Published: 22 December 2014

Committees

Minutes of the 160th Medicines Adverse Reactions Committee Meeting - 4 December 2014

MINUTES OF THE 160th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
4 DECEMBER 2014

The one hundred and sixtieth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 4 December 2014 at The Rydges, Wellington, New Zealand. The meeting commenced at 9am and closed at 3pm.

MARC MEMBERS PRESENT

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

MARC SECRETARIAT PRESENT

L Chan (MARC Secretary, Medsafe)

MEDSAFE STAFF IN ATTENDANCE

A Govender (Advisor, Pharmacovigilance)
R Jaine (Principal Clinical Advisor)
C James (Manager, Clinical Risk Management)
S Kenyon (Principal Technical Specialist, Pharmacovigilance)
R Pollock (Senior Advisor, Pharmacovigilance)
M Prescott (Advisor Science, Medicines Assessment)

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Dr N Cole and Dr S Jessamine.

1.2 Minutes of the 159th MARC Meeting

The minutes of the 159th meeting were accepted as a true and accurate record of the meeting.

1.3 Potential Conflicts of Interest

Committee members submitted their Conflicts of Interest Declaration forms to the Secretary. The Chair reminded the MARC members that in addition to conflicts disclosed in the declaration forms, members should declare conflicts of interest at the commencement of discussion of any relevant agenda item.

There were no potential conflicts of interest which were considered likely to influence the discussions or decisions of the MARC at this meeting.

[C Frampton, C Ryan and K Wallis joined the meeting at this time.]

2.0 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:

www.medsafe.govt.nz/profs/MARC/Minutes.asp

The Committee was provided with an update on agenda item 3.2.4 from the 158th meeting regarding levonorgestrel emergency contraception and weight based efficacy and agenda item 3.2.2 from the 159th meeting regarding Jadelle implant migration and related complications.

2.2 Medsafe Pharmacovigilance Activities

The Committee noted the report detailing Medsafe's recent pharmacovigilance activities.

2.3 Prescriber Update Volume 35, Number 4, December 2014

The Committee noted the topics to be included in the December 2014 edition of Prescriber Update which included recommendations from the Committee or issues that have been discussed in previous meetings.

2.4 Quarterly Summary of Medsafe Early Warning System

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

3.0 PHARMACOVIGILANCE ISSUES

3.1 Matters Referred to the MARC under Section 36 of the Medicines Act 1981

No items

3.2 Matters Referred to the MARC by Medsafe

3.2.1 Metformin and lactic acidosis

Background

The need for this safety review was identified from:

  • review of the most viewed Prescriber Update articles on the Medsafe website which identified that 'Metformin and Fatal Lactic Acidosis' (Apr 1998) as one of the top three articles
  • feedback from healthcare professionals regarding the contraindication for use of metformin in patients with creatinine clearance <60 ml/min indicates that this is not in line with the current use of metformin.

The purpose of this paper was to review the risk of fatal lactic acidosis associated with metformin use to determine if there is any new, useful information since the last Prescriber Update article that should be communicated to prescribers. In addition the need for the contraindication in renal impairment was reviewed in light of the benefits of metformin.

Discussion

The Committee discussed the pharmacokinetic properties of metformin. The use of population pharmacokinetic studies to develop dosing guidelines was explained to the Committee. The population pharmacokinetic model developed by Duong et al for metformin for various dosing regimens, dose formulations and degrees of renal function was considered to provide high quality evidence for appropriate doses in different degrees of renal impairment.

The Committee discussed whether metformin can induce lactic acidosis and if this is clinically important. The Committee noted that lactic acidosis can be induced with metformin overdose which indicates that the level of exposure is likely to be important. The Committee also noted that this is clinically important due to pharmacokinetic variability between patients and the mortality rate of metformin associated lactic acidosis. Therefore, the Committee were satisfied that metformin can induce lactic acidosis and this is clinically important. The Committee agreed that renal impairment and other conditions reducing tissue perfusion were risk factors for the development of lactic acidosis. The Committee considered the need for stopping metformin prior to and after the use of contrast agents and considered that this contraindication should remain.

The Committee noted that the acute events such as vomiting and diarrhoea could result in lactic acidosis.

Recent analysis of the fatality rate for patients with metformin associated lactic acidosis indicated that the rate had dropped from 50% to around 25%.

Based on the above, the Committee discussed and agreed on the changes that are required to update the metformin product data sheets, including the contraindications for use.

Recommendation 1

The Committee recommended that Medsafe request the sponsors of metformin products to update the data sheets.

Recommendation 2

The Committee recommended that Medsafe updates the 'Metformin and Fatal Lactic Acidosis' Prescriber Update article.

3.2.2 Bromhexine benefits and risks

Background

In 2009, Medsafe reviewed the use of cough and cold medicines in children with the assistance of the Committee and the Cough and Cold Review Group. This Group assessed the available safety and efficacy data to support the use of cough and cold medicines in children. The group considered that the use of cough and cold medicines containing only bromhexine should remain restricted to adults and children two years of age and over.

The purpose of this report was to review the available information on the benefits and risks of bromhexine, with a focus on:

  • allergic reactions, including anaphylactic reactions
  • severe cutaneous adverse reactions (SCARs)
  • use in the paediatric population.

Discussion

The Committee discussed the information that is available for the consumer at the time of purchasing a product containing bromhexine and the availability of other cough and cold medicines for children less than six years of age.

The Committee noted that there is an advisory statement to consult a healthcare professional before using in children aged two years and over which is required on labels for bromhexine containing products. The Committee discussed if this occurs in practice.

The Committee discussed the benefits and risks of harm with bromhexine. The evidence for benefit is weak. The reports of harm are predominantly hypersensitivity reactions.

The Committee agreed that the use of cough and cold medicines containing only bromhexine should be consistent across the available products and be restricted to adults and children six years of age and over.

Recommendation 3

The Committee recommended that the use of cough and cold medicines containing only bromhexine be restricted to adults and children six years of age and over.

Recommendation 4

The Committee recommended that Medsafe issues an alert communication to inform consumers and healthcare professionals on the results of this review.

3.2.3 Review of the early warning system

Background

The trans-Tasman early warning system (EWS) was a joint project between Medsafe and the Therapeutic Goods Administration (TGA) that started in June 2013. At the start of the EWS, Medsafe and the TGA committed to reviewing the system after 12 to 18 months.

There is no standard method for monitoring or investigating the effectiveness of medicine safety communications by regulators. There are two aspects to this topic, firstly, research on how to communicate concepts such as risk benefit effectively and secondly, research on how to measure the effect of communications.

The purpose of this paper was to seek advice from the Committee on the methods that may be useful for this type of investigation and how Medsafe can use these methods.

Discussion

The aims of the EWS were clarified for the Committee. These aims include influencing prescribing behaviour, providing comprehensive information, increasing transparency, to stimulate thought and provide reassurance.

The Committee discussed the various methods available such as surveys, focus groups, warnings and pop-ups in electronic systems such as prescribing software and social marketing. Although most of these methods are simple to conduct and do not require much resource, they are passive and general. The method that is used would need to be selected based on the type of communication that has been issued.

The potential for confirmation bias was noted by the Committee.

The Committee concluded that the EWS is potentially useful for Medsafe to increase transparency and improve the safe use of medicines. However, data are currently insufficient to fully evaluate this.

Recommendation 5

The Committee recommended that Medsafe should have further consideration of the methods to evaluate the effectiveness of the early warning system once additional communications have been issued.

3.2.4 Codeine-containing cough and cold medicines for use in children

Background

The Committee evaluated the use of codeine in children for pain relief in December 2012 and recommended that the use of codeine in children under one year of age be contraindicated in New Zealand due to the lack of evidence to support the safe use in this age group. The data sheet warnings and precautions were also strengthened with regards to CYP2D6 polymorphisms, and general toxicity and overdose information.

In April 2014, the European Medicines Agency's (EMA's) Pharmacovigilance Risk Assessment Committee (PRAC) started a review of codeine-containing medicines when used for cough and cold in children (aged below 18 years), due to concerns of morphine toxicity and respiratory depression.

The purpose of this review was to evaluate the available evidence on the benefit-risk balance of codeine-containing medicines when these medicines are used for cough and cold in children.

Discussion

The Committee was advised on whether codeine is used as a cough suppressant in upper respiratory tract infections in paediatric practice.

The Committee noted that over the counter preparations containing codeine are already restricted for use in children aged 12 years and over. However, the age restriction varies for those products which are prescription-only medicines.

The Committee was advised that the mechanism of action for codeine as a cough suppressant is not fully understood.

The Committee agreed that the use of codeine-containing medicines for cough and cold in children should be restricted to those aged 12 years and over.

Recommendation 6

The Committee recommended that Medsafe request the sponsors of codeine products to update the relevant data sheets.

Recommendation 7

The Committee recommended that Medsafe issues an alert communication to inform consumers and healthcare professionals on the results of this review.

3.2.5 MARC process review

Background

The purpose of this report was to seek input and advice from the Committee about some of its processes, including the availability of information on the Committee through the Medsafe website.

Discussion

The Committee discussed the type of information and level of detail that should be made available on the Medsafe website.

Conflicts of interest forms are submitted for each meeting and declared before the discussion of any relevant agenda item are included in the meeting minutes. The Committee agreed that this could be made more accessible on the Medsafe website.

Recommendation 8

The Committee recommended that the agenda of each meeting and names with a brief profile for each member should be published on the Medsafe website and conflicts of interest made more accessible.

4.0 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

4.1.1 Fatal Cases (Causal Cases Only)

Members were given a brief description of the fatal reports for which CARM had assessed the causality to be at least possible.

The Committee discussed case 113489 involving a patient who was discharged on multiple opiates. The Committee recommended that CARM should refer this case to the Health Quality and Safety Commission (HQSC).

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

4.1.2 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.

4.1.3 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.

4.1.4 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.

4.1.5 Special Reports: Serious Paediatric Adverse Drug Reactions (ADRs)

Key results for 2013 were briefly outlined for the Committee.

5.0 OTHER BUSINESS

5.1 ANZTPA Update

The Committee was advised that the governments in Australia and New Zealand have agreed to cease efforts to establish a joint therapeutic products regulator (ANZTPA).

6.0 ANNEXES

3.2.1 Metformin and lactic acidosis

  1. Metformin and Fatal Lactic Acidosis. 1998. Prescriber Update 16: 22-24.
  2. Duong JK, Kumar SS, Kirkpatrick CM, et al. 2013. Population pharmacokinetics of metformin in healthy subjects and patients with type 2 diabetes mellitus: simulation of doses according to renal function. Clin Pharmacokinet 52: 373-384.
  3. Salpeter SR, Greyber E, Pasternak GA, et al. 2010. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database of Systematic Reviews DOI: 10.1002/14651858.CD002967.pub4.
  4. Van Berlo-van de Laar IRF, Vermeij CG, Doorenbos CJ. 2011. Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration. J Clin Pharm Therap 36: 376-382.
  5. Richy FF, Sabido-Espin M, Guedes S, et al. 2014. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort. Diabetes Care 37: 2291-2295.
  6. Eppenenga WL, Lalmohamed A, Geerts AF, et al. 2014. Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study. Diabetes Care 37: 2218-2224.

3.2.2 Bromhexine benefits and risks

  1. Medsafe. 2009. Use of cough and cold medicines in children - Updated advice. Safety information. October 2009.
  2. European Medicines Agency. 2014. Start of review of ambroxol and bromhexine. 11 April 2014.
  3. Smith SM, Schroeder K, Fahey T. 2012. Over-the-counter (OTC) medications for acute cough in children and adults in ambulatory settings. Cochrane Database of Systematic Reviews DOI:10.1002/14651858/CD001831.pub4.
  4. McNeil Sweden AB. 2014. Referral under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data for ambroxol and bromhexine containing medicinal products - Response document [confidential]. 19 June 2014.
  5. Boehringer Ingelheim. 2014. Response to outstanding issues. 14 October 2014.
  6. Bisolvon data sheet (3 August 2012).

3.2.3 Review of the early warning system

  1. Dusetzina SB, Higashi AS, Dorsey ER, et al. 2012. Impact of FDA drug risk communications on health care utilisation and health behaviors a systematic review. Med Care 50: 466-478.
  2. Ceilley R, Eisenthal BS. 2009. The unintended effects of a boxed warning. J Clin Aesthetic Dermatol 2: 33-39.
  3. Bradford WD, Kleit AN. 2014. Impact of FDA actions, DTCA and public information on the market for pain medication. Health economics DOI: 10.1002/hec.3067.
  4. Du D, Zhour EH, Goldsmith J, et al. 2012. Atomoxetine use during a period of FDA actions. Med Care 50: 987-992
  5. Lu CY, Zhang F, Iakoma MD, et al. 2014. Changes in antidepressant use by young people and suicidal behaviour after FDA warnings and media coverage: quasi-experimental study. BMJ 348: g3596.
  6. Garg V, Raisch DW, McKoy JM, et al. 2013. Impact of United States Food and Drug Administration's boxed warnings on adverse drug reactions reporting rates and risk mitigation for multiple myeloma drugs. Expert opin drug saf 12: 299-307.
  7. Hoffman KB, Demakas AR, Dimbil M, et al. 2014. Stimulated reporting: the impact of US Food and Drug Administration- issued alerts on the Adverse Event Reporting System (FAERS). Drug Saf 37: 971-980.
  8. Hoffman KB, Dimbil M, Erdman CB, et al. 2014. The Weber effect and the United States Food and Drug Administration's Adverse Event Reporting System (FAERS): analysis of sixty-two drugs approved from 2006 to 2010. Drug Safety 37: 283-294.
  9. Chhabra P, Chen X, Weiss SR. 2013. Adverse event reporting patterns of newly approved drugs in the USA in 2006: an analysis of FDA Adverse Event Reporting System data. Drug Safety 36: 1117-1123.
  10. Yong PL, Bigman C, Flynn DN, et al. 2009. Messages about black box warnings. Drug Saf 32: 1147-1157.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 3pm.

Associate Professor D Reith
Chair, Medicines Adverse Reactions Committee

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