Revised: 20 May 2013

Committees

Minutes of the 143rd Medicines Adverse Reactions Committee Meeting - 23 September 2010

Held in the Board Room, Medsafe, Wellington. The meeting commenced at 9.30 am and closed at 4 pm.

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

INVITED GUESTS AND EXPERTS IN ATTENDANCE

1 MATTERS OF ADMINISTRATION

1.1 WELCOME AND APOLOGIES

1.2 MINUTES OF THE 142ND MARC MEETING

1.3 DATES OF FUTURE MARC MEETINGS

1.4 POTENTIAL CONFLICTS OF INTEREST

1.5 PRESCRIBER UPDATE

1.5.1 Schedule of Planned Prescriber Update Articles
1.5.2 Prescriber Update. Volume 31, Number 3. September 2010

2 STANDING AGENDA ITEMS

REPORT ON STANDING AGENDA ITEMS FROM PREVIOUS MEETINGS OF THE MARC

3 PHARMACOVIGILANCE ISSUES

3.1 CONSIDERATION OF SIBUTRAMINE-CONTAINING MEDICINES UNDER SECTION 36 OF THE MEDICINES ACT 1981

3.2 CONSIDERATION OF ANTITUSSIVE-EXPECTORANT AND ANTITUSSIVE-MUCOLYTIC COMBINATION COUGH AND COLD MEDICINES UNDER SECTION 36 OF THE MEDICINES ACT 1981

3.3 LEFLUNOMIDE SCHEDULED REVIEW

3.4 RISK OF OSTEOPOROSIS AND FRACTURES ASSOCIATED WITH PROTON PUMP INHIBITOR TREATMENT

3.5 CLOPIDOGREL AND PPIS-INTERACTION

3.6 REVIEW AND PROPOSALS FOR THE ADVERSE REACTIONS OF CURRENT CONCERN (ARCC) SCHEME

3.7 REVIEW OF THE QUARTERLY REPORT

4 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 CENTRE FOR ADVERSE REACTIONS MONITORING (CARM) SPONTANEOUS CASE REPORTS

4.1.1 Case reports
4.1.2 Fatalities Listing
4.1.3 List reports

4.2 QUARTERLY REPORTS FROM CARM AS AT 30 JUNE 2010

4.3 HUMAN PAPILLOMAVIRUS VACCINE (HPV) REPORTS

4.4 SEASONAL FLU VACCINE REPORTS

5 OTHER BUSINESS

5.1 Continuing Medical Education

6 REFERENCES

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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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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:

23 September 2010

MARC Members Present

Associate Professor M Rademaker (Chair)
Dr L Bryant
Associate Professor C Frampton
Dr F McClure
Associate Professor D Reith
Dr S Sime
Dr M Tatley
Prof P Ellis
Dr S Jayathissa
Dr K Wallis

MARC Secretariat Present

K Bridgewater (MARC Secretary)
A Cutfield (Advisor, Pharmacovigilance)
J Hart (Manager, Clinical Risk Management)
C James (Senior Advisor, Pharmacy)
S Kenyon (Senior Advisor, Pharmacovigilance)

Invited guests and experts IN ATTENDANCE

Dr R Savage (Medical Assessor, NZPhVC)
Dr E Yousuf (Principal Clinical Advisor, Medsafe)
K Daly (Team Leader, Compliance, Medsafe)
[..] (Senior Policy Analyst, Ministry of Health)

1. Matters of Administration

1.1 Welcome and Apologies

The Acting Chair welcomed the attendees to the meeting. A brief introduction and welcome to the two new members of the MARC committee, Dr. K Wallis and Dr. S Jayathissa was given.

The Committee noted the Terms of Reference and that two vacancies remain on the MARC Committee.

[..], a Senior Policy Analyst from the Immunisation Team, Ministry of Health, attended as an observer.

1.2 Minutes of the 142^nd MARC Meeting

The minutes of the 142^nd meeting of the Committee were accepted as a true and accurate record of the meeting.

1.3 Dates of Future MARC Meetings

The dates for the next two MARC meetings are scheduled for 2 December 2010 and 10 March 2011.

1.4 Potential Conflicts of Interest

Committee members submitted their Conflict 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.

1.5 Prescriber Update

1.5.1 Schedule of Planned Prescriber Update Articles

Discussion

The Committee noted the schedule of planned Prescriber Update articles.

1.5.2 Prescriber Update. Volume 31, Number 3. September 2010

Discussion

The Committee noted the latest edition of Prescriber Update.

2. STANDING AGENDA ITEMS

The Committee considered the list of issues monitored by MARC, Medsafe and NZPhvC. The Committee noted that there were no outstanding items from the previous meeting.

Report on Standing Agenda Items from previous meetings of the MARC

Background information on these issues is available on the Medsafe web site at www.medsafe.govt.nz/profs/MARC/Minutes.asp.

3. Pharmacovigilance Issues

3.1 Consideration of Sibutramine-Containing Medicines under Section 36 of the Medicines Act 1981

Background

Reductil®, Meridia and Reduxade are the only products containing sibutramine approved for use in New Zealand. These three medicines are all sponsored by Abbott Laboratories Ltd. Reductil was the first sibutramine-containing medicine approved for use in New Zealand in 2000. There are currently about 5000-6000 patients taking sibutramine in New Zealand.

In March 2002, the European Medicines Agency (EMA) initiated a review of sibutramine, following the suspension of the Reductil product licence in Italy, due to reports of fatalities following sibutramine use. After reviewing these cases, the Committee for Medicinal Products for Human Use (CHMP) considered the sibutramine risk-benefit balance to be favourable. However the sponsor of Reductil was required to conduct a large cardiovascular outcome study to compare sibutramine to placebo in overweight or obese subjects aged 55 years or older, who were at risk of cardiovascular events. As a result the sibutramine cardiovascular outcomes trial (SCOUT) was initiated by the sponsor.

A further review was triggered by the EMA in 2009 following the release of preliminary results from the SCOUT study, which showed a 16% increased risk of cardiovascular events in subjects taking sibutramine versus placebo. The CHMP concluded that the benefit-risk profile for sibutramine was unfavourable and recommended the suspension of the marketing authorisation for these medicines.

Following a review of the preliminary results of the SCOUT study and in response to the EMA's actions, the sponsor of Reductil, Abbott Laboratories, was issued with a notice under Section 36 of the Medicines Act 1981. The Section 36 notice required the sponsor to provide data in support of the safety and efficacy of their medicine in order to allow a full risk-benefit review to be conducted. The response was considered by Medsafe and the issue was referred to the appropriate committee (the MARC).

The Committee reviewed the risks and benefits of sibutramine in June 2010 (see minute item 3.1 from the June 2010 meeting). The Committee recommended that Medsafe obtain supplementary information from the sponsor of Reductil on patients who would be eligible to use sibutramine according to the current New Zealand data sheet.

The purpose of the September 2010 paper was to provide the Committee with a review of supplementary information obtained from the sponsor of Reductil for consideration.

Discussion

The Committee noted that the United States Food and Drug Administration (FDA) was also seeking advice on this issue from their expert advisory committee. At the time of the meeting, the FDA had not made a final decision.

The Committee reaffirmed its view that the SCOUT study showed an increased risk of cardiovascular (CV) events in patients at high CV risk including patients with pre-existing CV conditions.

The Committee noted that the newly presented data for the 'on label' population (those eligible for treatment according to the New Zealand data sheet) showed that patients lost weight. The clinical significance of this weight loss was questioned. The Committee also noted evident trends towards changes in blood lipid and glucose levels but again questioned the clinical significance.

The maintenance of weight loss on stopping treatment was also discussed. The Committee noted that studies investigating weight maintenance with sibutramine tended to show a trend to increase in weight towards the end of the study period. However no information was available on maintenance of weight loss after stopping treatment. It was also noted by the Committee that some patients are likely to use sibutramine intermittently for many years as their weight fluctuates.

The safety data for the 'on label' population was considered to be equivocal by the Committee due to low patient numbers and event numbers. There were trends towards higher heart rates and blood pressure in patients taking sibutramine. It was noted that patients at very high risk of adverse cardiovascular events were excluded from the SCOUT study and therefore the increased risk still noted was concerning. The clinical significance of small changes in blood pressure and heart rate in the studies reviewed were questioned.

The Committee questioned whether it was possible to identify patients at risk of cardiovascular events in an obese population. It was noted that the current Reductil data sheet only contraindicates patients with pre-existing cardiovascular conditions. However the Committee were concerned that many patients eligible for treatment could have a number of risk factors which would put them at high risk of adverse cardiovascular outcomes.

It was also noted that there is a paucity of medicinal treatments for obese and overweight patients wishing to lose weight.

The Committee considered that a final recommendation could not be made until further clinical expert advice had been sought regarding the significance of some points related to the benefits and risks for sibutramine (as outlined above).

It was noted that an extraordinary meeting of the Committee could be organised upon receipt of this information.

Recommendation

The Committee recommended that an expert opinion be sought on the clinical significance of the weight loss attributed to sibutramine. The Committee recommended that an expert opinion be sought on the clinical significance of the changes in blood lipid and glucose levels. The Committee recommended that an expert opinion be sought on the clinical significance of small changes in blood pressure and heart rate in patients taking sibutramine. The Committee recommended that, pending a final recommendation, the Reductil data sheet be reviewed to assess whether changes could be made to include information to improve the safe use of sibutramine. The Committee recommended that a joint letter from Medsafe and the MARC be sent to healthcare professionals updating on the progress of the review and reminding them to adhere to the contraindications in the data sheet.

*Secretary's note:
MARC Teleconference
11 October 2010
8:00 am- 8:20 am

Background

At the 143^rd meeting of the MARC held on 23 September 2010 it was recommended that expert advice be sought on the clinical significance of small changes in blood pressure and heart rate in patients taking sibutramine. It was also recommended that an expert opinion be sought on the clinical significance of the changes in body weight, blood lipid and glucose levels. This teleconference was held to present these data to the MARC for their consideration, provide an update on recent regulatory actions, and to make a final recommendation.

Medsafe provided the Committee with a summary of the expert clinical advice obtained from a cardiologist (Associate Professor Gerard Wilkins, a consultant physician in cardiology at Southern DHB) and an endocrinologist (Dr Jeremy Krebs, an endocrinologist at CCDHB).

Medsafe provided the Committee with an update on recent international regulatory action, including the FDA's conclusion that the risk-benefit balance for sibutramine is unfavourable and the decision of the company (Abbott) to withdraw sibutramine in a number of countries, including the US.

MARC members present: Linda Bryant, Assoc Prof Marius Rademaker, Prof Pete Ellis, Dr. Sharon Sime, Dr. Michael Tatley, Dr. Sisira Jayathissa, Dr. Katharine Wallis, Assoc Prof Chris Frampton

Medsafe staff present: Chris James, Susan Kenyon, Abby Cutfield, Kimberly Bridgewater, Jo Hart

Discussion

The Committee noted the actions taken by the company (Abbott) and the conclusions of the FDA that the risk-benefit balance for sibutramine is unfavourable.

The Committee noted the cardiologist's advice that reductions in blood pressure and heart rate would be expected with the weight loss experienced from sibutramine treatment. While these reductions should provide clinically significant benefits in terms of cardiovascular risk, the increases in blood pressure and heart rate in subjects treated with sibutramine may cancel out any improvement that would be expected from the weight loss. The Committee noted the expert advice that changes in blood pressure and heart rate observed with sibutramine in clinical studies were clinically significant and that this degree of change would be expected to increase the risk of adverse outcomes such as myocardial infarction.

The Committee noted the endocrinologist's advice that the degree of weight loss should be significant enough to positively influence cardiovascular risk factors. However, no weight loss studies had shown a reduction in mortality. It was noted that sibutramine should not be used in anyone with a pre-existing cardiovascular condition. It was noted that there may still be a place for sibutramine in patients with no cardiovascular disease but only if successful weight loss is achieved and with close monitoring.

The Committee considered that the clinical advice reinforced their view that the benefits of sibutramine were modest and that there was evidence of moderate harm. It was noted that although the SCOUT study was in an off-label population the Committee considered it would be difficult to identify those eligible patients at increased cardiovascular risk such as undiagnosed cardiovascular disease. Overall, the weight of evidence supported an unfavourable risk-benefit profile for sibutramine.

The Committee therefore concluded that the risk for an adverse cardiovascular event from sibutramine treatment outweighs any benefit of modest weight loss. The consents to distribute sibutramine-containing medicines should be revoked.

It was noted that the previous recommendations of the Committee from the 143^rd MARC meeting regarding data sheet updates and a letter to healthcare professionals had now become redundant.

Recommendation

The Committee recommended that the consents to distribute products containing sibutramine in New Zealand be revoked.

3.2 Consideration of Antitussive-Expectorant and Antitussive-Mucolytic Combination Cough and Cold Medicines under Section 36 of the Medicines Act 1981

Background

The MARC first reviewed the benefits and risks of over the counter (OTC) cough and cold medicines in children in 2007. The MARC concluded that the risk-benefit profile for the use of cough and cold medicines in children under 2 years of age was unfavourable and recommended that they be contraindicated in this age group.

In 2009 an independent expert review group, 'The Cough and Cold Review Group', consisting of representatives from the MARC, Plunket, the community, general practice, nursing, paediatrics, pharmacy and the pharmaceutical industry, was convened to review the benefits and risks of cough and cold medicines for use in children aged >2 years.

The Cough and Cold Review Group met on two occasions. After considering the data presented to them the Group made the following recommendations to Medsafe:

• All medicines indicated for the treatment of the symptoms of the common cold containing guaifenesin, ipecacuahna, dextromethophan, pholcodine, oral phenylephrine, pseudoephedrine, brompheniramine, chlorpheniramine, diphenhydramine, doxylamine, promethazine or triprolidine should be contraindicated in children <6 years of age.
• All medicines indicated for the treatment of the symptoms of the common cold containing only bromhexine or topical nasal decongestants (oxymetazoline, xylometazoline and intra-nasal phenylephrine) should remain contraindicated in children <2 years of age.

In addition the Group recommended that the sponsors of cough and cold medicines containing apparently illogical combinations of ingredients should be asked for justification to support the risk-benefit balance for these combinations.

Medsafe identified that there were only two products containing antitussive-expectorant or antitussive-mucolytic combination cough and cold medicines with Ministerial consent to distribute in New Zealand. These products were Robitussin Cough and Chest Congestion and Duro-Tuss Cough Liquid Expectorant.

On 25 September 2009, Medsafe issued the sponsors of Robitussin Cough and Chest Congestion, and Duro-Tuss Cough Liquid Expectorant with a notice under Section 36 of the Medicines Act 1981. The Section 36 notice requested that the relevant sponsor provide a justification, based on scientific data, for the combination of guaifenesin and dextromethophan in Robitussin Cough and Chest Congestion and the combination of bromhexine and pholcodine in Duro-Tuss Cough Liquid Expectorant. As no specific age group was specified, Medsafe considered that this notice pertained to the use of these products in all age groups.

Responses were received within the agreed timeframe. Medsafe considered the responses and found them to be inadequate. Therefore, the Group Manager, Medsafe acting under a power delegated by the Director-General of Health, referred this issue to the MARC. The MARC was asked to consider the available information on the risk-benefit profile of combination antitussive-expectorant and antitussive-mucolytic containing cough and cold medicines (including Robitussin Cough and Chest Congestion and Duro-Tuss Cough Liquid Expectorant) and provide advice on what further actions, if any should be taken.

*Please note that references for this minute item can be found in Section 6 of this document.

Discussion

To assist the Committee in their assessment of the benefits and risks of antitussive-expectorant and antitussive-mucolytic combination cough and cold medicines, Medsafe provided a risk-benefit review for the Committee to consider. The MARC was also provided with a copy of the sponsors responses to the Section 36 notices issued by Medsafe

The Committee noted the above reports.

The Committee noted that there was only one published study (Croughan-Minihane et al. 1993) that evaluated the efficacy of an antitussive-expectorant combination cough and cold medicine. This study evaluated the relative efficacy of the combination of guaiphenesin and dextromethorphan. It was noted that this study was underpowered and lacked a placebo arm, thus it could not be concluded that the combination was efficacious. The MARC noted that there were no studies evaluating the efficacy of a bromhexine-pholcodine combination. Overall the MARC concluded that there was insufficient evidence to support the efficacy of products containing these antitussive-expectorant and antitussive-mucolytic combinations in the treatment of cough and colds.

The Committee also considered the evidence to support the safety of these combination products in the treatment of cough and cold symptoms. The Committee noted that there have been few ADR reports for these combination products; however this is to be expected because there are very little clinical trial data and ADRs to OTC medicines are very poorly reported to spontaneous reporting schemes. However, the MARC noted that there had been at least one report of anaphylaxis, a potentially life-threatening event. The MARC also noted that there were theoretical reasons why suppressing a productive cough could be dangerous, particularly in patients with chronic respiratory conditions. It was noted that most international guidelines recommended against using combination antitussive-expectorant or antitussive-mucolytic combination cough and cold medicines to treat the symptoms of the common cold - some going as far as to describe such combinations as illogical. In addition, it was noted that the MHRA and Health Canada had contraindicated the use of such combination products for use in children aged <12 years.

After considering the available evidence for the safety and efficacy of these combination products, the majority of the Committee considered the risk-benefit balance to be unfavourable and recommended that consent be revoked for these products. However, the MARC considered that this recommendation should only apply to the combinations specifically reviewed (ie combinations of bromhexine and pholcodine and guaiphenesin and dextromethorphan). The MARC considered that in the future any applications to Medsafe seeking registration of an antitussive-mucolytic or antitussive-expectorant combination containing other combinations of ingredients must include adequate clinical data for evaluation.

Recommendations

The Committee recommended that consent be revoked for combination cough and cold medicines containing guaiphenesin and dextromethorphan or pholcodine and bromhexine.

The MARC recommended that Medsafe ensure that safety and efficacy data be included in any future applications for antitussive-expectorant or antitussive-mucolytic combination cough and cold medicines.

*Secretary's note:
The Minister's delegate considered the MARC's recommendations and advice provided to him by Medsafe and decided to:

• accept the MARC recommendation that safety and efficacy data be included in any future applications for antitussive-expectorant or antitussive-mucolytic combination cough and cold medicines; and
• not accept the MARC recommendation to revoke the consents for combination cough and cold products containing guaifenesin and dextromethorphan or pholcodine and bromhexine.

However, the Minister's delegate considers that:

• the use of antitussive-mucolytic or antitussive-expectorant ingredients in a cough and cold preparation appears to be an illogical combination taking into account the individual therapeutic effects of the active ingredients
• evidence to identify a patient group that would benefit from such a combination has not been supplied
• The use of cough and cold preparations with antitussive-mucolytic and antitussive-expectorant ingredient combinations should therefore be very carefully considered

Based on the available evidence, the Minister's delegate considers that any potential risks associated with the use of cough and cold products containing these illogical combinations can be managed by communicating the above key messages to healthcare professionals. Medsafe has been instructed to publish an article in Prescriber Update and liaise with the Pharmaceutical Society of New Zealand to reinforce these messages. In addition, all future advertising and promotional material in relation to Robitussin Cough & Chest Congestion and Duro-Tuss Cough Liquid Expectorant will be expected to be in keeping with the above key messages.

3.3 Leflunomide Scheduled Review

Background

The MARC has conducted an ongoing review of the safety of leflunomide since 2002. It was added to the Adverse Reactions of Current Concern (ARCC) scheme in March 2004 and remained there until the scheme was discontinued in June 2010. Leflunomide remained on the list for Scheduled Review in recent years to facilitate monitoring of reactions to combination therapy with other DMARDs and TNF-alpha inhibitors.

The purpose of the report was to provide the Committee with a summary of previous MARC discussions as well as an update on New Zealand reports, recent international regulatory action and other available data with respect to leflunomide. The report provided a final review of all adverse reactions to leflunomide upon the discontinuation of the ARCC scheme.

The MARC has previously reviewed in detail the risk of interstitial pneumonitis, severe infection and life threatening hepatitis associated with leflunomide with or without DMARDs. This has resulted in multiple data sheet updates and the publication of four Prescriber Update articles.

*Please note that references for this minute item can be found in Section 6 of this document.

Discussion

The Committee discussed the history of leflunomide on the ARCC. The Committee noted the 2010 NZPhVC report.

The Committee noted that the FDA had recently required the addition of a black box warning on the US prescribing information for leflunomide with regard to the risk of severe hepatic disorders.

The Committee considered that based on local experience, the data sheets for leflunomide should be revised to strengthen warnings regarding the risk of hepatoxicity and pneumonitis, especially with combination therapy, in particular, methotrexate, and the need for a cholestyramine washout procedure for leflunomide toxicity. The Committee considered that although all serious adverse reactions to leflunomide remain important, it no longer requires specific annual review by the MARC. The Committee agreed that the issue should be removed from the Scheduled Review list.

The MARC was reassured that New Zealand rheumatologists are well informed about the safety profile of leflunomide, however, other health care professionals could benefit from receiving further information.

The Committee noted that Medsafe and NZPhVC will continue monitoring leflunomide and bring any new information back to the MARC as necessary.

Recommendations

The Committee recommended the data sheets for leflunomide should be revised to strengthen warnings regarding the risk of hepatoxicity and pneumonitis, especially with combination therapy, in particular, methotrexate, and the need for a cholestyramine washout procedure for leflunomide toxicity.

The Committee recommended that an article be published in Prescriber Update reminding healthcare providers of the risks of pneumonitis and hepatic disorders.

The Committee recommended that leflunomide no longer remains on the list for Scheduled Review.

3.4 Risk of Osteoporosis and Fractures Associated with Proton Pump Inhibitor Treatment

Background

The review was initiated by Medsafe following advice published by other medicines regulators regarding the potential risk of osteoporosis and fractures in association with proton pump inhibitors. It was noted that the FDA has recently required updates to the product label. The Medsafe review included information obtained from epidemiological studies identified in the published scientific literature. Medsafe considered the results of the epidemiological studies published in the scientific literature to be equivocal and therefore referred this information to the MARC for advice.

A Medsafe paper reviewing published studies was presented to the Committee (see references).

*Please note that references for this minute item can be found in Section 6 of this document.

Discussion

To assist the Committee in their assessment of the risk of osteoporosis and fractures in association with proton pump inhibitor treatment, Medsafe provided a report reviewing the published studies (see reference list).

The Committee noted that the reported association in the majority of the published studies was modest. In particular, most of the studies were unable to account for all known risk factors for osteoporosis and fracture. This was particularly problematic for the following risk factors of calcium in the diet, exercise levels and exposure to sunlight (vitamin D), all known to be strongly associated with osteoporosis and fracture.

The Committee discussed whether any updates to the relevant data sheets were warranted as a result of this safety review and whether any communication on this topic was warranted at present.

Recommendations

The Committee recommended that the data did not warrant any regulatory action to be taken at this time.

The Committee recommended that the MARC be kept informed of any new developments.

3.5 Clopidogrel and PPIs-Interaction

Background

In early 2010 a pharmacokinetic interaction between clopidogrel and omeprazole was confirmed, based on the findings from two definitive pharmacokinetic/pharmacodynamic interaction studies.

Medsafe sought the Committee's advice on whether the currently available evidence was sufficient to confirm an interaction between clopidogrel and other individual proton pump inhibitors (PPIs), namely pantoprazole, lansoprazole and rabeprazole.

For any confirmed interaction, the Committee was asked to advise whether the interaction is clinically significant. The Committee was also asked what advice could be offered to prescribers.

*Please note that references for this minute item can be found in Section 6 of this document.

Discussion

To assist in its consideration of this issue the Committee was provided with a report from Medsafe summarising the available information on the possible interaction between clopidogrel and PPIs other than omeprazole and esomeprazole.

The Committee noted the September 2010 Medsafe report.

The Committee considered the available evidence in support of a pharmacokinetic interaction between clopidogrel and pantoprazole. The Committee considered that there was sufficient evidence in support of a pharmacokinetic interaction between clopidogrel and pantoprazole. It was noted however that the interaction was not as strong as that observed between clopidogrel and omeprazole.

The Committee considered that there was sufficient evidence to warrant inclusion of information on this pharmacokinetic interaction in the data sheets for clopidogrel and pantoprazole-containing medicines. However, the Committee was unable to draw any conclusion on the clinical significance of this interaction.

The Committee considered the evidence in support of an interaction between clopidogrel and lansoprazole, and between clopidogrel and rabeprazole. The Committee noted that there was some in vitro data to suggest that the interaction with rabeprazole may not be relevant in vivo. The Committee concluded there was insufficient data to enable any comment to be made on a potential interaction between clopidogrel and lansoprazole, and on a potential interaction between clopidogrel and rabeprazole.

The Committee considered that the available evidence did not allow the Committee to be able to offer any advice to prescribers on the clinical significance of interactions between clopidiogrel and either pantoprazole, lansoprazole, or rabeprazole.

The Committee noted that cytochrome P450 3A4 ('CYP3A4') is the major contributor to the activation of clopidogrel and there are also other inhibitors of CYP2C19. Therefore, the Committee considered there is also potential for pharmacokinetic interactions to arise from the concomitant use of CYP3A4 and other CYP2C19 inhibitors.

Recommendations

The Committee recommended that the data sheets for clopidogrel and pantropazole be updated to include information on the pharmacokinetic interaction.

The Committee recommended that the sponsors of lansoprazole and rabeprazole-containing medicines be requested to undertake a review of the potential interaction with clopidogrel.

The Committee recommended that potential interactions between clopidogrel and other CYP2C19 and CYP3A4 inhibitors be reviewed.

3.6 Review and Proposals for the Adverse Reactions of Current Concern (ARCC) Scheme

Background

The ARCC scheme was initially reviewed at the last MARC meeting (see June 2010 minute item 3.3). This paper was provided in response to the request from the Committee that Medsafe present options for modifying and running a scheme in the future.

Discussion

The Committee agreed that the scheme was best placed to highlight early potential safety signals for which further information from spontaneous reports would be helpful in investigating the signal further.

The scheme was seen also as an important method of encouraging healthcare professionals to report suspected adverse reactions.

The need to publicise and advertise the scheme to healthcare professionals was emphasised and the Committee made some recommendations. It was suggested by one member that in this regard, a creative logo be added as a visual aid on correspondence to remind subscribers to report events.

Recommendation

The Committee recommended that Medsafe and NZPhVC proceed with implementing a scheme.

3.7 Review of the Quarterly Report

Background

The Quarterly Report is produced by NZPhvC and provides an overview of suspected adverse reactions reported to the Centre for Adverse Reactions Monitoring. As part of the ongoing review of the pharmacovigilance processes and change of the Terms of Reference for the Committee, it was considered by Medsafe and NZPhvC that it was best to review the format of the report.

At the December 2009 meeting (minute item 4.1.2) the Committee recommended that NZPhvC and Medsafe review the format of the Quarterly Report. This paper proposed a new format for the Quarterly Report.

Discussion

The aim of the new format was to better highlight potential safety signals so that the Committee could provide advice regarding the significance of the signal. In general, the Committee agreed with the proposed new format.

The Committee discussed the proposed format of the report. Each section in the proposed report was reviewed and considered. Suggestions were made to change the reporting frequency over the year for some of the sections.

The Committee discussed how much information needed to included for each report from NZPhVC. The amount of time to produce the Quarterly Report was noted.

Recommendation

It was recommended that the new format be used for future meetings and that an audit of the new format for the quarterly report would be undertaken at the September 2011 meeting of the MARC.

4. Matters arising from the New Zealand Pharmacovigilance Centre

4.1 Centre for Adverse Reactions Monitoring (CARM) Spontaneous Case Reports

Note: In the discussion notes for each report, the case has been given a causality designation using terms and definitions developed by the World Health Organisation. The precise definitions are available on the website of the The Uppsala Monitoring Centre, which is the WHO Collaborating Centre for International Drug Monitoring - http://www.who-umc.org/

These designations (certain, probable, possible, unlikely, unclassified and unclassifiable) refer to the degree of certainty about the relationship between the medicine and the adverse event. The terms should not be understood literally. For example, "certain" means that the appropriate elements are present to match the international definition. It does not mean there is absolute certainty that the medicine caused the adverse event. Explanations of these terms can be found on the Medsafe website via the hyperlink at each causality designation.

The Committee was advised that the way in which the spontaneous case reports were presented to the MARC had been refined, with the focus of cases presented to the Committee being on advice and signal detection. The remainder of case reports are included as list reports, with an expanded section for relevant comments.

4.1.1. Case reports

4.1.1.1 Tramadol and serotonin syndrome (89873)

Discussion

CARM advised that it has received 168 reports in total for tramadol. Six of the reports were of serotonin syndrome. All were considered attributable to a tramadol interaction with an antidepressant or an opiate or more than one of these.

The Committee noted that there is no information on serotonin syndrome with interacting medicines or with tramadol alone in the warnings section of the data sheets.

The Committee noted that articles have previously been published in Prescriber Update, however, the Committee considered it would be timely to provide an updated list of serotonergic medicines and further information on serotonin syndrome for healthcare providers.

Recommendations

The Committee recommended that the tramadol datasheets be revised to include serotonin syndrome in the Warnings section.

The Committee also recommended that an updated list of serotonergic medicines be published in the next edition of Prescriber Update.

4.1.2. Fatalities Listing

Members were given a brief description of these reports, with the option of requesting that any particular reports be discussed at the current, or a subsequent meeting, if they considered that there was a safety issue that prescribers should be informed about or regulatory action was required.

The Committee noted the following case reports:

4.1.2.1 Adalimumab, Prednisone, methotrexate, frusemide, hydroxychloroquine (090499)
4.1.2.2 Clozapine (090415)
4.1.2.3 Cotrimoxazole, allopurinol, cyclophosphamide, fludarabine, methadone (089177)
4.1.2.4 Dianeal Nos (090239)
4.1.2.5 Dianeal Nos Icodextrin (090240)
4.1.2.6 Dianeal Nos, Icodextrin (090241)
4.1.2.7 Dianeal Nos, Icodextrin (090242)
4.1.2.8 Dianeal Nos, Icodextrin (090243)
4.1.2.9 Dianeal Nos, Icodextrin (090244)
4.1.2.10 Dianeal Nos (090245)
4.1.2.11 Dianeal Nos, Icodextrin (090338)
4.1.2.12 Dianeal Nos (090339)
4.1.2.13 Dianeal Nos (090340)
4.1.2.14 Dianeal Nos (090342)
4.1.2.15 Diclofenac, Omeprazole, paracetamol, oxycodone (090309)
4.1.2.16 HPV-2 Vaccine (090322)
4.1.2.17 Influenza Virus Vaccine inact., Doxazosin, Thyroxine, Paracetamol (089896)
4.1.2.18 Risperidone (089439)
4.1.2.19 Risperidone, Citalopram (090435)
4.1.2.20 Seretide, Salbutamol, Prednisolone (089415)
4.1.2.21 Tenecteplase, Heparin-unfractionated, Morphine sulphate, Clopidogrel, Metoprolol (089458)
4.1.2.22 Tenecteplase, Metformin, Atorvastatin, Losartan (089459)
4.1.2.23 Tenecteplase, Frusemide, Candesartan, Metformin, Metoprolol (089460)
4.1.2.24 Tenecteplase (090119)
4.1.2.25 Warfarin, Heparin-unfractionated (089417)

4.1.3 List reports

These reports typically contain insufficient data for an assessment to be made, or are due to disease progression. They also include non serious or well known reactions to medicines on the Adverse Reactions of Current Concern (ARCC) list. Members were asked to note these reports, with the option of requesting that any particular report/s be discussed at the current, or a subsequent meeting.

The Committee noted the following case reports:

4.1.3.1 Alendronate + cholecalciferol, acetylsalicylic acid, calcium carbonate, piroxicam, calciferol strong (090101)
4.1.3.2 Leflunomide, methotrexate, prednisone (089840)
4.1.3.3 Sitagliptin, simvastatin, frusemide, candesartan, acetylsalicylic acid (089851)
4.1.3.4 Yasmin, citalopram (089758)
4.1.3.5 Yasmin (090226)

4.2 Quarterly Reports from CARM as at 30 June 2010

Discussion

The Committee noted the quarterly reports from CARM as at 30 June 2010.

4.3 Human Papillomavirus Vaccine (HPV) reports

Discussion

The Committee noted the CARM reports of reactions to the HPV vaccine up to 31 July 2010.

The Committee noted that reports were typical for any vaccine profile.

4.4 Seasonal Flu Vaccine reports

Discussion

The Committee noted the CARM report of reactions to the seasonal flu vaccine up to 31 July 2010.

5. OTHER BUSINESS

5.1 Continuing Medical Education

[..] gave a presentation on meta-analysis.

6. References

3.1 Consideration of Sibutramine-Containing Medicines under Section 36 of the Medicines Act 1081

1. Review of supplementary data for sibutramine containing medicines - safety of sibutramine in the on-label (indicated) population.
2. Review of Study SB238 - a double blind, randomised placebo controlled study in obese adolescents.
3. Review of ongoing and completed studies identified in the Reductil Risk Management Plan.
4. Review of supplementary data on weight loss, second art benefits and vital signs (FDA request).
5. Review of psychiatric events associated with the use of sibutramine.
6. Review of benefits and risks for sibutramine-containing medicines provided by Medsafe - presented at the June MARC meeting.
7. Reductil data sheet.
8. Relevant Legislation: Section 36, Medicines Act 1981.

3.2 Consideration of Antitussive-Expectorant and Antitussive-Mucolytic Combination Cough and Cold Medicines under Section 36 of the Medicines Act 1981

1. Relevant Legislation: Section 36, Medicines Act 1981
2. Response to the Section 36 notice from Wyeth Consumer Healthcare
3. Response to the Section 36 notice from iNova Pharmaceuticals (Australia) Pty Ltd
4. Medsafe's review of the benefits and risks for combination antitussive/expectorant or antitussive/mucolytic containing cough and cold medicines
5. CARM case reports
6. Croughan-Minihane et al. (1993). Clinical Trial Examining Effectiveness of Three Cough Syrups. J Am Board Fam Pract 6: 109-115.

3.3 Leflunomide Scheduled Review

1. NZPhVC review of CARM and WHO data and literature with particular reference to leflunomide combination therapy.
2. Alcorn N, Saunders S, Madhok R. (2009). Benefit-risk assessment of leflunomide. An appraisal of leflunomide in rheumatoid arthritis 10 years after licensing. Drug Safety 32(12):1123-1134.
3. Savage R. (2008) Leflunomide - Update on serious toxicity. Prescriber Update 29(1):13-14.
4. FDA. FDA Drug Safety Communication: new boxed warning for severe liver injury with arthritis drug Arava (leflunomide). 13 Jul 2010. Available from: URL: http://www.fda.gov
5. ADRAC (2009) Is it leflunomide lung? Australian Adverse Reactions Bulletin 28:15(4).
6. Savage RL. (2010). Leflunomide in Combination Therapy for Rheumatoid Arthritis. (Commentary). Drug Saf. 33(6): 523-526.
7. Suissa S, Hudson M, Ernst P. (2006). Leflunomide use and the risk of interstitial lung disease in rheumatoid arthritis. Arthritis Rheum 54(5):1435-9. 8.
8. Savage RL, Highton J, Boyd IW, et al. (2006). Pneumonitis associated with leflunomide: a profile of New Zealand and Australian reports. Internal Medicine Journal 36(3):162-169.
9. McEwen J, Purcell PM, Hill RL et al. (2007) The incidence of pancytopenia in patients taking leflunomide alone or with methotrexate. Pharmacoepidemiology and Drug Safety 16(1): 65-73.
10. Sanofi-Aventis New Zealand Ltd. Arava®. 20 February 2009.
11. AFT-Pharmaceuticals. AFT-Leflunomide. 17 April 2009.
12. Medsafe. MARC Reviews and Regulatory Outcomes to Dec 2005. International Regulatory Actions.

3.4 RISK OF OSTEOPOROSIS AND FRACTURES ASSOCIATED WITH PROTON PUMP INHIBITOR TREATMENT

1. Australian Adverse Drug Reactions Bulletin 2009; 28:3.
2. FDA drug safety communication June 2010.
3. Vestergaard P, Rejnmark L and Mosekilde L (2006) Proton Pump inhibitors, Histamine H2 receptor antagonists and other antacid medications and the risk of fracture Calcif Tissue Int. 79: 76-83.
4. Yang Y-X, Lewis JE, Epstein S et al. (2006). Long-term proton pump inhibitor therapy and risk of hip fracture JAMA 296: 2947-2953.
5. Targownik LE, Lix LM, Metge CJ et al. (2008) Use of proton pump inhibitors and risk of osteoporosis-related fractures CMAJ 179: 319-26.
6. Yu EW, Blackwell T, Ensrud KE et al. (2008) Acid-suppressive medications and risk of bone loss and fracture in older adults Calcif Tissue Int 83: 251-9.
7. Kaye JA and Jick H (2008) Proton pump inhibitor use and risk of hip fractures in patients without major risk factors Pharmacotheraphy 28: 951-959.
8. Roux C, Briot K, Gossec L et al. (2009) Increase in vertebral fracture risk in postmenopausal women using omeprazole Calcif Tissue Int 84: 13-19.
9. Corley DA, Kubo A, Zhao et al. (2010) Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at risk patients Gastroent 139: 93-101.
10. Gray SL, LaCroix AZ, Larson J et al. (2010) Proton pump inhibitor use, hip fracture, and change in bone mineral density in post menopausal women Arch Intern Med 170: 765-771.
11. Targownik LE, Lix LM, Leung S et al. (2010) Proton pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss Gastroenterol 138: 896-904.

3.5 CLOPIDOGREL AND PPIs- INTERACTION

1. Medsafe. 2009. Clopidogrel and proton pump inhibitors - possible interaction. Prescriber Update 30(3): 18.
2. Medsafe. 2010. Clopidogrel and omeprazole - interaction now confirmed. Prescriber Update 31(1): 2.
3. Li X-Q, Andersson TB, Ahlström M, Weidolf L (2004) Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metabolism and Disposition. 32:821-827.
4. Neubauer H, Engelhardt A, Kruger JC, Lask S, Borgel J, Mugge A & Endres HG (2010) Pantoprazole does not influence the antiplatelet effect of clopidogrel - a whole blood aggregometry study after coronary stenting J Cardiovascular Pharmacol 56(1): 91-97.
5. Small DS, Farid NA, Payne CD, Weerakkody GJ, Li YG, Brandt JT, Salazar DE & Winters KJ (2008) Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel J Clin Pharmacol 48 (10): 475-84.
6. Hulot J-S, Wuerzner G, Bachelt-Loza C, Azizi M, Blanchard A, Peyard S, Funck-Brentano C & Gaussem P (2009) Effect of an increased clopidogrel maintenance dose or lansoprazole co-administration on the antiplatelet response to clopiodogrel in CYP2C19-genotyped healthy subjects Int Thromb and Haemost 8: 610-3.
7. Cuisset T, Frere C, Quilici J, Poyet R, Gaborit B, Bali L, Brissy O, Morange P-E, Alessi M-C, Bonnet L (2009) Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose JACC 54(13): 1149-53.
8. Siriswangvat S, Sansanayudh N, Nathisuwan S & Panomvana D (2010) Comparison Between the Effect of Omeprazole and Rabeprazole on the Antiplatelet Action of Clopidogrel. Circulation Journal. Advance Publication.
9. O'Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, Michelson AD, Hautvast RW, Ver Lee PN, Close SL, Shen L, Mega JL, Sabatine MS, Wiviott SD. (2009) Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials Lancet 374(9694): 989-97.
10. Stockl KM, Le L, Zakharyan A, Harada ASM, Solow BK, Addiego JE, Ramsey S (2010) Risk of hospitalisation for patients using clopidogrel with a proton pump inhibitor. Arch. Intern. Med. 170(8): 704-10.
11. Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM (2009) A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 180(7): 713-8.

The Acting Chair thanked members and the secretariat for their attendance and closed the meeting at 4 pm.

Associate Professor M. Rademaker
Acting Chair
Medicines Adverse Reactions Committee