INVITED GUESTS AND EXPERTS IN ATTENDANCE
1.2 MINUTES OF THE 145TH MARC MEETING
1.3 DATES OF FUTURE MARC MEETINGS
1.4 POTENTIAL CONFLICTS OF INTEREST
2.1 REPORT ON STANDING AGENDA ITEMS FROM PREVIOUS MEETINGS OF THE MARC
2.1.1 Hepatic failure with
paracetamol (92092)
2.1.2 Review of proposals for the M² Scheme
2.1.3 Additional papers relating to risk of venous
thromboembolism associated with combined oral contraceptives containing
drospirenone
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 Risk of malignancy associated
with angiotensin receptor blockers
3.2.2 Signal of increased risk of oesophageal cancer
associated with the use of oral bisphosphonates
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
Casually Associated with Critical Terms in Patients Over 80 Years
4.1.6 Human Papillomavirus Vaccine (HPV) reports
4.1.7 Seasonal Flu Vaccine reports
5.1 CONTINUING MEDICAL EDUCATION
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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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 forty-sixth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 9 June 2011 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9.30 am and closed at 2.10 pm.
marc members present
Associate Professor D Reith (Acting Chair)
Dr L Bryant
Dr S Sime
Dr M Tatley
Professor P Ellis
Associate Professor C Frampton
Dr S Jayathissa
Dr K Wallis
marc secretariat present
J McNee (MARC Secretary, Medsafe)
MEDSAFE STAFF IN ATTENDANCE
A Cutfield (Advisor, Pharmacovigilance)
J Hart (Manager, Clinical Risk Management)
C James (Senior Advisor, Pharmacy)
S Kenyon (Senior Advisor, Pharmacovigilance)
Dr S Jessamine (Group Manager, Medsafe)
Invited guests and experts IN ATTENDANCE
Dr R Savage (Senior Medical Advisor, New Zealand Pharmacovigilance Centre)
1. Matters of Administration
1.1 Welcome and Apologies
The Acting Chair welcomed the attendees to the meeting. Apologies were received from Associate Professor M Rademaker.
1.2 Minutes of the 145th MARC Meeting
The minutes of the 145th meeting of the Committee had previously accepted as a true and accurate record of the meeting.
1.3 Dates of Future MARC Meetings
The dates for the 2011 MARC meetings are scheduled for 8 September 2011 and 8 December 2011.
1.4 Potential Conflicts of Interest
Committee members submitted their Conflicts of Interest Declaration forms to the Secretary. The Acting 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 potential conflicts of interest which were considered likely to influence the discussions or decisions of the MARC at this meeting.
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 from the Medsafe website at www.medsafe.govt.nz/profs/MARC/Minutes.asp
Standing agenda items for which the MARC made further recommendations for action are summarised below.
2.1.1 Hepatic failure with paracetamol (92092) March 2011 minute item 2.1.2, December 2010 minute item 4.1.1.1
MARC Recommendations
In March 2011, the MARC recommended that the Committee write to the Paediatric Society, the Royal New Zealand College of General Practitioners, the Pharmaceutical Society and PHARMAC to highlight the problem of paracetamol overdosing in children, and to encourage the prescription and dispensing of small volumes of liquid preparations as a preventive measure.
The MARC recommended that Medsafe consider publishing an article in Prescriber Update to raise awareness about the safe prescribing of paracetamol in children.
Outcome
Medsafe is in the process of preparing a letter as recommended by the MARC. Medsafe is awaiting the outcome of a review on the new MHRA dosing recommendations so this can be included in the letter.
An article was published in the June 2011 edition of Prescriber Update to raise awareness about the safe prescribing of paracetamol in children.
Discussion
Medsafe advised the MARC of guidelines for liquid paracetamol dosing recently released by the UK MHRA. These guidelines introduce updated dosing advice to ensure that children get the optimal dose of paracetamol for their age. The dosage system for infant paracetamol has changed from two bands (three months to under one year, and 1 year to under 6 years) to four bands 3 - 6 months, 6 - 24 months, 2 - 4 years, and 4 - 6 years.
The dosage system for paracetamol six plus suspension has been updated from a single band of 6 - 12 years, to three separate age bands of 6 - 8 years, 8 - 10 years, and 10 - 12 years. The strength of infant paracetamol is 120mg/5ml and paracetamol six plus is 250mg/5ml.
The Committee considered that the NZ dosage instructions were appropriate. They noted that cases of chronic hepatotoxicity occurred when dosage instructions were not followed. They agreed that consumer education was an important factor in order to ensure the safe use of liquid paracetamol in the community.
Medsafe advised that the labeling guideline for paracetamol was in the process of being rewritten, which updated the warning statements required for paracetamol.
The Committee agreed that it was important to optimise the safety of liquid paracetamol in the community and recommended that Medsafe investigate the new advice released by the MHRA with respect to the adoption of the new dosing advice by NZ. They recommended that Medsafe take the required action to communicate information as necessary and report back to the MARC.
Recommendation 1
The MARC recommended that Medsafe investigate the new advice released by the MHRA with respect to the adoption of the new dosing advice by NZ. Medsafe will report back to the MARC as necessary.
2.1.2 Review of proposals for
the M² Scheme
March 2011 minute item 3.2.2, December 2010 minute item 2.1.2
MARC Recommendation
The MARC recommended that Medsafe investigate the feasibility of including the M² logo next to the monitored medicines on the data sheet and CMI search results pages on the Medsafe website.
Outcome
Medsafe has sought IT support to investigate the feasibility of this suggestion.
Secretary's note: since the time of the meeting, this issue has been implemented by Medsafe.
2.1.3 Additional papers relating
to risk of venous thromboembolism associated with combined oral contraceptives
containing drospirenone
Update from Pharmacovigilance Activities Paper
Background
The MARC had recently reviewed the risk of venous thromboembolism (VTE) associated with combined oral contraceptives (COCs) containing drospirenone. Since the MARC review, two further papers on this subject were published in April 2011. These papers were presented to the MARC at this meeting for their information.
Both studies compared the risk of non-fatal idiopathic VTE in women aged 15 to 44 years old, currently using COCs containing drospirenone to those currently using COCs containing levonorgestrel. The authors of both studies concluded that COCs containing drospirenone carried a 2- to 3-fold higher risk of VTE than those containing levonorgestrel.
Discussion
While the two studies were well designed and conducted, the MARC noted the results were limited by many of the inherent problems of observational database studies. The MARC noted that the results were of limited value from the regulatory perspective due to issues of generalisability and the lack of comparison with third generation combined oral contraceptives.
The MARC also noted it is unclear why the results of these studies differ from those in similar cohort studies published previously.
The MARC concluded that the evidence to date suggests that second generation combined oral contraceptives are associated with the lowest risk of VTE.
The MARC was also informed that the results of additional studies on this matter are expected to be published in 2011.
The Committee noted that most prescribers commenced therapy with a levonorgestrel containing product. It is generally accepted that the risk of VTE associated with combined oral contraceptives increases with increasing oestrogen dose The MARC therefore expressed concern that there were no fully funded combined oral contraceptives containing 20mcg ethinyloestradiol.
The Committee noted that the sponsor has been requested to provide further information and this would be brought back to the Committee if necessary.
Recommendation 2
The MARC recommended that Medsafe review available data as it arises and consider the need for changes to the data sheets and further communication as necessary.
Recommendation 3
The MARC recommended that a letter be written to PHARMAC highlighting the MARC's concern regarding the lack of a fully funded combined oral contraceptive containing 20mcg ethinyloestradiol.
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 Risk of malignancy associated with angiotensin receptor blockers
Background
In June 2010 Sipahi et al (2010) published a meta-analysis of nine randomised controlled clinical trials (RCTs) of angiotensin receptor blockers (ARBs) that included data on cancer incidence or mortality. The authors concluded that all ARBs are associated with a modestly increased risk of new cancer diagnoses, although they noted that it was not possible to draw conclusions about the exact risk associated with each individual ARB. The authors indicated that further investigation of this risk is required.
In response to the Sipahi et al study, both the European Medicines Agency (EMA) and the US FDA advised that they would be reviewing all the available data on ARBs to clarify whether there is an increased risk of cancer in patients taking these medicines.
To investigate this issue further, Medsafe conducted a literature review which identified another three meta-analyses and two cohort studies that investigated the risk of cancer in association with the use of ARBs. In addition, Medsafe asked the sponsors of all ARBs available in New Zealand to review their own data on the risk of malignancy in association with the use of ARBs.
Discussion
The MARC reviewed the 2011 report provided by Medsafe.
It was noted that a possible risk of cancer has previously been associated with other classes of anti-hypertensive medicines, and also with hypertension per se, but to date an association with cancer has not been confirmed with any class of antihypertensive medicine. It was also noted that many risk factors for hypertension are also risk factors for the development of cancer, including increasing age, smoking, heavy alcohol consumption, and obesity.
The MARC noted that although many authors have suggested that ARBs may have an effect on the development of cancer through their action on the renin-angiotensin system, there is no clear consensus as to whether the available experimental data is more supportive of a protective or harmful effect. Preclinical carcinogenicity studies were negative for all ARBs except for olmesartan, which is not approved for use in New Zealand. In addition, recent studies have suggested that ARBs may have a beneficial effect on the development of cancer, including prevention of non-melanoma skin cancers, and as an adjunct to chemotherapy in the treatment of renal cell carcinoma.
The MARC reviewed in detail the meta-analyses by Coleman et al (2008), Sipahi et al (2010), Bangalore et al (2011) and The ARB Triallists Collaboration (2011). They noted that the Coleman et al (2008) study investigated a possible association between anti-hypertensive medicines and the development of cancer and found no association for any of the anti-hypertensive classes studied, including ARBs. However, weaknesses identified included the short duration of follow-up such that an association could not be completely ruled out, and the inclusion of only four ARB studies. Of note, 3 of the 4 studies were also included in the Sipahi et al study.
The MARC reviewed the Sipahi et al (2010) study which found that ARBs were associated with a modestly increased risk of new cancer occurrence, specifically with the combination of an ACE inhibitor and an ARB, and a statistically significant increased risk of lung cancer. The Committee noted that there were many limitations to the Sipahi et al study that make interpretation of the results difficult including publication bias due to the inclusion of only publicly available data and likely selection and misclassification bias. In addition the authors did not have access to individual patient data so that adjustment for potential confounders such as smoking could not be done and time to event analyses could also not be calculated. It was also noted that the results are not likely to have reached statistical significance if the more appropriate random effects model was used.
The MARC noted that the Bangalore et al (2011) study included substantially more data (almost double the number of participants) than the Sipahi et al study. It was noted that the authors did not find an increased risk of cancer with ARBs compared to any control group using any of the statistically techniques employed. However, as with the Sipahi et al study, a statistically significant association was found with the ARB/ACE inhibitor combination compared to ACE inhibitor alone but only when a fixed effect model was used. As with the Sipahi et al study, this result was largely driven by the results of the ONTARGET study which contributed 93% of the data to this analysis.
The ARB trialists Collaboration (2011) included 15 large randomised controlled long-term trials, and unlike the previous studies, had access to some individual patient data and tabulated data from final study reports for the other studies included. This study included the largest number of patients who contributed cancer data to the study. The authors concluded that there was no statistically significant excess in cancer incidence with ARB treatment as a class or for any of the individual ARBs compared to controls. Unlike the Sipahi and Bangalore studies, they did not find a statistically significant association with the ARB/ACE inhibitor combination. It was noted that 7 studies were included in this analysis and the ONTARGET study only contributed 1/3 of the data, which increases the reliability of the result.
The Committee also noted that two large cohort studies (Pasternak et al (2011) and Huang et al (2011)) had been published which provided data on the real-world use of ARBs. Neither study found an association between the use of ARBs and the development of cancer.
The Committee noted that the FDA have recently completed a meta-analysis of 31 studies, and found no association between ARBs and cancer.
The Committee concluded that the currently available data does not support an association between the use of ARBs as a class and the development of cancer. They agreed that the short duration of all the studies reviewed was a limitation and therefore an increased risk of de novo cancer development could not be completely excluded. In addition, the available data is inadequate to exclude an association between individual ARBs and development of cancer or an association between ARBs and the development of specific cancers.
The MARC considered that the cardiovascular benefits of this class of medicines are likely to substantially outweigh any possible risk of developing cancer and therefore, no regulatory action is warranted at this time.
Recommendation 4
The MARC recommended that a Prescriber Update article be published to inform health professionals of the outcome of Medsafe and the MARC's review of this issue.
3.2.2 Signal of increased risk of oesophageal cancer associated with the use of oral bisphosphonates
Background
In June 2010 a case-control study by Green et al was published in the British Medical Journal reporting an increased risk of oesophageal cancer in association with oral bisphosphonates.
Following this, Medsafe wrote to the sponsors of oral bisphosphonates approved for use in New Zealand concerning a possible association with increased risk of oesophageal cancer. Bisphosphonates included in the review were: alendronate, etidronate, ibandronate, risedronate, and tiludronate.
Sponsors were asked to provide a review of the risk of oesophageal cancer with bisphosphonates, including the possibility of masking symptoms of irritation by using concomitant proton pump inhibitors. Sponsors were also asked for data on the long-term safety of bisphosphonates and the utility of drug holidays in reducing adverse effects.
Discussion
The MARC reviewed the 2011 report provided by Medsafe.
The Committee noted that both the Green et al (2010) and Cardwell et al (2010) studies were observational studies using the same database, and published contemporaneously in two different journals. They noted that the limitations of these studies were consistent with those in many observational studies, as had been discussed previously. They noted some discrepancies in the data between the two studies, given they were collected from the same database. The Committee noted that oesophageal cancer is reasonably rare, meaning a modest increase in relative risk raises questions about the clinical significance in the population. The Committee noted that given the limited follow-up period and the use of retrospective data, the association of bisphosphonates with cancer could be a signal but any effect, if it existed, was small. The Committee agreed that the studies described in this review do not provide convincing evidence of an association between bisphosphonates and oesophageal cancer; however an association cannot be fully excluded at this time.
Reviews provided by each sponsor of oral bisphosphonates that have consent in New Zealand provided little evidence in support of an association. The Committee noted that cases were commonly confounded by either past medical history, smoking, onset several months after discontinuation or onset after very short periods of treatment (one dose in one case) and masking of symptoms with concomitant use of proton pump inhibitors. Each sponsor made the conclusion following their review that there is no evidence of an association between oral bisphosphonates and oesophageal cancer. The Committee was advised that CARM has received no reports of oesophageal cancer in association with oral bisphosphonates.
The Committee considered the question of an optimal length of therapy and the value, if any, of 'drug holidays'. They noted that the product sponsors have provided very little information about the benefits of drug holidays. The Committee noted that an expert opinion had previously been obtained on this subject and this could be distributed to the members.
The Committee noted that Medsafe will review product Periodic Safety Update Reviews to determine if any new information that may be helpful has been identified since the last review. The MARC considered that there was insufficient evidence available at this time to confirm an association between the use of oral bisphosphonates and oesophageal cancer. The MARC recommended that Medsafe continue to monitor this association and report back to the MARC as necessary.
The Committee agreed it would be of value if the issue of oesophageal cancer in association with oral bisphosphonates was included in the products risk management plans, and Medsafe agreed to follow up and take appropriate action if necessary.
Recommendation 5
The MARC recommended that Medsafe continue to monitor this association and report back to the MARC as necessary.
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 were given the option of requesting that any particular reports be discussed at the current or a subsequent meeting if they considered that there may be a safety issue that prescribers should be informed about or for which regulatory action was required.
Discussion
The MARC noted the Report of Fatal Cases assessed as causal.
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 serous cases associated with medicines in children under 18 years were briefly outlined for the Committee. The Committee were given the opportunity to request further information on particular reports which may be discussed at a future meeting.
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 were given the opportunity to request further information on particular reports which may be discussed at a future meeting. [..]
The Committee noted that bulging fontanelle following vaccination has recently been raised as a signal by the WHO. It appears to be a transient condition which resolves quickly without treatment.
The MARC noted that the follow-up enterovirus PCR was awaited and recommended that these results be provided to the Committee when they became available.
Recommendation 6
The MARC recommended that NZPhvC provide follow-up results OF REPORT 94387 when they become available.
4.1.5 Special Populations: Serious Non-Fatal Cases Casually 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 had the opportunity to request further information on particular reports which may be discussed at a future meeting.
The Committee did not consider any of the reports required further action.
4.1.6 Human Papillomavirus Vaccine (HPV) reports
The Committee noted the CARM reports of reactions to the HPV vaccine up to 31 March 2011.
The Committee noted that the rate of reporting is continuing to decrease and that none of the reports required further action.
4.1.7 Seasonal Flu Vaccine reports
The Committee noted the CARM report of reactions to the seasonal flu vaccine up to 27 May 2011.
The Committee did not consider any of the reports required further action.
5. OTHER BUSINESS
5.1 Continuing Medical Education
Assoc. Prof David Reith gave a presentation on Drug Metabolism: Enzyme Kinetics.
6. REFERENCES
2.1.3 Additional papers relating to risk of venous thromboembolism associated with combined oral contraceptives containing drospirenone
- Jick S. and Hernandez R. (2011). British Medical Journal. 340: d2151
- Parkin L., Sharples K., Hernandez R. and Jick S. (2011). British Medical Journal. 340: d2139
3.2.1 Risk of malignancy associated with angiotensin receptor blockers
- Bangalore S et al (2011). Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. Lancet Oncol; 12: 65-82.
- Coleman CI et al (2008). Antihypertensive medication and their impact on cancer incidence: a mixed treatment comparison meta-analysis of randomised controlled trials. J Hypertension 26: 622-629.
- Huang C_C et al (2011). Angiotensin II Receptor Blockers and Risk of Cancer in Patients With Systemic Hypertension. Am J Cardiol; 107: 1028-1033
- Pasternak B et al (2011). Use of Angiotensin Receptor Blockers and the Risk of Cancer. Circulation; 123: 1729-1736.
- Sipahi I et al (2010). Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 2010; 11: 627-36.
- The ARB Trialists Collaboration (2011). Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancer in 15 trials enrolling 138 769 individuals. Journal of Hypertension 29: 623-635.
3.2.2 Signal of increased risk of oesophageal cancer associated with the use of oral bisphosphonates
- Green J et al. Oral bisphosphonates and risk of cancer of oesophagus, stomach and colorectum: case-control analysis within a UK primary care cohort. BMJ 2010;341:c4444;doi10.1136/bmj.c4444.
- Cardwell CR. Et al. Exposure to Oral bisphosphonates and risk of oesophageal cancer. JAMA 2010;304(6): 657-663.
- MSD. 26 April 2010. Alendronate data sheet (Fosamax). Published on www.medsafe.govt.nz.
- Arrow Pharmaceuticals Ltd. 16 August 2010. Arrow-etidronate data sheet. Published on www.medsafe.govt.nz.
The Acting Chair thanked members, the Secretariat and invited guests and experts for their attendance and closed the meeting at 2.10 pm.
Associate Professor D Reith Acting Chair
Medicines Adverse Reactions Committee
