Published: 2 August 2013
Committees
Minutes of the 154th Medicines Adverse Reactions Committee Meeting - 13 June 2013
MARC MEMBERS PRESENT
MARC SECRETARIAT PRESENT
MEDSAFE STAFF IN ATTENDANCE
INVITED GUESTS AND EXPERTS IN ATTENDANCE
1.1 Welcome and Apologies
1.2 Minutes of the 153rd MARC Meeting
1.3 Dates of Future MARC Meetings
1.4 Potential Conflicts of Interest
2. MEDSAFE PHARMACOVIGILANCE ACTIVTIES
2.1 Report on Standing Agenda Items from
Previous Meetings of the MARC
2.2 Medsafe Pharmacovigilance Activities
2.3 Prescriber Update Volume 34, Number 2, June 2013
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 Diclofenac and cardiovascular
risk.
3.2.2 Use of Boostrix (combined
diphtheria,tetanus, and tricomponent acellular pertussis vaccine) in pregnancy
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
4.1.6 Special Repoerts
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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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.
MEDICINES ADVERSE REACTIONS COMMITTEE 13 JUNE 2013 MEETING MINUTES
The one hundred and fifty-fourth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 13 June 2013 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9.10 am and closed at 2.50 pm.
MARC Members Present
Associate Professor D Reith (Chair)
Dr L Bryant
Dr N Cole
Dr S Jayathissa
Associate Professor P Jones
Associate Professor D Menkes
C Ryan
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)
Invited Guests and Experts in Attendance
Andi Shirtcliffe, Chief Advisor Pharmacy Focus attended for part of the meeting.
1 Matters of Administration
1.1 Welcome and Apologies
The Chair welcomed the attendees to the meeting. Apologies were received from Associate Professor C Frampton and Dr S Sime.
1.2 Minutes of the 153rd MARC Meeting
The minutes of the 153rd meeting were accepted as a true and accurate record of the meeting.
1.3 Dates of Future MARC Meetings
The dates for the remaining 2013 MARC meetings were scheduled for 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.
[…]
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 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.
2.2 Medsafe Pharmacovigilance activities
The Committee noted the report detailing Medsafe's recent pharmacovigilance activities. They noted the addition to the paper of the issue of pholcodeine and the risk of cross-reactivity with neuromuscular blockers and considered that there was insufficient evidence at this time for any further action.
The Committee discussed the issue of synovitis reported in association with pamidronate, a bisphosphonate. They considered that this association may be under-recognised and recommended that awareness be raised in ways such as via the Monitoring scheme and/or a Monitoring Communication on the Medsafe website.
Recommendation 1
The Committee recommended that awareness of the risk of synovitis in association with bisphosphonates be raised in ways such as via the Monitoring scheme and/or a Prescriber Update article.
2.3 Prescriber Update Volume 34, Number 2, June 2013
The Committee noted the latest edition of Prescriber Update.
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 Diclofenac and cardiovascular risk
[…]
Background
In October 2012, the European Medicines Agency (EMA) finalised a review of recently published information on the cardiovascular (CV) safety of non-steroidal anti-inflammatory drugs (NSAIDs). The EMA concluded that the latest evidence for diclofenac shows a consistent but small increase in the risk of cardiovascular adverse effects compared with other traditional or non-selective NSAIDs (eg, ibuprofen and naproxen), and similar to the risks of COX-2 selective inhibitors (eg, celecoxib). The EMA concluded that the benefit-risk balance remained positive, however a small increased CV risk could not be excluded. The EMA's Pharmacovigilance Risk Assessment Committee (PRAC) then further assessed all available data on diclofenac, although no decision had been made regarding any further action at the time of the MARC meeting.
In addition, further studies have now been published which also suggest an increased risk of CV complications with the use of diclofenac, and there has been significant media interest in this subject.
The Committee last formally reviewed the safety of NSAIDs in December 2007. At that time, the Committee concluded that all NSAIDs were associated with an increased risk of serious CVevents, including cardiac failure, myocardial infarction (MI) and stroke, which may increase with dose or duration of use. The Committee recommended that the lowest possible dose for the shortest period of time be used and long-term treatment with non-selective NSAIDs be regularly reviewed. Individual risk factors should be taken into account before prescribing an NSAID and the patient should be advised of the risk of harm and the warning signs of serious adverse reactions. All NSAID data sheets were updated to reflect these recommendations and a Prescriber Update article was published in May 2008 informing health professionals of the outcomes of the MARC evaluation.
The purpose of the 2013 Medsafe review was to evaluate the currently available data and determine whether any further advice or action was required regarding the CV risk associated with diclofenac.
The Committee was asked to advise whether:
- Any further action or advice is required regarding the safety of diclofenac, particularly in relation to cardiovascular risk (and if so what this action or advice should be).
- The results of this review should be communicated (and if so how).
Discussion
The Committee noted the 2013 Medsafe report, which reviewed the systematic reviews, meta-analyses, and other studies published on diclofenac since the previous MARC review in 2007.
The Committee was given a brief overview of the mechanism of action of NSAIDs. Traditional or non-selective NSAIDs block the effects of the two cyclooxygenase (COX) enzymes, known as COX-1 and COX-2, which are involved in the inflammatory process, whilst COX-2 inhibitors selectively block COX-2 enzymes only. It was noted that although diclofenac is considered to be a non-selective NSAID, diclofenac shows more of a preference for COX-2 inhibition.
The Committee noted that diclofenac is the second most commonly prescribed NSAID in New Zealand, after ibuprofen. Ibuprofen, diclofenac, and naproxen are also available without prescription, as either pharmacy only or pharmacist only medicines, therefore the use of all of these medicines will be higher than indicated by usage figures.
The Committee noted the information contained in current NSAID New Zealand data sheets, which was adopted following consultation by the Committee during 2006/2007. At this time, Medsafe liaised with the TGA to ensure consistency of product information between countries. The Committee noted that the data sheets have not been updated with regards to cardiovascular risk since this time. The United Kingdom/Europe's Summary of Product Characteristics were updated in a similar fashion in 2007. The United States and Canada similarly strengthened warnings around cardiovascular risk, with the United States FDA adding a black box warning regarding cardiovascular risk for all NSAIDs.
The Committee noted the information contained in the New Zealand Product insert, which was included in packs for sale as pharmacy-only and restricted medicines.
The Committee reviewed the latest studies included in the Medsafe report.
The Committee noted that of the recent meta-analyses, most include the same clinical studies, therefore the results are consistent.
The Committee discussed the limitations of the studies included in the review, such as the observational nature of most studies, and considered there to be a lack of information on the efficacy of the different medicines in individual patients, and dosage, regimen and indication for use. Many important confounders could not be adjusted for, such as smoking status, alcohol use, body mass index or obesity, over-the-counter NSAID use and use of other medications, They noted that many studies had a low number of overall events, leading to wide confidence intervals and an imprecise estimate of risk. They noted that, with subsequent risk values showing an increase of less than 1.5 times that of no NSAID use, this was only marginally statistically significant.
The Committee concluded that there was a small increase in the risk of cardiovascular events with the use of diclofenac, particularly with increasing dose and duration of use. They considered that if some of the confounders were adjusted for, the estimates of the risk may move closer to one and a null association. However, with the widespread use of diclofenac, the Committee agreed that even a small increased risk of cardiovascular adverse effects may translate to a large number of patients potentially affected.
The Committee was unable to determine from the new data a clear difference in risk between different NSAIDs. The Committee noted that other NSAID adverse reactions are also important, including the risk of gastrointestinal events, renal injury and severe skin reactions. The Committee noted that other types of pain relievers also have undesirable effects, which should be considered before prescribing.
The Committee considered that the information contained in the New Zealand diclofenac data sheets could be more specific. They recommended that key alterations were made to different sections of the data sheet as follows:
Indications section
- Diclofenac should only be prescribed when the benefits are considered to outweigh the potential risks (see Warnings and Precautions)
Warning and Precautions section:
- Patients who have had a recent myocardial infarction (within the last 6 to 12 months) should not use diclofenac.
- Patients on long-term treatment should be regularly reviewed with regards to efficacy, adverse effects, the development of cardiovascular risk factors, and the ongoing need for therapy. Consideration should be given to monitoring blood pressure, haemoglobin levels, and renal function.
- Prescribers should inform the individual patient of the possible increased risk when prescribing diclofenac for patients at high risk of cardiovascular events. This includes risk factors such as diabetes, ischaemic heart disease, cardiac failure, hyperlipidaemia, hypertension or smoking.
- Physicians and patients should remain alert for such events, even in the absence of previous cardiovascular symptoms. Patients should be informed about the signs and/or symptoms of cardiovascular toxicity and the steps to take should they occur.
The Committee considered that there could be more specific information relating to CV risk in the package insert for diclofenac-containing products that are available without prescription. They recommended that the information in the package inserts be consistent with that contained in the diclofenac data sheets. They also recommended that the Consumer Medicine Information (CMI) be similarly updated.
The Committee agreed that this information be further communicated by publishing a Prescriber Update article.
The Committee also agreed that an alert be added to the Early Warning system on the Medsafe website.
The Committee agreed that the overall benefit-risk balance of diclofenac remains positive.
Recommendation 2
The Committee recommended that alterations be made to the New Zealand diclofenac data including adding the following statements to the Indications and Warning and Precautions sections:
Indications section
- Diclofenac should only be prescribed when the benefits are considered to outweigh the potential risks (see Warnings and Precautions)
Warnings and Precautions section
- Patients who have had a recent myocardial infarction (within the last 6 to 12 months) should not use diclofenac. Patients on long-term treatment should be regularly reviewed with regards to efficacy, adverse effects, the development of cardiovascular risk factors and the ongoing need for therapy. Consideration should be given to monitoring blood pressure, haemoglobin levels, and renal function.
- Prescribers should inform the individual patient of the possible increased risk when prescribing diclofenac for patients at high risk of cardiovascular events. This includes risk factors such as diabetes, ischaemic heart disease, cardiac failure, hyperlipidaemia, hypertension or smoking.
- Physicians and patients should remain alert for such events, even in the absence of previous cardiovascular symptoms. Patients should be informed about the signs and/or symptoms of cardiovascular toxicity and the steps to take should they occur.
Recommendation 3
The Committee recommended that information in the package inserts be updated to be consistent with that contained in the diclofenac data sheets. They also recommended that the Consumer Medicine Information (CMI) be similarly updated.
Recommendation 4
The Committee recommended that this information be further communicated by publishing a Prescriber Update article.
Recommendation 5
The Committee recommended that an alert be added to the Early Warning system on the Medsafe website.
3.2.2 Use of Boostrix (combined diphtheria,tetanus, and tricomponent acellular pertussis vaccine) in pregnancy
Background
In December 2012, PHARMAC announced that diphtheria, pertussis and tetanus (Tdap, Boostrix®) vaccination would be funded for pregnant women between gestational weeks 28 and 38 during epidemics. As there is currently a pertussis epidemic in New Zealand, funding commenced on 1 Jan 2013.
Boostrix and Adacel® are approved diphtheria, pertussis and tetanus vaccines in New Zealand; however only Boostrix is funded. The use of Boostrix in pregnancy is not an approved indication and Medsafe has not reviewed an application from the company to support use in pregnancy. The purpose of the 2013 Medsafe paper was to review the available information on the benefits and risks and monitor the current situation.
The Committee was asked to advise whether:
- Any communication on this topic is required.
Discussion
The Committee noted the 2013 Medsafe report.
The Committee agreed that pertussis is an important cause of infant death both in New Zealand and worldwide, with most deaths occurring in those under six-weeks old. They noted that natural infection confers protection against pertussis only for between 4 and 20 years, and the protection following vaccination wanes after about 4 to 12 years. Despite high levels of infant vaccination, pertussis remains endemic with epidemics occurring every 2 to 5 years.
The Committee noted that the aim of vaccinating the mother during pregnancy was to boost maternal antibodies, which are then actively transferred to the infant before birth. These antibodies should then protect the infant until primary immunisation is complete at 6 months. The Committee was advised that vaccination of pregnant women was recommended in the United States after the strategy of cocooning the baby i.e. by vaccinating the mother post-partum and attempting to vaccinate other close contacts was deemed to have failed.
The Committee noted that diphtheria and tetanus vaccines have established safety records when used in pregnant women. Both diphtheria and tetanus vaccines are included in Category A in the Australian categorisation of risk in pregnancy. This is the lowest risk category and is for drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.
The Committee noted that there is some evidence of efficacy for pertussis vaccination in pregnancy; however most of the evidence relates to the whole cell vaccines used previously rather than current acellular vaccines. The Committee noted that the Medsafe report therefore focused on the efficacy and safety of acellular pertussis vaccination in pregnancy.
Between 1999 and 2012, over 55 million Boostrix doses have been distributed worldwide. No information is available on the number of pregnant women exposed to the vaccine.
The Committee noted that the recommendation for use of Boostrix is mainly based on the assumption that data from studies on whole cell pertussis vaccines and other acellular pertussis vaccines which show that protective immunity is produced when given to pregnant women applies to all pertussis vaccines. It is therefore assumed that transfer of maternal antibodies from the mother to the infant is similar no matter which vaccine is used. The Committee noted the general data available to support the hypothesis that maternal antibodies are transferred to the foetus prior to birth and that these could be protective. The timing of vaccination of the mother appears to be very important, with optimal protection appearing to occur when the mother is vaccinated around 30 weeks gestation.
The Committee noted that Boostrix is included in pregnancy Category B2 in the Australian categorisation of risk in pregnancy, as adequate human data on use during pregnancy and adequate animal reproduction studies are not available.
The Committee noted the study by Zheteyeva et al, which reviewed the reports to the US Vaccine Adverse Event Reporting System (VAERS) after Tdap in pregnant women between January 2005 and June 2010. They agreed that most of the events were those to be expected during pregnancy and there were no safety concerns identified in maternal, infant or foetal outcomes.
The Committee noted that Boostrix Periodic Safety Update Report (PSUR), which included a review of the company's pregnancy registry which has operated in the United States since 2005. No safety concerns were identified in this review; however the number of mothers exposed to Boostrix is currently too low to make any firm conclusions.
The Committee reviewed the reports received by CARM relating to the use of Boostrix in pregnant and non-pregnant women between the start of 2013 and the end of April, and did not identify any safety concerns. The Committee was advised of other studies currently being carried out in New Zealand, investigating the safety and efficacy in pregnant women. The Committee was reassured by the on-going monitoring being undertaken in the New Zealand studies and by the company via its pregnancy register.
The Committee was advised that the Ministry of Health's immunisation programme included a regular newsletter sent to general practitioners and midwives. They considered that this would be an effective way of encouraging reporting of any suspected adverse reactions to CARM, and recommended that a request be made to include this information in an upcoming newsletter.
The Committee agreed that the potential benefits of vaccinating pregnant women with Boostrix outweighed any potential risks, and agreed that no further action was required at this time.
Recommendation 6
The MARC recommended that the Ministry of Health's immunisation team be requested to include information in their communications with general practitioners and midwives to encourage reporting of any suspected adverse reactions to CARM.
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
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 did not consider any of the 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 discussed case report 105395 involving an interaction between the use of oral miconazole gel in association with warfarin resulting in an increased INR and haemorrhage. They recommended that this be the topic of a Prescriber Update article to remind healthcare professionals of this interaction.
Recommendation 7
The MARC recommended that a Prescriber Update article be published regarding the interaction between oral miconazole gel and warfarin.
4.1.6 Special Reports
The Committee did not consider any of the reports required further action.
5 Other Business
The MARC had some queries about the Intensive Medicines Monitoring Programme (IMMP), which Medsafe was able to clarify.
6 Annexes
3.2.1 Diclofenac and cardiovascular risk
- European Medicines Agency announcement on review of non-selective NSAIDs
- Voltaren Rapid 25 package insert
3.2.2 Use of Boostrix (combined diphtheria,tetanus, and tricomponent acellular pertussis vaccine) in pregnancy
- Bechini A, Tiscone E, Boccalini S et al 2012 'Acellular pertussis vaccine use in risk groups (adolescents, pregnant women, newborns and health care workers) a review of evidences and recommendations' Vaccine 30: 5179-90
- Gall SA 2012 'Prevention of pertussis, tetanus and diphtheria among pregnant postpartum women and infants' Clinical Obs and Gyne 55: 498-509
- Murphy TV, Slade BA, Broder KR 2008 'Prevention of pertussis, tetanus and diphtheria among pregnant and postpartum women and their infants: recommendations of the advisory committee on immunisation practices (ACIP)' MMWR 57: RR-4.
- Gall SA, Myers J, Pichichero M 2011 'Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels' AJOG 204: e1-5-
- Healy CM, Rench MA, Baker CJ 2013 'Importance of timing of maternal combined tetanus, diphtheria and acellular pertussis (Tdap) immunization and protection of young infants' CID 56: 539-544.
- Englund JA, Anderson EL, Reed GF et al 1995 'The effect of maternal antibody on the serologic response and the incidence of adverse reactions after primary immunization with acellular and whole cell pertussis vaccines combined with diphtheria and tetanus toxoids' Pediatrics 96:580-584.
- Zheteyeva YA, Moro PL, Tepper NK et al 2012 'Adverse event reports after tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines in pregnant women' AJOG 59: e1
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
