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Published: 7 July 2014

Minutes of the 158th Medicines Adverse Reactions Committee Meeting - 12 June 2014


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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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 OF THE 158th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
12 JUNE 2014

The one hundred and fifty-eighth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 12 June 2014 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9am and closed at 3.15pm.

MARC MEMBERS PRESENT

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

MARC SECRETARIAT PRESENT

L Chan (MARC Secretary, Medsafe)

MEDSAFE STAFF IN ATTENDANCE

A Govender (Advisor, Pharmacovigilance)
T Ireland (Medical Advisor, Clinical Risk Management)
R Jaine (Senior Medical Advisor, Clinical Risk Management)
S Kenyon (Principal Technical Specialist, Pharmacovigilance)
R Pollock (Advisor, Pharmacovigilance)
E Yousuf (Principal Clinical Advisor)

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

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

1.2 Minutes of the 157th MARC Meeting

The minutes of the 157th 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.

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.

Link to minutes of previous MARC meetings

2.2 Medsafe Pharmacovigilance Activities

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

2.3 Prescriber Update Volume 35, Number 2, June 2014

The Committee noted the latest edition of Prescriber Update. The Committee noted that the information provided is very succinct and well written. Ways in which to increase the uptake of Prescriber Update were discussed including using the publication in an educational role with medical students and postgraduate pharmacists.

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

3.1.1 Consideration of hydroxyethyl starch (HES) containing medicines under section 36 of the Medicines Act 1981

Background

The Medicines Adverse Reactions Committee (MARC) first reviewed the safety of hydroxyethyl starch at the 155th meeting in September 2013. At this time, the European Pharmacovigilance Risk Assessment Committee (PRAC) had recommended that products containing hydroxyethyl starch be suspended as the PRAC considered that the benefits did not outweigh the risks of harm.

The Committee considered at the 155th meeting that the available data were insufficient to make a firm conclusion on the benefits and risks of hydroxyethyl starch products. The Committee recommended that section 36 notices be issued to sponsors of hydroxyethyl starch containing medicines.

Following the receipt of section 36 notices by the New Zealand sponsors, two products remain on the market, Voluven and Volulyte. The remainder of the products were voluntarily withdrawn from the New Zealand market by the sponsors.

The purpose of this paper is to review the data provided by the sponsor in response to the section 36 notice.

The Committee was asked to advise on the balance of benefits and risks of harm for Voluven and Volulyte in:

The Committee was requested to make a recommendation, based on their assessment of the balance of benefits and risks, on the regulatory actions that are warranted.

The Committee could also suggest further risk mitigating strategies and advise on a communication plan.

Discussion

HiView3 is a computer modelling program that supports the appraisal and evaluation of different options helping to identify decisions. This program was used to help display the relevant effects of hydroxyethyl starch in a manner to help decision making. The use of this program was explained to the Committee.

The Committee discussed the methodology of the computer modelling being used to analyse the data.

The Committee were reminded that in order to manage risks, the use of hydroxyethyl starch has been contraindicated in patients with sepsis and is to be used as second line treatment in critically ill patients. In addition, more information has been added to the data sheet on the use of hydroxyethyl starch in patients with renal failure.

The Committee compared the risk-benefit balance for hydroxyethyl starch and crystalloid solutions (such as normal saline) in the different patient groups. 

Using the computer modelling to assist in the assessment of the risk-benefit balance, it appeared that the benefits and risks for both hydroxyethyl starch and crystalloid use in patients with sepsis and critically ill patients were very similar.  For surgical patients, hydroxyethyl starch appeared to have a better risk benefit profile than crystalloid. The Committee discussed why the risk-benefit balance differs between the different groups of patients. This could be due to differences in the physiology of critically ill patients compared with elective surgery patients, or the differences in the conduct of the clinical trials in the different patient groups.

The Committee noted methodological problems in the study conducted in critically ill patients which limit the conclusions which can be drawn from this study.

The Committee discussed how hydroxyethyl products are used in hospitals and whether there are local procedures around its use.

Regulatory actions taken by the European Medicines Agency (EMA), U.S. Food and Drug Administration (FDA) and Health Canada were also noted.

Recommendation 1

The Committee recommended that no further regulatory action is required to further restrict the use of hydroxyethyl starch in patients with sepsis, critically ill patients and surgical patients.

Recommendation 2

The Committee recommended that although hydroxyethyl starch is classified as a general sale medicine, Medsafe should impose a condition that data sheets are compulsory for all hydroxyethyl starch products.

Recommendation 3

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

Recommendation 4

The Committee recommended that Medsafe directly communicates the alert communication to the Australian and New Zealand College of Anaesthetists (ANZCA) and the College of Intensive Care Medicine of Australia and New Zealand.

3.2 Matters Referred to the MARC by Medsafe

3.2.1 Methylphenidate and risk of long-lasting erections

Background

On 17 December 2013, The U.S. Food and Drug Administration (FDA) issued a drug safety communication warning of the rare risk of long-lasting erections in males taking methylphenidate for attention deficit hyperactivity disorder (ADHD). The FDA has updated the drug labels (equivalent to the New Zealand data sheet) and patient medication guides for methylphenidate to include information on this risk.

The sponsors of Concerta and Ritalin were requested to provide Medsafe with a copy of their review on this issue.

The purpose of this paper is to review the available information on the risk of long-lasting erections with methylphenidate.

Discussion

The Committee noted that the number of reported cases of long-lasting erections with methylphenidate is limited. However, the Committee also noted that while this appears to be a very rare reaction, it is likely to be underreported.

The Committee discussed the possible mechanism for this reaction, including the role of dopamine and noradrenaline. The mechanism is complex as demonstrated by the case reports where the presence of methylphenidate or the withdrawal of methylphenidate could both cause a long-lasting erection.

The Committee was informed that the sponsor of Concerta has updated their data sheet to include information on long-lasting erections.

Recommendation 5

The Committee recommended that Medsafe request the sponsors of Ritalin and Rubifen to update the warnings and precautions section of data sheets to include class wording on the risk of priapism.

Recommendation 6

The Committee recommended that Medsafe request the sponsors of Ritalin and Rubifen to update the consumer medicine information (CMI) to include wording on seeking immediate medical attention if prolonged and painful erections develop.

Recommendation 7

The Committee recommended that Medsafe communicates this to healthcare professionals by including a general article on priapism in a future edition of Prescriber Update.

3.2.2 Benefit risk review of strontium ranelate (Protos)

Background

A recent European benefit risk review of strontium ranelate was triggered by data submitted as part of the routine benefit-risk assessment of the Periodic Safety Update Report (PSUR) covering the period 22 September 2011 to 21 September 2012.

The relevant safety concerns for strontium are the risks of serious skin disorders (drug rash with eosinophilia and systemic symptoms: DRESS), serious cardiac disorders and venous thrombotic events.

As a result of this review further restrictions were placed on the use of strontium in Europe.

The purpose of this paper is to review the benefits and risks of treatment with strontium ranelate.

Discussion

The Committee discussed the available data on the efficacy of strontium ranelate and its place in the treatment of osteoporosis. It was noted that in New Zealand, the use of strontium ranelate is as a third line agent after dietary and lifestyle measures and the use of bisphosphonates.  

It was noted that the available efficacy data suggests that strontium may be more effective than other medicines used for osteoporosis, but that the quantity of data was limited in comparison to that available for bisphosphonates.

The safety concerns of venous thromboembolism and serious adverse cardiac effects were identified after review of the pooled randomised controlled trial data. However investigation of these safety concerns using observational methods has not confirmed an association with strontium ranelate treatment.

The Committee was informed that a boxed warning has been added to the Protos data sheet which restricts strontium ranelate to only be used when other medicines for the treatment of osteoporosis are considered unsuitable.

Overall the Committee noted that the balance of benefits and risks of harm was favourable for patients with osteoporosis treated with strontium. The restrictions (contraindications and warnings) regarding use should be effective in reducing the risks of harm, if these are adhered to.

The Committee noted that strontium ranelate is not funded by PHARMAC which as a consequence means that it is not widely used.

The Committee concluded that no further regulatory action is required.

Recommendation 8

The Committee recommended that the balance of benefits and risks for use of strontium ranelate in women with osteoporosis and in line with the data sheet recommendations is favourable.

Recommendation 9

The Committee recommended that no further regulatory action is required to improve the balance of benefits and risks.

3.2.3 Domperidone benefit-risk review

Background

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) recently completed a safety review of domperidone-containing medicines. This review was carried out due to concerns about domperidone’s effects on the heart including QT prolongation, arrhythmias and the risk of sudden cardiac death.

The PRAC recommended that domperidone-containing medicines should be restricted to the management of nausea and vomiting symptoms only. The recommended dose should also be restricted to a maximum of 30 mg daily and duration restricted to a maximum of one week.

In March 2014, Medsafe issued a monitoring communication to inform consumers and healthcare professionals that this safety concern is being reviewed.

The purpose of this paper is to inform the Committee of the benefits and risks of domperidone and for the Committee to determine if any further action is required in light of the recommendations from the PRAC.

Discussion

The Committee was presented with data on efficacy and safety for several different indications in adults and children.

The Committee noted that the thorough QT study did not investigate doses above the current recommended dose of 80 mg/day. Extrapolation of the data above 80 mg/day would require an assumption that there is a linear relationship between area under the curve (AUC) and QT prolongation.

The Committee discussed whether ECG monitoring should be conducted for those patients at high risk of developing QT prolongation. The use of domperidone in this population is contraindicated, therefore ECG monitoring is not required by default. However, this could be presented more succinctly in the data sheet.

The Committee discussed the use of domperidone in the paediatric population where it is used predominantly in children with gut motility disorders and nausea and vomiting. Domperidone is not commonly used in children with symptoms of gastro-oesophageal reflux disease (GORD) where there is limited evidence for its use. The main adverse effects in the paediatric population relate to nervous system disorders including extrapyramidal effects which are covered in the data sheet.

The Committee noted that the paediatric doses recommended for domperidone in the New Zealand Formulary for Children (NZFC) are lower than what is currently recommended in the New Zealand data sheets. The lowest effective dose should be used in both adults and children, which is then increased as necessary.

The Committee noted that the off-label use of domperidone as a galactagogue is increasing.

The Committee noted that the European Medicines Agency (EMA) has restricted the duration of treatment with domperidone to a maximum of one week. However, the data do not appear to support an increased risk of sudden cardiac death with increasing length of treatment. In addition, because domperidone does not accumulate in the body, long-term use would not be associated with increasing plasma concentrations.

Recommendation 10

The Committee recommended that Medsafe request the sponsors of domperidone to update the indications, contraindications and warnings and precautions sections of the data sheets.

Recommendation 11

The Committee recommended that Medsafe request the sponsors of domperidone to update the data sheets with a reduced recommended daily dose for use in children.

Recommendation 12

The Committee recommended that Medsafe communicates the results of this review to healthcare professionals by including an article on domperidone in a future edition of Prescriber Update.

Recommendation 13

The Committee recommended that Medsafe communicates the results of this review directly to nurses and midwives through the New Zealand Nurses Organisation (NZNO) and New Zealand College of Midwives.

3.2.4 Levonorgestrel emergency contraception and weight-based efficacy

Background

Recent publications have indicated that levonorgestrel (1.5 mg) may not be effective as an emergency contraceptive for women who weigh more than 70 kg.

This safety concern originated from a meta-analysis of two randomised controlled trials sponsored by HRA Pharma, which compared the efficacy of levonorgestrel with ulipristal acetate for emergency contraception. HRA Pharma is the manufacturer of NorLevo, an emergency contraceptive medicine containing levonorgestrel. Neither NorLevo nor ulipristal containing medicines are available in New Zealand.

Medsafe in conjunction with the Therapeutics Goods Administration (TGA) issued a joint monitoring communication in February 2014 to inform consumers and healthcare professionals that this safety concern is being reviewed.

The purpose of this paper is to review the use of levonorgestrel (1.5 mg) and weight-based efficacy when used for emergency contraception.

Discussion

The Committee noted that the two randomised controlled trials were designed to compare the efficacy of levonorgestrel with ulipristal acetate, and were not initially designed to examine the effect of body weight on the effectiveness of emergency contraception. This is an important limitation.

The Committee noted that the data for the weight threshold where efficacy is reduced is limited.

The Committee discussed the pharmacokinetic and pharmacodynamic relationship between dose and effect. This relationship is not well defined.  The evidence for a decrease in efficacy in heavier women is sparse.  However, the Committee considered that women should be warned about a possible lack of effect.  The Committee noted the lack of information on effectiveness of higher doses of levonorgestrel in heavier women, and the potential usefulness of approaching the sponsor to examine this possibility.

The Committee noted that irrespective of weight, levonorgestrel may not prevent pregnancy in every case. However, it has good user acceptability and a favourable adverse effect profile compared to the available alternatives.

The Committee discussed how women should be informed that levonorgestrel may not be effective for women who weigh more than 70 kg. This should be verbally communicated by the prescriber during the consultation and there must be clear written information available.

Recommendation 14

The Committee recommended that Medsafe request the sponsors of emergency contraceptives containing levonorgestrel to update the data sheets to include information on weight-based efficacy.

Recommendation 15

The Committee recommended that Medsafe request the sponsors of emergency contraceptives containing levonorgestrel to update the consumer medicine information (CMI) to include information on weight-based efficacy.

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 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: Annual Review Fatal Cases (January 2013 – December 2013)

The annual review of fatal cases was briefly outlined for the Committee.

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

5.0 OTHER BUSINESS

5.1 ANZTPA Update

The Committee was advised of the progress of the ANZTPA Project to date.

5.2 New section on Medsafe website

The Committee was advised of a new ‘Dear Healthcare Professional Letters’ section on the Medsafe website.

Link to Dear Healthcare Professional Letters 

5.3 Relocation of Medsafe premises

The Committee was advised that Medsafe will be moving to temporary premises at the end of 2014 as part of the Ministry of Health’s initiative to have all Wellington offices in one location in 2017.

6.0 ANNEXES

3.1.1 Consideration of hydroxyethyl starch (HES) containing medicines under section 36 of the Medicines Act 1981

  1. Fresenius Kabi. Response to Medsafe New Zealand Section 36 Medicines Act 1981 Notice in relation to hydroxyethyl starch products [confidential].
  2. Minutes of agenda item 3.2.1 of the 155th MARC meeting. 12 September 2013.
  3. PrOACT-URL framework.
  4. Guidet B, Martinet O, Boulain T, et al. 2012. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Critical Care 16: R94.
  5. Annane D, Siami S, Jaber S, et al. 2013. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: The CRISTAL randomised trial. JAMA 310(17): 1809–1817.
  6. Myburgh J, Finfer S, Bellomo R, et al. 2012. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. NEJM 367: 1901–11.
  7. M.A.R.C.O. 2013. Systematic review and meta-analysis to compare hydroxyethyl starches with other volume expanders in cardiac surgery. 10 October 2013.
  8. Letters from the CHEST investigators to the company
  9. Voluven data sheet with tracked changes (7 May 2014)
  10. The SAFE study investigators. 2004. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. NEJM 350: 2247–56.

3.2.1 Methylphenidate and risk of long-lasting erections

  1. Janssen Research & Development. 2014. Clinical overview methylphenidate hydrochloride (Concerta) [confidential]. Update to the product information regarding alcohol effect, DSM criteria, priapism, libido disorder, libido decreased, and treatment of overdose. 31 January 2014.
  2. Concerta data sheet (11 April 2014).
  3. Novartis. 2014. Novartis’ response to Australian Therapeutics Goods Administration (TGA) request for information [confidential]. 13 March 2014.
  4. Ritalin FDA drug label (December 2013).
  5. Ritalin data sheet (31 January 2014).
  6. FDA. 2013. FDA warns of rare risk of long-lasting erections in males taking methylphenidate ADHD medications and has approved label changes. Drug Safety Communications. 17 December 2013.

3.2.2 Benefit risk review of strontium ranelate (Protos)

  1. Servier. 2013. Answers to the PRAC list of questions (strontium ranelate) [confidential]. June 2013.
  2. PrOACT-URL framework.
  3. Meunier PJ, Roux C, Ortolani S, et al. 2009. Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis. Osteoporos Int 20: 1663–1673.
  4. Reginster J, Felsenberg D, Boonen S, et al. 2008. Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis. Arthritis & Rheumatism 58(6): 1687–1695
  5. Cacoub P, Descamps V, Meyer O, et al. 2013. Drug rash with eosinophilia and systemic symptoms (DRESS) in patients receiving strontium ranelate. Osteoporos Int 24: 1751–1757.
  6. Breart G, Cooper C, Meyer O, et al. 2010. Osteoporosis and venous thromboembolism: a retrospective cohort study in the UK general practice research database. Osteoporos Int 21: 1181–1187.
  7. Cooper C, Fox KM, Borer JS. 2014. Ischaemic cardiac events and use of strontium ranelate in postmenopausal osteoporosis: a nested case-control study in the CPRD. Osteoporos Int 25: 737–745.
  8. Svanström H, Pasternak B, Hviid A. 2014. Use of strontium ranelate and risk of acute coronary syndrome: cohort study. Ann Rheum Dis 73: 1037–1043.
  9. Abrahamsen B, Grove EL, Vestergaard P. 2014. Osteoporos Int 25: 757–762.
  10. Protos data sheet (2 April 2014).

3.2.3 Domperidone benefit-risk review

  1. European Medicines Agency. 2014. PRAC recommends restricting use of domperidone. Benefits still considered to outweigh risks when given short-term and in low doses to treat nausea or vomiting. 7 March 2014.
  2. Medsafe. 2014. Drug induced QT prolongation and Torsades de Pointes.
  3. Motilium data sheet (24 December 2013). Prokinex data sheet (5 October 2012).
  4. Janssen Research & Development. 2013. Response to European Medicines Agency (domperidone) [confidential]. 30 September 2013.
  5. Janssen Research & Development. 2014. Response to European Medicines Agency (domperidone) [confidential]. 27 January 2014.
  6. Janssen Research & Development. 2013. Response to European Medicines Agency (domperidone) [confidential]. 25 April 2013.

3.2.4 Levonorgestrel emergency contraception and weight-based efficacy

  1. Medsafe. 2014. Effectiveness of emergency contraception may be reduced in women weighing more than 70kg. Medsafe Monitoring Communication. 27 February 2014.
  2. Glasier A, Cameron ST, Blithe D, et al. 2011. Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomised trials of ulipristal acetate and levonorgestrel. Contraception 84: 363–367.
  3. HRA Pharma. 2012. Effect of the weight on the efficacy of levonorgestrel as an emergency contraceptive. Statistical report. November 2012.
  4. Health Canada. 2014. Emergency contraceptive pills to carry warnings for reduced effectiveness in women over a certain body weight. Recalls & Alerts. 26 March 2014.
  5. European Medicines Agency. 2014. Review of emergency contraceptives started. Press release. 24 January 2014.
  6. Family Planning. 2014. Emergency contraception — a weighty issue. Forum. March 2014.

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 3.15pm.

Associate Professor D Reith
Chair, Medicines Adverse Reactions Committee

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