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Committees

Updated 20 May 2013

Minutes of the 129th Medicines Adverse Reactions Committee Meeting - 15 March 2007

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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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 128th 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 Schedule of Planned Prescriber Update Articles

2. ACTIONS ARISING

2.1 Report on Actions Arising from the 128th MARC Meeting, 14 December 2006

2.1.1 Infliximab/methotrexate/prednisone and secondary sepsis, dural abscess, tooth abscess, headache, coma [death] (CARM case 72110)
2.1.2 Clozapine and haematological malignancies
2.1.3 Alteplase and oedema [death] (CARM cases 70710, 70711 and 70712)
2.1.4 Baclofen and cardio-respiratory arrest, abdominal pain, hypertension, vomiting and coughing [death] (CARM case 70111)
2.1.5 COX-2 Inhibitors: Active Monitoring Review
2.1.6 Non-selective NSAIDs: Active Monitoring Review
2.1.7 COX-2 Inhibitors and Impaired Fracture Healing: Watching Brief Review
2.1.8 Omeprazole and headache (72715)
2.1.9 Roxithromycin, warfarin and decreased prothrombin (73165)
2.1.10 Sodium valproate and foetal valproate syndrome (73289)
2.1.11 Candesartan and palpitations (73162)
2.1.12 Bortezomib and thrombocytopenia [death] (72705)
2.1.13 Bortezomib and sudden death (72706)
2.1.14 Bortezomib and thrombocytopenia, progression of disease [death] (72707)
2.1.15 Bortezomib and progression of disease [death] (73141)
2.1.16 Oseltamivir and fixed drug eruption, erythematous rash (73140)
2.1.17 Leflunomide and polyneuropathy (72507)

2.2 REPORT ON ACTIONS ARISING FROM PREVIOUS MEETINGS OF THE MARC

2.2.1 Oral Terbinafine Serious Adverse Reactions
2.2.2 Quinine, Nocturnal Leg Cramps and Thrombocytopenia
2.2.3 Inhaled Long-Acting Beta-Adrenoceptor Agonists (LABAs) and the Risk of Fatal and Non-Fatal Asthma Exacerbations
2.2.4 SSRIs and Use in Pregnancy: Watching Brief Review
2.2.5 Ergot-Derived Dopamine Receptor Agonists, Other than Pergolide, and Fibrotic Reactions: Active Monitoring Review
2.2.6 Clozapine and myocarditis, heart failure, arrhythmia [death] (CARM case 66578)
2.2.7 Clozapine and Myocarditis
2.2.8 Influenza vaccine and sudden death (CARM case 71269)
2.2.9 Diclofenac/ibuprofen/prednisone and gastric ulcer, duodenal ulcer, intestinal ulceration, haematemesis, hypoproteinaemia (CARM case 71906)
2.2.10 Pioglitazone and neutropenia, thrombocytopenia, myeloid dysplasia (CARM case 71590)
2.2.11 Tramadol-Drug Interactions and Serious Reactions

2.3 REPORT ON UNRESOLVED ACTIONS ARISING FROM RECOMMENDATIONS OF THE MARC

2.3.1 Low Molecular Weight Heparins (LMWHs) in Renal Impairment

3. PHARMACOVIGILANCE ISSUES

3.1 APROTININ AND CARDIOVASCULAR, RENAL & CEREBROVASCULAR ADVERSE REACTIONS: WATCHING BRIEF REVIEW
3.2 VENLAFAXINE AND PANCREATITIS – WATCHING BRIEF REVIEW

4. MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 ADVERSE REACTIONS TO ROSIGLITAZONE & PIOGLITAZONE: ACTIVE MONITORING REVIEW 15
4.2 ADVERSE REACTIONS OF CURRENT CONCERN (ARCC) REVIEW 21
4.3 CENTER FOR ADVERSE REACTIONS MONITORING (CARM) SPONTANEOUS CASE REPORTS

4.3.1 Deaths
4.3.2 Cardiovascular
4.3.3 Endocrine Medicines
4.3.4 Hormones
4.3.5 Immunosuppressives
4.3.6 Nuerological / Psychiatric
4.3.7 Other Reports

4.4 QUARTERLY REPORTS FROM CARM AS AT 31 DECEMBER 2006

5. PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

6. NEW ZEALAND PHARMACOVIGILANCE-RELATED ACTIVITIES

7. INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

7.1 AUSTRALIA
7.2 CANADA
7.3 OTHER

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

9. OTHER BUSINESS

9.1 MARC WORKSHOP
9.2 REPORT ON THE MEETING WITH MINISTER HODGSON


MINUTES OF THE 129TH MEDICINES ADVERSE REACTIONS COMMITTEE MEETING,
15 MARCH 2007

The one hundred and twenty-ninth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 15 March 2007 at the Sunderland room, Wellington Airport Conference Centre, Wellington, New Zealand. The meeting commenced at 9:00am and closed at 2.15pm.

MARC members present

Professor T Maling (Chair)
Honorary Associate Professor M Rademaker
Dr H Kingston
Professor P Ellis
Dr D Reith
Ms L Bryant
Associate Professor C Frampton
Dr F McClure
Dr M Tatley (teleconference 11:30am to 12:15pm)
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 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).

Dr A Bolotovski (Senior Clinical Advisor, Medsafe) observed the meeting, and Ms J McNee (Medicines Control Advisor, Ministry of Health) observed the meeting until 12.30pm.

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. He welcomed Associate Professor C Frampton (Biostatistician) who was attending the full Committee meeting for the first time. Associate Professor Frampton gave a brief synopsis of his background.

1.2 Minutes of the 128th MARC Meeting

NZPhvC asked that an amendment be made to the minutes of the 128th MARC meeting, in the recommendation for minute item 4.1.2 Centre for Adverse Reactions Monitoring (CARM) Spontaneous Case Reports, Alimentary Medicines, Omeprazole and headache (72715). The recommendation "The Committee recommended that an article be written for publication in Prescriber Update informing prescribers of headaches as an adverse effect of omeprazole" should be changed such that the emphasis of the article is on recognising headaches in children as being a potential adverse effect of omeprazole. Medsafe agreed to this recommendation. The Committee decided not to amend the minutes.

Members otherwise agreed that the minutes of the 128th MARC meeting were a true and accurate record of the meeting. Hon. Assoc. Prof. M Rademaker, as Acting Chair of the 128th MARC meeting subsequently ratified the minutes.

1.2.1 Report to the Minister's Delegate

Members noted that all of the recommendations made at the 128th 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 14 June 2007. The subsequent MARC meetings were scheduled for 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 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.

Three 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 Schedule of Planned Prescriber Update Articles

Discussion

The members discussed whether there was a need to prioritise the articles for publication. NZPhvC updated the Committee that the articles on "Tramadol - serious side effects", and "Rosiglitazone" had been drafted. Medsafe updated the Committee that the article on "Clozapine and GI motility" was awaiting publication. The Committee agreed that there was no need to prioritise the articles for publication at this time.

Anticonvulsants and congenital malformations

The planned article on anticonvulsants and congenital malformations was discussed. The Committee had previously recommended that an article on anticonvulsants and malformations be written following a CARM case report on sodium valproate and foetal valproate syndrome (73289). The Committee considered that prescribers need to be reminded about the risk of congenital malformations with anticonvulsants, and the importance of pre-pregnancy counselling for all women of child bearing age taking anticonvulsants.

A member raised the issue of lithium and congenital malformations. As sodium valproate was used for bipolar affective disorder a member had received queries about lithium for bipolar affective disorder and congenital malformations. The Committee discussed whether the planned article could be extended to include lithium. The members considered that the issue of bipolar agents and congenital malformations was a separate topic and would be considered at another time if warranted.

2. Actions arising

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

2.1 Report on Actions Arising from the 128th MARC Meeting, 14 December 2006

Please refer to the minutes of the 128th MARC meeting, held on 14 December 2006, available on the Medsafe web site at www.medsafe.govt.nz/profs/adverse/Minutes128.htm for background information on these issues.

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

December 2006 minute item 2.1.9; September 2006 minute item 4.1.1.5

Issue

In December 2006 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.

Outcome

A Prescriber Update article will be authored by [..]

Discussion

NZPhvC updated the Committee that the article would also include information about the possibility of infection in general with anti-TNF agents.

The Committee noted the above and asked to be kept informed of the article once it had been written.

2.1.2 Clozapine and haematological malignancies

December 2006 minute item 2.2.3

Issue

In December 2006 the Committee recommended that Medsafe seek data on the total number of patients exposed to clozapine in New Zealand and report back to the Committee.

Outcome

Both Novartis and Douglas have been contacted. Douglas advised that, while their brand of clozapine (Clopine) is subsidised, they are not yet marketing it so there are no patients using their product. Novartis advised that, as of 13 February 2007, 3698 patients were currently taking their brand (Clozaril) and another 1518 patients have discontinued clozapine treatment; giving a total of 5216 patients exposed to clozapine in New Zealand. Pacific Pharmaceuticals also have a brand of clozapine (Zopine) which is approved but has never been marketed in New Zealand.

Discussion

The Committee considered the number of haematological malignancies reported to CARM was seven in a population of 5216 patients exposed to clozapine. The Committee noted that the malignancies were of varying cell types. However they tended to agree it was worthwhile to pursue age-standardised data on the frequency of haematological events using the denominator data obtained from Novartis. The members discussed using data linkage to obtain the age standardised rates of malignancies.

Recommendation

That Medsafe, in consultation with Assoc. Prof.Frampton, explore a protocol for obtaining age-standardised data on the frequency of haematological events with clozapine.

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

December 2006 minute item 2.3.2; September 2006 minute item 2.1.9; June 2006 minute item 4.1.1.4

Issue

In December 2006, the Committee recommended that the issue of alteplase and oedema could be removed from the list of unresolved actions arising from MARC recommendations.

Outcome

This issue has been removed from the list of unresolved actions.

Discussion

The Committee noted the above.

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

December 2006 minute item 2.3.3; June 2006 minute item 4.1.1.2

Issue

In December 2006, 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.

Outcome

This issue has been removed from the list of unresolved actions.

Discussion

The Committee noted the above.

2.1.5 COX-2 Inhibitors: Active Monitoring Review

December 2006 minute item 3.1

Issue

In December 2006 the Committee recommended that the issue of COX-2 Inhibitors should be removed from the active monitoring list.

In December 2006, 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.

Outcome

This issue has been removed from the active monitoring list.

Medsafe reviewed the data sheets for the COX-2 inhibitors and noted that while their content regarding GI safety information is similar in parts, there are some inconsistencies that need to be addressed. Before contacting the sponsors to request data sheet revisions, Medsafe will liaise with the TGA to ensure consistency between the product data sheets in each country.

Discussion

Medsafe is in the process of comparing the New Zealand and Australian data sheets for the COX-2 inhibitors with respect to GI safety. Following a review of the data sheets, Medsafe will contact the sponsors to request data sheet changes in line with the Australian data sheets, as appropriate.

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

2.1.6 Non-selective NSAIDs: Active Monitoring Review

December 2006 minute item 3.2

Issue

In December 2006, the Committee recommended amendments to non-selective NSAID product information [..] that should be adopted in New Zealand.

The Committee recommended that an article be 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.

Outcome

Medsafe is liaising with the TGA to ensure consistency of product information updates between both countries. Once this process has been completed, a Prescriber Update article and 'Dear Health Professional' letter will be disseminated.

Discussion

A member brought to the attention of the MARC an opinion paper by Psaty BM and Weiss NS "NSAID Trials and the Choice of Comparators - Questions of Public Health Importance", published in the New England Journal of Medicine in January 2007. In this article, the authors discuss the choice of comparator agents in COX-2 inhibitor trials funded by pharmaceutical companies. The members considered that, while the opinion paper was of interest, there was not sufficient evidence to warrant differing advice at the product information level. They reiterated their earlier view that prescribers need to consider the safety profiles of individual non-selective NSAIDs and patient risk profiles when prescribing these agents.

The Committee asked to be kept informed once the data sheet changes had been made.

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

December 2006 minute item 3.3

Issue

In December 2006, 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.

Outcome

This issue has been removed from the watching brief list.

Discussion

The Committee noted the above.

2.1.8 Omeprazole and headache (72715)

December 2006 minute item 4.1.2.1

Issue

In December 2006, the Committee recommended that an article be written for publication in Prescriber Update informing prescribers of headaches as an adverse effect of omeprazole.

Outcome

Medsafe will liaise with NZPhvC to draft a Prescriber Update article.

Discussion

See minute item 1.2. The Committee noted the above and asked to be informed once the Prescriber Update article had been written.

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

2.1.9 Roxithromycin, warfarin and decreased prothrombin (73165)

December 2006 minute item 4.1.4.2

Issue

In December 2006, 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.

Outcome

A Prescriber Update article will be authored by Medsafe.

Discussion

The Committee noted the above and asked to be informed once the Prescriber Update article had been written.

2.1.10 Sodium valproate and foetal valproate syndrome (73289)

December 2006 minute item 4.1.5.1

Issue

The Committee recommended 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 anticonvulsants.

Outcome

A Prescriber Update article will be authored, probably by Medsafe.

Discussion

See minute item 1.5.1. The Committee asked to be kept informed once the Prescriber Update article had been written.

2.1.11 Candesartan and palpitations (73162)

December 2006 minute item 4.1.8.1

Issue

In December 2006, 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.

Outcome

There is no mention of palpitations in the Australian PI, the UK SmPC, or the NZ data sheet for candesartan. The US PI lists palpitation as occurring with an incidence of 0.5% or greater in clinical trials.

The Australian TGA has received 7 reports of palpitations out of a total of 221 reports for candesartan. Causality was assessed as certain for one report (positive rechallenge), probable for two reports, and possible for the remaining four reports.

Medsafe will liaise further with the TGA on this issue and will request that palpitation is listed in the Adverse Effects - Post-Marketing section of the NZ data sheet for candesartan.

Discussion

The Committee noted the above and asked to be kept informed of the outcome of this issue.

2.1.12 Bortezomib and thrombocytopenia [death] (72705)

December 2006 minute item 4.1.1.1

Issue

In December 2006, 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'.

Outcome

NZPhvC have actioned this recommendation.

Discussion

The Committee noted the above.

2.1.13 Bortezomib and sudden death (72706)

December 2006 minute item 4.1.1.2

Issue

In December 2006, the Committee recommended that NZPhvC should add that the cause of death was disease progression and the causality was 'unlikely' for bortezomib.

Outcome

NZPhvC have actioned this recommendation.

Discussion

The Committee noted the above.

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

December 2006 minute item 4.1.1.3

Issue

In December 2006, 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.

Outcome

NZPhvC have actioned this recommendation.

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 Bortezomib and progression of disease [death] (73141)

December 2006 minute item 4.1.1.4

Issue

In December 2006, the Committee recommended that NZPhvC should change the causality from 'unclassifiable' to 'unlikely' for progression of disease.

Outcome

NZPhvC have actioned this recommendation.

Discussion

The Committee noted the above.

2.1.17 Leflunomide and polyneuropathy (72507)

December 2006 minute item 4.1.11.3

Issue

In December 2006, the Committee recommended that NZPhvC should change the causality from 'unlikely' to 'unclassified' for polyneuropathy

Outcome

NZPhvC have actioned this recommendation.

Discussion

The Committee noted the above.

2.2 Report on Actions Arising from Previous Meetings of the Medicines Adverse Reactions Committee (MARC)

2.2.1 Oral Terbinafine Serious Adverse Reactions

December 2006 minute item 2.1.1; 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 regarding outcomes of their review of the safety of oral terbinafine and regulatory actions taken, and report back to the MARC.

Outcome

[..], Novartis was asked by the TGA to submit case details for all reports of blood dyscrasias associated with terbinafine. Details for 60 international cases of pancytopenia were submitted; however, [..] Novartis did not include information for neutropenia and agranulocytosis. The pancytopenia data suggested no clear clustering of time to onset in the 4-6 week period after commencement of therapy, or in any other time period. However, these data did not address [..] the main concern relating to the onset time of neutropenia and agranulocytosis, and [..] disagreed that time-to-onset for specific blood dyscrasias could be extrapolated from the data for pancytopenia.

[..]

In December 2006, 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. Medsafe would continue to monitor the outcome of the ADRU analysis of the individual case reports provided by Novartis.

Discussion

The Committee considered that the issue of adverse reactions to oral terbinafine was still an important issue to resolve and that a satisfactory outcome had still not been reached. [..] A member queried the rationale that companies cannot be compelled to include a CMI because the CMI could change over time.

Medsafe reminded the members that an article had been published in Prescriber Update in November 2006 entitled "Serious Hepatic and Haematological reactions to terbinafine".

The members further discussed whether pharmacists could supply the CMI when the medicine is dispensed. They considered that pharmacists should be approached to provide the CMI.

Recommendation

The Committee recommended that Medsafe write to the Pharmacy Council of New Zealand and the Pharmaceutical Society of New Zealand (Inc) asking that they remind pharmacists about the adverse reactions of oral terbinafine.

2.2.2 Quinine, Nocturnal Leg Cramps and Thrombocytopenia

December 2006 minute item 2.1.3; 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

In December 2006, Medsafe wrote to the three sponsors of quinine sulphate tablets supplied to the New Zealand market. Medsafe advised sponsors that unless they were able to supply evidence to support the safe use of quinine for leg cramps, this indication needed to be withdrawn because the risk-benefit profile was no longer considered to be favourable.

Douglas Pharmaceuticals advised that they have discontinued the marketing of their brands (Quinoc-S 200 mg and 300 mg tablets, and Quinoc-F 200 mg and 300 mg tablets) in New Zealand; and that no stock remains on the market. Apotex agreed to remove the leg cramps indication from their brand of quinine sulphate (Apo-Quinine 200mg and 300mg tablets). The updated data sheet was published on the Medsafe web site in February 2007.

Pacific Pharmaceuticals supplies the only subsidised brand of quinine sulphate (Q200 and Q300 tablets). They agreed to voluntarily withdraw the indication of leg cramps from the data sheets and CMI.

Discussion

The Committee noted the above and asked to be kept informed of the Prescriber Update article.

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

December 2006 minute item 2.1.4; 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 consider publishing an article in Prescriber Update summarising the changes to the LABA data sheets.

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. AstraZeneca wished to discuss the wording changes required for the data sheets and a meeting was scheduled for 28 February 2007.

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

Discussion

Medsafe updated the Committee that they had met with AstraZeneca and the company had agreed to update the data sheets for Oxis Turbuhaler and Symbicort as requested. Medsafe advised the Committee that AstraZeneca will soon be launching a new formulation of Symbicort called Symbicort Rapihaler with a similarly amended data sheet.

The Committee noted the above and asked to be kept informed once the data sheet changes had been made, and of the Prescriber Update article.

2.2.4 SSRIs and Use in Pregnancy: Watching Brief Review

December 2006 minute item 2.1.5; 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) 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

A Prescriber Update article is being written.

Medsafe wrote to the SSRI sponsors in November 2006 with requests for data sheet changes as above. The sponsors of Apo-Paroxetine, Apo-Fluoxetine (Apotex); Paroxetine (AFT brand); Arrow-Citalopram (Arrow); Plinzene (Douglas brand of fluoxetine); Fluox (Pacific brand of fluoxetine) and Celepram (Pacific brand of citalopram) have agreed to make the data sheet changes as requested.

Lundbeck, the sponsor of Cipramil (citalopram) and Lexapro (escitalopram), has advised that they do not believe the data sheet changes in respect of their products are justified at this time.

The current data sheets for Cipramil and Lexapro includes text regarding respiratory symptoms in the newborn.

"Neonates exposed to Cipramil/Lexapro, other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalisation, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome."

Lundbeck believes modification of the class label at this time would be premature in view of the unknown and debatable mechanisms that might be involved in PPHN. This is supported by the outcome of the TGA's investigation of this matter, concluding that "…amendments to the currently approved PI for citalopram and escitalopram with respect to the PPHN issue based on the assumptive results of Chambers CD et al study with its limitations would be premature at this stage and should not be mandatory…".

Lundbeck has advised they will continue the close monitoring of all reported cases of pregnancy. Additional focus will be placed on evaluating respiratory function for events reported in newborns and this evaluation will be reflected in the next PSUR.

Eli Lilly, the sponsor of Prozac (fluoxetine), has advised that they do not believe the data sheet changes in respect of their products are justified at this time. In their response to the TGA on this issue they believe the current PI for fluoxetine adequately describes the risk-benefit assessment for possible development of adverse effects for infants exposed to fluoxetine in utero, including PPHN, and does not need to be amended.

They are further supported by the TGA's response on this matter, namely "…amendments to the currently approved PI for fluoxetine with respect to the PPHN issue based on the assumptive results of Chambers CD et al study with its limitations would be premature at this stage and should not be mandatory. The current approved PI for fluoxetine contains adequate precautionary statements on use in pregnancy. Furthermore, Eli Lilly's safety database has not uncovered strong signals on this issue".

Pfizer, the sponsor of Zoloft, had not yet responded.

Discussion

Medsafe informed the Committee that they had reviewed the responses from Lundbeck and Eli Lilly and considered them acceptable at this time. The Committee agreed with Medsafe's recommendations. Medsafe is still awaiting a response from Pfizer.

The Committee noted the above and asked to be kept informed of the response from Pfizer and of the Prescriber Update article.

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

December 2006 minute item 2.1.6; 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.

Outcome

All sponsors of bromocriptine products have made the requested data sheet amendments.

Discussion

The Committee noted the above.

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

December 2006 minute item 2.1.7; 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 has requested the post-mortem report and follow-up re-assessment and will bring the results back to the MARC in due course.

Discussion

NZPhvC informed the Committee that the post-mortem report had yet to be received.

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

2.2.7 Clozapine and Myocarditis

December 2006 minute item 2.1.8; 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 has contacted a cardiologist for an opinion and is awaiting a response before drafting a Prescriber Update article.

Discussion

The Committee noted the above and asked to be kept informed of the response from the cardiologist and the Prescriber Update article.

2.2.8 Influenza vaccine and sudden death (CARM case 71269)

December 2006 minute item 2.1.10; 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 is still awaiting the post-mortem results and will bring the report back to MARC once this has been received.

Discussion

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

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

December 2006 minute item 2.1.12; 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 update the data sheets as warranted.

Outcome

This recommendation will be actioned as part of the outcomes arising from the MARC review of the safety of the non-selective NSAIDs at the December 2006 MARC meeting.

Discussion

See minute item 2.1.6 for the Active Monitoring Review of Non-selective NSAIDs.

The Committee noted the above.

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

December 2006 minute item 2.1.13; 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

The haematological investigations from this case had been included in the NZPhvC report for the active monitoring review of rosiglitazone and pioglitazone and adverse events.

Discussion

NZPhvC informed the Committee that a further report on this case confirmed that this patient had died of chronic myeloid leukaemia. The causal association with pioglitazone was considered to be 'unlikely' for neutropenia, thrombocytopenia and myeloid dysplasia, and the CARM data base had been amended accordingly.

See minute item 4.1, for the annual active monitoring review of the safety of rosiglitazone and pioglitazone.

The Committee noted the above.

2.2.11 Tramadol-Drug Interactions and Serious Reactions

December 2006 minute item 2.2.4; 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. This was published in the October 2006 issue of Prescriber Update. The second article should be on serious adverse effects of tramadol, specifically serotonin syndrome and convulsions.

Outcome

The Prescriber Update articles are to be drafted by NZPhvC.

Discussion

NZPhvC advised the Committee that an article entitled "Tramadol - serious side effects' has been drafted.

2.3 Report on Unresolved Actions Arising from Recommendations of the MARC

The following list is 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 last MARC meeting included, as they are listed in the Report on Actions Arising from the 128th 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.

In December 2006, the Committee 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.

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.

3. Pharmacovigilance Issues

3.1 Aprotinin and cardiovascular, renal & cerebrovascular adverse reactions: watching brief review

References
Background

Medsafe provided a report for the MARC's annual watching brief review of the safety of aprotinin (Trasylol). The issue of aprotinin and cardiovascular, renal, and cerebrovascular adverse reactions was placed on the watching brief list in March 2006.

The purpose of the report was to inform the Committee of recent data and regulatory actions. The Committee was asked to evaluate the information provided; determine whether the risk-benefit profile of aprotinin has changed as a result of this new information; and if so, recommend appropriate regulatory action.

New Zealand regulatory action

In March 2006, Bayer provided Medsafe with two reports detailing further safety analyses for Trasylol. The reports were "A review of the use of aprotinin in CABG surgery" and "A review of comparative studies involving aprotinin".

In April 2006 the NZ data sheet for Trasylol was updated - the most significant amendment was alignment of the indications with global labelling.

In August 2006 Bayer provided Medsafe with a data package including the following reports:

  1. Bayer's Integrated Summary of Safety: use of aprotinin in CABG surgery
  2. A benefit-risk analysis for the use of Trasylol in CABG surgery
  3. Literature review of cardiovascular and cerebrovascular adverse events associated with aprotinin in cardiac surgery
  4. Literature review focusing on the impact of aprotinin on renal function during cardiac aortic surgery
  5. Medical research report for, "A multi-centre, randomised, double-blind, placebo-controlled, parallel design, two arm study to investigate the effect of aprotinin on transfusion requirements and blood loss in patients undergoing elective primary total hip replacement surgery".

In October 2006 Bayer informed Medsafe of new observational data regarding Trasylol from a retrospective study the company had commissioned. This study examined existing hospital data from 67,000 records of patients undergoing CABG surgery - 30,000 patients were treated with Trasylol and 37,000 were treated with alternate products (aminocaproic acid and tranexamic acid). The preliminary study report suggested that patients receiving Trasylol were at increased risk for death, kidney failure, congestive heart failure and stroke. Bayer acknowledged that it mistakenly did not share these data with the FDA prior to the FDA Cardiovascular-Renal Drugs Advisory Committee meeting held in September 2006 to assess the safety and efficacy of Trasylol. Bayer claimed these data were not shared immediately because they were preliminary in nature and raised significant questions on the study population, outcomes and methodology.

Bayer will provide Medsafe with a consolidated data package for this study when it has been prepared.

Reports to CARM

No reports for aprotinin have been received by CARM in the past 12 months.

International status and regulatory action

[..]

United States (FDA)

In September 2006, the FDA held a public advisory committee meeting (Cardiovascular-Renal Drugs Advisory Committee) to discuss the findings from two published observational studies, a Bayer worldwide safety review, and an FDA review of its own post-marketing database. Later in September the FDA was advised by Bayer that it had conducted an additional safety study of Trasylol and the preliminary findings suggested that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes. The FDA recommended that physicians should consider limiting Trasylol use to those situations where the clinical benefit of reduced blood loss is essential to medical management of the patient and outweighs the potential risks. Physicians should carefully monitor patients for the occurrence of toxicity, particularly to the kidneys, heart, or brain.

In December 2006 the FDA and Bayer Pharmaceuticals notified healthcare professionals of revisions to the prescribing information for Trasylol. The new labelling has a more focused indication, a new warning that Trasylol increases the risk of renal dysfunction and may increase the need for dialysis in the perioperative period, and stronger warnings about anaphylactic reactions (including a new contraindication for aprotinin exposure in the past 12 months).

United Kingdom(MHRA)

In September 2006, the MHRA issued a Dear Healthcare Professional letter and UK SmPC update regarding a tightened indication and the risk of renal dysfunction.

Medsafe recommendations

Medsafe recommended that the issue of cardiovascular, renal, and cerebrovascular adverse reactions with aprotinin remained on a watching brief. Medsafe will continue to monitor international regulatory activity and safety-related data, and report back to the MARC as necessary.

Medsafe recommended the following changes to the NZ data sheet for Trasylol - a tightened indication in line with the UK SmPC and the US PI; strengthened information on anaphylactic reactions in line with the US PI; and strengthened information on renal dysfunction in line with the US PI and UK SmPC.

Discussion

Medsafe informed the Committee that there was a randomised controlled trial (the BART study) looking at the relative efficacy of commonly used anti-fibrolytic agents in high-risk cardiac surgical patients being conducted in Canada. Results are expected in 2008 and will be brought to the attention of the MARC.

The members considered the strengthened information on anaphylactic reactions in the 'Contraindications', 'Special Warnings and Precautions' and 'Undesirable Effects - Allergic/anaphylactic reactions' in the US PI. They discussed the time frame for known or suspected previous aprotinin exposure during the last 12 months. They noted the analysis from the Bayer Global database on hypersensitivity where 138 patients out of 291 (47%) had documented previous exposure to Trasylol. There were 110 cases where there was information on the time of the previous exposure, where 99/110 (90%) had previous exposure within the prior 12 months. The Committee considered that hypersensitivity to a medicine does not reduce over time so including the 12 month time limit was somewhat arbitrary, but based on the data it was a reasonable time frame. A member commented that the word 'epinephrine' was used in the US PI 'Special Warnings and Precautions' section, and that 'adrenaline' was the more common term in New Zealand. Medsafe agreed to request a change to include 'adrenaline'. The MARC agreed to Medsafe's recommendations for proposed data sheet amendments in respect of anaphylaxis.

The members discussed the proposed tightened indications for Trasylol. They agreed the indications should be tightened so that Trasylol is indicated in patients who are at increased risk of bleeding. In the interests of harmonisation between Australia and New Zealand data sheets, the members agreed that the indication in the New Zealand Trasylol data sheet should be in line with the indication stated in the Australian Trasylol PI as follows:

"Prophylactic reduction of perioperative blood loss and reduction in the need for blood transfusion in adult patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery, especially where the risk of bleeding is high (impaired haemostasis, e.g. presence of aspirin), or where transfusion is unavailable or unacceptable."

The members agreed with Medsafe's recommendations for strengthened information on renal dysfunction in line with the US PI and UKSmPC.

Recommendations

The Committee recommended that the issue of aprotinin and cardiovascular, renal and cerebrovascular adverse reactions should remain on the watching brief list.

The Committee recommended that Medsafe bring back to the MARC any data that arises from the BART study, and continue to monitor international regulatory activity and report back to the MARC as appropriate.

The Committee agreed with Medsafe's suggested revisions for the NZ Trasylol data sheet.

3.2 Venlafaxine and Pancreatitis - Watching Brief Review

References
Issue

Medsafe provided a report for the MARC's 'Watching Brief' review of venlafaxine and pancreatitis. In March 2006 this issue was placed on the 'Watching Brief' list following a CARM case report of a patient who was taking venlafaxine and cilazapril who developed pancreatitis and died.

There is only one case report of pancreatitis with venlafaxine in the CARM data base, which was discussed at the March 2006 MARC meeting.

Venlafaxine is available in New Zealand as Efexor (not funded) and Efexor XR (fully subsidised). The Efexor XR data sheet (date of preparation: 7 June 2006) lists pancreatitis as a very rare (frequency: <0.01%) adverse effect.

As of November 2006, the total number of prescriptions dispensed for Efexor XR was 4179 (2941 for Efexor XR 75mg and 1238 for Efexor XR 150mg).

As of February 2007, the TGA ADRAC data base held a total of 1234 reports for venlafaxine, of which there is one case report of pancreatitis in a 53-year-old male.

In June 2006, the WHO database contained 64 reports of pancreatitis with venlafaxine, out of a total of 18173 reports for this medicine. The IC value was calculated, and found to be negative and stable (-0.03). To date, there are 70 reports in WHO database.

A search of PubMed conducted in February 2006 located no published case reports of pancreatitis with venlafaxine, and one paper (Spigset et al) investigating the statistical association of hepatic reactions and pancreatitis with SSRIs in the WHO data base. Using the Bayesian confidence propagation neural network (BCPNN) method, this paper showed that pancreatitis is not reported more commonly with venlafaxine compared to that expected on the basis of chance alone.

In Medsafe's opinion, the absence of new case reports or published papers suggests there is no emerging evidence of an association between venlafaxine and pancreatitis at this time. Therefore, Medsafe recommended that the issue of venlafaxine and pancreatitis be removed from the 'watching brief' list.

Discussion

The Committee noted that there had been no further reports or published papers suggesting an association between venlafaxine and pancreatitis since the last review. They agreed that the issue of venlafaxine and pancreatitis should be removed from the 'watching brief' list.

The committee agreed that there should be no further regulatory action at this time.

Recommendation

The Committee recommended that the issue of venlafaxine and pancreatitis should be removed from the 'watching brief' list.

4. Matters arising from the new zealand pharmacovigilance centre

4.1 Adverse Reactions to Rosiglitazone & Pioglitazone: Active Monitoring Review

References

Medsafe. Report for the MARC meeting. February 2007
NZPhvC. Report for the MARC meeting. February 2007
Actos data sheet. September 2006
Avandia data sheet. June 2006
Pharmac Consultation letter. Amendment to the terms of listing of pioglitazone on the Pharmaceutical Schedule. February 2007
GSK. Dear Health Care Provider letter. February 2007.
Grey, A et al (2007) The peroxisome-proliferator-activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomised,controlled trial. J Clin Endocrin Metab.
GSK. Summary of key results from ADOPT. November 2006.
Schwartz,A et al (2006) Thiazolidinedione Use and Bone Loss in Older Diabetic Adults. J Clin Endocrin Metab. 91(9):3349-3354

Background

Medsafe and NZPhvC provided reports for the MARC's annual active monitoring review of the safety of rosiglitazone and pioglitazone (thiazolidinediones or TDs). The purpose of the reports was to inform the Committee of recent data and regulatory action regarding rosiglitazone and pioglitazone. The Committee was asked to evaluate the information provided, determine whether the risk-benefit profile of rosiglitazone or pioglitazone has changed as a result of this new information, and if so make recommendations about appropriate risk management.

New Zealand regulatory action

In July 2006, GSK provided Medsafe with a data package, which included further analysis of a retrospective analysis of cardiovascular events in clinical trials (the Avandia Cardiovascular Event Modelling Project) and an epidemiological study (Coronary Heart Disease Outcomes in Patients receiving Antidiabetic Agents). At this time, GSK proposed amendments to the Avandia data sheet related to the risk of cardiac effects.

In November 2006, GSK provided Medsafe with a summary of key efficacy and safety results from the ADOPT (A Diabetes Outcome Progression Trial) study.

In February 2007 GSK notified Medsafe of a recently published study of rosiglitazone in nondiabetic postmenopausal women. The study showed that short-term therapy with rosiglitazone significantly reduced two selected markers of bone formation (procollagen type I N-terminal propeptide and osteocalcin) compared to placebo.

Further in February 2007, GSK notified Medsafe of a revised data sheet for Avandia to reflect the safety signal for bone fractures seen in the ADOPT study. A Dear Healthcare Professional letter was disseminated to New Zealand GPs, retail pharmacies, endocrinologists, general medicine physicians, rheumatologists, diabetes nurse specialists, diagnostic radiologists, obstetricians & gynaecologists, and orthopaedic surgeons. GSK will submit the amended datasheet to Medsafe after the March 2007 MARC meeting as further amendments to the datasheet may be requested as a result of this meeting.

NZPhvC analysis of CARM AND WHO REPORTS and Literature Review

NZPhvC provided the MARC with an analysis of reports in the CARM database and the WHO International Drug Monitoring database (Vigibase) for pioglitazone and rosiglitazone up to December 2006. The number of CARM reports for rosiglitazone is 22, and pioglitazone is 12. The number of reports in Vigibase is 8326 for rosiglitazone and 4029 for pioglitazone.

Literature review

NZPhvC provided the MARC with a literature review for adverse reactions from the last quarter of 2005 to January 2007.

Fluid retention and oedema

The most frequently reported adverse effects in the CARM database and Vigibase relate to fluid retention. The fluid retention is thought to be due to increased vascular permeability and sodium retention. Case reports from the NZPhvC indicate that oedema can be severe. There is some evidence that oedema may occur in "compartments" eg pleural effusion, pericardial effusion (spontaneous reports only), benign intracranial hypertension (one published report with rosiglitazone and one spontaneous report with pioglitazone) or exacerbate existing disease e.g. cardiac failure and macular oedema.

Cardiovascular Disease

Dyslipidaemias, hypertension and microalbuminuria are all recognised risk factors. Recent studies have also examined less traditional risk factors. The effect of thiazolidinediones on these risk factors/surrogate markers were discussed firstly to address the likelihood of TDs increasing or decreasing the risk of myocardial ischaemia, and also to examine whether there is evidence that the TDs have modulatory effects on the risk factors that might lead to adverse outcomes.

Dyslipidaemias

There were a large number of reports of hypertriglyceridaemia and hypercholesterolaemia in the CARM and WHO databases, making these two of the most commonly reported reactions. There are also a small number of reports of decreased HDLc.

Two meta-analyses have examined the effects of rosiglitazone and pioglitazone on lipids. The first found that rosiglitazone, compared with pioglitazone significantly increased LDLc and total cholesterol. Pioglitazone significantly lowered fasting triglyceride levels. The second meta-analysis findings were similar to the first but a further observation was that both medicines increased HDLc. A multicentre prospective placebo-controlled RCT supported the results of the meta-analyses in that pioglitazone decreased triglyceride levels and increased HDLc levels significantly more than rosiglitazone. Pioglitazone increased LDLc to a lesser amount than did rosiglitazone and pioglitazone also increased overall LDLc particle size and reduced LDLc particle concentration. At the last MARC review of the TDs, spontaneous reports to the NZPhvC and published case histories (including from the NZPhvC) provided evidence of a paradoxical fall in HDLc levels in some patients taking rosiglitazone. There have been two further case histories published where there have been unexpected decreases in HDLc levels together with hypertriglyceridaemia in patients taking rosiglitazone. Of further interest is that the reaction did not recur in these two patients when they took pioglitazone.

As yet the clinical implications of the effects of these two TDs on lipids is unknown but pioglitazone appears to have a less deleterious effect.

Hypertension

CARM has received one report of hypertension attributed to pioglitazone.

Vigibase holds 110 reports of hypertension attributed to rosglitazone and 82 for pioglitazone. The IC value for pioglitazone/hypertension is a low positive (IC <1.0). There is one published case report of accelerated hypertension during rosiglitazone therapy. A meta-analysis showed an overall small decrease in blood pressure in patients taking TDs. A systematic review of the literature published in 2006 showed that TDs were associated with small but significant decreases in blood pressure in many human studies including two long term RCTs. Because the decrease is usually small the clinical significance is uncertain.

Cardiovascular Outcomes

Only one study to date has examined cardiovascular outcomes with a TD, rather than risk factors or surrogate markers. The Prospective Pioglitazone Clinical Trial in Macrovascular Events study (PROACTIVE) was a randomised controlled study of 5238 patients with Type 2 diabetes who had evidence of macrovascular disease. Patients continued to take other glucose-lowering medicines. The primary endpoint was all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, revascularisation interventions of coronary or leg arteries and major amputation. For the primary endpoint fewer patients taking pioglitazone had at least one event than in the placebo group but this difference was not significant. For the secondary endpoint of myocardial infarction, stroke and all-cause mortality significantly fewer patients taking pioglitazone had at least one event. Critics have pointed out that if silent myocardial infarction and heart failure had been included in the secondary endpoint the difference would not have been significant.

On the basis of this one study there is, however, no evidence that pioglitazone increases the risk of myocardial ischaemia and related conditions even in patients with pre-existing macrovascular disease . However, there was no subgroup analysis of those also taking insulin, the group in whom myocardial ischaemic events were seen in rosiglitazone clinical trials.

Heart Failure

Heart failure and associated terms were reported for both medicines. The Actos (pioglitazone) data sheet describes a 24-week postmarketing study of 262 patients taking pioglitazone and 256 taking glyburide (glibenclamide) who had uncontrolled diabetes and class II or III heart failure. In this study 9.9% of patients taking pioglitazone were admitted to hospital because of heart failure compared with 4.7% taking glyburide. This pioglitazone adverse event was more marked if the patients were using insulin or were aged > 64 years at baseline.

Two large multicentre randomised control studies, the PROACTIVE and the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study have examined the incidence of heart failure. In the PROACTIVE study patients enrolled had Type II diabetes with macrovascular disease. Heart failure and heart failure leading to hospital admission occurred significantly more often in patients taking pioglitazone compared with placebo (11% v 8% and 6% v 4%) but there was no difference in the incidence of fatal heart failure. Patients in the DREAM study of rosiglitazone and ramipril to reduce progression to diabetes had impaired glucose tolerance and no known cardiovascular disease at entry. There was no indication that any were using insulin. Patients taking rosiglitazone developed heart failure significantly more often than those taking placebo (0.5% v 0.1%). A similar incidence was found in patients taking ramipril but this was not significantly different from placebo (0.5% v 0.2%).

Pulmonary hypertension and heart valve disorders

There was a strong positive IC value for pulmonary hypertension in Vigibase and in many of the reports cardiac failure was a co-reported term. It is also possible that reports of mitral insufficiency and aortic stenosis represent an exacerbation of the haemodynamic effects of these conditions as they are often reported in conjunction with cardiac failure. Chronic obstructive airways disease (COAD) was often co-reported with cardiac failure which may suggest a difficulty in diagnosis. COAD was not co-reported with pulmonary hypertension and so was unlikely to have caused it. There was one report of pulmonary hypertension with no co-reported adverse reaction terms and with recurrence on rechallenge.

Current and Proposed Advice regarding cardiac failure

The American Diabetes Association and the American Heart Association in a consensus statement advised that TDs should not be prescribed to diabetic patients with severe, i.e. New York Heart Association (NYHA), class III or IV heart failure. They also recommended cautious use in patients in class I or II categories.

Ophthalmic disorders
Macular oedema

There has been a review of 30 patients who had lower extremity oedema and macular oedema while taking pioglitazone or rosiglitazone. Eleven patients were observed for three months after cessation of glitazones. When the TD was discontinued a rapid reduction in macular oedema occurred in only four of the 11 patients, but eight had reduced oedema over two years.

There are reports of retinal haemorrhage and non-specified visual disorders in the CARM database and Vigibase. Retinal haemorrhage does occur in diabetic patients as well as macular oedema and the reports require further analysis.

Proptosis

In a recent study of 36 patients who were commenced on pioglitazone treatment, 13 patients exhibited a > 2 mm degree of eye protrusion and the remainder exhibited an increase of < 2 mm. By comparing the two groups it was found that patients with greater protrusion were more likely to have high adiponectin levels, thyroid disturbance and exposure to higher doses of pioglitazone.

Hepatic Disorders

A case report was published in 2006 of reversible hepatic failure following prolonged cholestatic hepatitis thought to be due to an idiosyncratic reaction to rosiglitazone. The patient tested positive for hepatitis B surface antigen but the viral load was very low and the nature of the hepatic injury was not typical of a hepatitis B virus effect. The authors quoted two other published reports of hepatic failure with rosiglitazone and there is also a further report of cholestatic hepatitis. Both hepatic failure and cholestatic hepatitis associated with rosiglitazone have positive IC values in Vigibase. It is likely that these are rare idiosyncratic reactions.

Of interest are the reports of hepatic steatosis (fatty liver) and cirrhosis in Vigibase. Despite these reports, in one study of 68 patients with nonalcoholic fatty liver disease one third had improved hepatic function tests after 24 weeks of rosiglitazone treatment although two developed transaminase levels more than three times the upper limit of normal. Counfounding by indication in the Vigibase reports is possible.

Haematological Disorders

CARM has received one report of thrombocytopenia with rosiglitazone, noted at the last review that there are 56 reports for rosiglitazone and 30 for pioglitazone in Vigibase. Although not a statistically prominent reaction several patients improved on dechallenge and there was one positive rechallenge. Since the last review a case report of thrombocytopenia has been published in which rosiglitazone-dependent antiplatelet antibodies were detected in the patient's blood.

Bone loss

Three recent reports suggest that TDs decrease bone mineral density in women and may increase fracture risk.

A summary of small numbers of published and unpublished reports of nephritis, musculoskeletal disorders, urticaria and peripheral neuropathy were also presented.

Discussion

The Committee noted the NZPhvC and Medsafe reports. They noted the increasing evidence of fluid retention and reports of cardiac failure with rosiglitazone and pioglitazone. They noted the results of the DREAM study were difficult to interpret. Patients in the study taking rosiglitazone had a significantly higher incidence of heart failure compared to patients taking placebo alone (0.5% compared to 0.1% for placebo). A similar incidence of heart failure was found in the ramipril arm of the study but this was not significantly different to placebo (ramipril 0.5% placebo 0.2%). The Committee noted the results of PROACTIVE study where there was a higher incidence of admission for heart failure in the pioglitazone treated group compared to placebo. However, there was no difference in the incidence of fatal heart failure between the two groups. They considered whether this new evidence changed the advice about use in heart failure and whether TDs should be contraindicated in this group.

The Committee discussed the differing advice given in the data sheet for pioglitazone where the company states that it can be used in patients with New York Heart Association (NYHA) grades 1 and 2, but not in grades 3 and 4, while for funding purposes in New Zealand, patients with any grade of heart failure are not eligible for subsidy. They noted that the Australian Heart Guidelines recommend that TDs are discontinued in all patients with heart failure but the American Diabetes Association and American Heart Association recommend that TDs should not be prescribed to patients with severe heart failure (NYHA grades 3 and 4).

The MARC noted there is evidence for significant fluid retention in some patients and therefore recommended that these products are not recommended for use in patients with any grade of heart failure. However, in patients with mild-moderate heart failure, if the potential benefit is thought to outweigh risk, the medicine should be initiated at the lowest recommended dose, and if further glycaemic control is required then increased cautiously to the next dose level following clinical evaluation to assess the risk of adverse drug reactions relating to fluid retention. NZPhvC will include this information in the article for publication in Prescriber Update reminding prescribers of the cardiovascular adverse drug reactions, CIs, warnings, and precautions for rosiglitazone and possibly pioglitazone.

The Committee considered the new data on the risk of MI. The PROACTIVE study in patients with macrovascular disease showed a reduced risk of MI with pioglitazone compared to placebo. Recent trials on rosiglitazone with insulin have shown an increased risk of MI, possibly through an effect on lipids. The Committee considered that the new data are inconclusive, and do not warrant differing advice on risk of MI at this time.

The Committee discussed GSK's proposed updates to the New Zealand datasheet for Avandia. The Committee accepted the proposed amendments with the following exceptions.

  1. The datasheet should be updated to convey that, due to the risk of significant fluid retention in some patients, Avandia is not recommended for use in patients with any grade of heart failure. If, however, the potential benefit is thought to outweigh risk in patients with mild-moderate heart failure, the medicine should be initiated at the lowest recommended dose, and if further glycaemic control is required then increased cautiously to the next dose level following clinical evaluation to assess the risk of adverse drug reactions relating to fluid retention.
  2. The MARC agreed with Medsafe that the paragraph below should not be included in the datasheet update - members agreed that the information is not useful to prescribers and the study referred to has several methodological limitations.

    "In a large observational study where people were well-matched at baseline, the incidence of the composite endpoint of "myocardial infarction and coronary revascularization" was 1.75 events per 100 person years for rosiglitazone containing regimens and 1.76 events per 100 person years for other anti-diabetic agents [Hazard ratio 0.93 (95% confidence interval 0.80 - 1.10)]."
  3. In addition, the MARC supported Medsafe's suggestion that the following text in the Avandia datasheet is deleted, and is replaced with the italicised text (which is currently in the US Product Information for Avandia).
  4. "Post marketing reports have been received rarely for rosiglitazone as monotherapy and in combination with other oral antidiabetic agents. It is known that the risk of developing heart failure is increased substantially in diabetic subjects compared to non-diabetic subjects."

    "In post-marketing experience in patients receiving thiazolidine therapy, serious adverse events with or without a fatal outcome, potentially related to volume expansion (e.g., congestive heart failure, pulmonary oedema, and pleural effusions) have been reported."
  5. The Committee agreed that the following underlined text is added to the 'Warnings and Precautions' section of the Avandia datasheet.
  6. "Cardiovascular: Rosiglitazone, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which can exacerbate or lead to signs and symptoms of congestive heart failure."

The Committee discussed TDs effect on lipids. It was noted that there is a variable effect of TDs on triglycerides, generally with increases in LDL and HDL. However, there have been reports of decreased HDL with rosiglitazone when added to a fibrate, or when used alone in a small group of patients. The Committee agreed with Medsafe's recommendation that the data sheet for rosiglitazone should be amended to include the following text from the Australian PI.

"Metabolism and nutrition disorders: Hypercholesterolaemia was reported in 3.4% of patients. The elevated total cholesterol levels were associated with an increase in both LDLc (n = 2,048) and HDLc (n = 2,177) and the ratio of total cholesterol:HDLc was unchanged or decreased in long-term studies (n = 886 after 12 months therapy). Overall, these experiences were generally mild to moderate and usually did not require discontinuation of treatment."

The Committee discussed Medsafe's recommendation to request that the product sponsor for rosiglitazone amends the NZ data sheet to include the following liver function information from the Australian PI. Members discussed the baseline and ALT levels and Medsafe agreed to review the data sheet for pioglitazone for monitoring liver function and amend the proposed wording for the rosiglitazone data sheet so that it is more in keeping with the pioglitazone data sheet.

"Monitoring of liver function: In clinical trials with Avandia, encompassing 2,492 patient years of exposure, there was no evidence of drug induced hepatotoxicity or elevations of ALT levels. In postmarketing experience with Avandia there have been rare reports of hepatocellular dysfunction, primarily evidenced by elevated hepatic enzymes. Causality has not been established. However, it is recommended that patients treated with Avandia undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with Avandia in all patients. Therapy with Avandia should not be initiated in patients with increased baseline liver enzyme levels (ALT > 2.5 x upper limit of normal). In patients with normal baseline liver enzymes, following initiation of therapy with Avandia, it is recommended that liver enzymes be monitored every two months for the first 12 months and periodically thereafter. Patients with mildly elevated liver enzymes (ALT levels 1 to 2.5 x upper limit of normal) at baseline or during therapy with Avandia should be evaluated to determine the cause of the liver enzyme elevation. If at any time ALT levels increase to > 3 x upper limit of normal in patients on therapy with Avandia, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain > 3 x the upper limit of normal, therapy with Avandia should be discontinued.

If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with Avandia should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued."

The Committee discussed Medsafe's recommendation that the NZ data sheet for Avandia is updated in line with the blood disorder-related text in the Australian PI. The Committee agreed to the addition of the below text but with some minor changes. Medsafe agreed to review the wording of the text before requesting the data sheet change.

"Blood disorders: Across all controlled clinical studies, decreases in haemoglobin and haematocrit (mean decreases in individual studies less than or equal to 1.0 g/dL and less than or equal to 3.3%, respectively) were observed for both Avandia alone and in combination with metformin or sulfonylurea. The changes occurred primarily during the first four to eight weeks of therapy and remained relatively constant thereafter. Anaemia (decreased haemoglobin) was reported at an incidence of 1.9% in double blind studies with Avandia. The incidence of anaemia was higher when Avandia was used in combination with metformin (7.1%) or with insulin (8.6%). Lower pretreatment haemoglobin/ haematocrit levels in patients enrolled in the metformin combination clinical trials may have contributed to the higher reporting rate of anaemia in these studies.

White blood cell counts also decreased slightly in patients treated with Avandia. The observed changes may be related to the increased plasma volume observed with treatment with Avandia and have not been associated with any significant haematological clinical effects."

Medsafe informed the Committee that the effect on bone fractures is considered a class effect and the sponsor of Actos will be making similar changes to the Actos data sheet as for Avandia. A Dear Health Professional letter regarding Actos has been distributed. Medsafe advised that a Dear Health Professional letter has also been sent by the sponsor of Avandia (GSK) advising prescribers of data sheet changes with respect to the effect on bone and cardiovascular effects. Members considered whether bone mineral density should be measured in people on TDs. The Committee asked Medsafe to seek the opinion of a specialist regarding whether there is value in bone densitometry or another biomarker for decreased bone density correlating with fractures in patients on TDs.

Recommendations

The Committee recommended that Medsafe seek an expert opinion on an appropriate measure of bone turnover that might indicate reduced bone density in TD treated patients.

The Committee recommended that all adverse reactions to rosiglitazone and pioglitazone should remain on the active monitoring list for annual review.

The Committee recommended that Medsafe contact the sponsors of rosiglitazone and pioglitazone to request the abovementioned datasheet revisions.

4.2 Adverse Reactions of Current Concern (ARCC) Review

Complementary and Alternative Medicines [CAMs]
(formerly Herbal and Natural remedies) - ARCC since October 1996

In March 2006, Medsafe and NZPhvC provided an abbreviated report of data to December 2005 for the review of the ARCC all adverse reactions to CAMs. This is an updated review incorporating data to December 2006. Due to the large number of products available, often containing multiple active ingredients, NZPhvC advises that it is difficult to undertake an exhaustive literature review on the issue. Inconsistencies in international trade names for CAM products make it difficult to search the WHO database for many of the products.

CARM Reports
Report Details Total
@31/12/2006
Prior to Listing Post Listing Since Last Review
No. of reports 289 41 248 29
No. of suspect CAMs 334 46 288 29
No. of reactions 572 64 508 59


excludes Foods, Drinks and Herbal stimulants (Party Pills)

Table 1 lists the details of the 29 reports received since the last review.

The number of CAM reports received have increased marginally on an annual basis. Given the widespread use of these agents by the public in a relatively unsupervised manner and in the absence of a regulatory setting such as those benefiting conventional medicines, it would seem prudent to continue to monitor these agents. The system could, however, be refined so that only those reports that describe serious and/or unusual events are reported to MARC at each quarterly meeting, with an annual summary/review of all reports.

The NZPhvC recommended that CAMs continue to be monitored as an ARCC with serious and/or unusual events reported to each MARC meeting and an annual ARCC submission of a summary/review of all reports.

Discussion

The Committee noted the NZPhvC report. They agreed with the NZPhvC recommendation to monitor CAMs as an ARCC with serious and/or unusual events reported to each MARC meeting and an annual ARCC submission of a summary/review of all reports. They agreed that given the proposed move to regulate CAMs in ANZTPA, that CAMS continue to be monitored as ARCCs and remain on the active monitoring list.

Recommendation

The Committee recommended that complementary and alternative medicines (CAMs) remain as Adverse Reactions of Current Concern on the active monitoring list.

The Committee recommended that NZPhvC report serious and/or unusual events to each MARC meeting and provide an annual ARCC submission.

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

Spontaneous reporting programme

All spontaneous reports presented at the MARC meeting have been assessed by the Centre for Adverse Reactions Monitoring (CARM) and responses have been sent to the reporters. The purpose of these responses is to assist the practitioner to discharge his/her responsibility to patients. These individual replies include as appropriate:

  • comment about causality;
  • information about similar suspected adverse reactions reported with the same or related medicines;
  • prescribing advice;
  • advice related to the care of the patient, including information that may assist the practitioner to make a risk:benefit assessment for future treatment; and
  • any specific action being taken by the Centre, including entering the reaction into the National Health Index against the patient's name, presenting the case report to the MARC, etc.

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.

4.3.1 Deaths

4.3.1.1 Adalimumab, Prednisone and pneumonia, septicaemia [death] (74216)

Discussion

The Committee considered that serious infection can occur with adalimumab and was documented in the data sheet. It was agreed that the article being written for publication in Prescriber Update on anti-TNF agents and dental cavity abscess is broadened to include risk of infection in general. The causal association with adalimumab and prednisone was considered to be 'possible' for pneumonia and septicaemia. The Committee considered that no further regulatory action is required at this time.

4.3.1.2 Golimumab, amoxycillin/clavulanic acid, isoniazid and diarrhoea, vomiting, colitis, septic shock, cardic arrest [death] (73358)

Discussion

The Committee noted that there was no information from a post mortem report and that this was necessary to assess the causality in this case. As the patient was taking part in a clinical trial more information could be obtained from the SCOTT committee.

The Committee recommended that NZPhvC should obtain a copy of the post mortem report if possible.

The causal association with golimumab, amoxycillin/clavulanic acid, isoniazid was considered to be 'possible' for diarrhoea, vomiting, colitis, septic shock, cardiac arrest.

Recommendation

The Committee recommended that NZPhvC should obtain a copy of the post mortem report and bring the results back to the MARC if warranted.

4.3.1.3 Leflunomide, methotrexate and endocarditis, septicaemia [death] (73577)

Discussion

The Committee noted that all adverse reactions to leflunomide were Adverse Reactions of Current Concern, on the active monitoring list, for review in June 2007.

The Committee noted the severity of infection in this case and that infection has been reported with leflunomide. The causal association with leflunomide and methotrexate was considered to be 'possible' for endocarditis and septicaemia. The Committee considered that no further regulatory action is required at this time.

4.3.1.4 Lumiracoxib and fall, fracture femur, pneumonia [death] (74180)

Discussion

The Committee considered the causal association with lumiracoxib was 'unlikely' for fall, fractured femur, pneumonia. The Committee considered that no further regulatory action is required at this time.

4.3.1.5 Sulphasalazine and bone marrow depression, multiple organ failure, pulmonary haemorrhage [death] (74087)

Discussion

The Committee discussed the relationship between pancytopenia and multiorgan failure if there is sepsis, but in this case sepsis was not noted.

The Committee considered the causal association with sulphasalazine was 'possible' for bone marrow depression, multiple organ failure, pulmonary haemorrhage. The Committee agreed that no further regulatory action was required at that time.

4.3.1.6 Tenecteplase and sudden death [death] (74192)

Discussion

NZPhvC noted the possibility of a reperfusion arrhythmia contributing to his death. The members felt that the time lag of nine days between the dose of tenecteplase and the patient dying was too long for a reperfusion arrhythmia to have contributed to his death. The Committee noted that there was insufficient information on cause of death to properly assess the causality with tenecteplase. NZPhvC had requested more information from the reporter on the cause of death but no information had been received at this time.

The causal association with tenecteplase was considered to be 'unclassified' for sudden death.

Recommendation

The Committee recommended that NZPhvC should await more information from the reporter on the cause of death in this case (74192) and bring the results back to the MARC.

4.3.2 Cardiovascular

4.3.2.1 Ezetimibe and hepatitis cholestatic (73514)

Discussion

The causal association with ezetimibe was considered to be 'possible' for cholestatic hepatitis. The Committee agreed that no further regulatory action was required at this time.

4.3.2.2 Quinapril, ethynodiol and hypospadias, testis disorder (73967)

Discussion

The Committee noted that quinapril has been associated with hypotension and decreased renal perfusion in utero, particularly in the second and third trimesters. A member noted some recent data showing skull abnormalities and decreased renal function following exposure to ACE inhibitors in the first trimester.

There are no reports of hypospadias in the WHO database or CARM with quinapril or ethylnodiol. The causal association with quinapril and ethynodiol was considered to be 'possible' for hypospadias and testis disorder. The Committee agreed that no further regulatory action was required at that time.

4.3.3 Endocrine Medicines

4.3.3.1 Pioglitazone and oedema (73841)

Discussion

See minute 4.1 on the watching brief review of glitazones.

The causal association with pioglitazone was considered to be 'possible' for oedema.

4.3.3.2 Rosiglitazone and oedema, dyspnoea (73842)

Discussion

See minute item 4.1.

The causal association with rosiglitazone was considered to be 'probable' for oedema, dyspnoea.

4.3.4 Hormones

4.3.4.1 Tamoxifen and retinal deposits (73804)

Discussion

NZPhvC noted that there has been one report of retinitis in the CARM database. They noted that the data sheets refer to retinal damage (at high doses for a long duration) as an adverse reaction. In this case the patient was receiving a standard dose and had been on tamoxifen for only nine months. The Committee noted that prescribers need to be reminded of this adverse effect, and that any changes in visual acuity are referred to an optometrist for examination.

The causal association with tamoxifen was considered to be 'possible' for retinal deposits.

Recommendation

The Committee recommended that a reminder article is published in Prescriber Update informing prescribers of retinopathy with tamoxifen.

4.3.5 Immunosuppressives

4.3.5.1 Adalimumab, leflunomide, prednisone and sepsis, tooth abscess (73951)

Discussion

NZPhvC noted that this was the second case of severe septicaemia and dental abscess with an anti-TNF agent in the CARM database. They noted the time lag between starting treatment with adalimumab and dental abscesses was four months.

The Committee noted that there have previously been reports of severe infection with adalimumab, and reports of infection with leflunomide. They noted that the issue of all adverse reactions to leflunomide was on the active monitoring list, for review in June 2007. The causal association with adalimumab, leflunomide and prednisone was considered to be 'probable' for sepsis and tooth abscess. The Committee agreed that no further regulatory action was required at that time.

4.3.5.2 Adalimumab, leflunomide and neoplasm malignant aggravated (74231)

Discussion

NZPhvC informed the MARC that the patient had a history of bladder cancer before starting treatment with adalimumab and leflunomide and had been treated with BCG. The report noted that for both leflunomide and the anti-TNF agents the IC values are positive for a number of common cancers, but not so much for bladder cancer. They noted that the duration to onset for malignant neoplasm in this patient was six months. The report noted an oncologist's opinion that a medicine should have been taken for at least six months before it can be considered to have promoted a cancer. As the anti-TNF agents are new, it was not sure if the association can be drawn between treatment with anti-TNF agents and cancer. The Committee noted the data from the British Society for Rheumatology Biologics Register may become available soon.

The causal association with adalimumab and leflunomide was considered to be 'possible' for neoplasm malignant aggravated.

4.3.5.3 Leflunomide and tuberculosis, anorexia, weight loss, fever, hepatitis granulomatous (73723)

Discussion

The Committee noted that TB reactivation was listed in the product data sheet for leflunomide.

They noted that the issue of all adverse reactions to leflunomide was on the active monitoring list, for review of June 2007.

The causal association with leflunomide was considered to be 'possible' for tuberculosis, anorexia, weight loss, fever and hepatitis granulomatous.

4.3.5.4 Leflunomide, adalimumab, prednisone and cerebral haemorrhage, hypertension aggravated, hemiparesis, dysphagia (73788)

Discussion

The Committee noted the data on hypertension with leflunomide, and considered that leflunomide and adalimumab may have contributed to the patients poorly controlled hypertension.

The causal association with leflunomide, adalimumab and prednisone was considered to be 'possible' for cerebral haemorrhage, aggravated hypertension, hemiparesis and dysphagia.

4.3.5.5 Lumiracoxib and dyspnoea, orthopnoea (74195)

Discussion

The causal association with lumiracoxib was considered 'possible' for dyspnoea and orthopnoea.

Recommendation

The Committee recommended that the NZPhvC should change the causality from 'probable' to 'possible' for lumiracoxib and dyspnoea and orthopnoea.

4.3.6 Neurological / Psychiatric

4.3.6.1 Gabapentin and oedema peripheral, pleural effusion, ascites, weight gain (73968)

Discussion

The Committee noted that peripheral oedema is listed in the datasheets for gabapentin and felodipine.

The Committee agreed that felodipine should be added to the list of suspect medicines, 'drug interaction' to the list of adverse reactions, and that the causal association with gabapentin and felodipine was considered 'possible' for 'drug interaction'.

4.3.6.2 Paroxetine and foetal heart rate abnormal (74012)

Discussion

The Committee commented that the outcome of the pregnancy was important to know to properly assess the causality of paroxetine. However, given the in utero exposure to paroxetine a 'possible' causality could not be ruled out.

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

The causal association with paroxetine was considered to be 'possible' for foetal heart rate abnormal.

4.3.7 Other Reports

The Committee noted the following case reports:

4.1.14.1 Alendronate (73521)
4.1.14.2 Warfarin (73590)
4.1.14.3 Leflunomide (73782)
4.1.14.4 Leflunomide (73783)
4.1.14.5 Leflunomide (73784)
4.1.14.6 Leflunomide (73787)
4.1.14.7 Leflunomide (73789)
4.1.14.8 Leflunomide (73823)
4.1.14.9 Leflunomide (74049)
4.1.14.10 Leflunomide (74050)
4.1.14.11 Capecitabine (74223)
Rituximab (73869)
Lumiracoxib (74016)
Lumiracoxib (74173)
Fluoxetine (74210)
Terbinafine (74009)
Anti=Flame Crème (73724)
Centrum Kids (74044)
ThermoDynamX (73568)
Turbo Extreme (73878)
Healtheries Zinc Plus (73512)

4.4 Quarterly Reports from CARM as at 31 December 2006

Discussion

NZPhvC presented the report, noting the low number of brand switch reports.

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

6. new zealand pharmacovigilance-related activities

7. international pharmacovigilance-related Activities

7.1 Australia

  • Minutes of the 297th meeting of the Adverse Drug Reactions Advisory Committee held on 15 December 2006.
  • Minutes of the 296th meeting of the Adverse Drug Reactions Advisory Committee held on 3 November 2006.
  • Australian Adverse Drug Reactions Bulletin. Vol. 25; No. 6. December 2006.
  • Australian Prescriber. Vol. 29; No. 6. December 2006. (Cover page only)

7.2 Canada

  • Health Canada. Canadian Adverse Reaction Newsletter. Vol. 17; Issue 1. Jan 2007.

7.3 Other

  • Singapore Health Sciences Authority. Adverse Drug Reaction News. Dec 2006
  • WHO Pharmaceuticals Newsletter. No. 6, 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.

9. OTHER BUSINESS

9.1 MARC Workshop

The Chair raised the issue of holding a workshop for the MARC members on issues relevant to the MARC. He requested that members send in suggestions for workshop topics to the Interim Manager of Medsafe.

9.2 Report on the meeting with Minister Hodgson

The Chair had requested a meeting with Minister Hodgson. Stewart Jessamine and Pete Ellis attended this meeting on 1 February 2007 to discuss the role of pharmacovigilance in New Zealand. The Minister was supportive of pharmacovigilance and maintaining pharmacovigilance capacity in New Zealand.

There being no further business, the Chair thanked members, guests and the secretariat for their attendance and closed the meeting at 2.15pm.

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