Committees

Updated 20 May 2013

Minutes of the 152nd Medicine Adverse Reactions Committee Meeting 6 December 2012

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

MEDSAFE STAFF IN ATTENDANCE

INVITED GUESTS AND EXPERTS IN ATTENDANCE

1. MATTERS OF ADMINISTRATION

1.1 WELCOME AND APOLOGIES

1.2 MINUTES OF THE 151st MARC MEETING

1.3 DATES OF FUTURE MARC MEETINGS

1.4 POTENTIAL CONFLICTS OF INTEREST

1.5 PRESCRIBER UPDATE

1.5.1 Prescriber Update. Volume 33, Number 3. September 2012

2. STANDING AGENDA ITEMS

2.1 REPORT ON STANDING AGENDA ITEMS FROM PREVIOUS MEETINGS OF THE MARC

3. PHARMACOVIGILANCE ISSUES

3.1 MATTERS REFERRED TO THE MARC UNDER SECTION 36 OF THE MEDICINES ACT 1981

3.2 MATTERS REFERRED TO THE MARC BY MEDSAFE

3.2.1 Use of codeine in children post-surgery and implications with ultra-rapid metabolisers
3.2.2 Proton Pump Inhibitors and pneumonia

4. MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 CENTRE FOR ADVERSE REACTIONS MONITORING (CARM) QUARTERLY REPORTS

4.1.1 Potential Safety Signals from Single Case Reports
4.1.2 Fatal Cases (Causal Cases Only)
4.1.3 Special Populations: Serious Cases Associated with Medicines in Children under 18 years (Causal Cases Only)
4.1.4 Special Populations: Serious Cases Reporting Adverse Events Following Immunisation Terms with Vaccines in Children under 18 years
4.1.5 Special Populations: Serious Non-Fatal Cases Causally Associated with Critical Terms in Patients Over 80 Years

5. ANNEXES

3.2.1 Use of codeine in children post-surgery and implications with ultra-rapid metabolisers
3.2.2 Proton Pump Inhibitors and pneumonia


Preface:

In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.

Names of individuals have also been deleted where that person's contribution is not in the public domain, or will not shortly be so. For example, the names of those to be approached to write an article are deleted, but the names of those who have contributed to a draft article are not usually deleted. In addition, names are not usually deleted when a contribution has been made in an official capacity.

The material listed as being considered on an issue is not intended to be exhaustive.

The recommendations of the Committee are in bold typeface.

Minutes:

The one hundred and fifty-second meeting of the Medicines Adverse Reactions Committee (MARC) was held on 6 December 2012 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9.00 am and closed at 2.50 pm.

marc members present

Associate Professor D Reith (Chair)
Dr N Cole
Associate Professor C Frampton
Associate Professor P Jones
Dr S Jayathissa
Associate Professor D Menkes
C Ryan
Dr S Sime
Dr M Tatley
Dr K Wallis

marc secretariat present

J Carey (MARC Secretary, Medsafe)

MEDSAFE STAFF IN ATTENDANCE

C James (Manager, Clinical Risk Management)
S Kenyon (Principal Technical Specialist, Pharmacovigilance)
R Pollock (Advisor, Pharmacovigilance)
A Taylor (Senior Advisor, Pharmacovigilance)
E Yousuf (Principal Clinical Advisor) - attended part of the meeting

Invited guests and experts IN ATTENDANCE

Dr R Savage

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Dr Linda Bryant.

1.2 Minutes of the 151st MARC Meeting

Some minor changes were made to the minutes of the 151st meeting. A correction was made to the title of Dr Tatley. The statement on page 17 of the minutes "The Committee considered that the inclusion of the remaining cases of suicide over one month after treatment ceased to be justified." was amended to "The Committee considered that the inclusion of the remaining cases of suicide, occurring more than one month after treatment ceased, needs to be justified." The Secretary agreed to make these changes. Otherwise, the minutes were accepted as a true and accurate record of the meeting.

1.3 Dates of Future MARC Meetings

The date for the 2013 MARC meeting were scheduled for 14 March, 13 June, 12 September, and 5 December.

1.4 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.

The Committee agreed that there were no potential conflicts that would influence the discussions or decisions of the MARC at this meeting.

1.5 Prescriber Update

1.5.1 Prescriber Update. Volume 33, Number 3. September 2012

Discussion

The Committee noted the latest edition of Prescriber Update.

2. STANDING AGENDA ITEMS

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. 151st MARC meeting 13 September 2012

3.2.1 Antidepressants and the risk of QT prolongation

3.2.2 Serotonin syndrome with the use of fentanyl, ondansetron, or donepezil in combination with a serotonergic agent

3.2.4 Varenicline tartrate IMMP study report

The Committee noted that updates will be provided on the above agenda items from the September 2012 at the next meeting of the MARC.

3. 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 Use of codeine in children post-surgery and implications with ultra-rapid metabolisers

Background

The purpose of this Medsafe review was to consider whether any further advice or action is required regarding the use of codeine in children, particularly post surgery such as tonsillectomy and/or adenoidectomy. This relates particularly to ultra-rapid metabolisers of codeine via CYP2D6.

In August 2012, the US Food and Drug Administration (FDA) announced a review of the use of codeine in children. This announcement followed the publication of three case reports of children reported to have developed serious adverse effects or who died after taking codeine for pain relief following tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome. In all of the published cases there was evidence of an inherited ability to rapidly convert codeine into morphine resulting in very high plasma levels. All cases had received doses of codeine that were within the typical dose range.

The FDA stated that they are considering if there are additional cases of inadvertent overdose or death in children taking codeine. The FDA was also considering if these adverse events occurred during treatment of other kinds of pain, such as post-operative pain following other types of surgery or procedures.

The European Pharmacovigilance Risk Assessment Committee (PRAC) is conducting a formal review evaluating the risk of toxicity of children who are cytochrome P450 2D6 (CYP2D6) ultra-rapid metabolisers. Recommendations are expected in February 2013.

Codeine is an opiate analgesic indicated for the relief of mild to moderate pain, the relief of symptoms of diarrhoea (except diarrhoea caused by poisoning) and as an antitussive in the control of non-productive cough. Between 0-15% of codeine is converted to morphine in the liver by the enzyme CYP2D6, and it is here that differences occur in metabolism. Patients with variants of the highly polymorphic CYP2D6 gene are classified as poor metabolisers, extensive metabolisers and ultra-rapid metabolisers. Poor metabolisers are unable to convert codeine to morphine efficiently resulting in suboptimal pain relief (as the conversion of codeine to morphine is required for analgesia), whilst ultra-rapid metabolisers may metabolise codeine too efficiently resulting in morphine intoxication and an increased risk of adverse effects.

Discussion

The Committee noted the 2012 Medsafe report.

They noted that usage figures showed the use of codeine in children in New Zealand is relatively low; however, there is evidence that both poor metabolisers and ultra-rapid metabolisers exist in New Zealand.

The prevalence of ultra-rapid metabolisers varies between different ethnic groups. The frequency of Caucasian ultra-rapid metabolisers is approximately 1% to 10%; the frequency in Maori and Pacific populations is unknown. The Committee considered that more information regarding the genetic variations would be a useful contribution to current knowledge.

The Committee noted that in the year 1 July 2009 until 30 June 2010, 57% of tonsillectomies or adenoidectomies publicly funded in New Zealand were performed as day procedures, with a mean stay in hospital of 1.1 days. 76% of these procedures were in children aged less than 15 years. The Committee noted that in general, first line pain relief on surgical wards includes ibuprofen and paracetamol. On discharge, the majority of patients are prescribed paracetamol and ibuprofen for analgesia, with codeine being occasionally prescribed for paediatric patients. The Committee considered that the case reports in the literature highlighted the fact that whilst the surgery and immediate post-operative periods may have been uneventful, it was when the children were recovering at home that morphine toxicity from codeine therapy occurred. The Committee agreed that because of the short hospital stay for the majority of paediatric patients, it was vital that parents and caregivers be fully informed about the risks and benefits of codeine if prescribed at discharge. In particular, they should be advised how to recognise signs of codeine toxicity and actions to take if this should occur.

The Committee considered that it is important for prescribers to realise the variation in metabolism of codeine between individuals. They noted that the frequency of ultra-rapid metabolisers at up to 10% is not rare, and recommended that this information be communicated to prescribers and healthcare professionals via a Prescriber Update article. They also recommended that this information be communicated directly to paediatric ENT surgeons and anaesthetists.

The Committee reviewed the current NZ data sheet for codeine. They agreed that the metabolism of codeine is complex. They noted that CYP2D6 activity is minimal in the foetal liver, but rapidly increases in the hours after birth, continuing to mature and develop in infancy. There is data suggesting that CYP2D6 activity is approximately 92% of that in adults at one year of age. The development of CYP2D6 activity may therefore affect dosing requirements in the paediatric population. The Committee agreed that the statement in the NZ codeine data sheet that codeine should rarely be administered to children less than 6 to 12 months old was not adequate and more definitive advice was necessary. The Committee noted that the use of codeine in children under the age of one year is contraindicated in the UK and recommended that the use of codeine in children under one year of age also be contraindicated in New Zealand due to a lack of evidence to support the safe use in this age group.

The Committee noted the brief warning statement in the data sheet regarding the variation between individuals in the metabolism of codeine. They recommended that this section be expanded to include the estimated prevalence of ultra-rapid metabolisers in the population, symptoms of morphine toxicity or adverse effects that could potentially occur in this population and what the patient or caregiver should do if symptoms occur.

The Committee noted the data sheet warning regarding the use of codeine in breast feeding mothers and the risk of toxicity in infants if the mother is an ultra-rapid metaboliser of codeine. They recommended that the warning section in the data sheet regarding the use in children be updated with a similar warning regarding the risk of codeine toxicity in this population, particularly post tonsillectomy and throat surgery.

The Committee noted that codeine is approved for use in children as a cough suppressant. Codeine was not included in the recent cough and cold review due to reclassification. Pholcodine however; was included and is now contra-indicated in children less than six years of age. The Committee considered that the use of codeine as a cough suppressant in children needs review and recommended that Medsafe undertake this review, and report back to the MARC.

Recommendation 1

The Committee recommended that a Prescriber Update article be published advising prescribers and healthcare professionals of the variation in metabolism of codeine between individuals and the possibility of adverse effects in ultra-rapid metabolisers. They also recommended that this information be communicated directly to paediatric ENT surgeons and anaesthetists.

Recommendation 2

The Committee recommended that the use of codeine in children under one year of age be contraindicated in New Zealand due to a lack of evidence to support the safe use in this age group.

Recommendation 3

The Committee recommended that the warning section in the New Zealand codeine data sheet be expanded to include the estimated prevalence of ultra-rapid metabolisers in the population, symptoms of morphine toxicity or adverse effects that could potentially occur in this population, and what the patient or caregiver should do if symptoms occur.

Recommendation 4

The Committee recommended that the warning section in the data sheet regarding the use in children be updated with a similar warning to that regarding the use of codeine in breast feeding mothers, advising of the risk of codeine toxicity in this population, particularly post tonsillectomy and throat surgery.

Recommendation 5

The Committee recommended that Medsafe undertake a review of the use of codeine as a cough suppressant in children, and the results of this review be reported back to the MARC.

3.2.2 Proton Pump Inhibitors and pneumonia

Background

The potential safety signal of proton pump inhibitors (PPIs) and increased risk of pneumonia has been reported as an outcome of a number of observational studies since 2004. More recently, a number of meta-analyses have been published which also concluded that PPI treatment increased the risk of pneumonia. The purpose of the Medsafe paper was to summarise the available evidence on this potential association and seek the Committee's advice on the strength of this evidence.

The Committee was asked to advise whether:

Discussion

The Committee noted the 2012 Medsafe report.

The Committee agreed that this is a complex issue. They reviewed the main points of the studies presented in the Medsafe report and agreed that the results of these studies are inconsistent, with some studies showing a positive association and other studies showing no association. They considered that confounding factors, including comorbidities and the use of other medicines, illustrated the difficulties in determining a direct relationship between the use of PPIs and any one specific outcome.

The Committee noted that the three meta-analyses performed based on data from published observational studies all found similar outcomes of a positive association. The Committee agreed that the results of the meta-analyses were limited by the design of the original observational studies which the analyses were based on, and this affected the validity of the results.

The Committee noted that a published analysis of randomised controlled trials contained in the sponsor's safety database for esomeprazole did not find an association with pneumonia. They noted however; that respiratory tract infections were not routinely specified outcomes in these trials, which limited confidence in the result.

The Committee considered that the observational studies were largely subject to a number of limiting factors including lack of validation of cases, residual confounding, lack of information on potential confounding factors, extent of exposure and misclassification bias.

The Committee noted that it has been hypothesised that pneumonia secondary to PPIs is due to increased gastric pH. The increase in gastric pH caused by PPIs may allow for several species of bacteria to grow in the stomach. This increase in gastric bacteria may lead to microaspiration and lung colonisation with a potential for causing pneumonia. The Committee noted the lack of a temporal association in that most studies found the greatest risk occurred shortly after initiation of a PPI, prior to the full gastric acid suppressing effect which occurrs around seven days after initiation of therapy. In addition the Committee noted that a microbiological study conducted in patients taking PPIs did not find an increase in pneumonia due to gastric bacteria. The Committee agreed that it was difficult to determine an accurate onset time for pneumonia and questioned if there were instances where PPIs were being prescribed for the treatment of the early symptoms of pneumonia.

The Committee agreed that there may be a weak association between PPIs and pneumonia but that there was insufficient information at this time to confirm a causal effect. They recommended that this issue be reviewed again should more information become available.

The Committee expressed concern regarding the extent of PPI use in New Zealand. They noted that BPAC have previously published an article on managing dyspepsia and heartburn in general practice, and agreed that an update would be timely. They recommended that BPAC be contacted regarding an updated article.

Recommendation 6

The MARC recommended that the issue of PPIs and pneumonia be reviewed again should more information become available.

Recommendation 7

The MARC recommended that BPAC be contacted regarding publishing an update to their previous article on managing dyspepsia and heartburn in general practice.

4 Matters arising from the New Zealand Pharmacovigilance Centre

4.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

Potential Safety Signals from Single Case Reports

No potential safety signals were identified by CARM this quarter.

4.1.2 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 noted the report of a case of cerebral haemorrhage in association with alteplase. They requested that CARM undertake a review of cases of cerebral haemorrhage in association with fibrinolytic agents and report back to the MARC.

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

4.1.3 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.

4.1.4 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.

4.1.5 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.

5 ANNEXES

3.2.1 Use of codeine in children post-surgery and implications with ultra-rapid metabolisers

  1. Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death. FDA Drug Safety Communication/ucm313631.

3.2.2 Proton Pump Inhibitors and pneumonia

  1. PPIs and pneumonia. September 2012. New Zealand Pharmacovigilance Centre.
  2. Giulano C et al. 2012. Are proton pump inhibitors associated with the development of community-acquired pneumonia? A meta-analysis. Expert Rev. Clin. Pharmacol 5(3):337-344.
  3. Eom C-S et al. 2011. Use of acid-suppressive drugs and risk of pneumonia: a systemic review and meta-analysis. CMAJ 183(3): 310-319.
  4. Hermos JA et al. 2012. Risk of Community-Acquired Pneumonia in Veteran Patients to Whom Proton Pump Inhibitors Were Dispensed. Clinical Infectious Diseases 54(1):33-42.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2.50 pm.

Associate Professor D Reith Chair
Medicines Adverse Reactions Committee