Revised: 20 May 2013

Committees

Minutes of the 128^th Medicines Adverse Reactions Committee Meeting - 14 December 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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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

1.1 Welcome and Apologies
1.2 Minutes of the 127^th MARC Meeting

1.2.1 Report to the Minister's Delegate

1.3 Dates of Future MARC Meetings

1.4 Potential Conflicts of Interest

1.5 Prescriber Update

1.5.1 Prescriber Update. Vol. 27, No. 2. November 2006
1.5.2 Schedule of Planned Prescriber Update Articles

2. ACTIONS ARISING

2.1 Report on Actions Arising from the 127^th MARC Meeting, 14 September 2006

2.1.1 Oral Terbinafine Serious Adverse Reactions
2.1.2 Anti-Tumour Necrosis Factor (Anti-TNF) Agents and the Risk of Hepatitis B Reactivation
2.1.3 Quinine, Nocturnal Leg Cramps and Thrombocytopenia
2.1.4 Inhaled Long-Acting Beta-Adrenoceptor Agonists (LABAs) and the Risk of Fatal and Non-Fatal Asthma Exacerbations
2.1.5 SSRIs and Use in Pregnancy: Watching Brief Review
2.1.6 Ergot-Derived Dopamine Receptor Agonists, Other than Pergolide, and Fibrotic Reactions: Active Monitoring Review
2.1.7 Clozapine and myocarditis, heart failure, arrhythmia [death] (CARM case 66578)
2.1.8 Clozapine and Myocarditis
2.1.9 Infliximab / methotrexate / prednisone and secondary sepsis, dural abscess, tooth abscess, headache, coma [death] (CARM case 72110)
2.1.10 Influenza vaccine and sudden death (CARM case 71269)
2.1.11 Phentermine and pulmonary hypertension [death] (CARM case 71961)
2.1.12 Diclofenac / ibuprofen / prednisone and gastric ulcer, duodenal ulcer, intestinal ulceration, haematemesis, hypoproteinaemia (CARM case 71906)
2.1.13 Pioglitazone and neutropenia, thrombocytopenia, myeloid dysplasia (CARM case 71590)
2.1.14 Pioglitazone and generalised oedema (CARM case 72087)
2.1.15 Thalidomide and hyperglycaemia (CARM case 71621)
2.1.16 Pamidronate and hypocalcaemia, tetany, laryngismus, respiratory arrest (CARM case 71566)
2.1.17 Paroxetine and developmental delay, congenital brain damage (CARM case 71816) 9

2.2 REPORT ON ACTIONS ARISING FROM PREVIOUS MEETINGS OF THE MARC

2.2.1 Safety of Topical Pimecrolimus in Infants
2.2.2 Topical Pimecrolimus and the Risk of Malignancy
2.2.3 Clozapine and Haematological Malignancies
2.2.4 Tramadol - Drug Interactions and Serious Reactions
2.2.5 Bisphosphonates and Osteonecrosis of the Jaw
2.2.6 Lipid-Lowering Agents and Psychiatric Adverse Reactions
2.2.7 Dextropropoxyphene/Paracetamol Combination Products and the Risk of Overdose

2.3 REPORT ON UNRESOLVED ACTIONS ARISING FROM RECOMMENDATIONS OF THE MARC

2.3.1 Low Molecular Weight Heparins (LMWHs) in Renal Impairment
2.3.2 Alteplase and oedema [death] (CARM cases 70710, 70711 and 70712)
2.3.3 Baclofen and cardio-respiratory arrest, abdominal pain, hypertension, vomiting and coughing [death] (CARM case 70111)

3. PHARMACOVIGILANCE ISSUES

3.1 COX-2 INHIBITORS: ACTIVE MONITORING REVIEW
3.2 NON-SELECTIVE NSAIDS: ACTIVE MONITORING REVIEW
3.3 COX-2 INHIBITORS AND IMPAIRED FRACTURE HEALING: WATCHING BRIEF REVIEW

4. MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

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

4.1.1 Deaths
4.1.2 Alimentary Medicines
4.1.3 Alternative Medicines
4.1.4 Antibacterial Medicines
4.1.5 Antiepileptic Medicines
4.1.6 Antineoplastic Medicines
4.1.7 Antiviral Medicines
4.1.8 Cardiovascular Medicines
4.1.9 Contrast Media
4.1.10 Endocrine Medicines
4.1.11 Immunosuppressive Medicines
4.1.12 Psychiatric Medicines
4.1.13 Respiratory Medicines
4.1.14 Other Reports

4.2 PHARMACOVIGILANCE ISSUES ARISING FROM REPORTS TO CARM

4.2.1 Introduction to Bortezomib
4.2.2 Foetal Valproate Syndrome

4.3 QUARTERLY REPORTS FROM CARM AS AT 30 SEPTEMBER 2006

5. PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

6. NEW ZEALAND PHARMACOVIGILANCE-RELATED ACTIVITIES

7. INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

7.1 Australia

7.2 Canada

8. SUMMARY LISTINGS OF CASE REPORTS CONSIDERED BY MARC (1997-2006)

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MINUTES OF THE 128^TH MEDICINES ADVERSE REACTIONS COMMITTEE MEETING,
14 DECEMBER 2006

The one hundred and twenty-eighth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 14 December 2006 at the Sunderland room, Wellington Airport Conference Centre, Wellington, New Zealand. The meeting commenced at 9:00am and closed at 2.50pm.

marc members present

Honorary Associate Professor M Rademaker (Acting Chair)
Dr H Kingston
Professor P Ellis
Dr D Reith
Ms L Bryant
Associate Professor C Frampton (teleconference 11:00am to 12:00pm)
Dr M Tatley
Dr S Jessamine

marc secretariat present

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

invited guests and experts

Dr R Savage (New Zealand Pharmacovigilance Centre) attended the meeting to provide expert advice on items related to the Centre for Adverse Reactions Monitoring (CARM).

1. Matters of Administration

1.1 Welcome and Apologies

The Acting Chair welcomed the attendees to the meeting. He welcomed a new member to the Committee Associate Professor C Frampton (Biostatistician) who attended part of the meeting by teleconference. Apologies were received from Dr F McClure who provided written comments for some agenda items, and Professor Tim Maling.

1.2 Minutes of the 127^th MARC Meeting

Members agreed that the minutes of the 127th MARC meeting and the special MARC meeting held on 14 September 2006 were true and accurate records of those meetings. The Acting Chair subsequently ratified the minutes.

1.2.1 Report to the Minister's Delegate

Members noted that all of the recommendations made at the 127th MARC meeting had been accepted by the Minister’s Delegate.

1.3 Dates of Future MARC Meetings

The date for the next MARC meeting was confirmed as being Thursday 15 March 2007. The subsequent MARC meetings were scheduled for 14 June 2007, 13 September 2007 and 13 December 2007.

1.4 Potential Conflicts of Interest

Committee members submitted their Conflict of Interest Declaration forms to the Secretary. The Acting Chair reminded the MARC members that, in addition to conflicts disclosed in the declaration forms, members should declare conflicts of interest at the commencement of discussion of any relevant agenda item.

Two members declared potential conflicts of interest. The Committee considered that these potential conflicts of interest would not influence the discussions or decisions of the Committee.

1.5 Prescriber Update

1.5.1 Prescriber Update. Vol. 27, No.2. November 2006

Discussion

The Committee complimented the Medsafe Pharmacovigilance team on the November 2006 edition of Prescriber Update.

A committee member reported receiving positive feedback on the statins and SSRI articles.

1.5.2 Schedule of Planned Prescriber Update Articles

Discussion

The Committee noted the schedule of planned Prescriber Update articles.

2. actions arising

The Committee considered the list of issues monitored by MARC, Medsafe and NZPhvC.

The Committee discussed the review timetable for issues monitored by MARC, Medsafe and NZPhvC as at December 2006 and agreed to postpone the active monitoring review of all adverse reactions to lefluonomide (ARCC), and the watching brief review of SSRI antidepressants and severe agitation, severe restlessness/akathisia, and/or increased suicidality, from March 2007 to June 2007.

Medsafe briefly informed the Committee of ADRAC’s new definitions for issues to be monitored and monitoring requirements. Medsafe agreed to provide more information on this to the Committee at the next meeting.

2.1 Report on Actions Arising from the 127^th MARC Meeting, 14 September 2006

Please refer to the minutes of the 127th MARC meeting, held on 14 September 2006, available on the Medsafe web site at www.medsafe.govt.nz/profs/adverse/Minutes127.htm for background information on these issues.

2.1.1 Oral Terbinafine Serious Adverse Reactions

September 2006 minute item 2.1.12; June 2006 minute item 9.2

Issue

In September 2006, the Committee recommended that Medsafe should continue to correspond with the Australian Therapeutic Goods Administration (TGA) regarding outcomes of their review of the safety of oral terbinafine and regulatory actions taken, and report back to the MARC.

In September 2006, the Committee recommended that NZPhvC should provide an analysis of the patient characteristics, particularly age, in the case reports to CARM of serious adverse reactions to oral terbinafine.

In September 2006, the Committee recommended that the issue of oral terbinafine and serious adverse reactions (blood dyscrasias, hepatotoxicity and dermatological reactions) should be placed on the active monitoring list.

Outcome

All sponsors of oral terbinafine products had agreed to make the requested data sheet changes.

Medsafe was continuing to correspond with the TGA regarding regulatory actions taken on oral terbinafine. ADRU had not yet analysed the individual case reports provided by Novartis. Product Information amendments had been requested in Australia and Medsafe intended to make further requests for amendments based on those made in Australia.

In September 2006, Novartis was asked by the TGA to include the Lamisil Consumer Medicine Information (CMI) as a package insert. Novartis responded that it had replaced the unacceptable package insert but would distribute CMI in accord with Therapeutic Goods Legislation S9A(2) which states that the CMI may be provided at the time of supply in the pack or in another manner where the information is given to the person to whom the goods are administered or dispensed. The Community Pharmaceutical Agreements include dispensing of CMI. Carton labels will be amended to state "Consumer product information is available from your pharmacist or doctor or from www.novartis.com.au". Novartis was concerned that the CMI could become out of date if included as a package insert.

NZPhvC analysed the characteristics of the 11 patients reported to have serious reactions to terbinafine in the CARM database over the last 5 years: There were six females and five males and the age range was 39 to 75 years with a mean of 62.2 years. (Age was not stated for one patient). One patient had a hepatic reaction. Another patient with pre-existing liver disease had a hepatic reaction. This patient also had neutropenia. No other pre-existing conditions were of importance in the other reports. Two patients were taking co-suspect medicines. There was no particular pattern of co-prescribed medicines that suggested interactions or contributing co-morbidity.

Of 134 patients with non-serious reaction reports over the same time period the age range was 18 to 82 years with a mean of 58.7 years (excluding a three year old female).

A short article entitled "Terbinafine: serious hepatic and haematological reactions" was published in the November 2006 edition of Prescriber Update.

The issue of oral terbinafine and serious adverse reactions (blood dyscrasias, hepatotoxicity and dermatological reactions) had been placed on the active monitoring list for review in September 2007.

Discussion

Medsafe reported further on the issue of the TGA request for Novartis to include the Lamisil CMI as a package insert. Medsafe commented that there is no guarantee that patients receive the consumer information as it relies on pharmacists supplying the package insert when the medicine is dispensed.

A member queried if terbinafine interacts with medicines metabolised by the CYP2D6 enzyme leading to raised serum concentrations. NZPhvC commented that there was no particular pattern of interaction with co-prescribed medicines in the 11 patients reported to have had serious reactions to terbinafine in the CARM database.

Medsafe would continue to monitor the outcome of the ADRU analysis of the individual case reports provided by Novartis.

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

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

September 2006 minute item 2.2.3; June 2006 minute item 2.1.4; March 2006 minute item 3.2

Issue

In September 2006, the Committee recommended that the issue of anti-TNF agents and hepatitis B reactivation should be removed from the active monitoring list.

In March 2006, 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.

Outcome

This issue had been removed from the active monitoring list.

Medsafe disseminated a Dear Healthcare Professional letter to rheumatologists, gastroenterologists and haematologists on 8 November 2006. The letter was also reprinted in the November 2006 edition of Prescriber Update, entitled 'Anti-TNF agents: Hep B'ware'.

Discussion

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

2.1.3 Quinine, Nocturnal Leg Cramps and Thrombocytopenia

September 2006 minute item 3.1; June 2006 minute item 4.1.3.1

Issue

In September 2006, the Committee recommended that Medsafe should pursue removal of the indication "prophylaxis and treatment of nocturnal recumbency leg muscle cramps, including those associated with arthritis, diabetes, varicose veins, thrombophlebitis, arteriosclerosis and static foot deformities" from quinine products.

In September 2006, the Committee recommended that, following resolution of the above, Medsafe should write an article for publication in Prescriber Update informing prescribers of the change to the indications for quinine.

Outcome

Medsafe had written to the quinine sponsors with requests for the data sheets changes as above.

Discussion

Medsafe was still in the process of pursuing the removal of the indication from all of the affected data sheets. Medsafe advised that one sponsor had responded by formally discontinuing their quinine product. Another sponsor has agreed to remove the indication from the data sheet. The one remaining sponsor has yet to respond.

The Committee noted the above and asked to be informed of the outcome of these recommendations.

2.1.4 Inhaled Long-Acting Beta-Adrenoceptor Agonists (LABAs) and the Risk of Fatal and Non-Fatal Asthma Exacerbations

September 2006 minute item 3.2

Issue

In September 2006, the Committee recommended that Medsafe should again ask AstraZeneca to update the Oxis Turbuhaler and Symbicort data sheets to include warnings on the risk of serious asthma exacerbations.

In September 2006, the Committee recommended that Medsafe should ask the Best Practice Advocacy Centre to consider revising its Asthma POEMs with the most recent evidence on the role and limitations of the LABAs in asthma management.

In September 2006, the Committee recommended that Medsafe should ask the New Zealand Guidelines Group to consider revising its Diagnosis and Treatment of Adult Asthma guideline with the most recent evidence on the role and limitations of the LABAs in asthma management.

In September 2006, the Committee recommended that Medsafe should consider publishing an article in Prescriber Update summarising the changes to the LABA data sheets.

In September 2006, the Committee recommended that the issue of LABAs and the risk of fatal and non-fatal asthma exacerbations should be placed on the watching brief list. The first annual review should include PHARMAC usage data for the mono-ingredient and combination inhaled corticosteroid/LABA products.

Outcome

Medsafe wrote to AstraZeneca in October and November 2006 requesting updates to the Oxis and Symbicort data sheets to include warnings on the risk of serious asthma exacerbations. A response had not yet been received.

The Best Practice Advocacy Centre (bpac) had drafted an article for publication entitled "Update on the use of LABA for the treatment of asthma". Medsafe had therefore not requested that bpac update their Asthma POEM.

Medsafe wrote to the NZ Guidelines Group in November 2006 asking that it give consideration to updating its Diagnosis and Treatment of Adult Asthma guideline with the most recent evidence on the role and limitations of the LABAs in asthma management.

A Prescriber Update article is to be drafted once the data sheet amendments are finalised.

The issue of LABAs and the risk of fatal and non-fatal asthma exacerbations had been placed on the watching brief list for review in September 2007.

Discussion

Medsafe informed the Committee that AstraZeneca wish to discuss the wording changes required for the data sheets but a meeting time had yet to be set.

The Committee noted the above and asked to be informed of the outcomes of these recommendations.

2.1.5 SSRIs and Use in Pregnancy: Watching Brief Review

September 2006 minute item 3.3; June 2006 minute item 2.2.8; March 2006 minute item 2.2.7; December 2005 minute item 2.1.7; September 2005 minute item 3.5

Issue

In September 2006, the Committee recommended that Medsafe should consider publishing an article in Prescriber Update alerting prescribers and lead maternity carers (LMCs) to the risks associated with the use of SSRIs in pregnancy.

In September 2006, the Committee recommended that Medsafe should ask all sponsors of SSRIs to update the data sheets as per the Aropax data sheet to describe the potential risk of persistent pulmonary hypertension in the newborn (PPHN) following foetal exposure.

In September 2006, the Committee recommended that Medsafe should ask the sponsors of Apo-Fluoxetine (Apotex) and Plinzene (Douglas brand of fluoxetine) to update the data sheets to describe the risk of neonatal withdrawal following foetal exposure.

In September 2006, the Committee recommended that Medsafe should ask the sponsor of Apo-Paroxetine (Apotex) to amend the data sheet categorisation of risk during pregnancy from Australian Drug Evaluation Committee category B3 to category C.

Outcome

Medsafe wrote to the SSRI sponsors in November 2006 with requests for data sheet changes as above. Responses had not yet been received from all of the sponsors.

A Prescriber Update article was to be drafted.

Discussion

Medsafe was still in the process of pursuing the data sheet changes above. Medsafe advised that Douglas had discontinued their brand of fluoxetine (Plinzene).

The Committee noted the above and asked to be informed once the data sheet changes had been made.

2.1.6 Ergot-Derived Dopamine Receptor Agonists, Other than Pergolide, and Fibrotic Reactions: Active Monitoring Review

September 2006 minute item 3.5

Issue

In September 2006, the Committee recommended that Medsafe should ask the bromocriptine product sponsors to update the data sheets in line with the Australian bromocriptine-BC Product Information with respect to the risk of pericardial effusion and constrictive pericarditis.

In September 2006, the Committee recommended that the issue of all ergot-derived dopamine receptor agonists (other than pergolide) and fibrotic reactions should be removed from the active monitoring list.

Outcome

Medsafe wrote to the bromocriptine sponsors in November 2006 with requests for data sheet changes as above. Responses had not yet been received.

The issue of all ergot-derived dopamine receptor agonists (other than pergolide) and fibrotic reactions had been removed from the active monitoring list.

Discussion

Medsafe was still in the process of pursuing the data sheet changes above.

The Committee noted the above and asked to be informed once the data sheet changes had been made.

2.1.7 Clozapine and myocarditis, heart failure, arrhythmia [death] (CARM case 66578)

September 2006 minute item 4.1.1.4

Issue

In September 2006, the Committee recommended that NZPhvC should await a copy of the post-mortem report in this case (66578), then review the causality assessment and bring the results back to the MARC.

Outcome

The NZPhvC had requested the post-mortem report and follow-up re-assessment and advised that the results would be brought back to the MARC in due course.

Discussion

NZPhvC informed the Committee that the post-mortem report had not yet been received.

The Committee noted the above and asked to be provided with the post-mortem results once they were available.

2.1.8 Clozapine and Myocarditis

September 2006 minute item 4.3.2

Issue

In September 2006, the Committee recommended that Medsafe should request expert opinion from a cardiologist on the predictive value of electrocardiograms, echocardiograms and serum cardiac markers for detecting myocarditis in patients treated with clozapine.

In September 2006, the Committee recommended that Medsafe should consider publishing a paragraph in Prescriber Update reminding prescribers of the risk of myocarditis with clozapine.

Outcome

Medsafe was still to contact a cardiologist for an opinion as recommended, and subsequently consider drafting a Prescriber Update article.

Discussion

Medsafe informed the Committee that it had not yet actioned this recommendation.

The Committee noted the above and asked to be kept informed in due course.

2.1.9 Infliximab / methotrexate / prednisone and secondary sepsis, dural abscess, tooth abscess, headache, coma [death] (CARM case 72110)

September 2006 minute item 4.1.1.5

Issue

In September 2006, the Committee recommended that NZPhvC should analyse the cases of oral cavity abscess with the anti-TNF inhibitors in the WHO database, and subsequently bring the results back to the MARC.

Outcome

NZPhvC provided the Committee with an analysis of the spontaneous reports in the WHO database (Vigibase) related to oral cavity abscess with anti-TNF agents to ascertain the proportion in which sepsis spread locally and/or disseminated systemically and to examine the effect of concurrent immunomodulating, antidiabetic, and bisphophonate treatment.

Investigation of Vigibase revealed that there were considerably more reports of oral cavity abscess proportional to total reports for the three anti-TNF agents adalimumab, etanercept and infliximab than for methotrexate and prednisone:

	Infliximab (n=13528)	Adalimumab (n=8179)	Etanercept (n=24722)	Methotrexate (n=10850)	Prednisone (n=7569)
Tooth caries	2	2	19	2	8
Oral Cavity Abscess	14	41	103	1	2
Brain Abscess	4	0	3	0	2

There was no evidence, further to the CARM case report (72110), in Vigibase that oral cavity abscesses occurring in patients taking anti-TNF agents might lead to devastating sepsis. There were no fatalities and no dissemination to the brain in the Vigibase reports.

For etanercept and adalimumab there was no evidence that the patient groups with further local or systemic infection were more likely to be exposed to other immunomodulating medicines than the patient groups where oral cavity abscess was the only infection. Also, use of the most common concurrently prescribed immunomodulating agents was similar between the groups.

For infliximab, despite a lower proportion of oral cavity abscess reports compared with total reports than for the other two anti-TNF agents, a higher proportion of patients with oral cavity abscess had further infection. Also, more patients with further infection were taking azathioprine and mercaptopurine than those with only oral cavity abscess in whom methotrexate and prednisone were the most common immunomodulating agents. A search of Vigibase revealed only one report for mercaptopurine and three for azathioprine where they were suspect medicines for oral cavity abscess and in three of these reports infliximab was also prescribed, so this is not a feature of these medicines when taken alone. It is possible however that these co-prescriptions represent a regime for Crohn's disease and the reports of sepsis described may result from Crohn's disease rather than a consequence of the oral cavity abscesses.

For all three anti-TNF agents, there was no difference between the groups with and without further infection to the oral cavity abscesses for use of alendronate and medicines indicating that the patients had diabetes. Numbers were low but if there was an influence it was likely to be small.

NZPhvC concluded that there was not enough evidence at present to recommend routine dental checks as part of the pre-treatment infection screen in patients commencing anti-TNF agents, although it could be valuable to add questions about dental health to the pre-treatment infection screen.

Discussion

NZPhvC advised that the case report presented to the MARC at the September 2006 meeting (CARM report 72110) was attributed to infliximab, not adalimumab as previously reported.

Since September 2006, the NZPhvC had received a case of dental abscess with adalimumab. This patient had developed septicaemia and was hospitalised. The patient was concurrently taking leflunomide, an immunomodulating agent. NZPhvC noted that leflunomide has also been associated with infections.

The Committee discussed whether dental checks prior to treatment and/or during treatment with anti-TNF agents should be advised. The members discussed the lack of information about time to onset in the Vigibase reports adding to the difficulty of drawing any causal association between oral cavity abscess and anti-TNF agents.

The Committee considered that there was still not enough evidence to distinguish whether these agents caused oral cavity abscess or if it was a complication of the patients' underlying disease.

It was noted that NZPhvC would look at the time lag between initiating the anti-TNF agent and the appearance of oral cavity abscess in order to assess if a pre-treatment dental check is relevant.

Recommendation

The Committee recommended that an article be written for publication in Prescriber Update, raising the awareness of a possible association between anti-TNF agents and dental cavity abscess, and describing the CARM case reports.

2.1.10 Influenza vaccine and sudden death (CARM case 71269)

September 2006 minute item 4.1.1.6

Issue

In September 2006, the Committee recommended that NZPhvC should bring this case (71269) back to the MARC once the post-mortem results were available.

Outcome

The NZPhvC was still awaiting the post-mortem results and would bring the report back to MARC once it had been received.

Discussion

The Committee noted the above and asked to be provided with the post-mortem results once they were available.

2.1.11 Phentermine and pulmonary hypertension [death] (CARM case 71961)

September 2006 minute item 4.1.1.7

Issue

In September 2006, the Committee recommended that NZPhvC should change the severity of this case report (71961) from 'not severe' to 'severe' and the causality from 'unclassified' to 'possible'.

In September 2006, the Committee recommended that Medsafe should ask the sponsor of Umine (phentermine) to update the data sheet to adequately address the risk of pulmonary hypertension, including contraindications in patients with pulmonary artery hypertension and with moderate to severe hypertension.

Outcome

The CARM database had been amended accordingly.

Medsafe wrote to Douglas Pharmaceuticals in November 2006 requesting data sheet updates for Umine. Douglas responded that Umine was not currently marketed in New Zealand and asked that a disclaimer statement be placed on the website data sheet advising that it might not be up to date.

Discussion

Medsafe advised that if the sponsor of Umine (Douglas Pharmaceuticals) were to market Umine the data sheet changes would be required.

Medsafe informed the Committee that the data sheet for the Duromine brand of phentermine, which is marketed in New Zealand, has already been updated to reflect the changes above.

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

2.1.12 Diclofenac / ibuprofen / prednisone and gastric ulcer, duodenal ulcer, intestinal ulceration, haematemesis, hypoproteinaemia (CARM case 71906)

September 2006 minute item 4.1.3.1

Issue

In September 2006, the Committee recommended that Medsafe should review the NSAID product data sheets with respect to the risk of lower gastrointestinal adverse effects and then request the product sponsors to update the data sheets as warranted.

Outcome

Action on this recommendation had been postponed pending the outcomes of the MARC review of the safety of the non-selective NSAIDs at the December 2006 MARC meeting.

Discussion

The Committee noted the above.

2.1.13 Pioglitazone and neutropenia, thrombocytopenia, myeloid dysplasia (CARM case 71590)

September 2006 minute item 4.1.4.2

Issue

In September 2006, the Committee agreed that haematological disorders, including neutropenia and thrombocytopenia, should be included in the ARCC review in March 2007. Results of haematological investigations in this case should also be sought for the review.

Outcome

This recommendation had been noted by NZPhvC.

Discussion

The Committee noted the above.

2.1.14 Pioglitazone and generalised oedema (CARM case 72087)

September 2006 minute item 4.1.4.3

Issue

In September 2006, the Committee agreed that the severity of the reports of oedema with the glitazones should be analysed for the ARCC review in March 2007.

Outcome

This recommendation had been noted by NZPhvC.

Discussion

The Committee noted the above.

2.1.15 Thalidomide and hyperglycaemia (CARM case 71621)

September 2006 minute item 4.1.5.1

Issue

In September 2006, the Committee recommended that NZPhvC should change the causality in this case report (71621) from 'probable' to 'possible'.

Outcome

The CARM database had been amended accordingly.

Discussion

The Committee noted the above.

2.1.16 Pamidronate and hypocalcaemia, tetany, laryngismus, respiratory arrest (CARM case 71566)

September 2006 minute item 4.1.6.1

Issue

In September 2006, the Committee recommended that NZPhvC should change the causality in this case report (71566) from 'certain' to 'probable'.

Outcome

The CARM database had been amended accordingly.

Discussion

The Committee noted the above.

2.1.17 Paroxetine and developmental delay, congenital brain damage (CARM case 71816)

September 2006 minute item 4.1.7.2

Issue

In September 2006, the Committee recommended that developmental delay should be added to the issue of 'SSRIs and use in pregnancy' monitored on the watching brief list.

Outcome

Developmental delay had been added to the issue of 'SSRIs and use in pregnancy' monitored on the watching brief list.

Discussion

The Committee noted the above.

2.2 Report on Actions Arising from Previous Meetings of the MARC

2.2.1 Safety of Topical Pimecrolimus in Infants

September 2006 minute item 2.1.5; June 2006 minute item 3.1

References

1. Medsafe report for the MARC. November 2006.
2. Novartis. Development of Elidel 1% Cream for Use in Infants Aged 3 Months to 2 Years. 8 June 2005.
3. Extract from the minutes of the 61^st meeting of the Medicines Assessment Advisory Committee (MAAC) held on 5 March 2002.
4. Paul C et al. Safety and tolerability of 1% pimecrolimus cream among infants: experience with 1133 patients treated for up to 2 years. Pediatrics. 2006:117(1);e118-28

Issue

In June 2006, the Committee recommended that Medsafe should ask Novartis to provide general safety data for the use of Elidel 1% cream in under 2-year-olds and subsequently bring these data back to the MARC.

In June 2006, the Committee recommended that Medsafe should obtain the Medicines Assessment Advisory Committee (MAAC) meeting minute regarding the approval of topical pimecrolimus for use in paediatric populations between 3 and 23-months of age. This should be provided to the MARC at the next meeting.

Outcome

Novartis supplied data on the safety of Elidel 1% cream in infants, entitled "Development of Elidel 1% Cream for Use in Infants Aged 3 Months to 2 Years. 8 June 2005." Novartis concluded that the available data supported the safety of Elidel 1% cream and that the safety profile in paediatric patients aged 3-23 months was adequate to allow its use in the treatment of mild to moderate atopic dermatitis in infants. Novartis stated, "When comparing the incidence of adverse events between infants and older children, no clinically significant differences are observed other than those expected from the differences in background incidence of childhood disease between the two populations." Novartis is conducting two long-term studies of the safety of Elidel 1% cream in infants, the final results of which will not be available until at least 2010.

The MARC was provided with a copy of the minute of the Medicines Assessment Advisory Committee (MAAC) meeting regarding the approval of topical pimecrolimus for use in paediatric populations between 3 and 23-months of age (5 March 2002).

Discussion

Medsafe reported that 1% topical pimecrolimus was approved for use in infants from 3 months to 2 years in 30 countries now. Members were interested to know whether the US and European regulatory agencies had approved 1% topical pimecrolimus for use in infants from 3 months of age. Novartis is currently pursuing an extension of the indication to include use in infants from 3 months of age in these countries. Medsafe reported that they were not yet aware of the outcome of this extension application.

The members noted the Novartis safety data demonstrating that systemic exposure is low in infants and young children. They considered Paul et al's review of the safety and tolerability of 1% topical pimecrolimus among infants based on 4 pharmacokinetic studies and 6 clinial trials among these patients. They noted the lack of data about the long-term safety of topical pimecrolimus (over 2 years) and low patient numbers, and wanted to be kept informed of the two Novartis-sponsored long-term studies.

Medsafe would bring to the Committee any further information regarding the US and European regulatory approval in infants from 3 months of age, and the safety data from the long-term studies.

The Committee recommended that no further regulatory action was required at that time.

2.2.2 Topical Pimecrolimus and the Risk of Malignancy

September 2006 minute item 2.1.5; June 2006 minute item 3.1

Issue

The Committee recommended that Medsafe should request that Novartis update the New Zealand data sheet for Elidel 1% cream in line with the Core Data Sheet. The following changes would be required at a minimum:

• Harmonisation of the 'Indications' section with the Australian Product Information.
• Inclusion of information on the risk of malignancy in the 'Adverse Effects' and 'Warnings and Precautions' sections of the data sheet.
• Harmonisation of the information on the positive findings of the monkey carcinogenicity study in line with the information contained in the European Summary of Product Characteristics.

The Committee recommended that Novartis should disseminate a Dear Healthcare Professional letter (following update of the data sheet) advising New Zealand prescribers of the available evidence regarding topical pimecrolimus and the risk of malignancy; the relevant changes to the Elidel cream data sheet and; that they should advise patients of the need for appropriate sun protective measures during Elidel cream use.

Outcome

In September 2006, Novartis submitted an Elidel 1% cream data sheet updated as requested by Medsafe with changes to the 'Indications' and 'Dosage and Administration' sections.

Novartis is drafting a Dear Healthcare Professional letter as recommended by the MARC.

Discussion

The Committee considered that it was likely that there would be a 2 to 5 year time lag between use of pimecrolimus and malignancy and the studies to date were not of long enough duration nor included a long enough follow-up to know if there were any adverse effects with this agent. It was considered that this information would most likely come from the two long-term studies that Novartis is conducting.

The Committee noted that topical pimecrolimus and the risk of malignancy was on the watching brief list due for review in June 2007 and that no further regulatory action was required at that time.

The Committee noted the above and asked to be kept informed about the Novartis Dear Healthcare Professional letter.

2.2.3 Clozapine and Haematological Malignancies

September 2006 minute item 2.2.8; June 2006 minute item 2.1.17; March 2006 minute item 2.5.2

References

1. Medsafe report for the MARC. November 2006.
2. Novartis. Clozaril (clozapine): Haematological Malignancies. 18 September 2006.
3. Parkin DM et al. Global Cancer Statistics, 2002. CA Cancer J Clin 2005:55;74-108

Issue

In March 2006, the Committee recommended that Medsafe should ask the clozapine sponsors to provide further data on the potential association between clozapine and haematological malignancies.

Outcome

IMMP had received two further reports since March 2006:

• 80-year-old male who died from non-Hodgkins lymphoma and had been taking clozapine for 1,492 days (IMMP report number = 70397).
• 77-year-old female who died from chronic leukaemia and had been taking clozapine for three years (report number = 70687).

In summary, IMMP had seven case reports at the time of this meeting: three of leukaemia and four of lymphoma in clozapine treated patients. Although IMMP had identified two more haematological malignancy reports in the last 7-8 months, it was not able to comment on the frequency of these events as it had not defined the denominator population in which these reports occurred. Also, there were many confounding factors which might have caused the spontaneous reporting rate to fluctuate.

In September 2006, Novartis, the sponsor of Clozaril (clozapine), provided Medsafe with a review of the cases of haematological malignancies reported to Novartis worldwide. It concluded that the existing data indicated that treatment with Clozaril did not have a direct effect in causing haematological malignancies.

In July 2006, Douglas Pharmaceuticals provided Medsafe with data on three spontaneous reports of haematological malignancies in association with Clopine (clozapine) worldwide. Clopine was not marketed in New Zealand at the time of this meeting, but was funded by PHARMAC.

Medsafe also provided the Committee with global cancer statistics from 2002 as background information.

Discussion

A member verbally presented a preliminary view from a haematological expert who thought it was difficult at this stage to draw a link between clozapine and haematological malignancies because of the variance in cell type and abnormalities in the IMMP reports. The members agreed with this view.

The Committee considered it was important to define the denominator population in which the reports have occurred in order to assess the frequency of events. In turn these data could be compared with data on overall rates of malignancy. The members considered possible sources of this information to be the sponsors and IMMP.

Depending on the outcome of the frequency of events, the Committee may decide to formally seek an expert haematological opinion to more clearly define the potential mechanism of action for a possible association between clozapine and haematological malignancies.

Recommendation

That Medsafe seek data on the total number of patients exposed to clozapine in New Zealand and report back to the Committee.

2.2.4 Tramadol - Drug Interactions and Serious Reactions

June 2006 minute item 2.1.14; March 2006 minute item 4.2.1

Issue

In March 2006, the Committee recommended that [..] should write two Prescriber Update articles 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.

Outcome

An article entitled 'Evidence for tramadol-warfarin interaction' was published in the November 2006 edition of Prescriber Update. The other article was being written.

Discussion

The Committee noted the above and asked to be kept informed about the second article.

2.2.5 Bisphosphonates and Osteonecrosis of the Jaw (ONJ)

September 2006 minute item 2.1.6; June 2006 minute item 3.2; March 2006 minute item 2.2.6; December 2005 minute item 2.1.4; September 2005 minute item 3.2

Issue

In September 2005, the Committee recommended that a Prescriber Update article be written to inform prescribers of the potential for ONJ to occur with bisphosphonate therapy and to reiterate management advice.

In June 2006, the Committee recommended that Medsafe should liaise with the authors regarding their planned New Zealand Medical Journal article.

Outcome

An article written by Professor Ian Reid entitled 'Bisphosphonates and osteonecrosis of the jaw' was published in the June 2006 edition of Prescriber Update.

A link to an article in the June 2006 edition of NZDA News (a publication of the New Zealand Dental Association) entitled "Bisphosphonates and osteonecrosis of the jaw - our current practice for removal of teeth in patients who are taking oral alendronate (Fosamax)" had been placed on the Medsafe web site. A short paragraph was also published in the November 2006 edition of Prescriber Update advising prescribers about the NZDA News article.

An article written by Mark Bollard, David Hay, Andrew Grey, Ian Reid, and Tim Cundy entitled "Osteonecrosis of the jaw and bisphosphonates - putting the risk in perspective" was published in the 1 December 2006 issue of the New Zealand Medical Journal.

Discussion

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

2.2.6 Lipid-Lowering Agents and Psychiatric Adverse Reactions

September 2006 minute item 2.1.1; June 2006 minute item 1.5.2; December 2005 minute item 4.2.2; September 2005 minute item 4.1.5.1

Issue

In September 2005, the Committee recommended that CARM should explore the option of writing a Prescriber Update article on the psychiatric adverse effects of the statins.

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

In June 2006, the Committee recommended that the scheduled Prescriber Update article on the psychiatric adverse effects of the statins should include information about ezetimibe.

Outcome

The following short articles were published in the November 2006 edition of Prescriber Update:

Psychiatric reactions with cholesterol-lowering agents

Statin reminder - myopathy, rhabdomyolysis and interactions

Watch for muscle disorders with ezetimibe too

Discussion

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

2.2.7 Dextropropoxyphene/Paracetamol Combination Products and the Risk of Overdose

September 2006 minute item 2.1.4; June 2006 minute item 2.2.9; March 2006 minute item 2.1.3; 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 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.

Outcome

An article entitled "Dextropropoxyphene/paracetamol combination products and risk of overdose" was published in the November 2006 edition of Prescriber Update.

Discussion

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

2.3 Report on Unresolved Actions Arising from Recommendations of the MARC

The following is a list of recommendations made by the MARC that have yet to be resolved. Prescriber Update articles are not included, as they are listed in the Schedule of Planned Prescriber Update Articles (see minute item 1.5.1). Nor are actions arising from the previous MARC meeting included, as they are listed in the Report on Actions Arising from the 126^th Meeting of the MARC (see minute item 2.1).

2.3.1 Low Molecular Weight Heparins (LMWHs) in Renal Impairment

December 2005 minute item 2.2.12; September 2005 minute item 2.2.6; June 2005 minute item 2.2.11; September 2004 minute item 2.1.6; June 2004 minute item 2.1.4; March 2004 minute item 2.1.8; December 2003 minute item 4.1.1.5

Issue

In June 2005, the Committee recommended that Medsafe should contact the DHBNZ Safe Use of Medicines Group to enquire on the progress of the development of a protocol for the safe use of LMWHs in patients with severe renal impairment.

Outcome

The DHBNZ Safe Use of Medicines Group responded to Medsafe in October 2005. Medsafe was informed that an alert was currently being developed to advise prescribers on the required enoxaparin dosage adjustment for patients with renal impairment (creatinine clearance <50mL/min). In view of a lack of data for other LMWHs this advice would not be extrapolated to the other LMWHs available in New Zealand. After consultation throughout New Zealand the Safe Use of Medicines Group determined that there was only limited ability to perform anti-Xa monitoring in New Zealand and therefore monitoring could not be recommended routinely.

In December 2005, the Committee noted the above and agreed that Medsafe should bring the DHBNZ Safe Use of Medicines Group protocol to the MARC once it was finalised.

Discussion

Members noted that the DHBNZ Safe Use of Medicines Group protocol on the safe use of LMWHs in patients with severe renal impairment was still in development.

2.3.2 Alteplase and oedema [death] (CARM cases 70710, 70711 and 70712)

September 2006 minute item 2.1.9; June 2006 minute item 4.1.1.4

Issue

In June 2006, the Committee recommended that NZPhvC should report back to the MARC once further information had been received from the sponsor on these three cases (70710, 70711 and 70712) and the report dates had been checked.

Outcome

As at November 2006, no further information had been received from the reporter.

Discussion

As at December 2006, no further information had been received. This issue could be removed from the list of unresolved actions.

Recommendation

The Committee recommended that the issue of alteplase and oedema could be removed from the list of unresolved actions arising from MARC recommendations.

2.3.3 Baclofen and cardio-respiratory arrest, abdominal pain, hypertension, vomiting and coughing [death] (CARM case 70111)

June 2006 minute item 4.1.1.2

Issue

In June 2006, the Committee recommended that NZPhvC should seek further information from the reporter in this case (70111).

In June 2006, the Committee recommended that NZPhvC should add 'withdrawal syndrome' to the adverse reaction terms in this case (70111) if the baclofen pump was found to have been faulty.

Outcome

Further information had been received about the events, but as yet this feedback had not contained information on the potential device failure. A further follow-up request had been initiated by the NZPhvC.

Discussion

As at December 2006, no further information had been received. This issue could be removed from the list of unresolved actions.

Recommendation

The Committee recommended that the issue of baclofen and cardio-respiratory arrest, abdominal pain, hypertension, vomiting and coughing could be removed from the list of unresolved actions arising from MARC recommendations.

3. Pharmacovigilance Issues

3.1 COX-2 Inhibitors: Active Monitoring Review

References

1. Medsafe report for the MARC. November 2006
2. Extracts from the minutes of MARC meetings related to COX-2 inhibitors and NSAIDs.
3. COX-2 inhibitor data sheets:
   1. Celebrex (celecoxib 100mg and 200mg capsules)
   2. Arcoxia (etoricoxib 60mg, 90mg and 120mg tablets)
   3. Prexige (lumiracoxib 100mg and 400mg tablets)
   4. Mobic (meloxicam 7.5mg tablets)
   5. Dynastat (parecoxib 40mg powder and diluent for injection)
4. NZPhvC report for the MARC. November 2006.
5. McGettigan & Henry (2006). Cardiovascular risk and inhibition of cyclooxygenase. A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 296(13): 1633-1644.
6. Kearney et al. (2006) Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 332: 1302-1308.
7. Zhang et al. (2006) Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events. JAMA. 296: 1619-1632.
8. ADAPT Research Group. Cardiovascular and Cerebrovascular Events in the Randomized, Controlled Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT). PLoS Clin Trials 1(7): e33.
9. Cannon et al. (2006) Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet. 368: 1771-1781.
10. Merck Research Laboratories. Common Technical Document: Extract from the Summary of Clinical Safety (pages 333-341). 29 September 2006.
11. Merck Sharp & Dohme. Arcoxia tablets data sheet. 21 October 2006.

Background

Medsafe provided a report for the MARC's annual active monitoring review of the safety of the COX-2 inhibitors. The issue of COX-2 inhibitors and cardiovascular reactions was placed on the watching brief list in September 2002. The issue of COX-2 inhibitors and hypertension, congestive heart failure, skin reactions, renal dysfunction and allergic reactions was placed on the watching brief list in March 2005. Upon review by the MARC in December 2005, these two issues were combined and placed on the active monitoring list for annual review; the first review being due in December 2006.

The purpose of the report was to inform the Committee by providing an update on recent data, evidence and regulatory actions. The Committee was asked to evaluate the information provided; determine whether the risk-benefit profile of the COX-2 inhibitors had changed as a result of the recent information; and if so, recommend appropriate regulatory action.

Safety issues with the COX-2 inhibitors were most recently discussed at the following MARC meetings: June 2006, December 2005, September 2005, June 2005 and March 2005. Additionally, the MARC reviewed this issue on 12 occasions between December 2000 and December 2004. The MARC was provided with copies of the relevant excerpts of the minutes of these meetings.

Products

The following table lists the COX-2 inhibitors approved in New Zealand at the time of this meeting.

COX-2	Brand name	Dose form	Indications	Sponsor
celecoxib	Celebrex	Capsules 100mg & 200mg	Symptomatic treatment of pain and inflammation in osteoarthritis and rheumatoid arthritis. For the management of acute pain and treatment of primary dysmenorrhea in adults.	Pfizer
celecoxib	Onsenal [not yet marketed]	Capsules 200mg & 400mg	Familial adenomatous polyposis.	Pfizer
etoricoxib	Arcoxia	Tablets 60mg, 90mg & 120mg	Acute and chronic treatment of the signs and symptoms of osteoarthritis and rheumatoid arthritis. Management of ankylosing spondylitis. Treatment of acute gouty arthritis. Relief of acute pain. Relief of chronic musculoskeletal pain.	MSD (Merck Sharp & Dohme)
lumiracoxib	Prexige	Tablets 100mg & 400mg	Symptomatic treatment of osteoarthritis (OA). Treatment of acute pain. Treatment of primary dysmenorrhoea.	Novartis
meloxicam	Mobic	Tablets 7.5mg	Symptomatic treatment of rheumatoid arthritis and osteoarthritis.	Boehringer Ingelheim
parecoxib	Dynastat	Injection 40mg	Single peri-operative dose for the management of post-operative pain.	Pfizer

Usage

The MARC was provided with sales data for the COX-2 inhibitors from January 2004 to September/ October 2006.

New Zealand regulatory action

Since COX-2 inhibitors were last discussed at the December 2005 MARC meeting, there had been no further regulatory action in New Zealand - with the exception of Medsafe's approval of Onsenal (celecoxib 200mg and 400mg capsules) in May 2006 for the sole indication of Familial Adenomatous Polyposis (FAP). Pfizer subsequently applied to have this indication removed from the data sheet for Celebrex.

Neither Bextra (valdecoxib) nor Vioxx (rofecoxib) had returned to the New Zealand (or international) market.

An update on the COX-2 inhibitors was last published in the December 2005 edition of Prescriber Update, informing prescribers of the cardiovascular safety-related changes to the data sheets.

Recent market changes

In November 2005, Novartis commenced the supply of Prexige (lumiracoxib) 400mg tablets to the New Zealand market; this was followed by Prexige 100mg tablets in September 2006. Novartis had committed to active post-marketing surveillance of Prexige by way of a Prescription-Event Monitoring study in the United Kingdom, as well as a cohort study using established health information databases, and drug utilisation studies using the IMS database in the UK population.

CARM and WHO data

NZPhvC provided the MARC with an analysis of the data received by CARM and WHO (Vigibase) related to the COX-2 inhibitors.

Thrombotic adverse reactions:

For cardiac thrombotic reactions there was clearly greater reporting of these adverse effects with the COX-2 inhibitors than with the non-specific NSAIDs in both the WHO and New Zealand databases. Within the COX-2 inhibitor group there were a proportionately greater number of reports with rofecoxib and etoricoxib than with celecoxib and valdecoxib in Vigibase, but no difference between diclofenac, ibuprofen and naproxen. The differences between COX-2 inhibitors were absent in the New Zealand data which included intensively monitored patients. These findings had been published based on a purely intensively monitored cohort. The differences between ibuprofen, naproxen, meloxicam, diclofenac, piroxicam and ketoprofen for cardiovascular reactions in the NZ CARM database were not due to thrombotic reactions.

Cardiac failure and hypertension:

The WHO data indicated proportionately greater reporting of cardiac failure and hypertension with rofecoxib and, by November 2006, etoricoxib compared with celecoxib and valdecoxib. This observation was first made for rofecoxib in 2002 and more recent publications had supported this finding. This finding was not currently present in the NZPhvC database.

Serious skin reactions:

Analyses of both the WHO and NZPhvC databases showed a clear signal for valdecoxib with markedly greater reporting of serious skin reactions, particularly Severe Cutaneous Adverse Reactions (SCARS), which include erythema multiforme, Stevens Johnson Syndrome and toxic epidermal necrolysis, compared with the other COX-2 inhibitors and most of the NSAIDs. For this reason, valdecoxib was withdrawn from the market in March 2005. Celecoxib, while not so clearly different as valdecoxib, also appeared to cause serious skin reactions to a greater extent than rofecoxib and etoricoxib.

Serious renal reactions:

The proportional reporting of serious renal disorders was a little greater for rofecoxib and etoricoxib in December 2004 and for etoricoxib in the 2006 database. While this was in keeping with the proportions for cardiac failure and hypertension, the differences were probably too small to be taken into consideration in assessing these medicines.

Gastrointestinal reactions:

The WHO findings for etoricoxib were unexpected, showing proportionately more reporting of serious gastrointestinal disorders compared with the other COX-2 inhibitors. This finding was not supported by the New Zealand data. However, it required further investigation as the EDGE study, which was considered by the MARC in March 2005, showed no clear difference between diclofenac and etoricoxib for gastroduodenal bleeding and ulcer complications, although the authors said that a difference may have been obscured by the uncontrolled use of aspirin and omeprazole in the study.

International status and regulatory action

Australia

The TGA did not take any regulatory action on COX-2 inhibitors in 2006.

United Kingdom

No regulatory action or new information was issued by the MHRA in 2006 specifically relating to the COX-2 inhibitors.

United States

No regulatory action or new information was issued by the FDA in 2006 specifically relating to the COX-2 inhibitors.

Canada

In December 2005, Health Canada completed a review of the cardiovascular (including cerebrovascular) side-effects of the COX-2-selective NSAIDs, i.e. celecoxib, meloxicam, rofecoxib, and valdecoxib. Health Canada recommended that the Basic Product Monograph Information for all NSAIDs (i.e. COX-2-selective NSAIDs, and the non-selective NSAIDs) be revised to describe the available data or lack of data on cardiovascular toxicity, the increased cardiovascular risk, and to recommend caution accordingly, particularly for patients with cardiovascular disease or with risk factors for cardiovascular disease. A contraindication to use in patients undergoing certain high-risk cardiovascular surgeries and a reminder to use these medicines at the lowest effective dose for the shortest time possible should be added to labelling. As more data on cardiovascular risk/safety become available, the labelling will be revised accordingly.

Europe

No regulatory action or new information was issued by the EMEA in 2006 specifically relating to the COX-2 inhibitors.

Recent literature

Medsafe provided the Committee with summaries and analysis of the following papers related to the safety of the COX-2 inhibitors:

• McGettigan & Henry (2006) Cardiovascular risk and inhibition of cyclooxygenase. A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 296(13): 1633-1644.
• Kearney et al. (2006) Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 332: 1302-1308.
• Zhang et al. (2006) Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events. JAMA. 296: 1619-1632.
• Caldwell et al. (2006) Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis. J R Soc Med. 99: 132-140.
• Mosis et al. (2006) Channeling and prevalence of cardiovascular contraindications in users of cyclooxygenase 2 selective nonsteroidal anti-inflammatory drugs. Arthritis & Rheumatism. 55: 537-542.
• Gislason et al. (2006) Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal anti-inflammatory drugs after acute myocardial infarction. Circulation. 113: 2906-2913.
• Solomon et al. (2006) Cardiovascular outcomes in new users of coxibs and nonsteroidal anti-inflammatory drugs. High-risk subgroups and time course of risk. Arthritis and Rheumatism. 54(5): 1378-1389.
• Levesque et al. (2006) Time variations in the risk of myocardial infarction among elderly users of COX-2 inhibitors. CMAJ. 174(11), online 1-8.
• Helin-Salmivaara et al. (2006) NSAID use and the risk of hospitalization for first myocardial infarction in the general population; a nationwide case-control study from Finland. European Heart Journal. 27(14), 1657-1663.
• Abstracts of the following articles were provided to the Committee:
• Jick et al. (2006) Nonsteroidal anti-inflammatory drugs and acute myocardial infarction in patients with no major risk factors. Pharmacotherapy. 26(10), 1379-1387.
• Andersohn et al. (2006) Cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs and the risk of ischemic stroke. Stroke. 37, 1725-1387.

Lumiracoxib

Medsafe provided the MARC with the relevant excerpts of the PSUR (covering 1 October 2005 to 31 March 2006) for Prexige (lumiracoxib) and a summary of following study:

• Matchaba P, Gitton X, Krammer G, et al. Cardiovascular Safety of Lumiracoxib: A Meta-analysis of All Randomised Controlled Trials ≥ 1 Week and up to 1 Year in Duration of Patients with Osteoarthritis and Rheumatoid Arthritis. Clinical Therapeutics 2005;27(8):1196-1214.

Celecoxib

Medsafe provided the MARC with extracts from the European Medicines Evaluation Agency (EMEA) review of celecoxib regarding the the APC (Adenoma Prevention with Celecoxib) and the PreSAP (Prevention of Colorectal Sporadic Adenomatous Polyps) trials. Medsafe also provided a summary of the findings of the recently published ADAPT trial:

• ADAPT Research Group. Cardiovascular and cerebrovascular events in the randomized, controlled Alzheimer's disease Anti-inflammatory Prevention Trial (ADAPT). PLoS Clin Trials 2006;1(7): e33.

Rofecoxib

Medsafe provided the MARC with information regarding the correction to the APPROVe study and the preliminary analyses of the off-drug extension of APPROVe:

• Bresalier R et al. Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial. N Engl J Med 2005;352:1092-102
• Correction. N Engl J Med 2006;355(2):221
• Nissen S. Adverse Cardiovascular Effects of Rofecoxib. N Engl J Med 2006;355(2):203-205

Etoricoxib

Medsafe provided the MARC with a summary and analysis of the MEDAL study, and data provided by Merck Research Laboratories:

• Cannon et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet. 2006;368:1771-1781.
• Merck Research Laboratories. Common Technical Document: Extract from the Summary of Clinical Safety (pages 333-341). 29 September 2006.

Medsafe recommendations

Medsafe considered the new information presented to the MARC supported the recommendations made by the MARC in March 2005 and that these recommendations remained valid. The new information did not alter the risk-benefit profile of the COX-2 inhibitors.

Medsafe recommended that the issue of COX-2 inhibitors and cardiovascular reactions, hypertension, congestive heart failure, skin reactions, renal dysfunction and allergic reactions be removed from the active monitoring list but that all significant new data regarding these issues be brought to the attention of the MARC as the data arise.

Medsafe agreed to continue to monitor the literature and liaise with international regulators regarding COX-2 inhibitor safety issues. In particular, Medsafe noted the safety concern of cardio-renal events reported in association with etoricoxib in the MEDAL study.

Discussion

The Committee noted the Medsafe review and recent meta-analyses data. The Committee noted that data on cardiovascular events was very limited for some agents. They agreed that the cardiovascular risk may be less with celecoxib ≤200mg, however the Committee agreed that the risk was still significant enough to warrant the cardiovascular warning statements in the celecoxib data sheet.

The Committee considered that while the new data has added substantially to the body of evidence previously considered by the Committee, it did not alter their view that all COX-2 inhibitors are associated with an increased risk of cardiovascular events regardless of dose. The Committee agreed there should be no change to the current data sheet warnings about COX-2 inhibitors and cardiovascular risk.

A member raised concern about the gastrointestinal effects of etoricoxib. The MEDAL Study showed that there was no difference between etoricoxib and diclofenac for complicated gastrointestinal events, but that etoricoxib had improved safety compared to diclofenac for symptomatic ulcers. Diclofenac has the lowest overall risk for gastrointestinal events amongst the conventional NSAID agents (except for low dose ibuprofen) but the risk is still higher compared to rofecoxib and etoricoxib. The Committee considered that the data on gastrointestinal events are not conclusive for a reduction in complicated gastrointestinal events with the COX-2 inhibitors. The Committee considered whether all COX-2 inhibitor data sheets should have a contra-indication for active or complicated ulceration.

The Committee discussed the incidence of stroke with the COX-2 inhibitors. While there is an elevated risk of MI with the COX-2 inhibitors, the risk of stroke is less clear. Medsafe informed the Committee that the incidence of myocardial infarction and stroke are grouped together in the product data sheets.

Recommendations

The Committee recommended that the issue of COX-2 Inhibitors should be removed from the active monitoring list.

The Committee recommended that Medsafe review the data sheets for all of the COX-2 inhibitors for GI risks and report back to the Committee at the next meeting.

3.2 Non-Selective NSAIDs: Active Monitoring Review

References

1. Medsafe report for the MARC. November 2006.
2. Extracts from the minutes of the MARC meetings related to non-selective NSAIDs.
3. TGA. Non-Steroidal Anti-Inflammatory Drugs Review - Request for ADEC Advice. May 2006. (Extracts)
4. Extract of the minutes of the September 2006 meeting of the Australian Adverse Drug Reactions Advisory Committee (ADRAC) (advance copy).
5. EMEA. Public CHMP Assessment Report for Medicinal Products Containing Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). 7 November 2006.
6. MHRA. Dear Healthcare Professional Letter: Safety of Selective and Non-Selective NSAIDs. October 2006.

Background

Medsafe provided a report for the MARC's annual active monitoring review of the safety of non-selective non-steroidal anti-inflammatory drugs (NSAIDs). In December 2005, the issue of non-selective NSAIDs and cardiovascular reactions was placed on the active monitoring list for annual review.

The purpose of the report was to inform the Committee by providing an update on recent data, evidence and regulatory action. The Committee was asked to evaluate the information provided; determine whether the risk-benefit profile of the non-selective NSAIDs had changed as a result of this new information; and if so, recommend appropriate regulatory action.

Products

The following table lists the NSAIDs available in NZ in oral dose form (i.e. tablets, capsules and oral liquid) at the time of this meeting:

NSAID	Medicine classification	Fully funded brands	Partially funded brands
Diclofenac	Pharmacy only: ≤ 12.5mg per solid dose form; max. 20 tablets per pack. Restricted Medicine: 12.5-25mg per solid dose form; max. 30 tablets per pack. Prescription only: > 25mg per solid dose form	Apo-Diclo Apo-Diclo SR Diclax SR	Voltaren D
Ibuprofen	General sales: ≤ 200mg per solid dose form; max. 25 tablets per pack. Pharmacy only: ≤ 200mg per solid dose form ≤ 4g per pack if a liquid form Restricted Medicine: ≤ 400mg per solid dose form; max. 50 tablets per pack. Prescription only: ≥ 200mg per solid dose form; no restriction on quantity. ≥ 4g per pack if a liquid form	I-profen Fenpaed (oral liquid)	Brufen Brufen Retard
Indomethacin	Prescription only	Rheumacin Rheumacin SR
Ketoprofen	Pharmacy only: ≤ 25mg per solid dose form; max. 30 tablets per pack. Prescription only: > 25mg per solid dose form		Oruvail
Mefenamic acid	Pharmacy only: ≤ 30 tablets per pack. Prescription only: > 30 tablets per pack		Ponstan
Naproxen	Pharmacy only: ≤ 250mg per solid dose form; max. 30 tablets per pack. Prescription only: > 30 tablets per pack	Naxen Naprosyn SR Synflex
Piroxicam	Prescription only	Piram-D
Sulindac	Prescription only		Daclin Clinoril
Tenoxicam	Prescription only	Tilcotil
Tiaprofenic acid	Prescription only		Surgam Surgam SA

CARM and WHO data

NZPhvC provided the MARC with an analysis of the data received by CARM to 30 September 2006, and WHO (Vigibase) from December 2004 to November 2006, relating to the non-selective NSAIDs.

Thrombotic adverse reactions

As well as a lesser proportion of reporting of cardiac thrombotic events with the non-specific NSAIDs compared with the COX-2 inhibitors in both the WHO and CARM databases, no clear difference was found between diclofenac, ibuprofen and naproxen except for a slight increase in reporting for naproxen between 2004 and 2006. The increase in reporting of cardiovascular adverse effects in the CARM database for ketoprofen and piroxicam was not due to thrombotic events. There were two reports of myocardial infarction with diclofenac and one with meloxicam.

Cardiac failure and hypertension

The WHO and CARM data show little difference between diclofenac, ibuprofen and naproxen for these adverse effects but the excess reporting of cardiovascular effects in the CARM database for piroxicam was largely due to cardiac failure (2) and hypertension (3).

Serious skin reactions

The CARM reporting of severe skin reactions attributed to piroxicam are of concern and warrant further investigation. There were 47 reports of photosensitivity reactions, but even if these are excluded, there is still a marked excess of severe skin reaction reports for this medicine, notably five reports of bullous eruptions.

A further analysis of SCARs and other severe skin reactions between individual NSAIDs and COX-2 inhibitors in the WHO database is probably merited.

Serious renal reactions

The greater reporting of renal disorders with naproxen, ibuprofen and diclofenac, in particular, compared with piroxicam and ketoprofen in the CARM database is unexpected, and the high reporting of interstitial nephritis with diclofenac requires investigation. No clear difference was found between naproxen, diclofenac and ibuprofen in the WHO database.

Gastrointestinal reactions

The WHO data for diclofenac, ibuprofen and naproxen and the CARM data for these three NSAIDs and three other NSAIDs were in keeping with published meta-analyses from pharmaco-epidemiological studies, except that meloxicam was not included in these studies and its ranking, though based on smaller numbers, needed further investigation. Of note was the consistent finding of a high risk with piroxicam and ketoprofen across studies, though New Zealand pharmaco-epidemiological data indicated that the risk with ketoprofen was probably much lower at daily doses of 150 mg or less.

International status and regulatory action

Australian TGA

In 2005, the TGA initiated an evaluation of the safety profiles of non-selective NSAIDs, focusing specifically on the risks of cardiovascular, gastrointestinal, and cutaneous adverse events with these agents. This Non-Steroidal Anti-Inflammatory Drugs Review was provided to MARC members for review.

[..]

Europe (EMEA)

In October 2005, the Committee for Medicinal Products for Human Use (CHMP) recommended a number of key elements for inclusion in non-selective NSAID Summary of Product Characteristics (SmPCs) to ensure consistency across Europe.

United States

In 2005, the United States Food and Drug Administration (FDA) asked all sponsors of marketed prescription NSAIDs, including the COX-2 selective NSAID celecoxib (Celebrex), to revise the labelling (package insert) for their products to include a boxed warning, highlighting the potential for increased risk of cardiovascular events and serious gastrointestinal bleeding associated with their use. In addition to the general labelling that was to apply to all NSAIDs, the Celebrex labelling would contain safety data from long-term trials with celecoxib.

The FDA also asked manufacturers of over-the-counter NSAIDs to revise their labelling to provide more specific information about the potential cardiovascular and gastrointestinal risks of their individual products, and remind patients of the limited dose and duration of treatment of these products in accordance with the package instructions.

In September 2006, the FDA notified consumers and healthcare professionals that concomitant ibuprofen and aspirin may interfere with the cardioprotective effects of aspirin. Ibuprofen can interfere with the anti-platelet effect of low-dose aspirin, potentially rendering aspirin less effective when used for cardioprotection and stroke prevention.

Canada

As part of Health Canada's December 2005 safety review of the COX-2-selective NSAIDs, it was noted that limited available evidence suggested the cardiovascular safety concerns associated with COX-2-selective NSAIDs also apply to most traditional drugs within the NSAID class, and that the degree of risk differs among NSAIDs. A lack of comparative randomised clinical trial data prevented the ranking of these drugs with respect to cardiovascular risk. Health Canada recommended that the Basic Product Monograph Information for all NSAIDs be revised to describe the available data or lack of data on cardiovascular toxicity, the increased cardiovascular risk, and to recommend caution accordingly, particularly for patients with cardiovascular disease or with risk factors for cardiovascular disease. It was also recommended that a contraindication to use in patients undergoing certain high-risk cardiovascular surgeries and a reminder to use NSAIDs at the lowest effective dose for the shortest time possible period be added to labelling. As data on cardiovascular risk/safety becomes available for a particular NSAID, the labelling would be revised accordingly.

Recent literature

Summaries of recently published literature regarding non-selective NSAIDs and cardiovascular events are listed under the COX-2 Inhibitors Active Monitoring Review (see minute item 3.1) and in the TGA Non-Steroidal Anti-Inflammatory Drugs Review.

Medsafe summary

Medsafe reviewed these new data and considered that, while the risk-benefit profile for non-selective NSAIDs remained favourable, it was important that risk management advice regarding risk of cardiovascular events be conveyed to NZ prescribers and consumers. Medsafe was in general agreement with the opinion and recommendations of the [..] and the European CHMP regarding the safety of non-selective NSAIDs.

The new data suggested that non-selective NSAIDs were associated with a small increase in the absolute risk for thrombotic cardiovascular events. The data also suggested there was variability in the risk of cardiovascular adverse events between individual NSAIDs - overall, high-dose diclofenac may be associated with a slightly higher risk compared with ibuprofen and naproxen. However, the level of relative risk increase is modest and the studies are limited by uncontrolled confounding. For other non-selective NSAIDs, the data on thrombotic cardiovascular risk were insufficient. In light of this, Medsafe considered the evidence was not yet clear enough to warrant differing advice for individual NSAIDs.

Medsafe was in agreement with the key messages issued in the UK and Europe, i.e.,

• The lowest effective dose of NSAID should be prescribed for the shortest time necessary for control of symptoms. The need for long-term treatment should be reviewed periodically.
• Prescribing should be based on the safety profiles of individual NSAIDs and on individual patient risk profiles (e.g., gastrointestinal and cardiovascular).
• Prescribers should not switch between NSAIDs without careful consideration of the overall safety profile of the products, a patient's individual risk factors, and patient preference.

Medsafe Recommendations

In conveying the key messages above, Medsafe recommended that:

• No distinction should be made between prescription-only and over-the-counter NSAIDs in terms of the risk management advice given; and
• No distinction should be made between individual NSAIDs and dosages in terms of the risk management advice given

Medsafe recommended that the above prescribing advice should be conveyed via:

• a Prescriber Update article; and
• NZ product data sheets for non-selective NSAIDs

Medsafe recommended that the NSAID product information amendments recommended by the [..] should be adopted in New Zealand.

Medsafe recommended that the issue of NSAIDs and cardiovascular reactions should be removed from the active monitoring list but that all significant new data regarding this issue should be brought to the attention of the MARC as the data arise.

Discussion

[..] Members discussed the increased risk of cardiovascular events with diclofenac ≥100mg but considered that the evidence was not strong enough to warrant differing advice at the product information level. They considered that in the interests of harmonisation, the non-selective NSAID product information amendments recommended by [..] be adopted.

[..]

[..]

The members discussed the increased cardiovascular risk with diclofenac ≥100mg and whether a distinction should be made in the risk management advice for individual agents at the prescriber education level. Members noted that diclofenac is the most widely prescribed NSAID with a significant number of patients on 150mg/day. Members briefly discussed the safety profiles of other NSAID agents and reiterated that prescribers need to consider the safety profiles of individual non-selective NSAIDs and patient risk profiles when prescribing these agents.

The Committee discussed the main messages in the MHRA, Dear Healthcare Professional Letter: Safety of Selective and Non-Selective NSAIDs, October 2006. They were in agreeance with the main messages and considered that this form the basis of an article to be published in Prescriber Update, and a Dear Healthcare Professional letter. Medsafe should consider including some information on individual agents and cardiovascular risk management.

Medsafe agreed to continue to monitor the literature and liaise with international regulators regarding the issue of non-selective NSAIDs and cardiovascular risk.

Recommendations

The members recommended that non-selective NSAID product information amendments recommended by the [..] should be adopted in New Zealand.

The Committee recommended that an article is written for publication in Prescriber Update to inform prescribers of current evidence regarding the safety of NSAIDs and to provide advice for the safe use of these agents.

The Committee recommended that the information in Prescriber Update form the basis of a Dear Healthcare Professional letter.

3.3 COX-2 Inhibitors and Impaired Fracture Healing: Watching Brief Review

Reference

1. Medsafe. Report for the MARC. November 2006.

Issue

The MARC first considered this issue in 2002, and recommended that it be placed on the watching brief list in 2003. In December 2005 the issue was reviewed and the Committee agreed that it should remain on the watching brief list for annual review.

The MARC had previously noted that it is theoretically plausible that the COX-2 inhibitors / non-selective NSAIDs might impair fracture healing and a clear association had been found in animal studies. However, clinical studies had not produced any consistent evidence of an association.

In New Zealand and internationally, no regulatory action had been taken on this issue to date.

There had been no case reports received by CARM for impaired fracture healing with the COX-2 inhibitors or non-selective NSAIDs. There were no appropriate terms in the WHO database to enable a search.

A review of the recent literature found a number of animal studies supporting this potential association. These studies were not reviewed in detail.

Beck et al (Oper Orthop Traumatol 2005) investigated the impact of NSAIDs on fracture healing in rats, discussed the effect of NSAIDs on bone metabolism, and reviewed the evidence for a clinical effect. The authors stated "Our results - together with a review of the current literature - leave little doubt about our conclusions: non-steroidal anti-inflammatories inhibit and delay fracture healing to a greater or lesser degree, depending on the individual preparation, even if to date only animal studies have yielded unequivocal support. All available findings and the mechanisms of action discovered hitherto permit no other conclusion. Findings can be extrapolated, at least with reservations, to the human organism. However, appropriate research to clarify the true facts with different NSAIDs is still necessary."

Naesh (NZMJ 2006) highlighted some of the aspects of short-term use (i.e. less than five days) of peri-operative use of NSAIDs. The authors stated "The use of NSAIDs in orthopaedic surgery is controversial - some experimental work points to NSAIDs having an inhibitory effect on bone healing. However, long experience and a widespread use of NSAIDs after fracture surgery has not highlighted any clinical problem."

Medsafe contacted two New Zealand endocrinologists for an expert opinion on this issue. Their response was:

The concerns based on animal studies remain but there is still no substantive evidence that this is a problem in clinical practice. Indeed, some of the observational clinical data are likely to be confounded by the possibility that those with non-union of fractures are more likely to need pain relief, so increases in NSAID use in these patients may be the result not the cause of their problem. Opioid use has been shown to have the same association (Bhattacharyya, T.et al, 2005, "Nonsteroidal antiinflammatory drugs and nonunion of humeral shaft fractures." Arthritis & Rheumatism 53(3): 364-7). A recent systematic review has not provided data that would suggest a change in policy (Koester, M. C. and K. P. Spindler, 2006, "Pharmacologic agents in fracture healing." Clinics in Sports Medicine 25(1): 63-73). Since new clinical studies are not appearing rapidly in this area, we are not sure that annual review is appropriate - perhaps it could be reconsidered in 3-4 years. We feel sure that if a major study is published earlier, it would come to Medsafe's notice.

Medsafe also contacted an expert from the United States for an opinion. He responded that the association probably does not have clinical significance and that the evidence does not warrant limiting the use of NSAIDs in high-risk patients (e.g. smokers, diabetics etc).

Discussion

The Committee considered that this issue remained of interest to the Committee and asked that Medsafe bring any significant data to the attention of the MARC as the data arise. The Committee agreed this issue should be removed from the watching brief list.

Recommendation

The Committee recommended that this issue is removed from the watching brief list, that no regulatory action be taken on this issue at this time, and that Medsafe bring any significant data to the attention of the MARC as the data arise.

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 web site of the WHO Collaborating Centre (http://www.who-umc.org/DynPage.aspx?id=22682). 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) Spontaneous Case Reports

4.1.1 Deaths

4.1.1.1 Bortezomib and thrombocytopenia [death] (72705)

Discussion

Also see minute item 4.3.1.

NZPhvC reported that a follow-up report had confirmed that the cause of death was disease progression.

NZPhvC informed the Committee that thrombocytopenia was a well-recognised adverse reaction to bortezomib.

The causal association with bortezomib was considered to be 'probable' for thrombocytopenia, and 'unlikely' for disease progression.

Recommendation

The Committee recommended that NZPhvC should change the causality from 'possible' to 'probable' for thrombocytopenia, and add that the causality for disease progression was 'unlikely'.

The Committee agreed that no further regulatory action was required at that time.

4.1.1.2 Bortezomib and sudden death (72706)

Discussion

Also see minute item 4.3.1.

NZPhvC commented that the indication was presumed to be multiple myeloma (indication previously not reported), and that the cause of death was due to disease progression. The causal association with bortezomib was considered to be 'unlikely' for disease progression.

Recommendation

The Committee recommended that NZPhvC should add that the cause of death was disease progression and the causality was 'unlikely' to bortezomib.

The Committee agreed that no further regulatory action was required at that time.

4.1.1.3 Bortezomib and thrombocytopenia, progression of disease [death] (72707)

Discussion

Also see minute item 4.3.1.

A follow-up report noted that the cause of death was probably an intracerebral bleed and that bortezomib may have been contributory. NZPhvC informed the Committee that thrombocytopenia was a well-recognised adverse reaction to bortezomib. The reported platelet count of 22 x 10⁹ would suggest that the severity was 'severe' for thrombycytopenia and disease progression.

The causal association with bortezomib was considered to be 'unclassified' for thrombocytopenia and 'unlikely' for progression of disease.

Recommendation

The Committee recommended that NZPhvC should change the severity from 'not severe' to 'severe' for thrombocytopenia and disease progression, and the causality be changed from 'unclassified' to 'unlikely' for disease progression.

The Committee agreed that no further regulatory action was required at that time.

4.1.1.4 Bortezomib and progression of disease [death] (73141)

Discussion

Also see minute item 4.3.1.

The Committee considered the causal association with bortezomib was 'unlikely' for progression of disease.

Recommendation

The Committee recommended that NZPhvC should change the causality from 'unclassifiable' to 'unlikely' for progression of disease.

The Committee agreed that no further regulatory action was required at that time.

4.1.1.5 Alteplase and cerebral haemorrhage [death] (72767)

Discussion

The Committee noted that a previous report of alteplase and death due to intracranial haemorrhage had been presented to the September 2006 meeting (CARM case report 72217).

The Committee noted that there was insufficient information available to assess if this patient was given an appropriate dose of alteplase; the dose administered implied the patient was 90kg. 81 mg alteplase was given which is the maximum dose for a 90kg person already taking aspirin. The timing of administration was the latest advisable for a positive benefit/risk balance.

Members noted that haemorrhage with alteplase was a well-described adverse reaction and was well-documented in the Actilyse data sheet.

The causal association with alteplase was considered to be 'possible' for cerebral haemorrhage. The Committee agreed that no further regulatory action was required at that time.

4.1.1.6 Tenecteplase and myocardial infarction [death] (73287)

Discussion

The Committee noted that this report and the following (minute item 4.1.1.7) were received from a product sponsor and very few details were provided. The Committee noted that there was insufficient information with which to fully assess the causality of tenectaplase and myocardial infarction.

The causal association with tenecteplase was considered to be 'unclassified' for myocardial infarction. The Committee agreed that no further regulatory action was required at that time.

4.1.1.7 Tenecteplase and myocardial infarction [death] (73288)

Discussion

See minute item 4.1.1.6

The causal association with tenecteplase was considered to be 'unclassified' for myocardial infarction. The Committee agreed that no further regulatory action was required at that time.

4.1.1.8 Isotretinoin and suicide [death] (72805)

Discussion

The Committee considered the report by NZPhvC and noted that the literature on this issue had previously been summarised in Prescriber Update in 2005. There were 93 reports for isotretinoin in the CARM database. Of these there were 2 reports of suicide, 2 reports of suicide attempt and 19 reports for depression.

The Committee considered that dermatologists were well aware of the potential association between isotretinoin and depression or other mood changes, and they were well aware of the need to counsel patients on a possible effect on mood and when to discontinue treatment. The Committee discussed whether GPs who prescribed these products need to be reminded of the possible association between isotretinoin and effect on mood. A Prescriber Update article was published in June 2005.

The causal association with isotretinoin was considered to be 'possible' for suicide. The Committee agreed that no further regulatory action was required at that time.

4.1.1.9 Pramipexole and sudden death (72709)

Discussion

The causal association with pramipexole was considered to be 'unclassified' for sudden death. The Committee agreed that no further regulatory action was required at that time.

4.1.1.10 Salmeterol and sudden death (73393)

Discussion

The Committee noted that there was insufficient information on duration of salmeterol use to properly assess the causality with salmeterol.

The Committee noted that the issue of inhaled LABAs and risk of fatal and non-fatal asthma exacerbations was monitored on the watching brief list, for review in September 2007.

The causal association with salmeterol, fluticasone, salbutamol, salbutamol/ipratropium and aspirin was considered to be 'unclassified' for sudden death. The Committee agreed that no further regulatory action was required at that time.

4.1.2 Alimentary Medicines

4.1.2.1 Omeprazole and headache (72715)

Discussion

The Committee noted that the dose of omeprazole was the maximum dose for healing in children >20kg. The Committee noted that this child had been started on omeprazole at 4 months of age and omeprazole was not indicated in infants under 1 year of age (product data sheet).

The Committee noted that headache was difficult to diagnose in children and may present as prolonged or worsening irritability.

The causal association with omeprazole was considered to be 'probable' for headache.

Recommendation

The Committee recommended that an article be written for publication in Prescriber Update informing prescribers of headaches as an adverse effect of omeprazole.

4.1.3 Alternative Medicines

4.1.3.1 LBS II and malignant neoplasm (72742)

Discussion

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

The causal association with LBS II was considered to be 'unlikely' for malignant neoplasm. The Committee agreed that no further regulatory action was required at that time.

4.1.4 Antibacterial Medicines

4.1.4.1 Dapsone and abnormal liver function, elevated C-reactive protein, haemolysis, hyperbilirubinaemia, pulmonary embolism (73152)

Discussion

The causal association with dapsone was considered to be 'probable' for abnormal liver function, elevated C-reactive protein, haemolysis and hyperbilirubinaemia, and 'unclassified' for pulmonary embolism. The Committee agreed that no further regulatory action was required at that time.

4.1.4.2 Roxithromycin, warfarin and decreased prothrombin (73165)

Discussion

The Committee considered that the interaction between roxithromycin and warfarin causing an increased INR was known. The Committee noted the interaction between erythromycin, warfarin and increased INR was well documented. The Committee considered that prescribers need to be reminded of this interaction.

The causal association with warfarin and roxithromycin was considered to be 'probable' for prothrombin decreased.

Recommendation

The Committee recommended that an article be written for publication in Prescriber Update informing prescribers of the interaction between roxithromycin and warfarin, and to include erythromycin.

4.1.5 Antiepileptic Medicines

4.1.5.1 Sodium valproate and foetal valproate syndrome (73289)

Discussion

See minute item 4.2.2 for discussion and recommendations on this issue.

The Committee considered that congenital malformations are a well known adverse event of all antiepileptic agents and that the degree of risk varies between the agents. The Committee discussed the counselling required for women on antiepileptic agents on the risks of foetal abnormalities.

The causal association with sodium valproate was considered to be 'probable' for foetal valproate syndrome.

Recommendation

That an article is written for publication in Prescriber Update on anticonvulsants and risk of congenital malformations, and the importance of pre-pregnancy counselling for all women of child-bearing age taking anti-convulsants.

4.1.6 Antineoplastic Medicines

4.1.6.1 Bortezomib and herpes zoster, neuralgia (72950)

Discussion

Also see minute item 4.3.1.

The causal association with bortezomib was considered to be 'possible' for herpes zoster and neuralgia. The Committee agreed that no further regulatory action was required at that time.

4.1.7 Antiviral Medicines

4.1.7.1 Oseltamivir and fixed drug eruption, erythematous rash (73140)

Discussion

The Committee noted that the WHO data included 3 reports of bullous eruptions that resolved on withdrawal. In light of this, the Committee considered that the causal relationship between oseltamivir and fixed eruption and erythematous rash was 'possible'.

Recommendation

The Committee recommended that NZPhvC should change the causality from 'probable' to 'possible' for oseltamivir and fixed drug eruption and erythematous rash.

The Committee agreed that no further regulatory action was required at that time.

4.1.8 Cardiovascular Medicines

4.1.8.1 Candesartan and palpitations (73162)

Discussion

The Committee considered that because the causal association with candesartan was considered to be 'certain' for palpitations that further investigation was warranted.

Recommendation

The Committee recommended that Medsafe review the Australian and International data sheets for candesartan and palpitations, and update the New Zealand data sheet if warranted.

4.1.9 Contrast Media

4.1.9.1 Iopromide, frusemide, ACE Inhibitor and acute renal failure, contrast nephropathy (73071)

Discussion

The causal association with iopromide, frusemide and ACE inhibitor was considered to be 'probable' for acute renal failure and contrast nephropathy. The Committee agreed that no further regulatory action was required at that time.

4.1.10 Endocrine Medicines

4.1.10.1 Pioglitazone and retinal haemorrhage, retinal oedema (73095)

Discussion

The Committee noted that all adverse reactions to pioglitazone and rosiglitazone were Adverse Reactions of Current Concern.

The causal association with pioglitazone was considered to be 'possible' for retinal haemorrhage and retinal oedema. The Committee agreed that no further regulatory action was required at that time.

4.1.11 Immunosuppressive Medicines

4.1.11.1 Adalimumab, prednisone and sepsis, staphylococcal infection, septic arthritis, abscess, urinary tract infection, intervertebral disc disorder, diarrhoea (73170)

Discussion

The Committee noted the severity and extensive infection in this case. The causal association with adalimumab and prednisone was considered to be 'probable' for sepsis, staphylococcal infection, septic arthritis, abscess, urinary tract infection and intervertebral disc disorder, and 'possible' for diarrhoea.

4.1.11.2 Adalimumab, prednisone and streptococcal pneumonia, sepsis, back pain (73171)

Discussion

The causal association with adalimumab and prednisone was considered to be 'possible' for streptococcal pneumonia, sepsis and back pain. The Committee agreed that no further regulatory action was required at that time.

4.1.11.3 Leflunomide and polyneuropathy (72507)

Discussion

The Committee noted that all adverse reactions to leflunomide were Adverse Reactions of Current Concern.

The Committee noted that the patient was on many medicines and considered this made the causal association with leflunomide 'unclassified' for polyneuropathy.

Recommendation

The Committee recommended that NZPhvC should change the causality from 'unlikely' to 'unclassified' for polyneuropathy.

4.1.12 Psychiatric Medicines

4.1.12.1 Citalopram and cleft palate (72986)

Discussion

The Committee noted that the issue of SSRI antidepressants and use in pregnancy (including developmental delay) was monitored on the watching brief list, for review in September 2007.

The causal association with citalopram was considered to be 'unclassified' for cleft palate. The Committee agreed that no further regulatory action was required at that time.

4.1.12.2 Fluoxetine, paroxetine and multiple malformations, foetal death (73336)

Discussion

The Committee noted that the issue of SSRI antidepressants and use in pregnancy (including developmental delay) was monitored on the watching brief list, for review in September 2007.

The causal association with fluoxetine and paroxetine was considered to be 'unclassifiable' for multiple malformations and foetal death. The Committee agreed that no further regulatory action was required at that time.

4.1.13 Respiratory Medicines

4.1.13.1 Salbutamol, ipratropium and glaucoma (72730)

Discussion

The causal association with salbutamol and ipratropium was considered to be 'possible' for glaucoma. The Committee agreed that no further regulatory action was required at that time.

4.1.14 Other Reports

The Committee noted the following case reports:

4.1.14.1 Yasmin (73091)
4.1.14.2 Quinine (73430)
4.1.14.3 Leflunomide (72844)
4.1.14.4 Adalimumab (73017)
4.1.14.5 Celecoxib (73013)
4.1.14.6 Lumiracoxib (72979)
4.1.14.7 Glucosamine (72764)
4.1.14.8 Black Cohosh (73155)
4.1.14.9 Weleda Catarrh Cream (72608)
4.1.14.10 StriVectin SD Cream (73129)
4.1.14.11 Dandy Detox Herbal Tea (72770)

4.2 Pharmacovigilance Issues Arising from Reports to CARM

4.2.1 Introduction to Bortezomib

Issue

NZPhvC provided the Committee with some background information on bortezomib to assist when considering the reports discussed in minute items 4.1.1.1-4 and 4.1.7.1. The data provided were sourced from the Valcade (bortezomib) data sheet (available at www.medsafe.govt.nz) and included the product's indications, mechanisms of action, effectiveness, adverse reactions and interactions.

Discussion

NZPhvC presented the report noting the adverse events of thrombocytopenia, peripheral neuropathy, a sense of weakness and neutropenia.

4.2.2 Foetal Valproate Syndrome

References

1. NZPhvC report for the MARC. November 2006.
2. Breen D and Davenport R. Teratogenicity of antiepileptic drugs: Women should consider stopping, minimising, or switching drugs before pregnancy. BMJ. 2006; 333: 615-6
3. Dean J et al. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. J Med Genet 2002; 39: 251-259
4. NEAD Study Group (Meador J et al). In utero antiepileptic drug exposure: Fetal death and malformations. Neurology 2006; 67: 407-412

Issue

Foetal valproate syndrome is caused by maternal use of valproic acid for the treatment of epilepsy during pregnancy. Common craniofacial anomalies include epicanthal folds, broad nose with a flat bridge, anteverted nostrils, shallow philtrum and a thin upper and thick lower lip. Associated disorders may include developmental delay, neurologic abnormalities congenital heart defects, finger abnormalities, and other defects.

The CARM report discussed under minute item 4.1.6.1 was received at about the time an editorial was published in the British Journal of Medicine (Breen and Davenport) regarding the teratogenicity of antiepileptic medicines. The editorial summarised observational data from pregnancy registries set up in various countries since the late 1990s. The following was found in the United Kingdom Epilepsy and Pregnancy Registry:

• 3500 females
• 4.2% congenital malformations for all anti-epileptics versus 3.5% with untreated epilepsy
• 6.0% congenital malformations with polytherapy versus 3.7% with monotherapy
• 6.2% congenital malformations with valproate monotherapy (highest)
• 2.2% congenital malformations with carbamazepine monotherapy (lowest)
• Lamotrigine > 200 mg daily similar to valproate ≤ 1000 mg daily

The Australian registry gave similar findings for valproate. The North American registry found 10.7% congenital malformations with valproate monotherapy.

Dean et al showed developmental delay occurring with maternal use of carbamazepine, valproate and phenytoin compared with a small number of control children of mothers with epilepsy who did not take any anti-epileptic.

The NEAD study was a prospective observational study across 25 epilepsy centres. It found that serious adverse outcomes for monotherapy ranged from 1% for lamotrigine to 20.3% for valproate.

Discussion

The Committee noted the report and discussed the issues around prescribing in women with epilepsy. The Committee agreed with the current advice, that the most effective medicine should be chosen, and prescribed at its lowest effective dose. The Committee noted the recommendation under 4.1.5.

4.3 Quarterly Reports from CARM as at 30 September 2006

Discussion

The Committee noted the quarterly reports from CARM as at 30 September 2006.

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.

• Black cohosh: Medsafe report for the MARC. November 2006.
• Kerkela R et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature Medicine. Advance publication online 23 July 2006; doi:10.1038/nm1446
• Hallas J. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ Published online 19 September 2006: doi:10.1136/bmj.38947.697558.AE
• Guarneri V et al. Long-Term Cardiac Tolerability of Trastuzumab in Metastatic Breast Cancer: The M.D. Anderson Cancer Center Experience. J Clin Oncol 2006; 24: 4107-4115
• FDA Alert. Information for Healthcare Professionals: Lamotrigine (marketed as Lamictal). 28 September 2006.
• Titus-Ernstoff L et al. Mortality in women given diethylstilbestrol during pregnancy. British J Cancer 2006; 95: 107-111

6. new zealand pharmacovigilance-related activities

• DHBNZ Safe and Quality Use of Medicines Newsletter. Vol. 2; No. 3, October 2006.

7. international pharmacovigilance-related Activities

7.1 Australia

• Minutes of the 294^th meeting of the Adverse Drug Reactions Advisory Committee held on 18 August 2006.
• Minutes of the 295^th meeting of the Adverse Drug Reactions Advisory Committee held on 22 September 2006.
• Australian Adverse Drug Reactions Bulletin. Vol. 25; No. 5. October 2006.
• Australian Prescriber. Vol. 29; No. 5. October 2006. (Cover page only)

7.2 Canada

• Canadian Adverse Reaction Newsletter. Vol. 16; Issue 4. October 2006.

8. Summary listings of case reports considered by the MARC (1997-2006)

• 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.

There being no further business, the Acting Chair thanked members, guests and the secretariat for their attendance and closed the meeting at 2.45pm.