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 12 SEPTEMBER 2013 MEETING MINUTES

The one hundred and fifty-fifth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 12 September 2013 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9.10 am and closed at 3.10 pm.

MARC Members Present

Dr S Jayathissa (Acting Chair)
Dr L Bryant
Dr N Cole
Associate Professor Chris Frampton
Associate Professor P Jones
C Ryan
Dr R Savage
Dr S Sime
Dr K Wallis

Associate Professor D Reith attended via teleconference

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)

Invited Guests and Experts in Attendance

Laurence Holding, Advisor Science (MAAC and MCC Secretariat) attended part of the meeting.

1 Matters of Administration

1.1 Welcome and Apologies

The Acting Chair welcomed the attendees to the meeting. Apologies were received from Associate Professor D Menkes and Dr M Tatley.

1.2 Minutes of the 153^th MARC Meeting

The minutes of the 154^th meeting were accepted as a true and accurate record of the meeting.

1.3 Dates of Future MARC Meetings

The date for the remaining 2013 MARC meeting was scheduled for 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.

2.3 Prescriber Update Volume 34, Number 3, September 2013

The Committee noted the latest edition of Prescriber Update.

2.4 Quarterly summary of Medsafe early warning system communications

The Committee noted the quarterly summary of Medsafe early warning system communications.

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 Safety of hydroxyethyl starch for fluid replacement therapy

Background

In November 2012 the European Medicines Agency (EMA) initiated a safety review regarding solutions for infusion containing hydroxyethyl starch (HES). The initial Pharmacovigilance Risk Assessment Committee (PRAC) recommendation was to suspend these medicines as the Committee considered that the benefits did not outweigh the risks. However, an appeal has been lodged and the final outcome unknown. The new review started at the end of June, the assessment is due in September and PRAC recommendation in October 2013.

HES solutions are used to replace lost blood volume in hypovolaemia and hypovolaemic shock as an alternative to other colloids such as albumin. They are used in critically ill patients with sepsis, burn or trauma injuries or patients who are undergoing surgery. The major safety concerns cited by EMA for these products are mortality and renal injury requiring dialysis.

The purpose of the 2013 Medsafe paper was to review the available information on the benefits and risks of hydroxyethyl starch (HES).

The Committee was asked to advise whether:

On the strength of the evidence there is an increased risk of mortality associated with the use of hydroxyethyl starch.
On the strength of the evidence there is an increased risk of renal injury associated with the use of hydroxyethyl starch.
All forms of hydroxyethyl starch have the same clinical effects and should be treated as a class or whether these should be considered on an individual product basis.
The evidence on the risks associated with use of hydroxyethyl starch show that these outweigh the benefits or could be managed, e.g. by changes to the way these products are used.
Additional regulatory action should be taken; and is so what?
Communication other than an update to the monitoring communication is required.

Discussion

The Committee noted the 2013 Medsafe report.

The Committee reviewed the summary of published papers and relevant non-published studies presented in the Medsafe report. Information on the most recent meta-analyses, larger randomised controlled trials, and recent observational studies, were provided to the Committee.

The Committee agreed that the currently available data are not sufficient to make a firm conclusion on the benefits and risks of hydroxyethyl starches. The Committee considered that the current information indicated that there was a safety signal in relation to use of HES in critically ill patients. However the Committee noted that there were some caveats to be taken into consideration with the recent randomised controlled trials. For example, the Committee noted that there was some evidence of overtreatment of some patients and inappropriate treatment of patients with renal failure in these studies.

The Committee considered that the meta-analyses were limited by the inclusion of different patient populations and different types of HES into a single analysis.

Overall, the Committee considered that the safety concern was restricted to critically ill patients. The use of HES in surgical patients did not raise any safety concerns. The Committee considered that there was sufficient evidence to indicate a difference in effects between different types of HES, as well as different crystalloids solutions.

In regard to the effects of HES on mortality the Committee considered that the published data showed a marginal effect, which may be dose dependent and limited to critically ill patients. In regard to the adverse effects of HES on renal function the Committee considered that the evidence appeared stronger but was again restricted to critically ill patients. The Committee considered that more information was needed to fully investigate these safety concerns. The Committee considered that given the nature of the safety concern that it would be appropriate for Medsafe to issue notices to sponsors under section 36 of the Medicines Act (1981).

The sponsor for Voluven and Volulyte has updated the data sheet to state that these products should not be used in some critically ill patients with certain health conditions. This is consistent with changes made to the Canadian product information.

The Committee agreed that these data sheet changes were appropriate to manage the potential risk, at the present time based on the available information.

A monitoring communication on this topic was issued by Medsafe on 8 July 2013. The Committee recommended that this be updated with the results of this review.

Recommendation 1

The Committee recommended that notices be issued to sponsors of HES containing products under section 36 of the Medicines Act (1981).

Recommendation 2

The Committee recommended that the monitoring communication, published on the Medsafe website be updated.

3.2.2 Review of statins and the risk of acute kidney injury

Background

Recently published studies have suggested a link between high-potency statins (measured by dose or LDL-lowering efficacy) and the development of acute kidney injury or renal failure. None of the New Zealand data sheets for statins specifically lists acute kidney injury except in the context of muscle injury or rhabdomyolysis.

The purpose of the 2013 Medsafe review was to review the currently available information to determine if there is evidence of an association.

The Committee was asked to advise whether:

An association between the use of statins and the direct development of acute kidney injury has been established.
Any regulatory action needs to be taken (and if so what this action should be).
The results of this review should be communicated other than in MARC’s remarks (and if so how).

Discussion

The Committee noted the 2013 Medsafe report, which reviewed recently published literature and information provided from statin sponsors.

The studies that prompted the Medsafe review, by Chung et al and Dormuth et al, amongst others, were reviewed by the Committee. The Committee noted a number of limitations of the studies and agreed that there were innate confounding factors that could not be accounted for. For example, high-potency statins are often used in patients at greater risk of adverse effects due to interactions with concomitant medicines and the presence of co-morbidities.

The Committee noted that high-potency statins were already known to be associated with a greater risk of adverse events, including rhabdomyolysis, than low-potency statins. The Committee also noted that subgroup analysis for patients with chronic renal failure showed no adverse effect on renal function reported.

The Committee was advised of statin reports submitted to the Centre of Adverse Reactions Monitoring (CARM) up to 30 June 2013, which fulfilled the criteria for kidney injury. Of the 38 cases reported, 24 also reported rhabdomyolysis or creatine kinase elevations, which are suggestive of muscle problems. The Committee noted that there have been relatively few reports of AKI compared with the number of statins that have been prescribed.

The Committee agreed that the evidence that statins cause AKI through a direct effect rather than secondary to rhabdomyolysis is weak. The balance of benefits and risk of harm for statins remains positive and no action was considered necessary at this time.

The Committee agreed that more information would be valuable and recommended that the topic of acute kidney injury not associated with rhabdomyolysis be added to the M² scheme.

Recommendation 3

The Committee recommended adding this potential association to the M² scheme.

3.2.3 Use of N-acetylcysteine in the management of paracetamol overdose

Background

In September 2012 the MHRA announced new guidance on the use of intravenous acetylcysteine (NAC). The purpose of the 2013 Medsafe paper was to review the MHRA guidance, current Australasian poisons centres advice and compare this advice with the information currently provided in the data sheets, to determine whether any changes to the data sheets were required.

The Committee was asked to advise whether:

The indications for N-acetylcysteine treatment of paracetamol need to be better defined and if so how?
The contraindication to hypersensitivity should be removed?
The nomogram included in the data sheets should be updated and if so which nomogram should be included?
The duration of the first infusion should be changed from 15-60 minutes to 1 hour?
The data sheet should include weight based dosing tables for adults and children?
Any additional information should be added to the data sheet warnings and precautions section on risk factors for hepatotoxicity?
Any additional information should be added to the data sheets regarding treatment of anaphylactoid reactions?
Any additional adverse reactions need to be added to the data sheet?

Discussion

The Committee noted the 2013 Medsafe report.

NAC was noted to be an extremely effective treatment for paracetamol overdose when treatment is started within 8 hours of the overdose. It is also useful when liver injury has already occurred. The Committee agreed that this should be more clearly outlined in the indications section of the data sheets.

The variability in absorption of paracetamol after mixed overdose and overdose of extended release tablets and the implications for treatment with NAC were discussed. The Committee recommended that additional information be added to the data sheet about treatment in these situations.

The Committee acknowledged the use of alternate dosing schedules, especially given the current complicated dose. However the Committee did not wish to change the dosing schedule without published scientific evidence of equivalent efficacy. However, acknowledging the potential for medication errors the Committee recommended the inclusion of weight based dosing tables for adults and children in the data sheets.

The Committee considered the different nomograms in use to guide the use of NAC in acute overdoses presenting for treatment within eight hours. The Committee concluded that the data sheets should be consistent with the Australasian guideline and that the data sheets should be updated to include this nomogram.

The Committee agreed that the data sheet contraindication to treatment for patients with hypersensitivity to NAC should be removed. However, the Committee recommended additional information should be added about these reactions and how to treat them.

The Committee carefully considered the data sheet changes proposed by Medsafe and made some additional amendments.

Recommendation 4

The Committee recommended that the data sheets for NAC containing medicines should be updated to:

Include more information on when it is appropriate to use NAC
Remove the contraindication
Include weight based dosing tables
Update the nomogram in line with that recommended by the Australasian guideline
Change the timing of the first NAC infusion to 60 minutes (1 hour)
Add additional information on anaphylactoid reactions
Add additional information on NAC effect on prothrombin time

3.2.4 Calcium supplements and cardiovascular events

Background

In May this year, the MARC received correspondence from Andrew Grey, Mark Bolland and Ian Reid from the University of Auckland regarding the safety and efficacy of calcium supplements.

The correspondence requested that the MARC consider this topic and referred to two meta-analyses of randomised controlled trials that have been published by this group since the last MARC review of this issue.

In 2008, the MARC considered the cardiovascular risks of calcium supplements in women (www.medsafe.govt.nz/profs/adverse/Minutes133.htm#3.5). This review followed the publication of a paper in the BMJ by Bolland et al. 2008 that concluded that calcium supplementation in healthy postmenopausal women is associated with an increased risk of cardiovascular events. This paper was a secondary analysis of the Reid et al. 2006 randomised controlled trial of 1471 healthy postmenopausal women in New Zealand. The MARC considered that data presented in this paper were inconclusive and no regulatory action was required at that time.

The authors of the letter consider that calcium supplements should be subject to prescribing restrictions, as is currently happening internationally for strontium ranelate.

The MARC was asked to advise whether:

the strength of the evidence supports an association
any regulatory action required for this safety concern
any communication is required, and if so what should be communicated and to whom?

Discussion

The MARC noted the 2013 Medsafe report.

The MARC noted that calcium is regulated as a dietary supplement in New Zealand under the Dietary Supplements Regulations 1985. These regulations specify a number of requirements for dietary supplements relating to matters such as composition, labelling and maximum permitted daily doses for many vitamins and minerals. There is no maximum dose specified in the Regulations for calcium. Some products have applied for approval as medicines.

There is no requirement for data sheets for calcium supplements in New Zealand as these are either dietary supplements or if they are approved by Medsafe they are general sales medicines.

The MARC reviewed recent meta-analyses and reanalyses of randomised controlled trials. The MARC noted recent analyses provided contradictory outcomes in relation to risk of cardiovascular events.

The MARC considered there were limitations to all the analyses including that cardiovascular events were not primary outcomes, patient data were not gathered in a standardised manner and there was a lack of information regarding dietary calcium intake.

The MARC concluded that this is insufficient evidence to support an association between the use of calcium supplements and adverse cardiovascular outcomes. The MARC considered no regulatory action is required at this time. The MARC recommended that Medsafe continue to monitor this issue as it does for all medicines.

The MARC agreed that a response be sent to the authors of the letter.

The MARC recommended that a Prescriber Update article be published to inform healthcare professionals of the outcome of this review.

Recommendation 5

The MARC recommended that a response letter be sent to the authors of the letter.

Recommendation 6

The MARC recommended that a Prescriber Update article be published to inform healthcare professionals of the outcome of this review of calcium supplements and cardiovascular events.

3.2.5 Propofol use for paediatric ICU sedation – do the benefits outweigh the risks?

Background

In 2011 Medsafe reviewed the data sheets for all propofol products with consent for distribution in New Zealand. It was noted that the New Zealand data sheets were not consistent with the UK Summary of Product Characteristics (SPC) which contraindicated the use of propofol in patients aged 16 years or younger for sedation in intensive care. The New Zealand propofol sponsors were requested to provide data to support the safety and efficacy of propofol for this indication; or to contraindicate its use for sedation of paediatric ICU sedation.

The sponsors of generic propofol products updated their data sheets as requested. However, AstraZeneca, the sponsor of the innovator brand Diprivan, declined to add a contraindication for use in paediatric patients requiring sedation in the ICU. The sponsor provided Medsafe with a review supporting this decision.

Propofol is an intravenous anaesthetic agent that was first approved for use in New Zealand in 1985. In New Zealand the indications for propofol were extended to include sedation of ventilated paediatric patients requiring ICU care in 2001. Propofol is contraindicated for use in paediatric ICU sedation in Europe, Canada and Australia and not recommended for use in the US, primarily due to the risk of propofol related infusion syndrome (PRIS).

The efficacy of propofol for paediatric ICU sedation was established in a single controlled clinical study that included more than 200 paediatric patients who received an infusion of propofol. Propofol was found to be non-inferior to standard sedative agents (primarily midazolam) in achieving adequate levels of sedation and was associated with reduced time to extubation. There were numerically more adverse effects with propofol (mostly due to hypotension) but the overall safety profile was consistent with that associated with its use as an anaesthetic agent. No cases of PRIS were identified in this study; however, it was underpowered to detect uncommon to rare adverse effects.

PRIS was first identified in 1998 in critically ill children receiving propofol for sedation in ICU, although subsequently cases were also identified in adults. PRIS is a serious and potentially fatal condition characterised by the development of cardiac failure, arrhythmias, metabolic acidosis, rhabdomyolysis, acute kidney injury, hyperlipidaemia and hepatomegaly. Identified risk factors for PRIS include propofol doses >4mg/kg/hour and/or infusion durations of >48 hours; concomitant use of catecholamines or steroids; critical illness; and high fat intake (including propofol’s fat emulsion) in combination with inadequate carbohydrate delivery. Cases of PRIS have also been reported with low doses, short durations and when propofol has been used as an anaesthetic.

The available data on PRIS is limited by the lack of any controlled data. The incidence of PRIS is unknown, although it appears to be uncommon to rare. Reported mortality rates in case series have ranged from 83% to 1.5%. The lowest rates have been reported in the most recent studies which may reflect increased awareness of the condition, early recognition and early management of suspected cases.

Although the pathogenesis of PRIS is not fully understood, most authors agree that it involves impairment of free fatty acid (FFA) utilisation (by propofol), resulting in failure of cellular energy production and cellular necrosis, under conditions where FFAs are the main energy supply (eg critical illness). Increased FFA levels may also have direct proarrhythmic effects. In addition, propofol has known cardiodepressant effects that are likely to worsen any underlying haemodynamic instability. It has been suggested that children may have an increased risk of PRIS due to lower glycogen stores and increased dependence on FFA as fuel in times of stress.

Advice received from New Zealand experts indicates that there is a clinical need for propofol in selected paediatric ICU patients. Advantages of propofol include rapid reversal which is an advantage in patients with head injuries in which LOC must be assessed regularly. The published literature indicates that propofol continues to be used internationally for ICU sedation in selected paediatric patients, even in countries such as Germany and Spain where such use is contraindicated.

After reviewing the available data on this issue the MARC was asked to advise on the following:

Is the available data sufficient to conclude that propofol use is causally associated with the development of propofol related infusion syndrome?
Is the balance of benefits and risks favourable for propofol in paediatric ICU sedation?
Does the MARC recommend any regulatory action or risk management strategies for the use of propofol in paediatric ICU sedation?
Is any communication with prescribers warranted?

Discussion

The Committee noted the 2013 Medsafe report.

The Committee noted that CARM has not received any reports of PRIS in children or adults in New Zealand.

The Committee noted that Starship Hospital has produced clear guidelines for the safe use of propofol in paediatric ICU patients that include a maximum dose of 4mg/kg/hr and a maximum duration of 24 hours. The MARC was satisfied that there remains a clinical need for propofol for sedation of paediatric ICU patients in New Zealand.

The MARC considered that propofol is an effective sedative agent for paediatric ICU patients which offers some advantages over alternative agents (eg more rapid recovery time). Members considered that PRIS is a rare, serious and potentially life threatening condition associated with propofol use, particularly high doses and long durations of use. It was noted that PRIS mortality rates have decreased over time which may be due to increased awareness and compliance with limits to dose and duration of propofol use.

After reviewing the available data on this issue, the MARC concluded that the benefits of short term propofol use at doses <4mg/kg/hour for up to 24 hours duration (and probably up to 48 hours) outweigh the potential risks of treatment for sedation of paediatric ICU patients.

The MARC recommended that all propofol data sheets should be updated to include more detailed information on the risk of PRIS occurring. The MARC also recommended that all New Zealand intensivists, paediatricians and anaesthetists should be informed of the outcome this review.

Recommendations

The MARC recommended that the New Zealand Diprivan data sheet be updated to include the following information:

Indications section:
- Age should be specified for all indications
Dosage and Administration section:
- The maximum dose of propofol for paediatric ICU sedation should be 4mg/kg/hr for a maximum of 24 hours
Warnings and Precautions section:
- A new warning with a bolded title Propofol Infusion Syndrome should be added. The warning should be in line with the information contained in the Canadian propofol data sheets and should include early warning signs, risk factors (including underlying conditions requiring ICU care), monitoring recommendations, and management advice. The warning should also indicate that paediatric patients may be at an increased risk of developing PRIS.

Recommendation 7

The MARC recommended that the generic propofol data sheets be updated as follows:

Addition of a Warning about PRIS in line with that added to the Diprivan data sheet
Removal of the contraindication for use in paediatric ICU sedation

Recommendation 8

The MARC recommended that New Zealand Intensivists, Paediatricians and Anaesthetists should be informed of the outcome of this review.

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.