Published: 3 October 2014

Committees

Minutes of the 159th Medicines Adverse Reactions Committee Meeting - 11 September 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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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 159th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
11 SEPTEMBER 2014

The one hundred and fifty-ninth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 11 September 2014 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9 am and closed at 3 pm.

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
Dr K Wallis

MARC SECRETARIAT PRESENT

L Chan (MARC Secretary, Medsafe)

MEDSAFE STAFF IN ATTENDANCE

A Govender (Advisor, Pharmacovigilance)
T Ireland (Medical Advisor, Clinical Risk Management)
C James (Manager, Clinical Risk Management)
S Kenyon (Principal Technical Specialist, Pharmacovigilance)
R Pollock (Senior Advisor, Pharmacovigilance)
S Varma (Advisor, Product Safety)
T Wang (Advisor Science, Medicines Assessment)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

Dr A Lala (Advance Trainee, Paediatrics)
Dr R Savage (Senior Medical Assessor, Centre for Adverse Reactions Monitoring)

1 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

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

1.2 Minutes of the 158th MARC Meeting

The minutes of the 158th 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.

Dr S Jayathissa declared that he had a conflict of interest relating to agenda item 5.2 as Chair of PHARMAC’s Pharmacology and Therapeutics Advisory Committee (PTAC). The Committee agreed that Dr Jayathissa’s involvement in this item would be restricted to provision of information at the request of the Committee.

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. The Committee discussed the standing agenda item regarding levonorgestrel emergency contraception and weight-based efficacy from the 158th MARC meeting.

Background information on these issues can be found in the minutes of previous MARC meetings on the Medsafe website:

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

[Assoc Prof C Frampton and Assoc Prof D Menkes joined the meeting at this time.]

2.2 Medsafe Pharmacovigilance Activities

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

The Committee noted that Medsafe has updated data sheets regarding an interaction between methotrexate and proton pump inhibitors.

2.3 Prescriber Update Volume 35, Number 3, September 2014

The Committee noted the latest edition of Prescriber Update. The Committee noted that the titles of the articles were interesting and appropriate.

The Committee discussed the article entitled 'Fake and Adulterated Medicines on the Internet — Operation PANGEA VII' and noted that the process for writing a prescription for a medicine purchased over the internet requires clarification.

*Secretary's note: Medsafe has clarified this process. This process was recently updated to ensure that patients cannot obtain imported unapproved medicines using a prescription written by a prescriber who expected the patient to obtain the product from a licensed pharmacy in New Zealand. Medsafe will now only accept authorisation given by a prescriber when it is written on the form Medsafe sends to the person importing the product. This form provides instructions to both the patient and the prescriber. The form is to be completed by the prescriber who is to return the form directly to Medsafe. A future Prescriber Update article is planned to inform prescribers of what to do when they receive one of these letters.

2.4 Quarterly Summary of Medsafe Early Warning System

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 Testosterone and risk of cardiovascular events

Background

In 2010, the FDA examined cardiovascular risks associated with testosterone therapy after the publication by Basaria et al of adverse event findings from the Testosterone in Older Men with Mobility Limitations (TOM) trial. No regulatory actions were taken by the FDA after the completion of this review due to insufficient evidence.

Subsequently, the publication of an article ‘Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels’ in the Journal of the American Medical Association (JAMA) by Vigen et al received worldwide attention. This has prompted further review by regulatory agencies.

The purpose of this report was to review the available information on cardiovascular risks (myocardial infarction, venous thromboembolism, stroke) associated with the use of testosterone. This report reviewed information available in the literature and information provided by the sponsors of testosterone products in New Zealand.

Discussion

The Committee discussed the three main studies regarding testosterone and risk of cardiovascular events. The TOM trial was stopped early, though it was noted that the adverse event rates reported by Basaria et al were low. Vigen et al employed statistical analysis using greater than 50 variables which is a large number of variables to adjust for. The study by Finkle et al used a comparator group which is questionable and the Committee noted that there is no strong evidence particularly to support the elevated myocardial infarction rates.

The Committee noted that the meta-analyses investigating this risk included small studies some of which were conducted some time ago.

The Committee concluded that based on findings in published literature there is no significant statistical evidence to support an association between testosterone therapy with myocardial infarction, venous thromboembolism, or stroke.

The Committee discussed that the diagnosis of hypogonadism requires both low testosterone blood levels and clinical symptoms of androgen deficiency. Ascertainment of clinical symptoms can be subjective and there is a lack of consensus on the testosterone level threshold that should be used to define testosterone insufficiency.

The Committee noted that as these events had been associated in men abusing testosterone it is possible the risk of cardiovascular events follows a J-shaped curve which is dependent either on testosterone levels or dose of testosterone replacement therapy used.

Recommendation 1

The Committee recommended that Medsafe request the sponsors of testosterone products to update the warnings and precautions section of data sheets.

Recommendation 2

The Committee recommended that Medsafe include an article on the safety of testosterone products in a future edition of Prescriber Update.

Recommendation 3

The Committee recommended that Medsafe communicate with the Best Practice Advocacy Centre (BPAC) requesting that they publish a general article on the appropriate prescribing of testosterone.

3.2.2 Jadelle - Implant migration and related complications

Background

In August 2010, PHARMAC initiated funding of Jadelle. In June 2013, Medsafe published an article in Prescriber Update about removal difficulties with Jadelle. At that point, the Centre for Adverse Reactions Monitoring (CARM) had received 21 reports of location or removal difficulties and exposure was estimated at 38,000 women. CARM continue to receive reports, therefore, Medsafe concluded that further investigation into this issue was warranted.

The purpose of this report was to review the available information on implant migration and related adverse events in patients who have received Jadelle Subcutaneous Implants. The specific adverse events discussed included implant insertion difficulties, implant migration, implant location difficulties, and implant removal difficulties.

Discussion

The Committee discussed possible mechanisms for the migration of Jadelle implants including insertion technique, the effect of subcutaneous fat, and the quality of the device.

The Committee was informed that there is a training programme available for Jadelle insertion and removal. This training is conducted by the sponsor company’s sales representatives. Although there is no requirement for certification, it is recommended that insertion and removal are performed by a trained provider and that enough procedures are undertaken to maintain the skills required.

The Committee discussed if Jadelle implants migrate regardless of insertion technique and if this could be due to an inherent issue with the implants. The Committee was informed that at this point in time, Jadelle implants have not been identified to migrate more or less frequently than previous subcutaneous contraceptive implants.

The Committee discussed the need to establish risk factors for implant migration.

The Committee noted that Jadelle implants are for long-term use of up to five years. As PHARMAC funding for this product began in 2010, there may be a number of removals performed in 2015.

The Committee discussed the incidence of migration in clinical trials compared to the number of spontaneous reports of migration and removal difficulties.

The informed consent process of how patients are informed on the risks of migration and removal difficulties was also discussed by the Committee. It was noted that these risks are covered in the data sheet and consumer medicine information (CMI) for Jadelle and it is assumed that the prescriber informs the patient of these risks during the consultation.

The Committee noted that there are certain prescriber groups such as Family Planning who perform insertions and removals more frequently than other prescribers.

Recommendation 4

The Committee recommended that Medsafe obtains more information on insertion and removal difficulties with Jadelle implants from Family Planning and the product sponsor.

3.2.3 Bromocriptine for treatment of premenstrual syndrome

Background

In December 2013, the Committee examined the benefits and risks of bromocriptine when used for suppression of lactation. At the time of this review, it was noted that bromocriptine was also indicated for treatment of premenstrual symptoms (and mastalgia). Since treatment of premenstrual symptoms is likely to continue for a longer time period than suppression of lactation the safety profile may be different.

Therefore, the purpose of this paper was to review data on the efficacy and safety of bromocriptine when used to treat premenstrual symptoms and mastalgia.

Discussion

The Committee discussed the strength of the evidence for the efficacy of bromocriptine in the use for premenstrual symptoms and mastalgia. The Committee noted there were some small trials that have been conducted, some of which claimed efficacy for some symptoms. However, the Committee did not consider this to be sufficient evidence to recommend bromocriptine use.

There was very little information on the safety of bromocriptine when used for PMS or mastalgia. The main side effects seen in clinical studies were nausea and vomiting. However more recent information has shown that bromocriptine may cause fibrosis and impulse control disorders in patients taking similar doses for other indications.

The Committee discussed whether it was possible to ascertain the indication for use from prescribing data of bromocriptine. The Committee was informed that this information is not collected and therefore it is not known how many women are using bromocriptine for this indication.

Recommendation 5

The Committee recommended that Medsafe request the sponsor of bromocriptine to remove the following indications from the data sheet:

  • Pre-menstrual symptoms:
    Mood disturbances, bloating, cyclical oedema and breast tenderness
  • Benign breast disease:
    Cyclical mastalgia with pre-menstrual syndrome with or without benign nodular or cystic conditions.
Recommendation 6

The Committee recommended that Medsafe communicate with the Best Practice Advocacy Centre (BPAC) requesting that they publish a general article on premenstrual symptoms (PMS) including the role of bromocriptine and its lack of efficacy in treating PMS.

3.2.4 Macrolide antibiotics and DRESS

Background

The April 2014 Canadian Adverse Reaction Newsletter included an article informing readers that Health Canada had received a report of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) suspected to be associated with azithromycin use.

Health Canada also referenced four published papers describing case reports of azithromycin associated DRESS and have advised that due to the seriousness of the condition, they are working with the Canadian sponsor of azithromycin to have the product monograph (data sheet) updated to include information about the risk of DRESS.

Since the possibility exists that this may be a class effect, the purpose of this report was to review the available information on a possible association between macrolides available in New Zealand and DRESS.

Discussion

The Committee discussed whether DRESS occurs as a class effect with all macrolides or is drug-specific. It was noted that the information on DRESS provided in New Zealand macrolide data sheets are varied.

It was noted that Medsafe had previously published a Prescriber Update article on DRESS.

The Committee noted that azithromycin is often prescribed in shorter courses compared to the other macrolides and DRESS usually begins between two weeks and two months of commencing the causal drug.

The Committee considered that there was insufficient evidence to support an association between DRESS syndrome and azithromycin, erythromycin, roxithromycin, or clarithromycin.

Recommendation 7

The Committee recommended that Medsafe communicate with the New Zealand Formulary (NZF) regarding DRESS as a future 'hot topic of the month'.

3.2.5 Oseltamivir (Tamiflu) for influenza

Background

A recently published meta-analysis stimulated media interest in the use of oseltamivir. The media interest was particularly focussed on usefulness of the reserves of oseltamivir held by District Health Boards (DHBs) and the Ministry of Health for use during an influenza pandemic.

The publication of the meta-analysis by Jefferson et al in the British Medical Journal (BMJ) formed the basis of this report. Additional information on efficacy was also provided from other sources for context.

The purpose of this report was to provide the Committee with a summary of information from these published articles.

Discussion

The Committee discussed the meta-analysis by Jefferson et al. It was noted that there were significant limitations to this analysis. Most significantly the authors themselves state that the large amount of data was overwhelming. The analysis was not transparent, for example the inclusion and exclusion criteria for the meta-analysis were not clear.

The Committee noted that the findings from this meta-analysis did not contradict information that is already included in the oseltamivir (Tamiflu) data sheet. In addition, this meta-analysis should be considered in the context of other similar meta-analyses assessing the efficacy and safety of oseltamivir.

The Committee also noted that the meta-analysis on reducing mortality by Muthuri et al showed that neuraminidase inhibitor treatment was associated with reduced mortality in adult patients admitted to hospital.

Overall, the Committee considered that although the benefit is modest, the risk of harm is also modest. The balance of benefits and risks for oseltamivir remains positive.

Recommendation 8

The Committee recommended that no action or advice is required regarding the safety and effectiveness of oseltamivir as a result of the publication of the meta-analysis by Jefferson et al.

4 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 report 112466 involving a patient who was administered tenecteplase in error rather than the recommended alteplase.

Recommendation 9

The Committee recommended that Medsafe include information on this safety concern reported in case 112466 in a future edition of Prescriber Update.

The Committee did not consider any of the other 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 discussed case report 112130 involving a patient who experienced a retroperitoneal haemorrhage and raised INR following a likely interaction between warfarin and roxithromycin.

Recommendation 10

The Committee recommended that Medsafe include an article in a future edition of Prescriber Update regarding interactions between warfarin and macrolides using case 112130 as a case study.

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

5 OTHER BUSINESS

5.1 ANZTPA Update

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

5.2 Benzbromarone

A fatal case from June 2004 was presented to the Committee. This patient was reported to have been taking benzbromarone which was not thought to have contributed towards their death.

The Committee considered that this fatal case was not due to an adverse drug reaction to benzbromarone. The Committee was satisfied that Medsafe is taking appropriate monitoring actions for benzbromarone through the Centre of Adverse Reactions Monitoring (CARM). The Committee recommended that no regulatory action is required from Medsafe. The Committee was satisfied that patients and prescribers are getting adequate information on which to base their decision when prescribing benzbromarone.

The Committee concluded that at this stage, no concerns have been identified relating to the use of benzbromarone in New Zealand.

6 ANNEXES

3.2.1 Testosterone and risk of cardiovascular events

  1. FDA. 2014. FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products. Drug Safety Communications. 31 January 2014.
  2. Health Canada. 2014. Possible cardiovascular problems associated with testosterone products. Information Update. 15 July 2014.
  3. European Medicines Agency. 2014. Review of testosterone-containing medicines started. 11 April 2014.
  4. Basaria S, Coviello AD, Travison TG, et al. 2010. Adverse events associated with testosterone administration. N Engl J Med 363(2): 109–122.
  5. Vigen R, O’Donnell C, Baron, AE, et al. 2013. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 310(17): 1829–1836.
  6. Finkle WD, Greenland S, Ridgeway G, et al. 2014. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 9(1): e85805.
  7. Bayer. 2014. Signal from two publications on testosterone replacement treatment and increased risk of myocardial infarction and stroke [confidential]. 26 March 2014.
  8. Bayer. 2014. Testosterone and venous thromboembolic events (pharmacovigilance expert statement) [confidential]. 16 July 2014.
  9. Merck Research Laboratories. 2014. Response to agency: National New Zealand [confidential]. August 2014.
  10. Pfizer. 2014. Response to New Zealand health authority [confidential]. July 2014.
  11. Reandron data sheet (20 January 2014). Andriol data sheet (8 April 2013). Depo testosterone data sheet (17 August 2006). Sustanon data sheet (21 June 2013). Androderm data sheet (1 July 2013).

3.2.2 Jadelle — Implant migration and related complications

  1. Medsafe. 2014. PSUR summary report. 22 July 2014.
  2. Centre for Adverse Reactions Monitoring. 2014. Reactions reported to CARM [confidential]. 21 July 2014.
  3. Accident Compensation Corporation. 2014. ACC treatment injury — Jadelle contraceptive implants. August 2014.
  4. World Health Organization. 2014. WHO ADR reports.
  5. World Health Organization. 2014. WHO ADR reports.
  6. World Health Organization. 2014. WHO ADR reports.
  7. World Health Organization. 2014. WHO ADR reports.

3.2.3 Bromocriptine for treatment of premenstrual syndrome

  1. Apo-Bromocriptine data sheet (28 April 2014).

3.2.4 Macrolide antibiotics and DRESS

  1. Health Canada. 2014. Azithromycin and drug reaction with eosinophilia and systemic symptoms. Canadian Adverse Reaction Newsletter 24(2): 2–3.
  2. Azithromycin prescribing in New Zealand.
  3. Zithromax data sheet (23 May 2013).
  4. Apo-Azithromycin data sheet (26 August 2010).
  5. Walsh S, Diaz-Cano S, Higgins E, et al. 2013. Drug reaction with eosinophilia and systemic symptoms: is cutaneous phenotype a prognostic marker for outcome? A review of clinicopathological features of 27 cases. Br J Dermatol 168(2): 391–401.
  6. Cascaval RI, Lancaster DJ. 2001. Hypersensitivity syndrome associated with azithromycin. Am J Med 110(4): 330–331.
  7. Pursnani A, Yee H, Slater W, et al. 2009. Hypersensitivity myocarditis associated with azithromycin exposure. Ann Intern Med 150(3): 225–226.
  8. Bauer KA, Brimhall AK, Chang TT. 2011. Drug reaction with eosinophilia and systemic symptoms (DRESS) associated with azithromycin in acute Epstein-Barr virus infection. Pediatr Dermatol 28(6): 741–743.

3.2.5 Oseltamivir (Tamiflu) for influenza

  1. Jefferson T, Jones M, Doshi P, et al. 2014. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 348: g2545.
  2. Jefferson et al. Consort template for clinical study reports.
  3. The Cochrane Collaboration’s tool for assessing risk of bias.

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

Associate Professor D Reith
Chair, Medicines Adverse Reactions Committee

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