Published: 29 April 2020

Committees

MINUTES OF THE 181st MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 181st MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

12 March 2020

The one hundred and eighty first meeting of the Medicines Adverse Reactions Committee (MARC) was held on 12 March 2020 at the Ministry of Health, 133 Molesworth Street, Wellington. The meeting commenced at 9am and closed at 2.30pm.

MARC MEMBERS PRESENT

Associate Professor D Reith (Chair)
Dr C Cameron (Chair for item 3.2.1)
Associate Professor D Menkes
L Te Karu
Associate Professor L Parkin
Research Associate Professor M Tatley
C Ryan
J Tatler
I Raiman
Dr K Eggleton

MARC SECRETARIAT PRESENT

J Prankerd (Senior Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE

S Kenyon (Manager, Clinical Risk Management)
G Hill (Senior Medical Advisor, Pharmacovigilance)
L Chan (Principal Technical Specialist, Pharmacovigilance)
M Storey (Senior Advisor, Pharmacovigilance)
V Cheer (Senior Advisor, Pharmacovigilance)
A Kerridge (Senior Advisor, Pharmacovigilance)

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Dr C Gresham, Dr S Hanna and Professor L Stamp.

1.2 Minutes of the 180th MARC Meeting

The minutes of the 180th 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 has been involved in a number of areas relating to paracetamol use in children. The Committee agreed they should discuss what parts of item 3.2.1 Associate Professor D Reith should participate in and this discussion was passed to Dr C Cameron to lead as Deputy Chair.

[Associate Professor D Reith left the meeting at this time]

The Committee discussed the ways Associate Professor D Reith has been involved in this topic and the appropriate level of involvement in the discussion.

The Committee decided that Associate Professor D Reith should be excluded from both the discussion and voting on this topic. The Committee agreed that Associate Professor D Reith may be needed for his technical expertise and should be available if the Committee had any questions. The Committee agreed that it is Associate Professor D Reith’s stated position, rather than expertise, that has excluded him from participating in the discussion and having a vote.

[Associate Professor D Reith re-joined the meeting at this time]

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 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

2.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

2.1.1 Overview of Reporting

As follow up to the December 2019 meeting, the Committee discussed the additional ethnicity information that had been provided in the CARM Quarterly Report. Limitations of data obtained through spontaneous adverse reaction reporting systems as well as the complexity of navigating the health system were explained to the Committee. Although, outside the scope of this Committee, they noted that more research is needed in other aspects of medicines use. The Committee agreed consideration of further options for presenting reports of serious non-fatal cases in Māori and Pasifika patients aged 65 years and above should be developed for the next CARM Quarterly Report for discussion.

Recommendation 1

The Committee recommended that CARM should, in discussion with committee members, develop further options for presenting data regarding Māori and Pasifika populations in the next Quarterly Report for consideration.

2.1.2 Safety Signals from Single Case Reports

The Committee discussed case 135517 where a patient experienced a haemorrhage thought to be due to a drug interaction between amiodarone and warfarin. The Committee discussed the importance of communicating between specialist, GP and community pharmacist about the need to test more frequently when medicines are changed to those that may increase the risk of bleeding.

Recommendation 2

The Committee recommended that an article is published in a future edition of Prescriber Update on the importance of communication.

2.1.3 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 135437 where a patient experienced a fatal cardiac arrest after taking flucloxacillin to which they had previously had an anaphylactic reaction. The Committee considered that this case highlights the importance of adding events into the National Medical Warning System and considered this should be included in a future Prescriber Update article on communication (see Recommendation 2).

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

2.1.4 Special Populations: Serious Cases Associated with Medicines in Patients under 18 years (Causal Cases Only)

Reports of serious cases associated with medicines in patients under 18 years were briefly outlined for the Committee.

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

2.1.5 Special Populations: Serious Cases Reporting Adverse Events Following Immunisation Terms with Vaccines in Patients under 18 years

Reports of events occurring in patients under 18 years were briefly outlined for the Committee.

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

2.1.6 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.

2.1.7 Causal and Serious Cases in Patients Aged 18 to 80 Years

Reports of events occurring in patients 18 to 80 years were briefly outlined for the Committee.

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

2.1.8 Special Reports: Annual Report ACC Cases (January 2019 – December 2019)

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

2.1.9 Special Reports: Lamotrigine Update

CARM gave an update of cases reported to CARM from 1 May 2019 to 21 February 2020 describing a reaction to a lamotrigine-containing product following the decision by PHARMAC to move to one funded brand of lamotrigine.

The Committee discussed the cases and considered there is no change in the nature of the reports from the last meeting.

The Committee noted fatal cases are still before the Coroner and they await the coronial findings.

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

[Associate Professor D Reith left the meeting at this time; item 3.2.1 chaired by Dr C Cameron]

3.2.1 Dosing of paracetamol in obese children

Background

Medsafe published an article in the September 2019 issue of Prescriber Update titled “Paracetamol – dangerous when not used correctly". It covered aspects of prescribing, dispensing and advice for caregivers based on medication errors. Under the title “Calculate the correct dose” the article stated the following:

  • Use weight-based dosing.
  • Use actual body weight, not ideal body weight.
  • Never exceed the recommended adult dose.

Since the article was published, concerns have been expressed to Medsafe regarding dosing in overweight and obese children. The main points were:

  • the implication is to use the same recommendation for dosing to very obese children
  • there was no scientific reference to the recommendation
  • the recommendation counteracts current practice in New Zealand where the dosing is adjusted to obese children especially for regular treatment, because of the risk of accumulated toxic effects.

Feedback on the article suggested that the recommendations should include an adjustment (by weight) for regular dosing of paracetamol to obese children due to the concern around upregulation of cytochrome P450 2E1 (CYP2E1).

No specific information on dosing of paracetamol in obese children is currently included in the data sheets or in the label requirements for over-the-counter (OTC) paracetamol products for children. Therefore, Medsafe is seeking advice on whether the data sheets and information relating to OTC paracetamol for children needs to be updated and if any further actions are required.

Discussion

The Committee discussed the available evidence on paracetamol dosing, including the pharmacokinetics of paracetamol in obese children and case reports of paracetamol toxicity in overweight or obese children.

Paracetamol pharmacokinetics differ between adults and children and the few studies found included mostly adult or adolescent patients and therefore not relevant to children. Data regarding pharmacokinetics of paracetamol in obese patients is very limited and uncertain and currently there is no clear evidence of CYP2E1 upregulation in obese children.

The Committee noted there is no standard definition of obesity in children and no standard method of calculating ideal body weight. The Committee considered this increases the potential for dosing errors if doses are adjusted. Additionally, the Committee noted that there may be difficulties associated with growth charts being out of date and or not adjusted for different ethnicities.

There is limited evidence for dose adjustment of paracetamol dosing to obese children. Pharmacokinetic and efficacy data would be needed to determine how much the dose (in mg/kg) should be reduced by in obese children, if any.

The Committee noted that Medsafe had reviewed the available safety data on paracetamol use in children. No cases of liver failure after paracetamol administration in overweight or obese children have been reported to the Centre for Adverse Reactions Monitoring (CARM). Data from the New Zealand National Poisons Centre did not indicate a problem and only one case report was found from other countries. In this case the reported average daily dose was below maximum daily dose from both actual and ideal body weight calculations.

The Committee considered there is insufficient evidence to recommend using adjusted body weight for paracetamol dosing. The Committee considered there is an information gap on cytochrome P450 activity and pharmacokinetics of paracetamol in obese children and more research should be done in obese children. The majority of the Committee agreed that data sheets and or the Label Statements Database should not be updated based on the information available at this time.

[Associate Professor D Reith re-joined the meeting at this time]

3.2.2 Ondansetron exposure in utero and risk of cleft palate

Background

The purpose of this report is to review the evidence for an increased risk of orofacial cleft defects associated with ondansetron exposure during the first trimester of pregnancy, and to assess whether there is a need for regulatory action in New Zealand to limit any potential risk to the fetus from exposure to ondansetron during the first trimester.

In 2019, the European Pharmacovigilance Risk Assessment Committee (PRAC) assessed the risk of birth defects following exposure to ondansetron during the first trimester of pregnancy. The assessment focused on two studies that had reported associations between in utero exposure to ondansetron and specific structural birth defects. The PRAC confirmed the safety signal for ondansetron and oral cleft defects and recommended that the European product information for ondansetron should be updated with information on the risk of orofacial malformations when administered during the first trimester of pregnancy, including a statement that ondansetron-containing medicines should not be used in the first trimester of pregnancy.

In response to this recommendation, the UK National Health System’s Teratology Information Service (UKTIS), in collaboration with the European Network of Teratology Information Services (ENTIS) issued a statement that they do not support the recommendations made by the PRAC.

Discussion

The Committee considered the strengths and limitations of the studies presented to them. The Committee agreed that although the effect size is small there is some evidence suggesting an increased risk of cleft palate when ondansetron is taken during the first trimester of pregnancy. The Committee noted the small increase in absolute risk of 3 in 10,000 pregnancies treated, but a 25% increase in the relative risk, and considered it is important for women to be fully informed of this risk.

The Committee discussed the severity of nausea and vomiting in pregnancy and hyperemesis gravidarum and considered it can be very significant to large numbers of women. The Committee also noted that this use of ondansetron is off label and appropriate prescribing regarding informed consent and written justification for off label use must be remembered.

The Committee considered the conclusion made by the European Medicine Agency’s (EMA) Pharmacovigilance Risk Assessment Committee and their recommended updates to product information in the European Union.

The majority of the Committee agreed that although the risk is small and there is some uncertainty in the data, the risk should be highlighted in New Zealand data sheets.

Recommendation 3

The Committee recommended that Medsafe writes to the sponsors requesting updates to New Zealand data sheets with information on the risk of cleft palate during the first trimester of pregnancy.

Recommendation 4

The Committee recommended an article is published in a future edition of Prescriber Update highlighting the Committee’s discussion and discussing the robustness of the evidence.

Recommendation 5

The Committee recommended Medsafe writes to the Society of Obstetric Medicine of Australia and New Zealand highlighting the Committee’s discussion.

3.2.3 Boostrix in pregnancy

Background

Pertussis (whooping cough) is a highly infectious bacterial respiratory infection. Immunisation with the pertussis vaccine is the best way to prevent pertussis infection.

Infants aged under 12 months, particularly those too young to be immunised, are at high risk of contracting severe disease. The pertussis immunisation programme therefore aims to protect infants in their first year of life. This includes maternal vaccination with pertussis vaccine during pregnancy through the passive transfer of maternal antibodies.

Pertussis vaccine is administered as a single injection that also contains diphtheria vaccine and tetanus vaccine (Tdap). There are two approved Tdap vaccines in New Zealand: Boostrix and Adacel. However, PHARMAC funding is for Boostrix and the criteria for funding during pregnancy recently changed – from 1 July 2019, women in their 2nd or 3rd trimester of each pregnancy are eligible for funded vaccine; it was previously funded for women between gestational weeks 28 and 38. This change aligns with the New Zealand Immunisation Handbook which recommends pregnant women are given the vaccine from 16 weeks of gestation of every pregnancy, preferably in the 2nd trimester, but at least 2 weeks before birth.

The Boostrix data sheet states its use may be considered during the 3rd trimester of pregnancy. Human data from prospective clinical studies on its use during the 1st and 2nd trimester of pregnancy are not available. Boostrix may be used during pregnancy when the possible advantages outweigh the possible risks for the fetus.

The purpose of this paper is to review the benefits and risks of Tdap vaccine (Boostrix) when administered to pregnant women in their 2nd trimester (from week 16).

Discussion

The Committee discussed the safety information for use in the second and third trimesters of pregnancy.

The Committee agreed that the data indicates the optimal time for pregnant women to be given the vaccine is at the end of the second trimester or start of the third trimester. The data did not indicate that use in the second trimester would expose pregnant women to additional risks.

The Committee noted the wording in the United Kingdom’s (UK) Summary of medicinal Product Characteristics (SmPC) as well as PHARMAC funding criteria and guidance in the New Zealand Immunisation Handbook.

The Committee considered the benefits and risks of Tdap vaccine being given to pregnant women in the second trimester (from week 16) and agreed that the benefit-risk profile during the second trimester is favourable. The Committee additionally recommended that the New Zealand data sheet should be harmonised with the UK’s SmPC which includes safety information from passive surveillance that has shown no vaccine related adverse effects on pregnancy or the health of the foetus/newborn child in women exposed to Boostrix in the second and third trimester.

Recommendation 6

The Committee recommended Medsafe writes to the sponsor requesting updates to the Boostrix (combined diphtheria, tetanus and pertussis vaccine) New Zealand data sheet.

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 41, Number 1, March 2020

The Committee noted the latest edition of Prescriber Update. The Committee discussed further promotion through pharmacy schools would be useful and provided contacts to Medsafe.

4.4 Quarterly Summary of Medsafe Safety Communications

The Committee noted the quarterly summary of Medsafe safety communications.

5.0 OTHER BUSINESS

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
Date: 20th April 2020

Dr C Cameron
Chair (item 3.2.1), Medicines Adverse Reactions Committee
Date: 20th April 2020

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