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Committees

Published: 23 December 2013

Minutes of the 156th Medicines Adverse Reactions Committee Meeting - 5 December 2013

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

MEDSAFE STAFF IN ATTENDANCE

1. MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies
1.2 Minutes of the 155th MARC Meeting
1.3 Potential Conflicts of Interest

2. MEDSAFE PHARMACOVIGILANCE ACTIVTIES

2.1 Report on Standing Agenda Items from Previous Meetings of the MARC
2.1.1 Calcium supplements and cardiovascular events
2.2 Medsafe Pharmacovigilance Activities
2.3 Prescriber Update Volume 34, Number 4, December 2013
2.4 Quarterly Summary of Medsafe Early Warning System

3 PHARMACOVIGILANCE ISSUES

3.1 Matters Referred to the MARC under Section 36 of the Medicines Act 1981.
3.2 Matters Referred to the MARC by Medsafe.
3.2.1 Use of proton pump inhibitors and risk of adverse cardiovascular outcomes.
3.2.2 Risk-benefit review of bromocriptine.
3.2.3 Spiriva (tiotropium) Respimat update.
3.2.4 Short acting beta agonists in the treatment of premature labour – do the benefits outweigh the risks?.

4. MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports.

4.1.1 Potential Safety Signals from Single Case Reports
4.1.2 Fatal Cases (Causal Cases Only)
4.1.3 Special Populations: Serious Cases Associated with Medicines in Children under 18 years (Causal Cases Only)
4.1.4 Special Populations: Serious Cases Reporting Adverse Events Following Immunisation Terms with Vaccines in Children under 18 years
4.1.5 Special Populations: Serious Non-Fatal Cases Causally Associated with Critical Terms in Patients Over 80 Years

5. OTHER BUSINESS

5.1 Continuing Education
5.2 ANZTPA Update
5.3 Other Publications of Interest
5.4 Dates of Future MARC Meetings

6. ANNEXES

3.2.1 Use of proton pump inhibitors and risk of adverse cardiovascular outcomes
3.2.2 Risk-benefit review of bromocriptine
3.2.3 Spiriva (tiotropium) Respimat update
3.2.4 Short acting beta agonists in the treatment or premature labour – do the benefits outweigh the risks?

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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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 156th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
5 DECEMBER 2013

The one hundred and fifty-sixth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 5 December 2013 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9.05 am and closed at 2:35 pm.

MARC MEMBERS PRESENT

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

MARC SECRETARIAT PRESENT

N Sharpe (Acting MARC Secretary, Medsafe)

MEDSAFE STAFF IN ATTENDANCE

M Bonne (Medical Advisor, Clinical Risk Management)
R Jaine (Senior Medical Advisor, Clinical Risk Management)
C James (Manager, Clinical Risk Management)
S Kenyon (Principal Technical Specialist, Pharmacovigilance)
R Pollock (Advisor, Pharmacovigilance)
A Taylor (Senior Advisor, Pharmacovigilance)
E Yousuf (Principal Clinical Advisor)

1. MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Associate Professor P Jones.

1.2 Minutes of the 155th MARC Meeting

The minutes of the 155th 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. 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.

2.1.1 Calcium supplements and cardiovascular events
September 2013 minute item 3.2.4

Recommendation 5

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

Outcome

A response letter was sent to the authors on 4 October 2013.

A letter in response to the MARC letter was received from Andrew Grey and Mark Bolland on 19 November 2013 (see section 2.2.1).

Recommendation 6

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

Outcome

The article will be published in the December 2013 edition of Prescriber Update.

Discussion

The Committee noted the letter received from Andrew Grey and Mark Bolland on 19 November 2013. The Committed considered that there was no need to further address the matter unless new data becomes available and Medsafe refers the matter back to the MARC for review.

There were no other standing agenda items for which the MARC made further recommendations.

[Dr L Bryant 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 had updated the data sheets for Simvastatin and Amiodarone in response to reports that the co-administration of Simvastatin and Amiodarone increased the plasma concentrations of Simvastatin. The Committee considered this to be an important interaction which should be further investigated in relation to other statins.

Recommendation 1

The MARC advised Medsafe to investigate the issue and consider whether a Prescriber Update article was warranted.

[Associate Professor C Frampton joined the meeting at this time.]

2.3 Prescriber Update Volume 34, Number 4, December 2013

The Committee noted the latest edition of Prescriber Update. The Committee noted they were very impressed with the quality of the publication.

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 Use of proton pump inhibitors and risk of adverse cardiovascular outcomes

Background

There have been a number of recent publications investigating a possible association between proton pump inhibitors (PPIs) and adverse cardiovascular events. These publications focus not only on the interaction between clopidogrel and PPIs but also discuss the possibility of an interaction between PPIs and aspirin and direct effects of PPIs.

The interaction between clopidrogrel and PPIs (particularly omeprazole) was discussed at the 143rd meeting of the MARC following warnings issued by the FDA. At that point there was little to no information on the clinical significance of the proposed interaction between clopidogrel and omeprazole or whether the interaction extended to all PPIs.

The purpose of this paper was to update the MARC on data regarding the clinical significance of the interaction between clopidogrel and PPIs. In addition data on a possible interaction with aspirin and evidence for direct effects of PPIs were reviewed.

The Committee was asked to advise whether:

Discussion

The Committee noted the 2013 report provided by Medsafe which summarised recent meta-analyses and systemic reviews.

The Committee was advised that since the MARC reviewed the initial data on the interaction between PPIs and clopidogrel a large number of clinical studies have been published. These studies include randomised studies investigating platelet aggregation ex vivo in both healthy volunteers and patients, observational studies and a randomised controlled trial. The Committee noted that for brevity, the studies in the Medsafe report included mainly published meta-analyses and systematic reviews.

The meta-analyses of studies measuring the reactivity of platelets ex vivo in patients and healthy volunteers showed that PPIs adversely affected biomarkers of clopidogrel effect. However this has not translated into a clear cut effect on clinical outcomes such as major adverse cardiac events (MACE) outcomes, myocardial infarction (MI), or all-cause mortality.

The Committee noted a study by Douglas et al comparing different analysis methods. An increase in adverse cardiovascular outcomes was noted using a cohort analysis but not using a self-controlled case analysis. Analysis using the cohort method found that the outcome was not specific as there was an increase in non-vascular mortality as well as cardiac mortality. The effect of concomitant use of non-CYP2C19 inhibiting medicines had the same effect as use of CYP2C19 inhibitors. The Committee agreed that this analysis indicated that patients taking PPIs had more comorbidities which were not fully adjusted for by a cohort analysis.

The Committee was advised that there are several limitations noted with the outcomes in these meta-analyses. Where an increase in risk was identified from a meta-analysis it was small, around 40% increase (OR/HR 1.4). No clear difference was found between different PPIs despite differences in their in vitro ability to inhibit CYP2C19. In some analyses the increase in risk of adverse cardiovascular outcomes was only found in patients taking PPIs who were at high risk of these events; no increased risk was found in low risk patients taking PPIs. The Committee discussed whether patients should be screened for CYP2C19 polymorphism and this may be more important than any potential interaction with PPIs.

The Committee discussed additional limitations of the studies including systematic biases. Patients taking PPIs were older, more likely to have heart failure, renal failure, diabetes mellitus, dyslipidemia, history of MI and peripheral vascular disease. These important confounding factors cannot be completely eliminated with the aid of multivariable analysis. Many potential confounding factors such as smoking status, hypertension, family history were not considered in the studies.

The Committee was advised that the COGENT study was a randomised controlled clinical trial on this topic. It showed no clinical evidence of a PPI-clopidogrel interaction but the result is not definitive due to premature termination due to lack of funding.

The Committee noted that the weight of the available data on a potential interaction between PPIs and aspirin shows that there is no relevant clinical effect. The same problems with bias found above exist when investigating this effect in observational studies.

The Committee noted that the data on direct effects appear to be measuring the amount of confounding in the study rather than a direct adverse effect.

The Committee discussed the possibility that the administration of any gastroprotective medicine is more common in patients at higher baseline cardiovascular risk. Therefore PPI use is likely to be a marker of cardiovascular risk rather than a causal factor. There may also be a level of confounding by indication, as MACE may present as epigastric pain and mimic gastrointestinal complaints.

Recommendation 2

The Committee recommended that whilst there is evidence that proton pump inhibitors affect clopidogrel activity ex vivo, the available evidence suggests that this does not translate into adverse clinical outcomes. The Committee observed that available data indicates that patients who take PPIs have a greater number of co-morbidities that may predispose them to cardiovascular endpoints.

Recommendation 3

The Committee recommended that based on the evidence presented, there is no increased risk of adverse cardiovascular outcomes when PPIs are used with aspirin.

Recommendation 4

The Committee recommended that the evidence did not show that PPIs directly cause adverse cardiovascular outcomes.

Recommendation 5

The Committee recommended that no further communication, other than in MARC's remarks in the Prescriber Update, was required.

3.2.2 Risk-benefit review of bromocriptine

Background

In September 2013, the European Medicines Agency (EMA) started a review of bromocriptine-containing medicines when taken by mouth for preventing or suppressing lactation in women following childbirth. The review of bromocriptine was requested by the French medicines agency following concern over rare but potentially serious or fatal side effects. This includes cardiovascular side effects (such as heart attack and stroke), neurological side effects (such as seizures), and psychiatric side effects (such as hallucinations and manic episodes). The main concern from the French medicines agency was that lactation is a natural process that eventually stops if the infant is not breastfed, there are other authorised products available if there is a need to suppress lactation, and therefore the risk of serious side effects are not acceptable.

This report provided the Committee with a summary of the available information on the benefits and risks of bromocriptine, when used to prevent or suppress lactation. The review did not address the use of bromocriptine for other indications.

The Committee was asked to advise whether:

Discussion

The Committee noted the 2013 Medsafe report, which included a review of usage figures, systemic reviews, case reports, and other studies for the use of bromocriptine for lactation suppression.

The Committee reviewed usage figures for bromocriptine and cabergoline in New Zealand from 2009-2010 until 2012-2013. The use of bromocriptine has reduced by approximately 30% over the past 4 years, whilst the use of cabergoline has remained stable. The Committee noted that usage figures could not be separated by indication or by single or repeat therapy.

Medsafe advised the Committee they were awaiting responses from the Royal Australian and New Zealand College of Obstetricians and Gynaecologists and the New Zealand College of Midwives on the current guidelines regarding the use of bromocriptine, cabergoline, or other treatments for lactation suppression. The Committee noted that contact with the Royal New Zealand College of General Practitioners may also be useful.

The Committee noted that literature reporting on the efficacy and adverse reactions of bromocriptine is limited but shows that bromocriptine is effective for lactation suppression and only minor adverse effects have been reported. The Committee noted that case reports for the adverse reactions of concern were also presented.

Medsafe advised that the datasheets for bromocriptine appropriately outline the risks of the serious, but rare adverse reactions of concern.

The Committee noted that cabergoline has similar efficacy to bromocriptine for the suppression of lactation and is associated with better compliance as it is administered as a single one-off dose and also has a better tolerability profile.

The Committee discussed non-pharmacological methods for suppression of lactation as well as no treatment. The Committee noted that psychological support and monitoring is an important component in the care of women who have experienced still birth or abortion. Although there is the risk of rare, but serious adverse effects associated with the use of bromocriptine, the Committee agreed that on balance, bromocriptine should remain an available option for the treatment of lactation suppression.

Recommendation 6

The Committee recommended that bromocriptine should be restricted to second-line therapy for the suppression of lactation.

Recommendation 7

The Committee recommended that bromocriptine use should not be restricted to after stillbirth or abortion and that the postpartum lactation indication should not be removed. The Committee accepted that there will be some women who have not had a still birth or abortion who may still require pharmacological treatment for the suppression of lactation.

Recommendation 8

The Committee recommended that communication regarding the recommendations should be decided after Medsafe has reviewed the responses from the College of Royal Australian and New Zealand College of Obstetricians and Gynaecologists and New Zealand College of Midwives.

3.2.3 Spiriva (tiotropium) Respimat update

Background

This report provided the Committee with a further update regarding concerns about the risk of mortality with Spiriva (tiotropium) - in particular, the Respimat device. The MARC last reviewed Spiriva in March 2013 following the publication of two editorials calling for the withdrawal of the tiotropium Respimat soft mist inhaler (SMI).

At the March 2013 MARC meeting it was noted that the sponsor (Boehringer Ingelheim) was conducting a large trial (TIOSPIR), designed to address the mortality imbalance between tiotropium Respimat and Handihaler. The results of the TIOSPIR trial have now been published.

This report also summarised three pharmacokinetic (PK) studies that have compared the PK data of Handihaler and Respimat.

The Committee was asked to advise whether:

Discussion

The Committee noted the 2013 Medsafe report.

The Committee reviewed the pharmacokinetic studies comparing the Handihaler and Respimat devices. The studies have produced varying results when comparing the PK values of 5 mcg (via Respimat) and 18 mcg (via Handihaler). The AUC and Cmax ratios for the two doses range from 78% to 135%. Overall, there is no consistent picture of either higher or lower exposure when comparing the devices at the approved doses.

The Committee was advised that since the March 2013 MARC Report, the results of the TIOSPIR trial have been published.

The Committee reviewed results of the TIOSPIR study. TIOSPIR is a randomised, double-blind, parallel group trial conducted by the sponsor Boehringer Ingelheim designed to evaluate the safety and efficacy of tiotropium Respimat compared to Handihaler. The study found that Respimat (at either 2.5 mcg daily or 5 mcg daily) was non-inferior to Handihaler (18 mcg daily) with regards to risk of death. Respimat was also not associated with a greater risk of COPD exacerbation compared to Handihaler. Medsafe considers that these results show that the risk benefit remains positive at the licenced dosage.

The Committee noted that the TIOSPIR study is very well-designed. The Committee discussed whether the benefit:risk profile had changed in light of the results of this study.

The Committee noted that Respimat remains approved but not marketed in New Zealand. Only the Handihaler is funded in New Zealand. Whilst Medsafe is unaware of the future marketing plans for Respimat, the Committee was advised that an application has recently been received by Medsafe for the addition of another proposed indication for Spiriva Respimat as add-on maintenance treatment for the improvement of asthma symptoms. The application is currently under review.

The Committee discussed communicating the decision to Pharmac and noted the importance of being aware of the activities of the Pharmac Pharmacology and Therapeutics Advisory Committee (PTAC) regarding products being reviewed by PTAC and products that are coming up for funding. Medsafe will contact Pharmac to obtain PTAC meeting minutes.

Recommendation 9

Having reviewed the TIOSPIR Study, the Committee is reassured that there is no evidence of increased mortality for the Respimat device compared with the Handihaler device when used at the approved doses.

Recommendation 10

The Committee recommended that Medsafe directly communicate this decision to Pharmac in the form of a short letter.

3.2.4 Short acting beta agonists in the treatment of premature labour - do the benefits outweigh the risks?

Background

On 6 September 2013, the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) completed a review of the benefit-risk balance for the use of short-acting beta agonists (hexoprenaline, fenoterol, ritodrine, salbutamol, terbutaline and isoxsuprine) for obstetric indications.

The PRAC concluded that the benefits of intravenous SABA formulations continue to outweigh the risks of treatment in the majority of patients when used for the short-term management of uncomplicated tocolysis. However the PRAC recommended that SABAs should be contraindicated in patients with pre-existing ischaemic heart disease or those patients with significant risk factors for ischaemic heart disease and in patients with threatened abortion during the first and second trimester of gestation. The PRAC recommended that all patients receiving intravenous SABAs these parenteral medicinal products the blood pressure and heart rate, electrolyte and fluid balance, glucose and lactate levels and potassium levels should be monitored throughout treatment.

The PRAC concluded that for the oral and suppositories formulations, in view of the identified risks of serious cardiovascular events, and very limited efficacy data, that the benefit-risk balance is not favourable and therefore these medicinal products should no longer be approved for use in any obstetric indications.

Preterm labour (PTL) is defined as the onset of labour between 20 and 37 weeks completed gestation (with gestational age being defined as the number of completed weeks since the first day of the last menstrual period). The available data indicates that <10% of women who present with PTL will give birth within 7 days of presentation, and 50% of women hospitalised for PTL give birth at term. PTB is the major cause of neonatal morbidity and mortality and is responsible for 75-90% of all neonatal deaths not due to lethal congenital malformations, and 50% of childhood neurological disabilities. The rationale for treatment of PTL is to improve neonatal outcomes. It is estimated that approximately 6% of live births in New Zealand are pre-term.

In New Zealand, salbutamol is the only approved SABA with oral or injectable formulations. Currently, only the injectable formulation is approved for use in the treatment of premature labour. However, the data sheets for the oral and injectable salbutamol products indicate that oral salbutamol is occasionally used for long term management of PTL.

Medsafe prepared a report for the MARC on the risks and benefits of non-inhalational formulations of short acting beta agonists (SABAs) when used to inhibit premature labour.

The MARC was asked to advise whether:

Discussion

The MARC noted the 2013 Medsafe report.

The MARC noted that SABAs (including salbutamol) have established efficacy in delaying delivery for at least 48 hours in women presenting with PTL, which allows time for the administration of steroids and/or magnesium or to facilitate transfer to a facility with neonatal intensive care services.

The MARC noted that tocolysis with SABAs has not been shown to have an independent beneficial effect on neonatal outcomes.

The MARC noted that the New Zealand injectable salbutamol data sheets indicate that cardiovascular adverse events such as pulmonary oedema and myocardial ischaemia have been reported during treatment for premature labour. The data sheets advise that ECG monitoring, and monitoring of cardiorespiratory function should be undertaken in all patients. However the MARC noted that more detailed safety information is included in the Australian Ventolin Obstetric Injection data sheet.

The MARC noted that CARM has not received any reports of cardiovascular adverse events associated with the use salbutamol for premature labour. However, the PRACs review identified a number of serious cardiovascular adverse events associated with oral and IV salbutamol use, which in some cases resulted in the death of the mother and/or foetus. The MARC noted that these events were primarily associated with prolonged use of salbutamol.

The Committee considered that it would probably be difficult for women to tolerate treatment for more than 48 hours due to the development of unpleasant side effects such as tachycardia, tremor, and nausea. A member of the Committee advised that in at least one New Zealand guideline, terbutaline is recommended for emergency tocolysis. Medsafe informed the MARC that as no injectable terbutaline products are approved for use in New Zealand, terbutaline must be supplied under section 29 of the Medicines Act 1981 for this purpose.

The Committee noted that in the New Zealand and Australian premature labour guidelines that were reviewed, nifedipine is recommended as first line treatment for tocolysis. The use of SABAs is restricted to women who have either failed treatment with nifedipine or in whom nifedipine is contraindicated. The Committee was reassured that the guidelines all included extensive information on the risks and benefits of treatment with salbutamol, and offered clear advice on monitoring requirements and guidance on when salbutamol should be stopped.

At the completion of their review, the MARC concluded that the benefits of short term treatment (≤ 48 hours) with intravenous salbutamol outweigh the risks when used in appropriate patients to inhibit premature labour.

The MARC agreed with the EMAs conclusion that the risks associated with maintenance treatment with oral salbutamol outweigh any possible benefits in women presenting with premature labour.

Recommendation 11

The MARC recommended that the data sheet for injectable salbutamol be updated in line with the EMA recommendations and should include the additional safety information included in the Australian data sheet.

Recommendation 12

The MARC recommended that oral salbutamol should be contraindicated for use in all obstetric indications.

4. MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

4.1.1 Potential Safety Signals from Single Case Reports

No potential safety signals were identified by CARM this quarter.

4.1.2 Fatal Cases (Causal Cases Only)

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

The Committee discussed case report 107845 involving fatal haemorrhage on dabigatran and considered whether an article in PU was warranted, highlighting the issue of rapidly deteriorating renal function and potential for medicines to be affected, using dabigatran as a case example.

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

4.1.3 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.

4.1.4 Special Populations: Serious Cases Reporting Adverse Events Following Immunisation Terms with Vaccines in Children under 18 years

Reports of events occurring in children under 18 years were briefly outlined for the Committee.

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

4.1.5 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.

Discussion

The Committee discussed case reports 107961 and 108356 involving simvastatin and erythromycin.

Recommendation 13

The Committee recommended that Medsafe communicate with Health Quality and Safety Commission and the Best Practice Advocacy Centre (BPAC) regarding the prescribing of statins in particular co-prescribing with macrolide antibiotics and when to de-prescribe statin in the elderly.

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

4.1.6 Special Reports

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

5. OTHER BUSINESS

5.1 Continuing Education

W. Jayne and S. Berresford from Springer gave a presentation and demonstration on Pharmacovigilance Insight.

5.2 ANZTPA Update

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

5.3 Other Publications of Interest

No Items

5.4 Dates of Future MARC Meetings

The dates for the 2014 MARC meetings were scheduled for 13 March, 12 June, 11 September, and 4 December.

6. ANNEXES

3.2.1 Use of proton pump inhibitors and risk of adverse cardiovascular outcomes

  1. Minutes of 143rd meeting
  2. PHARMAC usage data
  3. CARM report
  4. Chen J, Chen S-Y, Lian J-J et al 2013 'Pharmacodynamic impacts of proton pump inhibitors on the efficacy of clopidogrel in vivo-a systemati review' Clin Cardiol 36: 184-189
  5. Kwok CS, Jeevanantham V, Dawn B et al 2013 'No consistent evidence of differential cardiovascular risk amongst proton pump inhibitors when used with clopidogrel: meta-analysis' Int J Cardiol 167: 965-974.
  6. Focks JJ, Brouwer MA, van Oijen et al MGH 2013 'Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome-a systematic review' Heart 99: 520-527
  7. Huang B, Huand Y, Li Y et al 2012 'Adverse cardiovascular effects of concomitant use of proton pump inhibitors and clopidogrel in patients with coronary artery disease: a systematic review and meta-analysis' Arch Med Res 43: 212-224
  8. Kwok CS, Loke YK 2012 'Effects of proton pump inhibitors on platelet function in patients receiving clopidogrel A systematic review' Drug Safety 35: 127-139
  9. Gerson LB, McMahon D, Olkin I et al 2012 'Lack of significant interactions between clopidogrel and proton pump inhibitor therapy: Meta-analysis of existing literature' Dig Dis Sci 57: 1304-1313
  10. Hulot J-S, Collet J-P, Silvain J 2010 'Cardiovascular risk in clopidogrel-treated patient according to cytochrome P450 2C19*2 loss of function allele or proton pump inhibitor coadministration: A systematic meta-analysis' J Am Coll Cardiol 56:134-43
  11. Siller-Matula JM, Jilma B, Schroer K et al 2010 'Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis' J Thromb Haemostasis 8: 2624-2641
  12. Douglas IJ, Evans SJW, Hingorani et al 2012 'Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs' BMJ 345: e4388

3.2.2 Risk-benefit review of bromocriptine

  1. No items

3.2.3 Spiriva (tiotropium) Respimat update

  1. Mortality associated with use of tiotropium (Spiriva) - MARC report, September 2011
  2. Spiriva (tiotropium) Respimat update - MARC report, March 2013
  3. van Noord J, Cornelissen P, Aumann J, et al. The efficacy of tiotropium administered via Respimat Soft Mist Inhaler or HandiHaler in COPD patients. Respir Med 2009;103:22-9
  4. Ichinose M, Fujimoto T, Fukuchi Y. Tiotropium 5 mcg via Respimat and 18 mcg via HandiHaler; efficacy and safety in Japanese COPD patients. Respir Med 2010;104:228-36
  5. Wise RA, Anzueto A, Cotton D, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med 2013;369: 1491-501
  6. Wise et al - study supplement and appendices

3.2.4 Short acting beta agonists in the treatment or premature labour - do the benefits outweigh the risks?

  1. Comparison of New Zealand and Australian data sheets
  2. CARM data

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2:35 pm.

Associated Professor D Reith
Chair, Medicines Adverse Reactions Committee

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