Revised: 20 May 2013

Committees

Minutes of the 125^th Medicines Adverse Reactions Committee Meeting - 16 March 2006

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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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

TABLE OF CONTENTS

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

INVITED GUESTS AND EXPERTS

1. MATTERS OF ADMINISTRATION

2. ACTIONS ARISING

3. PHARMACOVIGILANCE ISSUES

3.1 Aprotinin And Risks In Cardiac Surgery
3.2 Anti-Tumour Necrosis Factor (TNF) Alpha Agents And The Risk Of Hepatitis B Reactivation
3.3 All Serious Or Unexpected Adverse Reactions To Rosiglitazone: Standing Agenda Item

4. MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

5. PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

6. NEW ZEALAND PHARMACOVIGILANCE-RELATED ACTIVITIES

7. INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

7.1 Australia
7.2 Canada
7.3 Singapore
7.4 WHO

8. SUMMARY OF CASE REPORTS CONSIDERED BY MARC (1997-2005)

9. OTHER BUSINESS

9.1 Oral Presentations on WHO and ISoP Pharmacovigilance Conferences
9.2 Future Arrangements for Pharmacovigilance in New Zealand

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Minutes:

The one hundred and twenty-fifth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 16 March 2006 at the De Havilland room, Wellington Airport Conference Centre, Wellington, New Zealand. The meeting commenced at 9:00am and closed at 3:30pm.

marc members present

Assoc. Prof. T. Maling (Chair until 1:00pm)
Assoc. Prof. M. Rademaker (Acting Chair from 1:00pm)
Prof. D. Skegg (until 2:30pm)
Dr H. Kingston
Dr F. McClure
Prof. P. Ellis
Dr M. Tatley
Dr S. Sime

marc secretariat present

Ms S. Von Afehlt (Senior Pharmacy Advisor/Editor of Prescriber Update, Medsafe)
Dr K. Moses (Pharmacovigilance Advisor/MARC Secretary, Medsafe)

invited guests and experts

Dr R. Savage (Centre for Adverse Reactions Monitoring, New Zealand Pharmacovigilance Centre).
Dr M. Harrrison-Woolrych (Intensive Medicines Monitoring Programme, New Zealand Pharmacovigilance Centre) attended until 2:30pm.
Dr C. Cameron (Clinical Pharmacology registrar, Capital and Coast District Health Board) observed the meeting.

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. There were no apologies. Prof. Maling (Chair) left the meeting at 1pm. Prof. Rademaker agreed to act as Chair from this time. Prof. Skegg and Dr Harrison-Woolrych left the meeting at 2:30pm.

1.2 Minutes of the 124^th MARC Meeting

The members agreed that the minutes of the 124^th MARC meeting were a true and accurate record of the meeting. The Acting Chair of that meeting subsequently ratified the minutes.

1.2.1 Report to the Minister's Delegate

The Committee noted that one recommendation from the December 2005 MARC meeting, regarding minute item 2.2.7 Dextropropoxyphene/Paracetamol Combination Products and the Risk of Overdose, had been rejected by the Minister's Delegate on the advice of Medsafe (see minute item 2.1.3 for further details). Following discussion, the Committee supported this decision. They agreed to review this issue again in December 2007.

The Committee noted that that an article reviewed by the MARC at the December 2005 meeting for minute item 2.1.3 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk had since been retracted by the Lancet as the data had been fabricated (see minute item 2.1.1 for further details). Medsafe considered that the Committee's recommendation on this issue did not need to be rescinded. The Committee supported this decision.

1.3 Dates of Future MARC Meetings

The date for the next MARC meeting was confirmed as being Thursday 15 June 2006. The subsequent MARC meetings were scheduled for 14 September 2006 and 14 December 2006.

1.4 Potential Conflicts of Interest

Committee members submitted their Conflict of Interest Declaration forms to the Secretary. The Chair reminded 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 considered to influence the discussions or decisions of the Committee.

Clarification was sought by Medsafe as to whether potential conflicts of interest should be published in detail on Medsafe's web site. It was noted that details of potential conflicts of interest were disclosable under the Official Information Act 1982. It was decided that MARC minutes on the web site should state whether potential conflicts were present or absent, but that details attributing those declarations to individuals should not be published.

1.5 Prescriber Update

1.5.1 Prescriber Update Article for MARC Comment: Stilboestrol - Gone But Not Forgotten.

Reference

1. Paul C, Harrison-Woolrych M. Stilboestrol – Gone But Not Forgotten. Pre-peer review version for MARC comment.

Discussion

The Committee provided the editor of Prescriber Update with comments on the pre-peer review version of the article entitled Stilboestrol - Gone But Not Forgotten. Members suggested Medsafe should forward a post-publication copy of the article to the Treatment Injury and Patient Safety Branch of the Accident Compensation Corporation for their information.

The Chair raised the issue of the editorial peer-review process for Prescriber Update articles. An author of an article currently being finalised had expressed dissatisfaction with part of the editorial process. Medsafe explained that this was a matter between Medsafe and the author, and steps had been taken to resolve the author's concerns.

1.5.2 Schedule of Planned Prescriber Update Articles.

Discussion

The Committee noted the schedule of planned Prescriber Update articles.

2. actions arising

2.1 Report on Actions Arising from the 124^th MARC Meeting, 15 December 2005

Please refer to the minutes of the 124^th MARC meeting, held on 15 December 2005, available on the Medsafe web site at www.medsafe.govt.nz/Profs/adverse/Minutes124.htm for background information surrounding these issues.

2.1.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk.

December 2005 minute item 2.1.3; September 2005 minute item 3.1

Issue

In December 2005, the Committee recommended that non-specific NSAIDs and cardiovascular adverse effects, including congestive heart failure, should be placed on the active monitoring list.

Outcome

On 4 February 2006, subsequent to the December 2005 MARC meeting, the Lancet published a full retraction of the article by Sudbo et al, which was reviewed by the Committee for this agenda item. The retraction occurred in response to confirmation from Prof. Anders Ekbom, who chaired the investigating commission appointed by the University of Oslo, that the paper contained fabricated data. The MARC agreed at the December 2005 meeting that the Sudbo et al study had not added significantly to the body of evidence regarding the risk of cardiovascular events associated with the use of non-specific NSAIDs. Therefore, it was Medsafe's view that the Committee's recommendation to actively monitor this issue did not need to be rescinded.

Discussion

The Committee noted the above and supported Medsafe's decision.

2.1.2 Review of Adverse Reactions of Current Concern

December 2005 minute item 2.1.5; September 2005 minute item 3.3

Issue

In December 2005, the Committee recommended that Medsafe and NZPhvC should discuss how best to formalise processes around the review of Adverse Reactions of Current Concern.

Outcome

As recommended by the MARC in December 2005, Adverse Reactions of Current Concern (ARCC) were now standing agenda items. At every MARC meeting, Medsafe and NZPhvC would provide information on CARM and WHO cases, international regulatory action and recent literature for each ARCC issue. These reports would also provide links to other sections of the dossier which contained information on ARCC, for instance, CARM spontaneous reports and the CARM Quarterly Report.

A trial of the 'adverse reaction of the month' slide for Grand Rounds was in the process of being negotiated and set-up for pilot in February. The first slides had been prepared.

Discussion

The Committee noted the extensive reports prepared for this meeting for the Adverse Reactions of Current Concern (ARCC) issues (see minute items 4.4.1, 2 and 3). They considered that it might prove to be onerous for Medsafe and NZPhvC to prepare such reports for every meeting. NZPhvC agreed to provide the MARC with clarification of the methodology used in reviewing the ARCC issues.

Following discussion under each agenda item, the Committee agreed that ARCC issues should be moved from the standing agenda item list to the active monitoring list. Members also noted the list of issues monitored, and the explanation of the monitoring categories, and asked that the list continue to be updated and included in each dossier.

NZPhvC informed the Committee that the pilot had fallen through, but that a system had been set up for 'adverse reaction of the month' slides to be presented at hospital Grand Rounds. NZPhvC showed the Committee the draft slides that had been prepared. It was explained that this strategy would be gradually implemented around New Zealand. NZPhvC informed the MARC that the slides might require some explanation the first time they were presented, and asked that MARC members make themselves available to attend Grand Rounds if possible. The Committee made several suggestions to NZPhvC for effectively disseminating the slides.

Recommendation

The Committee recommended that Adverse Reactions of Current Concern issues should be moved from the standing agenda item list to the active monitoring list.

2.1.3 Dextropropoxyphene/Paracetamol Combination Products and the Risk of Overdose

December 2005 minute item 2.2.7; September 2005 minute item 2.1.2; June 2005 minute item 3.1

Issue

In December 2005, the Committee recommended that the indications in the data sheets for dextropropoxyphene/paracetamol combination products should be updated to limit use to the treatment of chronic pain of moderate severity for patients in whom treatment with therapeutic doses from alternative therapeutic groups, including combination products, had been used and found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient.

In December 2005, the Committee recommended that Medsafe should request that PHARMAC consider restricting the funding of dextropropoxyphene/paracetamol combination products to Special Authority.

In December 2005, the Committee recommended that Medsafe should explore the option of publishing an article in Prescriber Update recommending that dextropropoxyphene/paracetamol combination products should not be used except in appropriate clinical situations, and to increase awareness of the risk of inadvertent overdose with concomitant alcohol use.

In December 2005, the Committee recommended that the issue of dextropropoxyphene/ paracetamol combination products and the risk of overdose should be reviewed in two years, including analysis of an industry census of patient use, overdose data from the New Zealand Poisons Centre, prescription data and usage data.

Outcome

Medsafe recommended to the Minister's Delegate that he reject the MARC recommendation that "Medsafe should request that PHARMAC consider restricting the funding of dextropropoxyphene/paracetamol combination products to Special Authority" for the following reasons:

• Medsafe considered that Special Authority would not be an effective mechanism for targeting the appropriate patient population.
• These products were currently only partially funded by PHARMAC. Special Authority would increase funding for eligible patients, thereby increasing access to these products.
• This recommendation could be revisited in two years, once some experience in the effects of the other restrictions had been gained.

Medsafe wrote to the dextropropoxyphene/paracetamol combination product sponsors in February 2006 requesting changes to the indications in the data sheets, as above. Additionally, the sponsors were requested to provide Medsafe with proposals for an industry census of patient use of these products, the results of which were to be reviewed by the MARC in December 2007.

The Prescriber Update article was to be drafted once the data sheet changes were finalised.

Discussion

The Committee noted the above and agreed that this issue should be reviewed in December 2007.

2.1.4 Pergolide and Cardiac Valvulopathy.

December 2005 minute item 2.2.10; September 2005 minute item 2.2.4; June 2005 minute item 2.2.6; December 2004 minute item 3.3

Issue

In December 2005, the Committee recommended that Medsafe should ask the pergolide sponsor to send a 'Dear Healthcare Professional' letter reiterating MARC's advice that pergolide should only be used for its approved indications, and specifically advising prescribers that pergolide should not be used off-label to treat restless legs syndrome.

The Committee recommended that the scheduled Prescriber Update article on pergolide and cardiac valvulopathy should be rescinded.

Outcome

Medsafe was informed in February 2006 that a 'Dear Healthcare Professional' letter would be sent to New Zealand prescribers within the next few weeks.

Discussion

The Committee noted that a 'Dear Healthcare Professional' letter had been distributed on 15 February 2006 advising prescribers that pergolide should not be used off-label to treat restless legs syndrome. The Committee agreed that no further regulatory action was required at that time.

2.1.5 Review of Watching Briefs

December 2005 minute item 3.1; September 2005 minute item 3.4

Issue

In December 2005, the Committee recommended that, in the future, pharmacovigilance issues of concern should be monitored and reviewed under one of three categories: watching brief, active monitoring or standing agenda item.

Outcome

The following issues were removed from the watching brief list on recommendation of the MARC in December 2005. These issues were no longer monitored under any of the above three categories:

• Bupropion and Cardiovascular Adverse Effects (December 2005 minute item 3.1.1)
• Selective Serotonin Reuptake Inhibitors (SSRIs) and Withdrawal Reactions (December 2005 minute item 3.1.5)
• Topiramate and Serious Psychiatric Reactions (December 2005 minute item 3.1.8)
• DTaP/IPV/Hep B/HiB Vaccine and Sudden Death (December 2005 minute item 3.1.10)
• Cephazolin and Pancreatitis(December 2005 minute item 3.1.11)
• MMR Vaccine and Arthritis (December 2005 minute item 3.1.12)
• Domperidone and QT Prolongation (December 2005 minute item 3.1.13)
• Over-the-Counter (OTC) Medication Errors (December 2005 minute item 3.1.14)
• Pergolide and Cardiac Valvulopathy (December 2005 minute item 3.1.15)
• Valproate and Foetal Abnormalities (December 2005 minute item 3.1.16)

One watching brief issue remained to be reviewed, namely tramadol and hepatic reactions. This was to be reviewed at the June 2006 MARC meeting.

Discussion

The Committee noted the above and asked that the list of monitored issues be included in the dossier for every meeting.

2.1.6 Selective Serotonin Reuptake Inhibitors (SSRIs) and Haemorrhage – Watching Brief Review

December 2005 minute item 3.1.2

Issue

In December 2005, the Committee recommended that the SSRI data sheets should be updated to adequately address the risk of abnormal bleeding and to be consistent with one another.

In December 2005, the Committee recommended that Medsafe should write a paragraph for publication in Prescriber Update informing prescribers of the risk of abnormal bleeding with SSRIs, and emphasising the risks of co-prescribing NSAIDs/aspirin.

In December 2005, the Committee recommended that SSRIs and haemorrhage should be removed from the watching brief list, following resolution of the above regulatory actions.

Outcome

Medsafe was in the process of contacting the SSRI sponsors regarding the data sheet updates. The Prescriber Update article was to be drafted once the data sheet changes were finalised.

Discussion

The Committee noted the above and agreed that Medsafe should report back to the MARC once these recommendations had been actioned.

2.1.7 COX-2 Inhibitors/Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Impaired Fracture Healing – Watching Brief Review

December 2005 minute item 3.1.3

Issue

In December 2005, the Committee recommended that Medsafe should write again to experts in this area, seeking an updated opinion on the clinical risk of impaired fracture healing with COX-2 inhibitors/NSAIDs.

In December 2005, the Committee recommended that COX-2 inhibitors/NSAIDs and impaired fracture healing should continue to be monitored on the watching brief list.

Outcome

The New Zealand Orthopaedic Association (NZOA) informed Medsafe that none of their New Zealand members had the relevant expertise to offer advice on this issue. The NZOA considered that further clinical studies were required before this question could be answered definitively.

Medsafe had not yet been able to contact any other experts regarding this issue.

Discussion

The Committee noted the New Zealand Orthopaedic Association response and asked that Medsafe continue to attempt to contact experts for advice on this issue.

2.1.8 Rosiglitazone and Pancreatitis – Watching Brief Review

December 2005 minute item 3.1.4

Issue

In December 2005, the Committee recommended that the NZPhvC should contact the UMC suggesting that the data in Vigibase on rosiglitazone and pancreatitis be re-analysed with a view to publication if the signal was considered strong enough.

Outcome

This project had been initiated.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.9 Selective Serotonin Reuptake Inhibitors (SSRIs) and Withdrawal Reactions – Watching Brief Review

December 2005 minute item 3.1.5

Issue

In December 2005, the Committee recommended that Medsafe should review the evidence regarding the risks of withdrawal reactions with citalopram, and consider asking the product sponsors to update the data sheets.

The Committee recommended that SSRIs and withdrawal reactions should be removed from the watching brief list.

Outcome

Medsafe was in the process of reviewing the evidence on this issue.

Discussion

The Committee noted the above and asked that Medsafe report back to the MARC once the evidence had been reviewed on this issue.

2.1.10 Rosiglitazone and Cardiac Failure – Watching Brief Review

December 2005 minute item 3.1.7

Issue

In December 2005, the Committee recommended that all serious or unexpected adverse reactions to rosiglitazone should be on the standing agenda item list.

In December 2005, the Committee recommended that Medsafe should request updated data from GlaxoSmithKline and subsequently consider updating the rosiglitazone data sheet regarding the cardiovascular risks.

In December 2005, the Committee recommended that Medsafe should explore the option of publishing a short paragraph in Prescriber Update on the cardiovascular adverse effects of rosiglitazone, and to remind prescribers about the contraindications and relative contraindications for use. Following further investigation of the literature and case reports by NZPhvC, this article could be extended to also include pioglitazone, and/or other adverse reactions to thiazolidinediones if warranted.

In December 2005, the Committee recommended that NZPhvC should explore the option of presenting adverse reactions to rosiglitazone at Grand Rounds.

Outcome

GlaxoSmithKline provided further data to Medsafe on the cardiovascular safety of Avandia, which was included in the references provided for minute item 3.3.

The decision to extend the breadth of the Prescriber Update article was pending the outcome of the review by NZPhvC.

A trial of an 'adverse reaction of the month' slide for Grand Rounds was in the process of being negotiated and a pilot was scheduled for February. Slides for this issue had been completed and were to be included in the program.

Discussion

See minute item 3.3 for a review of the standing agenda item 'all adverse reactions to rosiglitazone'. See minute item 2.1.2 for discussion on the slides prepared for presentation at Grand Rounds.

2.1.11 Herbal Preparation and Mixed Hepatitis and Jaundice (68104)

December 2005 minute item 4.1.2.1

Issue

In December 2005, the Committee recommended that NZPhvC should obtain a sample of the Korean herbal preparation and provide it to Medsafe for analysis.

Outcome

The NZPhvC contacted the general practitioner reporter, who in turn established from the patient that the patient no longer had a sample of the herbal preparation. Therefore, it was not possible to obtain a sample for analysis.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.12 Nitrofurantoin and Dyspnoea, Cough and Pulmonary Infiltration (67409)

December 2005 minute item 4.1.3.1

Issue

In December 2005, the Committee recommended that Medsafe should consider publishing a paragraph in Prescriber Update reminding prescribers about the importance of monitoring for respiratory adverse effects of nitrofurantoin and informing patients of the warning symptoms.

Outcome

This short reminder was to be authored by Medsafe.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.13 Warfarin/Tramadol and Purpura, Decreased Prothrombin (67421)

December 2005 minute item 4.1.9.1

Issue

In December 2005, the Committee recommended that NZPhvC should investigate whether concomitant administration of norfloxacin and nitrofurantoin could have had an additive effect on the International Normalised Ratio (INR) in this case.

In December 2005, the Committee recommended that NZPhvC should further analyse the other reports of interactions with tramadol in the CARM and WHO databases.

In December 2005, the Committee recommended that an article should be written for publication in Prescriber Update on the interaction between tramadol and warfarin, and if merited, a more extensive article on tramadol adverse effects.

In December 2005, the Committee recommended that Medsafe should ask Pharmaco NZ Ltd to provide assurance that the Zytram data sheet would be updated to address the interaction with warfarin.

Outcome

A report on tramadol interactions was prepared by NZPhvC for this meeting. The potential influence of norfloxacin or nitrofurantoin was also addressed in the report.

The Prescriber Update article on the interaction between tramadol and warfarin was to be authored by NZPhvC, who were to advise if the article would also cover other adverse reactions with tramadol.

Medsafe wrote to Pharmaco in February 2006 to request that the data sheet for Zytram be updated to include details of the potential interaction with warfarin. A response was awaited from Pharmaco.

Discussion

See minute item 4.2.1 for a review of tramadol interactions and serious reactions, including a decision on the Prescriber Update article.

The Committee agreed that Medsafe should report back to the MARC once a response had been received from Pharmaco.

2.1.14 Ezetimibe and Muscle Disorders

December 2005 minute item 4.2.2

Issue

In December 2005, the Committee recommended that Medsafe should consider publishing a paragraph in Prescriber Update on muscle disorders with ezetimibe.

Outcome

This article was to be written by NZPhvC.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2 Report on Actions Arising from Previous Meetings of the MARC

2.2.1 MARC Membership – Vacant Positions

December 2005 minute item 2.2.1; September 2005 minute item 2.1.1; June 2005 minute item 1.1.1.

Issue

In June 2005, the Committee recommended that Medsafe should investigate possible candidates for MARC membership, with expertise in pharmaco-epidemiology.

In December 2005, the Committee was informed that the process to be undertaken for appointing Committee members under the new Minister of Health had been clarified. The Committee asked Medsafe to develop a list of interested candidates for the next MARC meeting.

Outcome

Medsafe had received a verbal expression of interest from a candidate who might be able to fulfil the pharmaco-epidemiology role.

Given the deferral of the establishment of the Australia New Zealand Therapeutic Products Authority (ANZTPA), Medsafe asked that the MARC identify the skill set required to ensure the ongoing operation of the MARC. Medsafe noted that here had been some discussion of skill set identification at previous MARC meetings. Medsafe would use the required skill set to formulate a list of interested candidates with those skills.

Discussion

Following discussion, the Committee agreed that the following skills were required to ensure the ongoing operation of the MARC:

• Epidemiology (there should be an epidemiologist present at every meeting)
• Clinical pharmacology (essential)
• General medicine (could be the same person as the clinical pharmacologist)
• Psychiatry
• General practice (at least two members, for example from urban and rural areas)
• Dermatology
• Paediatrics
• Clinical pharmacy

Therefore, members considered that a pharmaco-epidemiologist, a paediatrician and a clinical pharmacist were urgently required for membership of the MARC. The Committee considered that it would also be of value for members to have interests in woman's health, complementary medicines, immunology and dental health. They noted that the Committee was also required to have two ex officio members, one each from Medsafe and from NZPhvC.

Recommendation

The Committee recommended that Medsafe should investigate appointing a pharmaco-epidemiologist, a paediatrician and a clinical pharmacist to the MARC.

2.2.2 The Legacy of Diethylstilboestrol (DES)

September 2005 minute item 2.1.3; June 2005 minute item 3.2.

Issue

In June 2005, the Committee recommended that the author should be asked to identify and consult with experts in this area, and having done so, write a Prescriber Update article updating prescribers about the current evidence and to remind them about monitoring recommendations.

Outcome

An article on DES had been authored, which was currently undergoing peer-review. A copy was included in the March 2006 dossier for MARC comment.

Discussion

See minute item 1.5.1 for members' comments on a pre-peer review copy of the article entitled Stilboestrol – Gone But Not Forgotten.

2.2.3 Flucloxacillin and Renal Failure Acute, Rash Maculopapular, Pruritus (CARM case 63623)

September 2005 minute item 2.1.11; June 2005 minute item 4.2.1.1

Issue

In June 2005, the Committee recommended that CARM should review the post-mortem report for this case and report back to MARC.

Outcome

The reporter responded to inform the NZPhvC that no autopsy had been performed, therefore, no further information was available.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.4 Phenytoin, Fluorouracil and Ataxia, Dizziness, Drug Level Increased (CARM case 62606)

September 2005 minute item 2.1.10; June 2005 minute items 4.1.10.1

Issue

In June 2005, the Committee recommended that the data sheet for 5-fluorouracil should be updated to address the interaction with phenytoin.

Outcome

Pfizer updated the Dilantin data sheet as requested, in December 2005.

Medsafe was awaiting a response from Mayne Pharma regarding the requested updates to the data sheets for the Mayne Pharma brands of phenytoin and 5-fluorouracil.

Discussion

The Committee expressed disappointment that Mayne Pharma had not responded to this request. They asked that Medsafe report back to the MARC once a response had been received.

2.2.5 Influenza Vaccine and Nausea, Faintness, Fever, Cardiac Arrest (CARM case 66615)

September 2005 minute item 4.1.8.1

Issue

In September 2005, the Committee recommended that CARM should seek further information on case report 66615, influenza vaccine and nausea, faintness, febrile, cardiac arrest, and report back to the MARC.

Outcome

NZPhvC sought further information from the reporter in this case, however, no feedback had been received.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.6 Bisphosphonates and Osteonecrosis of the Jaw

September 2005 minute item 3.2

Issue

In September 2005, the Committee recommended that the Pamisol data sheet should be updated in line with the Aredia and Zometa data sheets. Novartis and Mayne Pharma should highlight osteonecrosis of the jaw as a heading in the 'Warnings and Precautions' sections of their data sheets.

Outcome

Medsafe contacted Mayne-Pharma in November 2005 to request that the Pamisol data sheet be updated in line with the Aredia and Zometa data sheets. A response had not yet been received by Medsafe.

Discussion

The Committee expressed disappointment that Mayne Pharma had not responded to this request. They asked that Medsafe report back to the MARC once a response had been received.

2.2.7 Paroxetine and Use in Pregnancy

September 2005 minute item 3.5

Issue

In September 2005, the Committee recommended that the data sheets for all paroxetine products should be updated as per the proposed data sheet for Aropax.

Outcome

In December 2005, Medsafe informed the Committee that GlaxoSmithKline had agreed to further update the New Zealand data sheet for Aropax to reflect the most recent data, and that Medsafe was in the process of reviewing these changes. The data sheet for Aropax was subsequently updated as required.

Medsafe had not yet requested that the data sheet for the generic brand Paroxetine be updated with the most recent data, but would do so in the near future.

Discussion

The Committee noted the above and asked that Medsafe report back to the MARC once the data sheet changes had been finalised.

2.2.8 Analysis of IMMP Events Reported for Sibutramine

December 2005 minute item 2.1.11; September 2005 minute item 4.2.1

Issue

In September 2005, the Committee recommended that Medsafe should obtain and review the US product information for sibutramine.

Outcome

In December 2005, the Committee was informed that Medsafe had requested that Abbott include dyspepsia/gastritis and bruising/ecchymosis as adverse effects in the sibutramine data sheet. Abbott updated the sibutramine data sheet as requested in February 2006.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

3. pharmacovigilance issues

3.1 Aprotinin and Risks in Cardiac Surgery

References

Medsafe report for the MARC. March 2006

1. FDA Public Health Advisory. Aprotinin Injection (marketed as Trasylol). 8 February 2006.
2. FDA. Questions and Answers on Aprotinin (marketed as Trasylol). 7 February 2006.
3. Mangano DT et al. The Risk Associated with Aprotinin in Cardiac Surgery. N Engl J Med. January 2006. 354(4); 353-365.
4. Cooper J. Indications for and use of Aprotinin in NZ. Email 9 February 2006.
5. Bayer Healthcare Pharmaceuticals. Initial Response to the Mangano et al Publication. 26 January 2006. (Cover letter dated 3 February 2006).
6. Moxey et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database of Systemic Reviews. Abstract only. 1, 2006.
7. Sedrakyan A et al. Effect of Aprotinin on clinical outcomes in coronary artery bypass graft surgery: A systemic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg. 2004;128:442-8
8. Frumento RJ et al. Stroke After Cardiac Surgery: A Retrospective Analysis of the Effect of Aprotinin Dosing Regimens. Ann Thorac Surg 2003;75:479-84
9. Schweizer A et al. Aprotinin does not impair renal haemodynamics and function after cardiac surgery. Br J Anaesth 2000;84:16-22
10. Karkouti K et al. Blood Conservation and Transfusion Alternatives – A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion Accessed early online doi:10.1111/j.1537-2995.2006.00724.x
11. Fauli A et al. Kidney-specific proteins in patients receiving aprotinin at high- and low-dose regimens during coronary artery bypass graft with cardiopulmonary bypass. Euro J Anaesth 2005;22:666-671
12. Fergusson DA. Commentary: The Risk Associated with Aprotinin in Cardiac Surgery. Network for Advancement of Transfusion Alternatives. Accessed online 22 February 2006. http://www.nataonline.com/Art.php3?NumArticle=4064
13. Bayer NZ Ltd. Trasylol solution data sheet. 17 October 2000.
14. Bayer Healthcare. Company Core Data Sheet – Aprotinin. Version 12. 30 November 2005.

Issue

On 26 January 2006, the New England Journal of Medicine (NEJM) published an article by Mangano et al reporting an association between the use of aprotinin in coronary artery bypass graft surgery (CABG) with cardiopulmonary bypass and the development of serious renal and cardiovascular adverse reactions. The study was a three-way comparative, open-label, observational prospective study of three medicines used in CABG to reduce the risk of peri-operative bleeding, namely aprotinin, tranexamic acid and aminocaproic acid. The authors reported an increased risk of renal failure and dialysis with aprotinin versus placebo in patients undergoing complex cardiac surgery (odds ratio (OR) 2.59, 95% confidence interval (CI) 1.36-4.95) and primary surgery (OR 2.34, 95% CI 1.27-4.31). The primary surgery group treated with aprotinin also had a statistically significant increased risk of myocardial infarction, and stroke/encephalopathy. All three agents reduced blood loss to a similar degree. The authors did not report any increased risk of adverse outcomes for patients treated with either tranexamic acid or aminocaproic acid, or with no anti-fibrinolytic treatment.

At the time of this meeting, Trasylol (aprotinin) and Cyclokapron (tranexamic acid) were registered and available in New Zealand. Amicar (aminocaproic acid) had been registered but discontinued. Only aprotinin was approved for use in cardiopulmonary bypass surgery. Information obtained from specialist anaesthetists in New Zealand indicated that, due to cost, tranexamic acid was the most commonly used product. Aprotinin was reserved for use in complicated cases, or in cases where bleeding was considered to be more likely to occur. Data from the product sponsor indicated that approximately 1,500 patients per annum in New Zealand may be treated with aprotinin for a number of different indications, including during CABG surgery.

On 8 February 2006, the United States Food and Drug Administration (FDA) issued a public health advisory based on the Mangano et al paper. The FDA advised clinicians of an apparent increase in risk of complications associated with use of aprotinin, and recommended that clinicians monitor patients exposed to aprotinin for episodes of toxicity to the kidneys, heart and central nervous system. In addition, they advised that physicians should consider limiting use of aprotinin to situations where the clinical benefit of reduced blood loss was essential to patient management and outweighed the potential risks.

In New Zealand, of a total of nine reports for aprotinin in the CARM database since 1981, there were two reports of hypotension in patients exposed to aprotinin during major surgery. In the remaining seven reports the suspect medicine was a urokinase product in which aprotinin was present in very low quantities as an excipient. There were no reports of renal, cardiovascular or cerebrovascular adverse reactions in the CARM database. The New Zealand Trasylol datasheet contained information in the 'Warnings and Precautions' section and in the 'Undesirable Effects' section describing increased risk of myocardial infarction and renal failure in patients undergoing CABG who were treated with aprotinin. The data sheet stated that in several studies the increased risk of cardiovascular events was thought to be secondary to inadequate heparinisation.

Medsafe considered that the main issue was whether the single large-scale observational study published in the NEJM was sufficient to overturn the extensive existing randomised controlled trial data published in the literature. The design of the observational study had a number of problems, including selection bias and likely residual and unidentified confounding. The existing data from randomised studies made a strong case that the use of aprotinin was not associated with an increased risk of renal dysfunction, myocardial infarction or stroke. Further research examining the safety of aprotinin in prospective randomised studies was awaited.

Discussion

The Committee noted the background on this issue, as detailed above, and the reference papers provided. They commented that the Mangano et al paper had a strong design and there had been good attempts made to control for bias and confounding. However, the study also had several limitations. Firstly, the subjects were not randomised which could have resulted in selection bias and confounding by severity of disease. The data included in the paper indicated that the characteristics of the patients in each treatment group were not identical and there was some evidence to suggest that patients treated with aprotinin were more likely to have had pre-existing renal problems than those in the other groups. Additionally, the end-points of the study were related to the condition being treated and therefore the outcomes were likely to be linked to the underlying severity of the disease.

The Committee noted that the results of the Mangano et al study directly contradicted the findings of a number of randomised placebo-controlled studies and meta-analyses, including a Cochrane report. Members noted that most of these earlier studies had small numbers of subjects resulting in them being underpowered. There was also a possibility of selection bias in some of these studies despite the randomisation.

The Committee considered that the Mangano et al study did not provide definitive answers on this issue. They noted that there were four randomised, double-blind, placebo-controlled trials currently being undertaken globally by Bayer HealthCare, the results of which would be provided to Medsafe in due course. There was also at least one other three-way randomised trial being undertaken. Bayer HealthCare had also informed Medsafe that they were undertaking an integrated safety analysis on the renal, cardiac and cerebrovascular safety of aprotinin, and were conducting a thorough literature search. Again, the results would be provided to Medsafe in due course.

The Committee considered that it would be of value for Medsafe to write to New Zealand's five cardiac surgery units (Auckland, Waikato, Wellington, Christchurch and Dunedin) to inform them of the findings of the Mangano et al study in the context of previous research on this issue. The units should also be asked to comment on their current practice regarding the use of anti-fibrinolytics in cardiac surgery, whether they have any concerns about aprotinin and what the basis of any concerns might be. Members also considered that this issue should be placed on the watching brief list.

Recommendations

The Committee recommended that Medsafe should write to New Zealand's cardiac surgery units, informing them of the findings of recent research on aprotinin in cardiac surgery, and asking for their expert opinion.

The Committee recommended that the issue of aprotinin and the risks of cardiovascular, renal and cerebrovascular adverse reactions in cardiac surgery should be placed on the watching brief list.

3.2 Anti-Tumour Necrosis Factor (TNF) Alpha Agents and the Risk of Hepatitis B Reactivation

References

Medsafe report for the MARC. March 2006.

1. Health Canada Endorsed Important Safety Information on anti-TNFα Therapy (2006): ENBREL (etanercept), HUMIRA (adalimumab), and REMICADE (infliximab). http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/anti-tnf_therap_hpc-cps_e.html.
2. Xunrong L et al (2001). Hepatitis B virus (HBV) reactivation after cytotoxic or immunosuppressive therapy- pathogenesis and management. Reviews in Medical Virology; 11:287-299. DOI: 10.1002/rmv.322.
3. Esteve M et al (2004). Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis. Gut; 53:1363-1365. doi:10.1136/gut.2004.040675
4. Ostuni P et al (2003). Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis; 62:686-687.
5. Wendling D et al (2005) Reactivation of a latent precore mutant hepatitis B virus related chronic hepatitis during infliximab treatment for severe spondyloarthropathy. Ann Rheum Dis; 64: 788-789. doi: 10.1136/ard.2004.031187
6. Wyeth response to Medsafe (2006). Enbrel- Health Canada Notification on TNF inhibitors and reactivation of Hepatitis B.
7. Schering-Plough. Remicade Powder for Injection data sheet. 17 December 2004.
8. Wyeth NZ Ltd. Enbrel Powder and Water for Injection data sheet. 28 October 2004.
9. Abbott Australasia Pty Ltd. Humira Solution for Injection data sheet. 15 April 2004.

Issue

On 13 January 2006, the Canadian sponsors for the anti-tumour necrosis factor (anti-TNF) alpha agents Enbrel (etanercept), Remicade (infliximab) and Humira (adalimumab) distributed a Health Canada-endorsed 'Dear Healthcare Professional' letter informing Canadian prescribers of the following information on the risk of hepatitis B virus (HBV) reactivation:

Based on review of recent post-marketing reports:

• Hepatitis B virus (HBV) reactivation has been reported very rarely in patients with chronic hepatitis B infection receiving the anti-TNF alpha agents ENBREL, HUMIRA, and REMICADE.
• Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating anti-TNF alpha therapy. Those identified as chronic HBV carriers (i.e. surface antigen positive) should be monitored for signs and symptoms of active HBV infection throughout the course of therapy and for several months following discontinuation of therapy.
• Reactivation of HBV is not unique to anti-TNF alpha agents and has been reported with other immunosuppressive drugs.

At the time of this meeting there were three anti-TNF agents with ministerial consent for marketing in New Zealand. Infliximab (Remicade) and adalimumab (Humira) are monoclonal antibodies directed against TNF alpha, and etanercept (Enbrel) is a soluble TNF-receptor that binds to TNF and prevents interaction with its receptors. At the time of this meeting Enbrel was fully funded for the treatment of juvenile rheumatoid arthritis and Humira was fully funded for the treatment of severe rheumatoid arthritis, under Special Authority, provided the initial application was made by a specialist.

Although New Zealand as a whole was considered to be a low prevalence region for chronic HBV infection, there was a relatively high prevalence of infection in people of Māori, Pacific Island and Asian ethnicity. A study published in 2005 (Robinson et al, NZMJ) estimated that there were more than 65,000 people with chronic HBV in New Zealand, the majority of whom did not know that they were infected. Therefore, Medsafe considered that any medicine or class of medicines that might increase the risk of HBV reactivation might have significant public health consequences in New Zealand.

The diagnosis of HBV reactivation requires demonstration of preceding chronic HBV infection followed by seroconversion to active HBV infection. Of note, HBV reactivation follows a two-stage process. There is an initial period of enhanced viral replication (during immunosuppression) followed by rapid immune-mediated destruction of hepatocytes upon recovery of immune function. The majority of the damage to hepatocytes occurs following discontinuation of the cytotoxic or immunosuppressive therapy.

There had not been any reports to CARM of HBV reactivation in association with Remicade, Enbrel or Humira. The New Zealand anti-TNF product data sheets contained extensive information on the risk of infection in association with the use of these medicines and, in particular, the risk of reactivation of tuberculosis. However, there was no specific information included on a potential risk of reactivation of chronic HBV infection.

In January 2006, Medsafe contacted the New Zealand anti-TNF sponsors to request that the New Zealand data sheets be updated in line with the changes required by Health Canada. Abbott Australasia informed Medsafe that the New Zealand data sheet for Humira would be updated as soon as the company core data sheet changes had been finalised. Schering-Plough proposed changes to the New Zealand Remicade data sheet in the 'Warnings and Precautions; Hepatobiliary Events' and 'Other Infections' sections.

In January 2006, Wyeth informed Medsafe that, due to the inadequacies of the currently available data, the New Zealand Enbrel data sheet would not be updated to include any information on the risk of HBV reactivation. However, in response to a second request from Medsafe, Wyeth agreed to reconsider the issue.

Medsafe considered that, based on current evidence, it was not possible to infer a causal relationship between anti-TNF therapy and the development of HBV reactivation. However, HBV reactivation was a well-recognised complication of immunosuppressive therapy and hence it was biologically plausible that medicines with immunomodulatory effects, such as the anti-TNF agents, might increase the risk of HBV reactivation.

Medsafe provided the Committee with a review of the currently available evidence on this issue. These data were limited to case reports and uncontrolled studies (usually involving infliximab), the majority of which were confounded by the concomitant use of other immunosuppressants. In addition, it was likely that HBV reactivation was under-reported as the diagnosis required serological evidence of both chronic HBV infection and HBV reactivation, and these markers were not always measured in patients with abnormal liver function tests during anti-TNF therapy.

Despite the limitations of the available data, Medsafe considered that there was sufficient evidence to support a precautionary stance on this issue, particularly in view of the high prevalence of chronic HBV infection in New Zealand's Māori, Pacific Island and Asian communities.

Discussion

The Committee noted the background on this issue, as detailed above, and the reference papers provided.

Medsafe informed the Committee that the issue of hepatitis B virus (HBV) reactivation with anti-TNF agents had been discussed with a consultant rheumatologist, who advised that rheumatologists might not have been aware of this issue. He advised that rheumatologists did not routinely test for HBV markers in patients prescribed anti-TNF agents. Additionally, abnormal liver function tests were not unexpected in these patients and therefore rheumatologists would have been unlikely to investigate further. He supported dissemination of information on this issue.

The Committee noted that chronic HBV infection was a considerable public health issue in New Zealand, particularly among Māori, Pacific Island and Asian peoples. They noted that the incidence of HBV was higher in particular geographical areas, such as the central North Island. They commented that due to the different epidemiology of HBV infection in New Zealand compared to other countries, including Australia, it was possible that a different risk-management strategy would be required in New Zealand to manage the risks of HBV reactivation.

NZPhvC commented that the indications and funding for anti-TNF agents in New Zealand were broadening, which was likely to lead to wider use in the future. The Committee noted that Humira had only been funded since January 2006 and hence usage was likely to increase. Members considered that this would increase the potential public health impact of HBV reactivation.

Medsafe informed the Committee that Wyeth had responded to a second request to update the Enbrel data sheet. Wyeth stated that they were awaiting the results of negotiations with other regulators before making data sheet changes in New Zealand. Members were extremely concerned that Wyeth had not yet complied with Medsafe's request. They considered that Wyeth's response was inappropriate and asked that Medsafe contact Wyeth again to inform them of the findings of the MARC and to reiterate the request for data sheet changes.

The Committee commented that, although anti-TNF agents were only funded under Special Authority when the initial application was made by a specialist, general practitioners were likely to be involved in continuing care of these patients. Therefore, members considered that all prescribers should be made aware of the issue of HBV reactivation via a 'Dear Healthcare Professional' letter. The letter should:

• inform prescribers of the changes to the anti-TNF agent data sheets.
• advise prescribers to test hepatitis B serology in all patients prior to initiating treatment with an anti-TNF agent.
• advise prescribers that patients should continue to be monitored following discontinuation of therapy, as the risk of HBV reactivation may be greatest at this time.

Members commented that it was likely that the anti-TNF agents could reactivate other infectious viral diseases, such as hepatitis C virus (HCV) or human immunodeficiency virus (HIV). They asked that Medsafe continue to monitor the literature for risks of reactivation of other viral infections.

The Committee agreed that it was not necessary to publish a Prescriber Update article in addition to the 'Dear Healthcare Professional' letter at this time. The need for an article could be reviewed in one year.

Recommendations

The Committee recommended that Medsafe should require the sponsors of all three anti-tumour necrosis factor alpha agents to include a consistent warning statement in the data sheets regarding the risk of hepatitis B virus reactivation, including the need to test hepatitis B serology prior to initiating therapy.

The Committee recommended that Medsafe should disseminate a 'Dear Healthcare Professional' letter to all prescribers, once the data sheet changes for the anti-tumour necrosis factor alpha agents had been finalised.

The Committee recommended that the issue of hepatitis B reactivation with anti-tumour necrosis factor alpha agents should be placed on the active monitoring list.

3.3 All Serious or Unexpected Adverse Reactions to Rosiglitazone: Standing Agenda Item

References

1. NZPhvC report for MARC. Rosiglitazone - CARM and WHO reports. March 2006.
2. Medsafe report for MARC. Rosiglitazone – literature review. March 2006.
3. GlaxoSmithKline Regulatory Affairs. Rosiglitazone – Further Interim Results from Retrospective Analysis of Cardiovascular Events in Clinical Trials. 25 January 2006.
4. Shoko M. et al. Antidiabetic Drugs and Heart Failure Risk in Patients With Type 2 Diabetes in the U.K. Primary Care Setting. Diabetes Care Vol 28, Number 1. Jan 2005.
5. Masoudi FA et al. Thiazolidinediones, Metformin, and Outcomes in Older Patients with Diabetes and Heart Failure. Circulation. 2005;111:583-590.
6. Hartung DM et al. Risk Of Hospitalization for Heart Failure Associated with Thiazolidinedione Therapy: A Medicaid Claims-Based Case-Control Study. Pharmacotherapy. 25(10):1329-36, October 2005.
7. Marceille JR et al. Chronic Heart failure-related interventions after starting rosiglitazone in patients receiving insulin. Pharmacotherapy 2004;24(10):1317-1322.
8. Nissen SE et al. Effect of Muraglitazar on Death and Major Adverse Cardiovascular Events in Patients with Type 2 Diabetes Mellitus. JAMA. November 23/30, 2005 –Vol 294, No 20.
9. Nesto et al. Thiazolidinedione Use, Fluid Retention, And Congestive Heart Failure - A consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care. Volume 27, number 1. January 2004.
10. Home PD et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation in Diabetes (RECORD): study design and protocol. Diabetologia (2005) 48: 1726-1735.
11. Levin F et al. Rosiglitazone – induced proptosis. Arch Opthalmol. 2005 Jan; 123(1):119-21.
12. Colucciello M. Vision loss due to macular oedema induced by rosiglitazone treatment of diabetes mellitus. Arch Opthalmol. 2005 Sept;123(9):1273-5
13. Digman et al. Leukopenia and Thrombocytopenia Caused by Thiazolidinediones. Ann Int Med. 143(6): 465-6
14. GlaxoSmithKline NZ Ltd. Avandia tablets data sheet. 15 November 2004. www.medsafe.govt.nz/profs/Datasheet/a/Avandiatab.htm

Issue

In December 2005, the MARC reviewed the list of existing watching briefs. At that time there were three issues involving rosiglitazone on the watching brief list, namely pancreatitis, cardiac failure and lipid abnormalities. One of the Committee's recommendations was that all adverse reactions to rosiglitazone should be placed on the standing agenda item list. Therefore, for this meeting an extensive report was provided to the MARC, detailing case reports to CARM and the World Health Organisation (WHO), and recent literature.

CARM and WHO data indicated that fluid retention and cardiac failure were numerically and statistically the most frequent adverse reactions attributed to rosiglitazone. The WHO data indicated that hepatobiliary reactions were the next most prominent group. Dyslipidaemias were also documented in both databases and confirmed in the literature. Macular oedema had recently been recognised and prescribers had been informed of this issue. Hepatic disorders were also of concern as the first thiazolidinedione (glitazone), troglitazone, was withdrawn due to hepatotoxicity.

NZPhvC suggested that a number of suspected reactions should be monitored if they were not yet adequately described in the literature. In particular, foetal aortic stenosis, anaemia, serious cardiovascular disorders, serious hepatic disorders, arthritis, pancreatitis, salivary gland enlargement/sialoadenitis, alopecia and skin ulceration. NZPhvC noted that myocardial infarction and other manifestations of ischaemic heart disease were difficult to assess from spontaneous reports, particularly when the patients had multiple risk factors. However, in view of the dyslipidaemia reports NZPhvC considered that cardiovascular adverse events should continue to be monitored. There were similar difficulties in assessing the cases of neoplasms from spontaneous reports. NZPhvC considered that effects on renal function should also be monitored.

The literature review found further studies examining the signal of rosiglitazone with myocardial infarction and congestive cardiac failure. There were also further case reports of the use of rosiglitazone associated with macular oedema and proptosis, and one well documented case of leucopenia and thrombocytopenia associated with sequential rosiglitazone and pioglitazone treatment.

Medsafe considered that the data contained in the reviewed studies did not resolve any of the possible signals previously identified for rosiglitazone. Medsafe noted that it would be several years before a prospective, randomised study would deliver definitive answers on the risks with rosiglitazone.

At the time of this meeting the data sheet for Avandia (rosiglitazone) included information about increased risk of fluid retention and cardiac failure in the 'Warnings and Precautions' section. Oedema, weight gain and fluid retention were listed as common side effects of rosiglitazone monotherapy. Congestive cardiac failure, pulmonary oedema and events typically associated with myocardial ischaemia were listed as common side effects when rosiglitazone was added to insulin therapy in reviews of clinical trial adverse events. The section on 'Post-marketing Data' included congestive cardiac failure and pulmonary oedema as rare adverse events. While rosiglitazone was not funded by PHARMAC at the time of this meeting, Medsafe considered that the data sheet for rosiglitazone should be updated to reflect the emerging information about rosiglitazone monotherapy and congestive cardiac failure.

While possible new signals for the glitazone group of agents continued to emerge, Medsafe considered that the data did not warrant inclusion of rosiglitazone as a standing agenda item. Medsafe recommended that it should be removed from this category and added to the active monitoring list.

Discussion

The Committee noted the background on this issue, as detailed above, and the reference papers provided.

NZPhvC informed the Committee that an article was being written on salivary gland enlargement and sialoadenitis for submission to the Uppsala Monitoring Centre's Signal publication. Additionally, NZPhvC informed the MARC that they were undertaking further investigation into rosiglitazone and serious hepatic or cardiovascular adverse effects in the WHO database.

NZPhvC commented that there was evidence from international spontaneous reports that glitazones increase the risk of congestive cardiac failure, alone or in combination with insulin or other oral hypoglycaemic therapies, and the Committee agreed with this assessment. NZPhvC observed that the evidence for the exacerbation of existing cardiac failure was limited. Members noted the Shoko et al cohort study on cardiac failure risk. They commented that the findings of this study reiterated anecdotal evidence that the risk of congestive cardiac failure was highest in the first year of treatment, then subsequently decreased.

The Committee noted that GlaxoSmithKline had informed Medsafe that the core safety information for Avandia had been updated with respect to congestive cardiac failure. Members considered that the New Zealand data sheet should be similarly updated with the current evidence on this issue.

Medsafe reminded the Committee that in December 2005 they had recommended that a short paragraph be published in Prescriber Update the on the cardiovascular adverse effects of rosiglitazone, and to remind prescribers about the contraindications and relative contraindications for use. Following further investigation of the literature and case reports by NZPhvC, this article could be extended to also include pioglitazone, and/or other adverse reactions to thiazolidinediones if warranted (see minute item 2.1.10). The Committee agreed that this recommendation remained appropriate.

The Committee considered that, in the future, monitoring should be extended to include pioglitazone. Pioglitazone was fully funded at the time of this meeting and therefore usage was expected to be higher than for rosiglitazone. Members considered it would be valuable to assess whether the potential adverse effects identified for rosiglitazone were class effects. The Committee discussed whether adverse reactions to rosiglitazone and pioglitazone should be placed on the Adverse Reactions of Current Concern list.

The Committee recommended under minute item 2.1.2 that Adverse Reactions of Current Concern issues should be moved from the standing agenda item list to the active monitoring list.

Recommendations

The Committee recommended that Medsafe should ask GlaxoSmithKline to update the Avandia data sheet with the most recent evidence on the risk of congestive cardiac failure with rosiglitazone.

The Committee recommended that the issue of all adverse reactions to rosiglitazone should be removed from the standing agenda item list.

The Committee recommended that all adverse reactions to rosiglitazone and pioglitazone should be placed on the Adverse Reactions of Current Concern (ARCC) list. (Note: All ARCCs are monitored on the active monitoring list.)

4. matters arising from the new zealand pharmacovigilance centre

Note: In the comment associated with each report, the case has been given a causality designation using terms and definitions developed by the WHO. The precise definitions are available on the website of the WHO Collaborating Centre 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 the terms used by CARM and MARC can be accessed by hyperlink at each causality designation.

4.1 Centre for Adverse Reactions Monitoring (CARM) Case Reports

4.1.1 Deaths

4.1.1.1 Cotrimoxazole / quinapril / digoxin / metoprolol / spironolactone / potassium chloride and acute renal failure, hyperkalaemia, bradycardia and cardiac arrest/myocardial infarction [death] (69337)

Discussion

NZPhvC informed the Committee that in the CARM database for co-trimoxazole there were a total of 455 reports, with two for hyperkalaemia, six for renal impairment/failure and two for interstitial nephritis.

The Committee noted that the data sheet for Trisul (co-trimoxazole) contained information in the 'Warnings and Precautions' section advising caution in the elderly, and in the 'Adverse Reactions' section on hyperkalaemia and impaired renal function.

NZPhvC considered that diarrhoea in a patient taking diuretics, leading to dehydration, may well have been the cause of this patient's renal failure and that quinapril may have then compounded this. In the presence of renal failure the combination of quinapril, potassium supplements and spironolactone probably caused the hyperkalaemia. The elevated digoxin levels due to the renal failure may have caused the bradycardia. However, NZPhvC noted that the diarrhoea was controlled on discharge and her serum creatinine was not elevated, therefore they considered it was possible that co-trimoxazole had triggered the renal failure.

Members noted that this patient was elderly, with complex co-morbidity. Members noted that the patient had experienced a sudden deterioration over three days, and that this was likely to have been due to decreased renal blood flow. They considered that this was more likely to have been a haemodynamic event secondary to her underlying medical conditions than the influence of medications.

The causal association with cotrimoxazole, quinapril, digoxin, metoprolol, spironolactone and potassium chloride was deemed to be 'possible' for renal failure acute, hyperkalaemia, bradycardia, cardiac arrest/myocardial infarction. The Committee agreed that no further regulatory action was required at that time.

4.1.1.2 Drotrecogin alpha and intracranial haemorrhage [death] (70007)

Discussion

The Committee noted that drotrecogin alpha had anti-thrombotic, profibrinolytic and anti-inflammatory properties. It was indicated for use in the reduction of mortality in adult patients with severe sepsis (i.e. sepsis associated with acute organ failure) who had a high risk of death as determined by APACHE II(I), a scoring system based on the patient's general health and the severity of their illness. Use was contraindicated in patients with a high risk of bleeding.

The Committee noted that, anecdotally, usage of this product in New Zealand was likely to be small. Members commented that most New Zealand hospitals have protocols in place for the use of drotrecogin alpha. They noted that the literature supported the risk of bleeding.

The causal association with drotrecogin alpha was deemed to be 'possible' for intracranial haemorrhage. The Committee agreed that no further regulatory action was required at that time.

4.1.1.3 Imatinib and malignant neoplasm [death] (69422)

Discussion

The Committee noted that this patient died of a progression of disease, and considered that this was a case of treatment failure rather than an adverse reaction.

NZPhvC explained that all reports of deaths were required to be brought to the MARC, and that a summary list of all deaths was also presented in the Quarterly Report.

The causal association with imatinib was deemed to be 'unclassified' for malignant neoplasm. The Committee agreed that no further regulatory action was required at that time.

4.1.1.4 Imatinib and malignant neoplasm [death] (69425)

Discussion

The Committee noted that this patient died of a progression of disease, and considered that this was a case of treatment failure rather than an adverse reaction.

The causal association with imatinib was deemed to be 'unclassified' for malignant neoplasm. The Committee agreed that no further regulatory action was required at that time.

4.1.1.5 Octreotide and myocardial infarction, adrenal cortex dysplasia, hyperparathyroidism [death] (69423)

Discussion

NZPhvC informed the Committee that no evidence had been found in the WHO database, the literature or in the product data sheet for an association between octreotide and the adverse reactions experienced in this case. The Committee agreed that the adverse reactions in this case were unlikely to be associated with octreotide.

The causal association with octreotide was deemed to be 'unlikely' for myocardial infarction, adrenal cortex dysplasia and hyperparathyroidism. The Committee agreed that no further regulatory action was required at that time.

4.1.1.6 Venlafaxine / cilazapril and pancreatitis, abdominal pain, vomiting, fever [death] (69410)

Discussion

Also see minute item 4.1.8.6 for a further report for the same patient.

NZPhvC informed the Committee that in the CARM database there were six reports of pancreatitis with cilazapril from a total of 272 reports, and for venlafaxine there were no reports of pancreatitis from a total of 15 reports. In the WHO data base the IC values were negative for pancreatitis with both cilazapril and venlafaxine. The product data sheet for Efexor (venlafaxine) stated that pancreatitis was very rare, and the data sheet for Inhibace (cilazapril) stated that isolated cases of pancreatitis had been reported. In the literature there was a case series of pancreatitis with ACE-inhibitors. There were no literature references found for pancreatitis with venlafaxine.

The Committee commented that it was possible that this case was of an acute exacerbation of chronic pancreatitis. The Committee considered that the issue of pancreatitis with venlafaxine warranted monitoring and asked that it be placed on the watching brief list.

The causal association with venlafaxine and cilazapril was deemed to be 'possible' for pancreatitis, abdominal pain, vomiting and fever.

Recommendation

The Committee recommended that the issue of venlafaxine and pancreatitis should be placed on the watching brief list.

4.1.2 Alimentary Medicines

4.1.2.1 Ranitidine / pantoprazole and gynaecomastia (69227)

Discussion

NZPhvC informed the Committee that in the CARM database of a total of 252 reports for ranitidine there were 6 reports of gynaecomastia in adults. There were no reports of gynaecomastia for pantoprazole, although for omeprazole there were 6 reports of gynaecomastia in adults from a total of 399 reports. In the WHO database NZPhvC found reports of gynaecomastia attributed to ranitidine, pantoprazole and also omeprazole, but in none of them was the route of administration transplacental or via breast milk. NZPhvC could find no literature reports of gynaecomastia occurring because of transplacental or transmammary transfer of these or related medicines.

The Committee commented that transient gynaecomastia is common in male and female newborns, and usually resolves in a few weeks. They considered that it would be of value for NZPhvC to contact the reporter in this case to ask about resolution of the condition.

Members considered that it would be of value for NZPhvC to seek expert advice from a pediatrician regarding the epidemiology and natural history of gynaecomastia in newborns and bring the results back to the MARC.

The causal association with ranitidine and pantoprazole was deemed to be 'possible' for gynaecomastia.

Recommendations

The Committee recommended that NZPhvC should contact the reporter in this case (69227) to ask about resolution of the gynaecomastia in this three-week-old baby.

The Committee recommended that NZPhvC should seek expert advice from a paediatrician on gynaecomastia in newborns.

4.1.3 Alternative Medicines

4.1.3.1 GRINZ party pill and convulsion (67975)

Discussion

The Committee noted that all adverse reactions to complementary and alternative medicines were Adverse Reactions of Current Concern.

NZPhvC informed the Committee that in the CARM database there were eight reports for party pill products, nine reports for benzylpiperazine (BZP)–containing products and one report for a trifluoromethylphenylpiperazine (TFMPP)-containing product. Two of the reports, other than this one and the following case report (69326), were associated with convulsions. Members commented that a study undertaken at Christchurch Hospital (2005) had reported 15 episodes of seizure following BZP ingestion.

Members commented that the potential for BZP to lower the seizure threshold was anecdotally well known from its use in animals.

Members queried whether it was appropriate for case reports of adverse reactions to medicines taken for recreational purposes to be brought to the MARC. Medsafe and NZPhvC agreed that only case reports of adverse reactions to medicines taken for therapeutic purposes should be brought to the MARC.

The Committee commented that it might be valuable for the Expert Advisory Committee on Drugs (EACD) to be provided with CARM data on adverse reactions to party pill products.

The causal association with GRINZ was deemed to be 'possible' for convulsion.

Recommendations

The Committee recommended that, in the future, case reports of adverse reactions to products taken for recreational purposes should not be brought to the MARC.

The Committee recommended that NZPhvC should discuss with the Expert Advisory Committee on Drugs (EACD) the possibility of providing CARM adverse reaction data for party pill products to the EACD.

4.1.3.2 Party pill BZP (not otherwise classifiable) and tonic-clonic convulsions (69326)

Discussion

The Committee noted that all adverse reactions to complementary and alternative medicines were Adverse Reactions of Current Concern.

See minute item 4.1.3.1 for discussion and recommendations on this issue.

The causal association with party pill BZP (not otherwise classifiable) was deemed to be 'possible' for tonic-clonic convulsions.

4.1.3.3 Slimfast and fever, neutropenia (69406)

Discussion

The Committee noted that all adverse reactions to complementary and alternative medicines were Adverse Reactions of Current Concern.

NZPhvC informed the Committee that Slimfast contained 60mg benzylpiperizine (BZP) among other herbal ingredients. The Committee noted that this product was being taken for a therapeutic purpose, namely weight loss. The Committee queried whether Medsafe's compliance team were aware of this product and the therapeutic claims being made.

NZPhvC informed the Committee that in the WHO database for ginkgo biloba there were five reports of agranulocytosis, one of granulocytopenia and six of leucopenia.

The causal association with Slimfast was deemed to be 'probable' for fever and neutropenia.

Recommendation

The Committee recommended that the Medsafe pharmacovigilance team should determine whether Medsafe's compliance team were aware of Slimfast and the therapeutic claims being made.

4.1.4 Antithrombotic Medicines

4.1.4.1 Enoxaparin and respiratory tract malformation (69949)

Discussion

NZPhvC informed the Committee that in the CARM database there were a total of 50 reports for enoxaparin, of which there were none for foetal disorders. Enoxaparin was Australian Drug Evaluation Committee (ADEC) pregnancy category C (drugs which, owing to their pharmaceutical effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible).

Members noted that DrugDex 2005 stated enoxaparin was the anticoagulant of choice for pregnant women at risk of venous thrombosis.

The causal association with enoxaparin was deemed to be 'possible' for respiratory tract malformation. The Committee agreed that no further regulatory action was required at that time.

4.1.4.2 Heparin and thrombocytopenia (69852)

Discussion

NZPhvC informed the Committee that this case was one of a cluster of four cases of heparin-induced thrombocytopenia (HIT) which occurred in one centre when the Artex brand of heparin became unavailable due to supply difficulties (also see minute item 4.1.4.3). All except one of the patients had undergone coronary artery bypass graft surgery (CABG). The vein grafts had been soaked in the Artex brand of heparin and the patients were administered a different brand. There had been no further cases reported following this cluster.

NZPhvC explained that CARM had contacted drug information pharmacists at the three other main centres, as well as a clinical pharmacologist and a renal physician to ascertain whether they were aware of an increase in cases of HIT, or an increase in usage of danaparoid. The clinical pharmacologist and the renal physician did not consider that the numbers of cases of HIT in their hospitals were greater than expected. CARM was asked by the clinical pharmacologist to ascertain experience in other countries, however responses had not yet been received.

Members noted that thrombocytopenia was a well known adverse reaction to heparin.

The causal association with heparin was deemed to be 'possible' for thrombocytopenia and brand switch. The Committee agreed that no further regulatory action was required at that time, however asked that NZPhvC report back once experience in other countries was known.

4.1.4.3 Heparin and antibodies drug specific (69900)

Discussion

See minute item 4.1.4.2 for discussion and recommendations on this issue.

The causal association with heparin was deemed to be 'probable' for antibodies drug specific. The Committee agreed that no further regulatory action was required at that time, however asked that NZPhvC report back once experience in other countries was known.

4.1.5 Dermatological Medicines

4.1.5.1 Tacrolimus / azathioprine / prednisone and skin disorder, pustular rash (69948)

Discussion

NZPhvC informed the Committee that the CARM database held the following reports:

• Tacrolimus – total reports 12, foetal disorders 0, pustular skin reactions 0.
• Azathioprine – total reports 99, foetal disorders 0, acneiform rash 1.
• Prednisone - total reports 110, foetal disorders - death intrauterine, multiple malformations 1, acne 1.

NZPhvC explained that DrugDex 2005 stated a causal relationship between tacrolimus and teratogenic effects in humans had not been found. For azathioprine given in pregnancy DrugDex stated reduced immunoglobulin levels and infections were known adverse effects for the infant. Also, it was stated that severe combined immunodeficiency had occurred in a preterm infant following maternal administration of azathioprine and prednisone throughout pregnancy.

Members noted that this infant had been treated with antibiotics, therefore bacterial aetiology was possible. They commented that tacrolimus was known to be associated with secondary infections. Members commented that a pustular rash of the newborn was common and was usually inflammatory rather than infective.

The Committee asked that all three medicines be recorded as suspect in this case and that the reaction term 'skin malformation' should be changed to 'skin disorder'.

The causal association with tacrolimus, azathioprine and prednisone was deemed to be 'possible' for skin disorder and rash pustular.

Recommendation

The Committee recommended that azathioprine and prednisone should be added to the list of suspect medicines in this case (69948) and that the reaction term 'skin malformation' should be changed to 'skin disorder'.

4.1.6 Hormones

4.1.6.1 Somatropin and enuresis, congenital anomaly, lipoma (70008)

Discussion

The Committee noted that a tethered spinal cord is a congenital anomaly which may manifest symptoms in mid-childhood. The influence of somatropin might have complicated the condition due to its effects on growth processes. Members noted that Floating-Harbor syndrome includes a range of structural malformations including genitourinary malformations.

Members considered that the adverse reaction term 'congenital anomaly' did not correctly describe the situation in this case, and asked that CARM find a more appropriate term.

The causal association with somatropin was deemed to be 'possible' for enuresis, congenital anomaly (to be reviewed) and lipoma.

Recommendation

The Committee recommended that CARM should find a more appropriate reaction term than 'congenital anomaly' for this case (70008).

4.1.7 Musculoskeletal Medicines

4.1.7.1 Alendronate and oculomotor nerve paralysis, conjunctivitis, exophthalmos, limb pain, oedema (69660)

Reference

Kiuru et al. Bisphosphonates and ocular side effects. Poster presented by the Uppsala Monitoring Centre, 2005.

Discussion

NZPhvC informed the Committee that in the CARM database there were a total of 157 reports for alendronate, of which there were 12 ocular reactions including six of conjunctivitis, scleritis or uveitis. One report of optic neuritis was considered non-causal. There was one report of diplopia when reading. There were three reports of leg oedema with alendronate, nine of myalgia, one of pain limb and seven of synovitis.

The Committee was provided with a poster reporting ocular reactions to bisphosphonates, derived from Vigibase (the WHO database). The paper concluded "It appears that ocular inflammation can occur when any member of this class of medicine is used and healthcare professionals should therefore be aware of this possibility. Recognition of adverse ocular events in association with bisphosphonate therapy should alert clinicians to the need for ophthalmic evaluation and possibly consideration of discontinuation of therapy.

NZPhvC informed the Committee that a Prescriber Update article on the inflammatory adverse effects of alendronate was being written by NZPhvC.

The Committee commented that it was not possible to determine from the information provided the aetiology of the limb pain, for example, oedema or inflammation.

The causal association with alendronate was deemed to be 'probable' for oculomotor nerve paralysis, conjunctivitis, exophthalmos, limb pain and oedema. The Committee agreed that no further regulatory action was required at that time.

4.1.8 Psychiatric Medicines

4.1.8.1 Citalopram / fentanyl and neonatal respiratory depression (69860)

Discussion

The Committee noted that the issue of SSRI antidepressants and teratogenicity was on the watching brief list.

The Committee noted that the neonate in this case required re-ventilation between 16 and 46 hours old. They commented that the half-life of fentanyl was short (about 4 hours) and that the half-life of citalopram was about one and a half days. Therefore, citalopram was more likely to be associated with the continued respiratory depression in this case, although fentanyl was also implicated.

NZPhvC informed the Committee that the neonatal effects of maternal selective serotonin reuptake inhibitor (SSRI) use were well documented in the literature, including breathing and suction problems. These effects had been noted with all SSRI products.

The Committee noted that the current data sheets for citalopram products made no reference to neonatal effects, and agreed that the data sheets should be updated.

The causal association with citalopram and fentanyl was deemed to be 'probable' for neonatal respiratory depression.

Recommendation

The Committee recommended that Medsafe should ask the citalopram product sponsors to update the data sheets with information on the risks to neonates following maternal use.

4.1.8.2 Paroxetine and imperforate anus, genital malformation (69579)

Discussion

The Committee noted that the issue of SSRI antidepressants and teratogenicity was on the watching brief list.

Also see minute items 4.1.8.3 and 4 for further case reports of congenital abnormalities with paroxetine.

The Committee queried whether it would be valuable to provide the Therapeutic Goods Administration (TGA) with CARM data on adverse reactions to medicines taken in pregnancy for development of the Australian Drug Evaluation Committee (ADEC) pregnancy categories.

Members agreed that this issue should remain on the watching brief list.

The causal association with paroxetine was deemed to be 'possible' for anus imperforate and genital malformation. The Committee agreed that no further regulatory action was required at that time.

4.1.8.3 Paroxetine / flecainide and ventricular septal defect (69997)

Discussion

The Committee noted that the issue of SSRI antidepressants and teratogenicity was on the watching brief list.

See minute items 4.1.8.2 and 4.1.8.4 for further case reports of congenital abnormalities with paroxetine.

The causal association with paroxetine and flecainide was deemed to be 'possible' for ventricular septal defect. The Committee agreed that no further regulatory action was required at that time.

4.1.8.4 Paroxetine / lithium and ventricular septal defect, abnormal reflexes (69446)

Discussion

The Committee noted that the issue of SSRI antidepressants and teratogenicity was on the watching brief list.

See minute items 4.1.8.2 and 4.1.8.3 for further case reports of congenital abnormalities with paroxetine.

The causal association with paroxetine and lithium was deemed to be 'possible' for ventricular septal defect and reflexes abnormal. The Committee agreed that no further regulatory action was required at that time.

4.1.8.5 Venlafaxine and serotonin syndrome (69901)

Discussion

The Committee noted that venlafaxine was only funded under Special Authority for patients with "treatment resistant" depression. They also noted that this patient was on the maximum daily dose of venlafaxine.

The Committee queried the diagnosis of serotonin syndrome in this case. They commented that the increased tone in the lower limbs, gait abnormalities, agitation and twitching could have been extrapyramidal adverse effects. The altered level of consciousness, however, was not a common extrapyramidal adverse effect. The noted that the report was from a hospital doctor who had stated "Diagnosed with serotonin syndrome." The Committee asked that NZPhvC contact the reporter again to query what the criteria were for diagnosing serotonin syndrome in this case.

The causal association with venlafaxine was deemed to be 'probable' for serotonin syndrome.

Recommendation

The Committee recommended that NZPhvC should contact the reporter again to query what the criteria were for diagnosing serotonin syndrome in this case (69901).

4.1.8.6 Venlafaxine / cilazapril and urinary retention, aggravated renal failure (69409)

Discussion

See minute item 4.1.1.6 for a further case report for this patient.

NZPhvC informed the Committee that the Efexor (venlafaxine) data sheet stated that dose reduction was recommended in renal impairment, and that urinary impairment was a common adverse effect.

The causal association with venlafaxine and cilazapril was deemed to be 'possible' for urinary retention and renal failure aggravated. The Committee agreed that no further regulatory action was required at that time.

4.1.9 Vaccines

4.1.9.1 MeNZB vaccine and Wegener's granulomatosis (68760)

Discussion

The Committee noted that the presentation in this case was unusual for Wegener's granulomatosis, and queried the accuracy of the diagnosis especially in the absence of histological data. NZPhvC informed the Committee that further follow-up information had been sought from the reporter, who stated that the diagnosis of Wegener's granulomatosis was clear.

NZPhvC informed the Committee that of a total of 2,018 adverse reaction reports for MeNZB there were no others for Wegener's granulomatosis. There were two reports for Henoch-Schonlein purpura (HSP), two for Kawasaki disease, five for purpura/purpuric rash and four for thrombocytopenic purpura. They explained that a review of HSP and Kawasaki disease had been undertaken for the MeNZB Independent Safety Monitoring Board who concluded that there was no increased incidence of these conditions over the background rates.

The causal association with MeNZB vaccine was deemed to be 'unlikely' for Wegener's granulomatosis. The Committee agreed that no further regulatory action was required at that time.

4.1.10 Other Reports

4.1.10.1 Leflunomide (69938)
4.1.10.2 Ezetimibe (69931)
4.1.10.3 PhD Wax Systems (68855)
4.1.10.4 HSII (69627)
4.1.10.5 Silberhorn Deer Velvet (69681)
4.1.10.6 Thermotrim Max (69996)
4.1.10.7 V Drink (69858)

4.2 Pharmacovigilance Issues Arising from Reports to CARM

4.2.1 Tramadol - Drug Interactions and Serious Reactions

Reference

R. Savage, NZPhvC, report for MARC, March 2006.

Issue

At the December 2005 MARC meeting an interaction between tramadol and warfarin was discussed and it was noted that there were other reports of serious adverse events attributed to drug interactions with tramadol in the CARM database. The Committee recommended that the NZPhvC should further analyse reports of interactions with tramadol in the CARM and WHO databases.

Examination of the WHO (Vigibase) and CARM databases found that the most commonly reported serious adverse reactions for tramadol that were considered to be the outcome of a suspected interaction were:

• Elevated International Normalised Ratio (INR) with warfarin,
• Serotonin syndrome with medicines that elevate serotonin levels, and
• Convulsions with medicines that lower the seizure threshold.

Elevated International Normalised Ratio (INR)

There were four reports for tramadol in the CARM database of elevated International Normalised Ratio (INR) with warfarin. None of these cases provided clear documentation that an interaction with tramadol was the most likely explanation for the change in INR. In one of the CARM reports an overdose of warfarin might have been taken. In another case the dose of warfarin was unnecessarily increased and this patient also took roxithromycin. The remaining two cases provided the best evidence for a tramadol/warfarin interaction, although antibiotics might have contributed. However, an Australian case series and at least one published case report provided firmer evidence.

In December 2005, the MARC recommended that an article should be written for publication in Prescriber Update on the interaction between tramadol and warfarin, and if merited, a more extensive article on tramadol adverse effects. NZPhvC considered that it might also be appropriate for the Prescriber Update article to advise that other interacting medicines, such as antibiotics, might further increase the INR. In December 2005, the MARC also recommended that the Zytram data sheet be updated to address the interaction with warfarin in line with the data sheets for the other brands of tramadol (see minute item 2.1.13).

Serotonin syndrome

At the time of this meeting there were three reports in the CARM database of serotonin syndrome with tramadol. In all three reports the patients were taking both tramadol and other medicines that could increase serotonin levels. Tramadol was added to long-term treatment with other serotonergic medicines in two cases. In the remaining case serotonin syndrome occurred when the dose of tramadol was increased in a patient taking both paroxetine and tramadol. The reports suggested that high doses of either tramadol or the interacting medicine might trigger serotonin syndrome.

The WHO database (Vigibase) held 86 reports of serotonin syndrome attributed to tramadol. A high proportion of these reports originated from Australia. The 55 most recent reports were examined and it was found that 31 were attributed to interactions. In 24 of these reports the interacting medicines were selective serotonin and/or noradrenaline re-uptake inhibitors (SSRIs and/or SNRIs), predominantly sertraline. SSRIs also predominated in reports which were listed as co-suspect rather than interacting with tramadol.

The Australian Adverse Drug Reactions Bulletin contained articles in both 2001 and 2004 that warned of the potential for tramadol to cause serotonin syndrome when prescribed with other medicines that elevate serotonin levels.

Convulsions

CARM had received ten reports of convulsions attributed to tramadol. Six of these were for tramadol alone and four were for interacting medicines. Over the past five years, apart from vaccines, tramadol had been the most commonly reported medicine for convulsions. The data sheet for Tramal contained information on seizure risk, and the risk of interactions with drugs which reduce the seizure threshold.

International reports confirmed that tramadol alone could cause convulsions at therapeutic doses. High doses of tramadol and administration of concomitant medicines that lowered the seizure threshold were also described. It was clear from the Australian and New Zealand reports that tramadol was being used in a post-operative setting, which raised the issue of potential interactions with agents used in general anaesthesia.

NZPhvC informed the MARC that a slide on the issue of convulsions with tramadol was being prepared for presentation at Grand Rounds. It was to advise that the risk of seizures increased with:

• Greater than recommended doses
• Co-prescription of medicines lowering seizure threshold
• History of seizures

Discussion

The Committee noted that tramadol was not funded in New Zealand at the time of this meeting. Members noted anecdotes that usage of tramadol was increasing in New Zealand.

The Committee noted that the CARM cases on the interaction between tramadol and warfarin were confounded. They agreed that the recommendations made at the December 2005 MARC meeting remained appropriate. (Also see minute item 2.1.13).

Members noted that there had been three reports to CARM of serotonin syndrome with tramadol over the past five years.

The Committee noted that there were ten reports of convulsions in the CARM database attributed to tramadol, but that concomitant administration of other seizure threshold-lowering medicines confounded several of these reports. They noted that over the past five years, apart from vaccines, tramadol had been the most commonly reported medicine for convulsions. Members commented that, anecdotally, tramadol was increasingly being used in a peri-operative setting. In this situation there were likely to be many concomitant medicines administered, which made interpretation of adverse reaction data difficult.

NZPhvC informed the Committee that the data sheet for Tramal stated that the maximum daily dose for parenteral administration was 600mg. This dose was inconsistent with that in DrugDex 2005, which advised a maximum dose of 400mg daily. Medsafe agreed to investigate this situation further.

The Committee agreed that it would be valuable for NZPhvC to discuss the tramadol issues with the Australian Adverse Drug Reactions Unit. They also agreed that there should be two Prescriber Update articles written on tramadol, as detailed below.

Recommendation

The Committee recommended that two Prescriber Update articles should be written on tramadol. The first should be on increased International Normalised Ratio (INR) when tramadol is administered with warfarin and/or other medicines known to increase INR. The second article should be on serious adverse effects of tramadol, specifically serotonin syndrome and convulsions.

4.3 Quarterly Reports from CARM as at 31 December 2005

Discussion

The Committee noted the quarterly reports from CARM as at 31 December 2005.

NZPhvC explained that brand-switch reports for citalopram (Arrow-citalopram brand) had declined considerably compared with the previous quarter.

Members noted that there had been nine reports to CARM of interstitial nephritis with omeprazole in the year to December 2005. Medsafe informed the Committee that a reminder paragraph was to be published on this issue in the next edition of Prescriber Update.

4.4 Adverse Reactions of Current Concern Reviews

4.4.1 Leflunomide - Adverse Reaction of Current Concern Review

References

1. Medsafe/NZPhvC report for the MARC, March 2006.
2. Aventis Pharma Ltd. Arava tablets data sheet. 2 June 2004.

Background

At the December 2005 MARC meeting, members asked that Adverse Reactions of Current Concern (ARCC) issues be standing agenda items, for review at each meeting. This is the first such review for leflunomide. All adverse reactions to leflunomide had been monitored under ARCC since April 2004 due to increasing use of this disease-modifying agent in the management of rheumatoid arthritis, and the serious nature of some adverse reactions reported both locally and internationally.

Leflunomide was first approved in New Zealand in March 2000 as a prescription medicine. Arava (Aventis Pharma) was the only leflunomide product approved in New Zealand at the time of this meeting, and was indicated for "the treatment of rheumatoid arthritis, to improve signs and symptoms, to retard joint destruction and to improve functional ability and quality of life. ARAVA may be used in patients who have failed to respond to other treatments or as a first line of treatment in patients who have a contraindication to other treatments." The MARC discussed leflunomide on 11 occasions between December 2002 and December 2005, inclusive.

In the CARM database there were 51 reports for leflunomide at the time of this meeting. Respiratory, gastrointestinal, hepatic and haematological disorders were most commonly reported, in keeping with the known adverse reaction profile of leflunomide. The most commonly reported reaction was diarrhoea. The reports to CARM were closely reflected in Vigibase and many were statistically prominent (positive IC value) from the background data. There were three reports to CARM of hypertension or aggravated hypertension and the WHO data emphasised the problem of hypertension with leflunomide.

The hepatic, haematological, and respiratory adverse effects were reasonably well established at the time of this meeting. In comparison with other disease-modifying antirheumatic drugs (DMARDs) bullous skin reactions, diarrhoea, weight loss, colitis and hypertension appeared to occur more commonly with leflunomide. There was also good evidence for an association with peripheral neuropathy and moderate evidence for an association with lupus erythematosus rash.

NZPhvC considered that the suspected reactions that required closer monitoring were:

• reduced resistance to infection (and which types of infection occur),
• delayed wound healing (and possibly vasculitis),
• severe colitis/diverticulitis,
• cardiac failure,
• atrial fibrillation,
• myocardial infarction and
• renal failure.

One study reviewed by NZPhvC (Martin KF et al. Clin Exp Rheumatol. 2005) indicated that in clinical practice 70% of patients discontinued leflunomide because of adverse reactions or because of a lack of efficacy. This was in keeping with experience with some other DMARDs.

Discussion

The Committee noted the extensive report provided, detailing the cases reported to CARM and the WHO, as well as New Zealand and international regulatory action and a review of recent literature.

Medsafe informed the Committee that an article on leflunomide and pneumonitis was to be published in the next edition of Prescriber Update.

The Committee considered that the warnings in the datasheet for Arava were appropriate based on current evidence.

The Committee recommended under minute item 2.1.2 that ARCC issues should be moved from the standing agenda item list to the active monitoring list. They agreed that leflunomide should remain on the ARCC list.

4.4.2 SSRIs - Adverse Reactions of Current Concern Review

References

Medsafe report for the MARC, March 2006.

1. Henry C, Demotes-Mainard J (2006). SSRIs, Suicide and Violent Behaviour: Is there a need for a better definition of the depressive state? Current Drug Safety. 2006:1;69-62
2. Simon G et al (2006). Suicide Risk during Antidepressant Treatment. Am J Psychiatry 163:41-47. doi 10.1176/appi.ajp.163.1.141
3. Bostwick J M. (2006). Do SSRI's Cause Suicide in Children? The Evidence is Underwhelming. Journal of Clinical Psychology: 62(2): 235-241. doi: 10.1002/jclp.2.226
4. Cheung A et al (2006). The use of antidepressants to treat depression in children and adolescents. CMAJ 174(2): 193-200.
5. Gunnell D et al (2005). Selective serotonin reuptake inhibitors (SSRI) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trails submitted to the MHRA's safety review. BMJ, Feb 2005; 330: 385; doi:10.1136/bmj.330.7488.385
6. Fergusson D et al (2005). Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. BMJ 2005;330:396, doi:10.1136/bmj.330.7488.396
7. Martinez C et al (2005). Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study. BMJ 2005;330:389, doi:10.1136/bmj.330.7488.389
8. Aursnes I et al (2005). Suicide attempts in clinical trials with paroxetine randomised against placebo. BMC Medicine 2005; 3:14. doi 10.1186/1741-7015-3-14
9. Didham R (2005). Suicide and self-harm following prescription of SSRIs and other antidepressants: confounding by indication. Br J Clin Pharmacol. Doi:10.1111/j.1365-2125.2005.02480.x

Background

At the December 2005 MARC meeting, members asked that Adverse Reactions of Current Concern (ARCC) issues be standing agenda items, for review at each meeting. This is the first such review for the selective serotonin re-uptake inhibitors (SSRIs). The issues of SSRIs and severe agitation, severe restlessness/akathisia and/or suicidality were placed on the ARCC list in October 2002. This followed the publication of a Prescriber Update article in September 2002 on "Agitation, Restlessness and Suicidal Behaviour with Fluoxetine, Paroxetine and Sertraline".

At the time of this meeting there were six SSRI antidepressants with ministerial consent for marketing in New Zealand. Fluoxetine was approved in 1988, sertraline was approved in 1992, fluovoxamine was approved in 1995, paroxetine and citalopram were approved in 1997 and escitalopram was approved in 2002. The SSRI antidepressants were indicated for use in the treatment of conditions such as depression, obsessive compulsive disorder, panic disorder, social phobia, generalised anxiety disorder, post traumatic stress disorder, bulimia nervosa and premenstrual dysphoric disorder. The MARC discussed issues pertinent to this ARCC on five occasions between June 2003 and June 2005, inclusive.

In the CARM database there were a total of 1,229 reports for fluoxetine, paroxetine, sertraline and citalopram. In the last quarter there had been 15 reports. For the reactions of current concern, there were a total of 103 reports, with three in the last quarter (two for agitation and one for akathisia). In the WHO database there were positive IC values for all four of the above medicines with agitation, hyperkinesia and suicide attempt (this term includes suicide and suicidal tendency).

In July 2005, the United States Food and Drug Administration (FDA) issued a Public Health Advisory to inform US prescribers that a review was presently being conducted to determine whether there was an increased risk of suicidal behaviour in adults taking antidepressants. Whilst awaiting the outcome of this review US prescribers were advised to follow the present monitoring advice detailed in all antidepressant product information.

Medsafe considered that there was some evidence to suggest the use of SSRI antidepressants in adults might increase the risk of suicidality, particularly in the early stages of treatment. However, the risk:benefit ratio for the SSRIs in the treatment of moderate to severe adult depression remained favourable.

Medsafe considered that the current New Zealand SSRI data sheets adequately warned prescribers of the potential risks associated with the use of these medicines and the need to monitor patients carefully, particularly during the initial stages of treatment.

Discussion

The Committee noted the extensive report, detailing the cases reported to CARM and the WHO, as well as New Zealand and international regulatory action and a review of recent literature, and the references provided.

Members commented that the ratio of suicides to suicide attempts was, anecdotally, 1:20, and that approximately half of suicide attempts did not result in hospitalisation. They noted that the Cheung et al paper stated "Studies of completed suicides showed that, among the subjects who had been prescribed antidepressants, few (less than 10%) tested positive for antidepressants at autopsy." The MARC also noted that the Simon et al study found that the greatest risk of suicide was in the month prior to starting antidepressant therapy and then in the month following initiation of therapy.

The Committee commented that the regulatory action taken regarding the risk of suicidality in children appeared to have been effective. In addition, they agreed that the current data sheet statements were adequate regarding the risk of suicidality in adults.

The Committee noted this issue had been on the ARCC list for almost four years, and that reports to CARM had substantially decreased in recent quarters. Members considered that an adequate level of awareness amongst prescribers had been achieved on this issue and that therefore it should be removed from the ARCC list. They agreed that it should be placed on the watching brief list pending the United States Food and Drug Administration (FDA) review of the risk of suicidal behaviour in adults taking antidepressants.

Recommendations

The Committee recommended that severe agitation, severe restlessness/akathisia and/or suicidality with selective serotonin re-uptake inhibitors (SSRIs)should be removed from the Adverse Reactions of Current Concern list.

The Committee recommended that the issues of selective serotonin re-uptake inhibitors (SSRIs) and severe agitation, severe restlessness/akathisia and/or suicidality should be placed on the watching brief list pending the outcome of the United States Food and Drug Administration (FDA) review of the risk of suicidal behaviour in adults taking antidepressants.

4.4.3 Complementary and Alternative Medicines - Adverse Reactions of Current Concern Review

Reference

1. NZPhvC/Medsafe report for the MARC, March 2006

Background

At the December 2005 MARC meeting, members asked that Adverse Reactions of Current Concern (ARCC) issues be standing agenda items, for review at each meeting. This is the first such review for complementary and alternative medicines. The issue of all adverse reactions to complementary and alternative medicines (CAMs) was placed on the ARCC list in October 1996 when CARM received increasing numbers of reports of adverse reactions to CAMs. CAMs include herbal medicines, bee products, homoeopathic products, dietary supplements, minerals, and any other medicines containing animal or plant extracts.

For this meeting Medsafe and NZPhvC provided an abbreviated report for the review of this ARCC. Due to the large number of products available, often containing multiple active ingredients, it was difficult to undertake an exhaustive literature review on this issue. Inconsistencies in international trade names for CAM products made it difficult to search the WHO database for many of the products. NZPhvC searched the WHO database for this meeting only for those ingredients featured in case reports to CARM.

At the time of this meeting there were a total of 256 reports to CARM for CAMs, encompassing 490 reactions and 299 suspect CAM products. In the last quarter there had been seven reports.

Discussion

The Committee noted the above.

The Committee recommended under minute item 2.1.2 that ARCC issues should be moved from the standing agenda item list to the active monitoring list. They agreed that complementary and alternative medicines should remain on the ARCC list.

4.5 Intensive Medicines Monitoring Programme (IMMP)

References

1. Medsafe cover report to accompany IMMP papers on clozapine
2. IMMP report for MARC. Clozapine and Severe Gastrointestinal Motility Impairment: a case series and review. March 2006
3. IMMP report for MARC. Clozapine and Haematological Malignancies. March 2006.
4. IMMP report for MARC. Alopecia Associated with Quetiapine and Clozapine. March 2006.
5. Novartis NZ Ltd. Clozaril tablets data sheet. 4 August 2004.

Background

Clozapine was first approved in New Zealand in 1993 as a prescription medicine. At the time of this meeting there were two clozapine products marketed in New Zealand, Clopine (Douglas) and Clozaril (Novartis). Clozapine was indicated in the treatment of resistant schizophrenic patients only, ie. schizophrenic patients who are non-responsive to or intolerant of classical antipsychotics.

At the time of this meeting clozapine could only be prescribed by:

• Medical practitioners who are vocationally registered under the Medical Practitioners Act 1995 in the branches of psychological medicine or psychiatry, and
• Medical practitioners employed as registrars in psychological medicine or psychiatry who are under the supervision of persons of the kind referred to above.
• Persons prescribing the medicine must comply with the requirements of the New Zealand Guidelines for the use of Atypical Anti-Psychotic Drugs (3rd Edition January 2002) and the requirements of local Hospital and Health Service Protocols for the use of clozapine.

Both Clopine and Clozaril were fully funded when prescribed under the conditions above. Clozapine had been monitored on the IMMP since December 2000.

4.5.1 Clozapine and Severe Gastrointestinal Motility Impairment

Issue

Although efficacious, clozapine was known to cause a number of adverse effects including agranulocytosis and constipation. Other consequences of impaired gastrointestinal motility were less well described. IMMP identified eight case reports of severe gastrointestinal motility impairment disorders in patients taking clozapine; oesophageal dysmotility (two), paralytic ileus, bowel perforation, bowel infarction, severe constipation and toxic megacolon (two). Of these, two were fatal.

A review of the WHO database and the literature identified further cases of severe gastrointestinal motility impairment, some with fatal outcomes, in patients taking clozapine. IMMP proposed that clozapine might impair gastrointestinal motility through effects on 5-HT and muscarinic receptors. Pharmacodynamic and genetic factors might vary individuals' susceptibility to such adverse effects. Patients taking clozapine should be asked about constipation routinely and clinicians should be vigilant for the emergence of evidence of other, potentially fatal, adverse effects on gastrointestinal motility.

The Clopine and Clozaril data sheets both contained information on gastrointestinal motility-related adverse effects in the 'Warnings and Precautions – Anticholinergic Effects' and 'Adverse Effects' sections.

Discussion

The Committee noted the report prepared by IMMP, summarised above.

Members commented that constipation was a well known adverse reaction with clozapine; however, it was less well known that dysmotility could affect the entire gastrointestinal tract.

Members commented that, although clozapine could only be prescribed by specialists, general practitioners also needed to be aware of the potential for gastrointestinal dysmotility with clozapine and should question patients on related symptoms.

The Committee considered that prescribers might not be adequately aware of this issue, and asked that a Prescriber Update paragraph be written. They commented that it might be of value to subsequently re-publish the Prescriber Update article in the Royal Australian and New Zealand College of Psychiatrists newsletter.

Recommendations

The Committee recommended that a short paragraph should be written for publication in Prescriber Update on the impairment of gastrointestinal motility with clozapine.

4.5.2 Clozapine and Haematological Malignancies

Background

Clozapine was known to cause agranulocytosis (about 0.9% incidence at 1 year) and neutropenia. For this reason all patients prescribed clozapine in New Zealand at the time of this meeting had regular haematological monitoring, with the results being entered into sponsor-administered databases and adverse reactions subsequently reported to NZPhvC.

A review of the IMMP database found no reports of haematological malignancies for risperidone, quetiapine or olanzapine. In the clozapine database there were two reports of leukaemia and three reports of lymphoma.

For some years there had been isolated reports in the published literature of cases of leukaemia in patients taking clozapine (Psychiatric Bulletin November 2000 24:432). This issue was raised again at the International Society of Pharmacovigilance (ISoP) meeting in late 2004 when an analysis of reports of haematological malignancies in the WHO-UMC database was presented. This review found 113 reports of 'malignant haematological diseases' in total – 106 for clozapine, six for olanzapine and one for quetiapine. Of these, 83 reports were of leukaemia and 30 were of malignant lymphoma. It was not stated whether the search included risperidone, but presumably it did and no reports of haematological malignancies were identified. The authors commented that "these numbers are considerably higher than expected from the background of the database" and suggested further investigation. As at 30 June 2005, a review of the WHO database found positive IC values for lymphoma malignant, leukaemia granulocytic, leukaemia lymphocytic and leukaemia.

As clozapine and its metabolites had been shown to be toxic to haemopoietic precursors, IMMP suggested that there appeared to be a potential mechanism by which clozapine could induce haematological malignancies.

At the time of the meeting neither the Clozaril nor the Clopine data sheets contained information on the risk of haematological malignancies.

Discussion

The Committee noted the report prepared by IMMP, summarised above.

IMMP explained that there were limitations to the spontaneous reporting data from which this potential signal had arisen. As all clozapine patients in New Zealand were regularly haematologically monitored, and the sponsors were obliged to report all adverse effects to NZPhvC, rare adverse events such as haematological malignancies might be picked up sooner, and would more likely be attributed to clozapine treatment.

Members commented that there was difficulty in the diagnosis and classification of haematological malignancies. They also noted that the haematological malignancies reported to IMMP were very varied and were known to have diverse aetiologies. They queried what the background rate of these malignancies might be.

The Committee considered that it would be valuable for the clozapine sponsors to provide further data on this potential signal.

Recommendations

The Committee recommended that Medsafe should ask the clozapine sponsors to provide further data on the potential association between clozapine and haematological malignancies.

4.5.3 Alopecia Associated with Quetiapine and Clozapine

Background

Alopecia (hypotrichosis) is a condition which involves the loss of some or all of the hair from the head and sometimes from other parts of the body. Alopecia may be a distressing condition and has been associated with increased psychological and psychiatric sequelae, including increased rates of anxiety and depression. The aetiology of alopecia is sometimes uncertain, but it can be drug-induced and has been associated with several psychotropic medicines. Alopecia had previously been reported in patients taking risperidone and olanzapine, but not with quetiapine or clozapine.

The cases identified from the IMMP database provided some evidence of an association between alopecia, clozapine and quetiapine, which had not previously been described. Whilst there were only two cases for each medicine in the IMMP database, additional case reports from the WHO and the TGA provided data to support a potential causal association. IMMP considered that there was some evidence to suggest a class effect of the atypical antipsychotics and alopecia.

A literature search failed to reveal any published case reports for alopecia with clozapine or quetiapine. The New Zealand datasheets for clozapine and quetiapine did not list alopecia as an adverse reaction at the time of this meeting.

Drug-induced hair loss has two main mechanisms. It may affect anagen, which results in cessation of mitosis and shedding of hairs within days to weeks; or induce premature telogen, or resting phase, resulting in hair loss occurring two to four months after starting treatment. It was not known how antipsychotics induced alopecia at a molecular level.

Discussion

The Committee noted the report prepared by IMMP, summarised above.

Members commented that mood stabilisers such as lithium and sodium valproate had been reported to commonly cause hair loss.

The Committee noted that one of the IMMP alopecia cases with clozapine had occurred post-partum. They commented that post-partum alopecia was common, and therefore this case was potentially confounded, which should be considered when assessing the data. Members noted that the IMMP cases for quetiapine both had a positive de-challenge, which strengthened the argument for a causal association.

Members noted that there was no objective method for assessing hair loss. IMMP explained that onset and recovery time is variable and there may not be a direct relationship between medicine intake and hair loss. Spontaneous reports often lacked outcome information as it could take some time for recovery to be apparent. People on the atypical antipsychotic medicines were often on multiple psychotropic medicines, others of which might be implicated in the causality of this adverse effect.

IMMP informed the Committee that a paper was being prepared on this issue for submission to a peer-reviewed journal.

4.5.4 Other IMMP Business

The Acting Chair enquired as to whether any new medicines were being added to the IMMP list. IMMP replied that no new medicines were being added.

Secretarial Note

The Ministry of Health is currently funding monitoring of the following issues on the Intensive Medicines Monitoring Programme (IMMP) under its contract with the University of Otago:

• Atypical antipsychotics and paediatric use (prospective cohort study)
• Atypical antipsychotics and nocturnal enuresis (prospective cohort study)
• Atypical antipsychotics and cerebrovascular accident (data linkage study)

IMMP examines a safety issue when a project proposal has been prepared outlining the proposed objectives, methodology and costs in line with the contract between Medsafe and the University of Otago. This must subsequently be accepted by the Ministry of Health as being a cost-effective study that has the potential to provide a public health benefit.

4.6 Intensive Vaccines Monitoring Programme (IVMP)

Reference

1. Intensive Vaccines Monitoring Programme (IVMP) Update. February 2006.

4.6.1 MeNZB Adverse Event Assessments

1. CARM. MeNZB Adverse Event Assessments – Summary of spontaneous reports following MeNZB vaccination received by CARM for the period 19 July 2004 to 05 February 2006.
2. Summary of Centre for Adverse Reaction Monitoring reports of MeNZB adverse events. Report to the ISMB - Spontaneous reports 19 July 2004 to 27 November 2005. December 2005.

Discussion

The Committee noted that the pattern of adverse reactions remained unchanged. They noted that the Independent Safety Monitoring Board had reviewed the spontaneous adverse reaction reports received by CARM and had expressed no concerns regarding the safety of the MeNZB vaccine.

5. pharmacovigilance issues for information only

The following information was included in the meeting dossier, however, the Committee did not discuss this material. It included updates on issues already known to the Committee, commentaries, review articles and preliminary information on emerging issues. Members were asked to read this material, with the option of requesting that it be discussed.

• ADRU report for ADRAC. Tumour Necrosis Factor Inhibitors. February 2006.
• Dale KM et al. Statins and Cancer Risk. JAMA. January 2006. 495(1); 74-80
• Jespersen CM et al. Randomised placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ. Jan 2006; 332: 22 - 27 ; doi:10.1136/bmj.38666.653600.55
• Chambers CD et al. Selective Serotonin-Reuptake Inhibitors and Risk of Persistant Pulmonary Hypertension of the Newborn. N Engl J Med. Feb 2006.354(6); 579-87
• Reuters Health. Smallpox Vaccination Rarely Linked to Adverse Reactions. JAMA. 2005;295:2734-2750.

6. new zealand pharmacovigilance-related activities

• Jessamine S. Living in the shadow of "Big Reg" – Improving the effectiveness of pharmacovigilance centres responses to high profile product withdrawals. Presented at WHO National Centres Annual Meeting. September 2005.
• Tatley M, Savage R. Statins and Adverse Psychiatric Reactions. Presented at WHO National Centres Annual Meeting. September 2005.
• Excerpts from the 28^th annual meeting of the representatives of the national centres participating in the WHO Programme for International Drug Monitoring.
• Hill G. Memory Impairment associated with sibutramine. NZ Doctor. 25 January 2006.
• Harrison-Woolrych M et al. QT interval prolongation associated with sibutramine treatment. Br J Clin Pharmacol. 2006. Accessed early online doi:10.1111/j.1365-2125.2006.02574.x
• Harrison-Woolrych M et al. Bruising associated with sibutramine: results from postmarketing surveillance in New Zealand. International Journal of Obesity advance online publication 21 February 2006; doi: 10.1038/sj.ijo.0803268
• DHBNZ Safety and Quality Use of Medicines Group Newsletter. 2005; 1(5)
• Record of the Pharmacology and Therapeutics Advisory Committee Meeting held on 17 and 18 August 2005.
• Record of the Pharmacology and Therapeutics Advisory Committee Meeting held on 16 and 17 November 2005.

7. international pharmacovigilance-related Activities

7.1 Australia

• Minutes of the 287^th meeting of the Adverse Drug Reactions Advisory Committee held on 16 September 2005.
• Minutes of the 288^th meeting of the Adverse Drug Reactions Advisory Committee held on 27 October 2005.
• Minutes of the 289^th meeting of the Adverse Drug Reactions Advisory Committee held on 16 December 2005.
• Adverse Drug Reactions Bulletin. Vol. 24; No. 6. December 2005.
• Adverse Drug Reactions Bulletin. Vol. 25; No. 1. February 2006.
• Australian Prescriber. Vol. 28; No. 6. December 2005. (Cover page only)
• Australian Prescriber Vol. 29; No. 1. February 2006. (Cover page only)

7.2 Canada

• Canadian Adverse Reaction Newsletter. Vol. 16; Issue 1. January 2006.

7.3 Singapore

• Adverse Drug Reaction News. Vol. 7; No. 3. December 2005.

7.4 WHO

• The Uppsala Monitoring Centre. Signal. November 2005. (Cover page only).

8. Summary of case reports considered by MARC (1997-2005)

• CARM case reports considered by the MARC since 1997, by medicine class.
• Vaccine adverse reaction reports considered by the MARC since 1997.
• Complementary and alternative medicine (CAM) case reports considered by the MARC.

9. Other business

9.1 Oral presentations on WHO and ISoP Pharmacovigilance Conferences

NZPhvC provided the Committee with a synopsis of the issues of interest presented at the 28th Annual Meeting of the WHO Programme and the International Society of Pharmacovigilance (IsoP) conference in 2005.

In particular, the issue of patient safety, presented at the WHO annual meeting, was discussed. The conclusions were that:

• incidences of medical error should be reported widely, so that lessons can be learnt from them.
• a 'no-blame' culture should be developed.
• there should be a central agency to record, assess and communicate medical errors.
• a clear distinction should be made between medication errors and adverse reactions.
• it is important to identify system errors, rather than individual errors.

9.2 Future Arrangements for Pharmacovigilance in New Zealand

Discussion

The Chair sought an update on current thinking about the future arrangements for pharmacovigilance in New Zealand following the establishment of the Australia New Zealand Therapeutic Products Authority (ANZTPA). As this was not a scheduled agenda item the most appropriate Medsafe staff members were not present at the meeting to update the Committee.

The Chair asked the Committee members for their opinions on what was needed to ensure continuity of a sound pharmacovigilance strategy in New Zealand. He sought assurance from Medsafe that there would be adequate consultation during the development of pharmacovigilance plans for the ANZTPA.

Medsafe informed the Committee that the document 'Pharmacovigilance in a Trans-Tasman Agency' had yet to be finalised. Comments on the draft document, including those previously provided by the Committee and NZPhvC, had been taken into consideration, and were to be reviewed again before the document was finalised. Medsafe assured the Committee that consultation would be sought at the appropriate time.

The Committee noted that pharmacovigilance in New Zealand had a high local and international reputation, and that care must be taken to preserve this situation. In particular, it was essential to ensure that the importance of pharmacovigilance was recognised and that pharmacovigilance in the ANZTPA had adequate resourcing.

The Committee agreed to a number of recommendations, as detailed below.

Recommendations

The Committee recommended that the MARC Chair should contact the Chair of the Australian Adverse Drug Reactions Advisory Committee (ADRAC) to discuss the future of pharmacovigilance in the ANZTPA.

The Committee recommended that the MARC Chair should write to Medsafe, to highlight the Committee's request, as a Ministerial expert advisory committee, to participate in the development of the Australia New Zealand Therapeutic Products Authority (ANZTPA) pharmacovigilance strategy.

The Committee recommended that the MARC Chair should write to the Minister of Health to emphasise the importance of pharmacovigilance in New Zealand.

The Committee recommended that the Secretary of MARC should invite the Manager of Medsafe, the Deputy-Director General (Public Health) and the Minister of Health to attend a MARC meeting.

The Committee recommended that the MARC Chair should make a presentation to the Quality Safe Use of Medicines group on pharmacovigilance in New Zealand.

There being no further business, the Acting Chair thanked members, guests and the secretariat for their attendance and closed the meeting at 3:30pm.