines that depress the central nervous system (CNS).

There are a number of opioids and benzodiazepines available in New Zealand.

The purpose of this paper was to review the information on concomitant use of CNS depressants.

Discussion

The Committee discussed usage trends of opioids, benzodiazepines and other CNS depressants in New Zealand. In primary care, the Committee noted that there are an increasing number of patients with chronic pain who are managed with opioids, sometimes with benzodiazepines concomitantly. It was noted that although no usage data for zopiclone was presented, zopiclone is likely to be one of the most prescribed sedative hypnotics in New Zealand and the prescribing of quetiapine is likely to be increasing. Usage trends for co-prescribing of opioids, benzodiazepines and other CNS depressants is also not known, however, it is likely that these are being co-prescribed.

Deaths due to concomitant use of opioids, benzodiazepines and other CNS depressants could be the result of different factors such as suicide, accidental overdose or occur in the context of a terminal illness. In addition, data suggest more deaths occur when opioids are used alone or in combination with benzodiazepines compared with fewer deaths when benzodiazepines are used alone. The risk of death when benzodiazepines are used alone increases with comorbidity and concomitant use of a secondary sedating agent. It is possible that prescribing of incorrect doses and prescribing to people who are opioid-naïve increases the risk of death when opioids and benzodiazepines are used concomitantly. Deaths due to methadone are likely to be due to QT prolongation.

The Committee discussed the availability of over-the-counter codeine and other opioids. Codeine is metabolised by CYP2D6 into morphine, which is a problem particularly for ultra-fast metabolisers. It was noted that a submission on the reclassification of codeine currently classified as a pharmacy only medicine to a more restrictive classification has been proposed to the Medicines Classification Committee for discussion at their next meeting on 16 May 2017. The Committee also discussed the availability of other opioids contained in cough and cold products.

The Committee noted that overprescribing is likely to be an issue and that there is the possibility that some of the supply is diverted. The Committee noted that opioids such as morphine can be prescribed with a maximum quantity of one month supply per prescription. The change in quantity of supply would require a change to the Misuse of Drugs Regulations 1977. Funding of opioids, benzodiazepines and other CNS depressants is stipulated by PHARMAC and it is possible that restricting the funding on each prescription could help. However, it is important that any changes to restrict supply does not result in barriers for palliative care patients and prescribers as an unintended consequence. It was noted that monitoring of controlled drug prescribing is conducted by another section of the Ministry of Health.

The Committee noted work conducted by the Health Quality & Safety Commission on the use of opioids by District Health Boards to identify areas of wide variation. Interventions by the Best Practice Advocacy Centre were also noted. The Committee was unaware of any specific intervention on co-prescribing of CNS depressants. There has been some activity to reduce oxycodone prescribing resulting in a decreasing trend of oxycodone use. A recent study has shown that primary management of insomnia should be non-pharmacologic. The Committee noted that prescribing of opioids and benzodiazepines is often initiated in secondary care. Therefore, the Committee agreed any action taken to influence prescribing practices of healthcare professionals should include both primary and secondary care.

Proposed information to be included in drug labels (equivalent of data sheets in the United States) as required by the FDA for benzodiazepines and opioids was noted. The Committee considered that similar information would be desirable in the New Zealand data sheets of these products.

Recommendation 5

The Committee recommended Medsafe requests the sponsors of benzodiazepine and opioid products update the data sheets on the concomitant use of CNS depressants, including opioids and benzodiazepines.

Recommendation 6

The Committee recommended Medsafe communicates the outcome of this discussion in a future edition of Prescriber Update.

Recommendation 7

The Committee recommended the Medicines Classification Committee considers strengthening the classification of codeine when contained in cough and cold products and to revisit the classification of other opioids contained in cough and cold products.

Recommendation 8

The Committee recommended Medsafe communicates with PHARMAC on restricting the funding of opioids and sedative hypnotics that can be obtained on each prescription.

Recommendation 9

The Committee recommended Medsafe communicates with the Best Practice Advocacy Centre about an education programme on co-prescribing of opioids and sedative hypnotics and to draw their attention to the CDC recommendations for prescribing opioids for chronic pain outside of active cancer, palliative and end of life care.

Recommendation 10

The Committee recommended Medsafe communicates with the Health Quality & Safety Commission to acknowledge their work in this area and to draw their attention to the Committee's discussion on this topic as well as the CDC recommendations for prescribing opioids for chronic pain outside of active cancer, palliative and end of life care.

Recommendation 11

The Committee recommended Medsafe communicates this discussion to DHB hospitals through the national Chief Medical Officers group, highlighting the Committee's concerns that prescribing of opioids, benzodiazepines and other CNS depressants concomitantly are often initiated in hospitals and this may continue into primary care. Attention should be drawn to the CDC recommendations for prescribing opioids for chronic pain outside of active cancer, palliative and end of life care.

Recommendation 12

The Committee recommended communication with the Royal New Zealand College of General Practitioners to endorse an audit tool for general practitioners to check their opioid prescribing and co-prescribing practices.

3.2.2 Varicella vaccine: Overview of benefits and risks of harm

Background

From 1 July 2017 the immunisation schedule will be amended as follows:

Varicella vaccine

The PHARMAC website has further information on this change in funding: www.pharmac.govt.nz/news/notification-2016-07-28-immunisation-schedule/

Therefore the use of Varilrix will increase in New Zealand. There are two main concerns about introducing universal varicella vaccination.

Sub-optimal vaccination uptake may change the age distribution of primary infection to older age groups where the disease is more serious and associated with a higher risk of complications.

The other main concern is based on the hypothesis that exogenous exposure to wild varicella virus may boost the immune response in seropositive individuals and help to control latent infection and reactivation to zoster.

The purpose of this paper was to outline the benefits and risks of harm of varicella vaccination (against chickenpox). This paper did not discuss the use of varicella vaccines for shingles.

Discussion

The Committee noted New Zealand data showing an increase in hospitalisations due to varicella over time. However, this is likely due to increases in the population size and increasing use of immunosuppressive therapy. Data shows that for some people infection with varicella is significant and there is a significant burden on the health system. This is in line with data from other countries.

It is estimated that currently, varicella vaccine is purchased privately quite extensively. Data indicates that up to a third of children have been vaccinated against varicella through the private market. This is also evidenced by adverse reaction reporting to varicella vaccine to date. However, the inclusion of varicella vaccine on the immunisation schedule is important to ensure that all children have equal access.

The Committee noted that although varicella vaccine has been available in Japan for the longest period of time, the United States has the highest uptake. The duration of availability of varicella vaccine is important because this gives an indication of herpes zoster severity and rates, which are highest in the elderly. However, rates and severity of herpes zoster would also be affected by whether there is a funded herpes zoster vaccination programme.

The Committee discussed the likely reasons for funding only one dose of varicella vaccine. This seems to be the practice in other countries where initially one dose is funded with reliance on circulating wild varicella virus to act as the booster for the second dose. Eventually, the circulating wild varicella virus and circulating immunity reduces and a second dose of varicella vaccine is then required.

The Committee noted that the Ministry of Health is likely to have planned activities to promote uptake of varicella vaccine including providing background information to healthcare professionals and consumers.

The Committee noted that Medsafe has previously communicated on the risk of medication error between Varilrix and Zostavax and considered that another reminder could be helpful. The Committee considered that reporting of adverse reactions to varicella vaccine is important and should be encouraged.

It was proposed that the Centre for Adverse Reactions Monitoring prepares monthly reports summarising suspected adverse drug reaction (also known as adverse events following immunisation) reports to varicella vaccine. These reports will be closely monitored by Medsafe and provided to the Committee.

Recommendation 13

The Committee considered Medsafe's proposed monitoring for the inclusion of varicella vaccine on the National Immunisation Schedule to be adequate.

Recommendation 14

The Committee recommended Medsafe encourages reporting of adverse reactions to varicella vaccine and reminds healthcare professionals of the differences between Varilrix and Zostavax in the MARC's Remarks section of Prescriber Update for this meeting.

3.2.3 Use of anaesthetic and sedative agents in children - Neurotoxicity & effects on brain development

Background

In December 2016, the United States Food and Drug Administration (FDA) published a safety communication on the use of anaesthetic and sedation medicines in young children and pregnant women. The FDA are requiring warnings to be added to these medicine data sheets. Following the FDA communication, Health Canada announced that it is reviewing the safety of medicines used for general anaesthesia and sedation in children under 3 years old or in pregnant women during their third trimester.

The purpose of this paper was to review information on the use of general anaesthetics and sedative agents in children, particularly those aged under 3 years. Agents used for local anaesthesia were not included in this review.

Discussion

The Committee discussed the available evidence on this topic. Animal studies have been conducted in a range of species from rodents to primates. These studies show that use of anaesthetics during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. While these findings from animal studies are concerning, the clinical significance for humans is not known.

Clinical studies conducted in humans are predominantly observational and have shown conflicting results. It is not clear if the association is a true effect of anaesthetic agents, the surgery or underlying condition requiring surgical intervention, or due to uncontrolled confounding of other factors. Some of these studies had small sample sizes with insufficient power to detect a true effect. Inclusion criteria involved many different types of surgeries within the same study and between studies. In addition, there were many different measures used for neurodevelopmental outcome. The age range studied also varied and information on duration and type of anaesthesia were not always available. Overall, the Committee considered there was insufficient evidence for an association between the use of anaesthetics in children and risk of neurotoxicity at this time.

Given the ethical considerations around this safety concern, the strength of the evidence is unlikely to change significantly in the near future.

Based on the limitations of the available clinical studies conducted in humans, the Committee considered that weighing the benefits and risks of surgery or procedures requiring anaesthesia should be considered on a case-by-case basis. The consequences of not having surgery or a procedure requiring anaesthesia should be discussed with parents and caregivers. It is important for parents and caregivers to be able to make an informed decision in conjunction with the healthcare professionals looking after their child.

The Committee noted the proposed information to be included in the FDA drug labels (equivalent of data sheets in the United States) for anaesthetic and sedative agents. Overall, the Committee considered that the proposed information informs the public about the current debate on this topic and similar information should be included in the New Zealand data sheets. The Committee also considered that the Australian and New Zealand College of Anaesthetists should be informed of the Committee's discussion and recommendations on this topic.

Recommendation 15

The Committee considered that the evidence for an association between the use of anaesthetics in children and risk of neurotoxicity was equivocal, but that parents should be informed about this safety concern.

Recommendation 16

The Committee recommended Medsafe requests the sponsors of anaesthetics update the data sheets with warnings on the risks of neurotoxicity with information similar to that required by the United States Food and Drug Administration.

Recommendation 17

The Committee recommended Medsafe includes information on this discussion in the MARC's Remarks section of Prescriber Update for this meeting.

Recommendation 18

The Committee recommended communication with the Australian and New Zealand College of Anaesthetists to inform them of the Committee's discussion, the agreement with the United States Food and Drug Administration drug safety communication and the need for the general public to be informed of the current debate on this issue.

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 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.

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

4.1.5 Special Reports: Annual Report ACC Cases (January 2016 - December 2016)

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

The Committee discussed the type of ACC cases of adverse events to medicines resulting in treatment injury that are required to be provided to Medsafe and forwarded to the Centre for Adverse Reactions Monitoring. It was noted that ACC is required to assess treatment injury claims for 'risk of harm to the public'. If ACC believes after considering the specific circumstances of a treatment injury that a sentinel event has occurred, this is reported to the relevant authority responsible for patient safety. Therefore some of these events are reported to the Director General of Health and Medsafe.

The Committee considered Medsafe should contact ACC to explore the possibilities for widening the criteria of cases that are provided to Medsafe.

Recommendation 19

The Committee recommended Medsafe approaches ACC to explore possibilities for widening the criteria for sharing cases of adverse events to medicines resulting in treatment injury with Medsafe.

5.0 OTHER BUSINESS

5.1 Therapeutic products regulation project - Update

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

5.2 Removing warnings of theoretical risks from data sheets - Discussion

Medsafe sought clarification from the Committee as to whether warnings based only on theoretical risks should be included in data sheets.

The Committee discussed theoretical risks and what this means. Whether theoretical risks are included in a data sheet could depend on the length of time a product has been on the market. This is because a theoretical risk could exist and after a length of time, evidence from real-life accumulates.

The Committee considered that information should be made available to the level of what a reasonable consumer in a particular circumstance would want to know.

Overall, the Committee considered that it was unreasonable to issue a general ruling that no theoretical risks should be included in data sheets. The Committee agreed that Medsafe should make this decision on a case-by-case basis.

Recommendation 20

The Committee considered warnings based on theoretical risks with no actual evidence of harm could be included in the data sheet. The decision should be made by Medsafe on a case-by-case basis.

6.0 ANNEXES

3.2.1 Concomitant use of opioids, benzodiazepines and other CNS depressants and the risk of serious side effects

  1. Opioid- and benzodiazepine-containing products available in New Zealand (as at 22 November 2016).
  2. Summary of relevant data sheet wording for opioid- and benzodiazepine-containing products available in New Zealand (as at December 2016).
  3. Opioid- and benzodiazepine-containing products available in New Zealand listed by sponsor.
  4. U.S. Food and Drug Administration. 2016. FDA Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. Available at: www.fda.gov/Drugs/DrugSafety/ucm518473.htm (accessed 10 February 2017).
  5. Centers for Disease Control and Prevention. 2016. CDC guideline for prescribing opioids for chronic pain - United States, 2016. Available at: www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm (accessed 10 February 2017).

3.2.2 Varicella vaccine: Overview of benefits and risks of harm

  1. Case reports of adverse reactions to varicella vaccine published in the literature.
  2. Overview of cases reported to the Centre for Adverse Reactions Monitoring.

3.2.3 Use of anaesthetic and sedative agents in children - Neurotoxicity & effects on brain development

  1. U.S. Food and Drug Administration. 2016. FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. Available at: www.fda.gov/Drugs/DrugSafety/ucm532356.htm (accessed 15 March 2017).
  2. Health Canada. 2016. Health Canada reviewing potential negative effects of general anesthetics and sedatives on young children and fetuses. Available at: http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/61598a-eng.php (accessed 15 March 2017).

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

Associate Professor D Reith
Chair, Medicines Adverse Reactions Committee

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