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Committees

Updated 21 May 2013

Minutes of the 133rd Medicines Adverse Reactions Committee Meeting - 20 March 2008

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

1 MATTERS OF ADMINISTRATION

2 STANDING AGENDA ITEMS

2.1 REPORT ON STANDING AGENDA ITEMS FROM PREVIOUS MEETINGS OF THE MARC MEETING

2.1.1 Lumiracoxib and liver toxicity
2.1.2 Rubifen SR (methylphenidate SR) brand switch - aggressive and defiant behavioural reactions
2.1.3 The safety and efficacy of cough and cold medicines for use in children
2.1.4 Aprotinin and increased mortality risk
2.1.5 Alteplase and haemorrhage intracranial [death] (75765)
2.1.6 Simvastatin, enalapril and pancreatitis [death] (76148)
2.1.7 Adalimimab and cerebral haemorrhage [death] (75961)
2.1.8 Peginterferon Alfa 2a and pneumonia [death] (76001)
2.1.9 Clozapine and neutropenia, lymphopenia,anaemia [death] (76419)
2.1.10 Symbicort and exacerbation of asthma [death] (75986)
2.1.11 Tramadol and drug dependence (narcotic) (75728)
2.1.12 Influenza vaccine and myelitis transverse, encephalitis (76080)
2.1.13 Lipid-lowering agents and psychiatric adverse reactions: Active Monitoring Review
2.1.14 Oral terbinafine and serious adverse reactions (blood dyscrasias, heptatotoxicity and dermatological reactions ) –Active Monitoring Review
2.1.15 Issues monitored by the MARC, Medsafe and NZPhvC as at June 2007
2.1.16 Diclofenac and duodenal ulcer haemorrhagic, oesophagitis [death] (74905)
2.1.17 Salmeterol and bronchospasm aggravated (death) (75086)
2.1.18 Lamotrigine and convulsion [death] (74826)
2.1.19 Quetiapine,paroxetine,and neuroleptic malignant syndrome,pneumonia inhalation[death] (74373)
2.1.20 Clozapine and haematological malignancies
2.1.21 Oral Terbinafine Serious Adverse Reactions
2.1.22 Tenecteplase and sudden death [death] (74192)
2.1.23 COX-2 Inhibitors: Active Monitoring Review
2.1.24 Clozapine and myocarditis, heart failure, arrhythmia [death] (CARM case 66578)
2.1.25 Clozapine and Myocarditis
2.1.26 Influenza vaccine and sudden death (CARM case 71269)
2.1.27 Low Molecular Weight Heparins (LMWHs) in Renal Impairment

3 PHARMACOVIGILANCE ISSUES

3.1 SSRI ANTIDEPRESSANTS AND THE RISK OF SUICIDALITY
3.2 ALL ADVERSE REACTIONS TO ROSIGLITAZONE AND PIOGLITAZONE (ARCC*), PARTICULARLY FRACTURE/BONE DENSITY
3.3 ALL ADVERSE REACTIONS TO COMPLEMENTARY AND ALTERNATIVE MEDICINES (ARCC*)
3.4 ANTI-EPILEPTICS AND THE RISK OF SUICIDALITY
3.5 CARDIOVASCULAR RISKS OF CALCIUM SUPPLEMENTS IN WOMEN

4 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

5 PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

6 INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

6.1 UNITED KINGDOM

7 SUMMARY LISTINGS OF CASE REPORTS CONSIDERED BY THE MARC (1997- 2007)

8 OTHER BUSINESS

8.1 AUSTRALIA AND NEW ZEALAND THERAPEUTICS PRODUCTS AUTHORITY (ANZTPA) UPDATE


MINUTES OF THE 133rd
MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
20 March 2008

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.

MEDICINES ADVERSE REACTIONS COMMITTEE
20 March 2008
MEETING MINUTES

The one hundred and thirty third meeting of the Medicines Adverse Reactions Committee (MARC) was held on 20 March 2008 at the Sunderland Room, Wellington Airport Conference Centre, Wellington, New Zealand. The meeting commenced at 8:30 am and closed at 3.30 pm.

MARC members present

Professor T Maling (Chair)
Dr H Kingston
Dr F McClure
Associate Professor D Reith
Dr L Bryant
Associate Professor C Frampton
Associate Professor M Rademaker
Professor P Ellis
Dr M Tatley
Dr S Sime

marc secretariat present

Dr A Forde (Acting Principal Technical Specialist, Medsafe)
Ms S Von Afehlt (Senior Pharmacy Advisor/Editor of Prescriber Update, Medsafe)
Ms A Cutfield (Advisor, Pharmacovigilance)
Ms J McNee (MARC Secretary)

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. There were no apologies. Professor Maling (Chair) left the meeting at 3pm. Professor Ellis agreed to act as Chair from this time. Associate Professor Reith left the meeting at 2.40pm. Associate Professor Rademaker left the meeting at 3.15pm.

Dr Forde left the meeting at 11am and returned at 2pm. Dr Stewart Jessamine (Interim Manager, Medsafe) attended the meeting from 2 pm.

1.2 Minutes of the 131st and 132nd MARC Meetings

The minutes of the 132nd meeting of the Committee were accepted as a true and accurate record of the meeting. The Committee noted that the minutes of the 131st meeting were signed by the Chair out of session.

1.3 Dates of Future MARC Meetings

The date for the next MARC meeting was confirmed as being 12 June 2008. The subsequent MARC meeting dates for 2008 were scheduled for 11 September and 11 December.

Secretary's note:

The date of the June meeting has now been changed to 29th May 2008.

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.

One member declared a potential conflict of interest. The Committee considered that this potential conflict 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 Committee noted the schedule of planned Prescriber Update articles.

1.5.2 Draft article "Clozapine and achy breaky hearts (myocarditis and cardiomyopathy)"

Discussion

The first draft of the article Draft article "Clozapine and achy breaky hearts (myocarditis and cardiomyopathy)" was discussed. The Committee made several suggestions for improvements to the article, which the Editor noted.

2. STANDING AGENDA ITEMS

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

The Committee noted that there were outstanding items on the 'Standing Agenda Item' list, for which further information had been awaited for some time but had not been received to date. The Committee agreed that if the information being sought, with the exception of Coroner's Reports, was not received by the time of the next MARC meeting, then that outstanding item should be removed from the 'Standing Agenda Item' list. The rationale is that the reason the information being sought had not been supplied was probably due to the information not being available, and as a result, the Committee would be unable to consider the matter further.

2.1 Report on Standing Agenda Items from previous meetings of the MARC Meeting

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

2.1.1 Lumiracoxib and liver toxicity
December 2007 minute items 2.1.1 and 3.1, September 2007 minute item 3.1

Issue

In September 2007, the Committee recommended that NZPhvC should seek further information about the CARM case report (76287) and report back to the MARC.

In December 2007, the Committee recommended that regulatory action be reconsidered once the outcome of the European Medicines Agency's (EMEA) full regulatory review of the risks and benefits of lumiracoxib became available.

Outcome

NZPhvC has received follow up information which indicated normal hepatic function prior to starting lumiracoxib with complete recovery on discontinuing it. Two months after starting lumiracoxib the alkaline phosphatase level was mildly elevated but was normal a week later during which time the dose of lumiracoxib had been increased to 400 mg daily. Two months later the LFTS were markedly abnormal. However new information is that the patient also started to take erythromycin 5 days prior to this measurement.

The NZPhvC will therefore add erythromycin as a suspect medicine to this report and the causality with both lumiracoxib and erythromycin will be coded as "possible".

Following the outcome of the EMEA's full regulatory review, the consent for Prexige 100mg tablets was revoked in New Zealand by Medsafe on 20 December 2007. A pharmacy-level recall of available stock was instigated and a letter was issued to health professionals to explain that the benefits of lumiracoxib no longer outweighed the risks of harm.

Discussion

The Committee noted the above.

2.1.2 Rubifen SR (methylphenidate SR) brand switch - aggressive and defiant behavioural reactions
December 2007 minute item 2.1.2, September 2007 minute item 3.2

Issue

In September 2007, the Committee recommended that Medsafe write to the sponsors of Rubifen SR under Section 36 of the Medicines Act 1981 requesting that they provide further data in support of Rubifen SR.

The Committee recommended that Medsafe contact the sponsor of Rubifen SR and request that the data sheet is updated to include information on the risk of aggressive and defiant behaviours.

The Committee recommended that Medsafe report back to the MARC when the results of further testing of the Rubifen SR product are available.

In December 2007, the Committee recommended that Medsafe and NZPhvC provide the MARC with an update on Rubifen SR (methylphenidate SR) brand switch - aggressive and defiant behavioural reactions at its next meeting.

Outcome

Medsafe sought further information from the Rubifen product sponsor including the following:

Medsafe was supplied with all data that were requested. After evaluation of the data supplied, Medsafe's Evaluation Team concluded that there was no evidence of a manufacturing or pharmaceutical chemistry fault which could explain the unusual ADRs experienced by some patients taking Rubifen SR. In addition, it was noted that the sponsor had not received any reports of psychiatric adverse drug reactions in association with Rubifen SR, other than those received from CARM.

Therefore, Medsafe has not been able to elucidate the cause of the unusual brand-switch reactions that occurred in patients taking Rubifen SR.

Reports from Medsafe and NZPhvC were included in the March 2008 dossier.

Discussion

The Committee noted the February 2008 Medsafe and NZPhvC reports.

NZPhvC advised that the number of reports received had decreased since PHARMAC agreed to make the previously subsidised Ritalin SR product available to affected patients. The pattern of reports remained essentially unchanged.

Medsafe advised that the datasheet for Rubifen SR was being updated to bring it in line with the Ritalin datasheet, by including information on the risk of aggressive and defiant behaviours occurring.

The Committee queried the length of time that PHARMAC will continue to make the previously subsidised Ritalin SR product available to affected patients and recommended that they be contacted to in order to obtain this information.

Recommendation

The Committee recommended that PHARMAC be contacted to determine the length of time that the Ritalin SR product will be provided to affected patients.

The Committee recommended that the issue of Rubifen SR (methylphenidate SR) brand switch - aggressive and defiant behavioural reactions be placed on the 'scheduled review' list for a 12-monthly review.

2.1.3 The safety and efficacy of cough and cold medicines for use in children
December 2007 minute item 3.3

Issue

In December 2007, the Committee recommended that all cough and cold medicines be contraindicated in children under two years of age.

The Committee recommended that Medsafe investigate options for disseminating advice to consumers in line with that issued by Health Canada regarding the safe use of cough and cold medicines in children.

The Committee recommended that further information and expert advice be sought from different professional bodies such as the Paediatric Society, the College of General Practitioners and the College of Physicians regarding the safety and efficacy of cough and cold medicines in children over two years.

The Committee recommended that the Medicines Classification Committee (MCC) consider rescheduling the active ingredients in cough and cold medicines from pharmacy only medicines to pharmacist only medicines.

Outcome

On 17 January 2008 the United States Food and Drug Administration (FDA) announced that it had completed its review of the safety of cough and cold medicines used in children and infants under 2 years of age. The FDA recommended that these medicines should not be used in children aged under 2 years of age because serious and potentially life-threatening side effects can occur. The FDA also indicated that they had not yet completed their review of the safety of these medicines in children between 2 and 11 years of age.

In response to the FDA's Public Health Advisory on this issue, on 18 January 2008, Medsafe produced a media release outlining the MARC's recommendation that cough and cold medicines should not be used in children aged under 2 years of age. In addition, the general advice issued by Health Canada in October 2007 was disseminated.

[..]

An advisory on the use of cough and cold medicines in children from the Health Sciences Authority, Singapore, was included in the March dossier.

Medsafe is currently in the process of actioning the other recommendations of the December MARC meeting. In addition, Medsafe intends to seek further input from the Committee regarding the use of cough and cold medicines in children aged 2-11 years of age, once the collection of further data on this issue (including the results of the FDA's analyses of ADR data) is completed.

Discussion

The Committee noted that Medsafe is currently in the process of actioning the recommendations of the December MARC meeting. As part of this process, Medsafe will contact the Pharmaceutical Society of New Zealand and the Pharmacy Guild, to request that they disseminate information to pharmacists.

The Committee noted the above.

2.1.4 Aprotinin and increased mortality risk
December 2007 minute item 3.4

Issue

In December 2007, the Committee recommended that the issue of aprotinin and increased mortality risk be reviewed once the final results of the BART study are available.

Outcome

The results of the BART study will be brought to the MARC when they are available.

Discussion

The Committee noted the above.

2.1.5 Alteplase and haemorrhage intracranial [death] (75765)
December 2007 minute item 4.1.1.1

Issue

In December 2007, the Committee recommended that NZPhvC seek further information about this case and report back to the MARC.

Outcome

The NZPhvC is still awaiting further information. This will be brought to MARC's attention when it is available.

Discussion

NZPhvC advised that further information about this case had been received. They advised that the hospital had an extensive stroke thrombolysis guideline in place, including risk:benefit ratio and use in the elderly. It appeared that in this instance, the patient did fit within the criteria of their particular risk/benefit guideline.

2.1.6 Simvastatin, enalapril and pancreatitis [death] (76148)
December 2007 minute item 4.1.1.2

Issue

In December 2007, the Committee recommended that NZPhvC add enalapril as a suspect medicine in this case.

Outcome

The NZPhvC has amended the database to reflect enalapril as a suspect medicine.

Discussion

The Committee noted the above.

2.1.7 Adalimimab and cerebral haemorrhage [death] (75961)
December 2007 minute item 4.1.1.5

Issue

In December 2007, the Committee noted that further information about this case had been requested but not yet received.

Outcome

Follow-up information from the NZPhvC was received for the above report.

Further description of event

This 39-year-old male patient had severe rheumatoid arthritis which commenced at the age of 16 years. At the time of his intracranial haemorrhage in June 2007 he was taking methotrexate (weekly), prednisone and ketoprofen all of which he had taken for 13 years. Cilazapril and adalimumab had both been recently commenced.

In May 2006 he had commenced leflunomide but was advised to discontinue in November 2006 because of hypertension (blood pressure 200/120). He was admitted to hospital in January 2007 with diarrhoea and vomiting and disordered hepatic function, leflunomide was then discontinued and cilazapril 1 mg daily commenced. Adalimumab was started in May 2007 for rheumatoid arthritis (RA) after a normal chest X-ray. He received one or at most two doses before sudden collapse and loss of consciousness. He was admitted to hospital Intensive Care Unit for supportive care (intubation and ventilation). CT head showed inoperable pontine/mid brain intracranial haemorrhage with extension into 3rd and 4th ventricles. The patient subsequently died a few hours after extubation.

Comment. No specific references to intracranial haemorrhage associated with adalimumab have been found. However, there is one other report in the CARM database of a patient who developed cerebral haemorrhage after receiving adalimumab for five months. He had a history of uncontrolled hypertension. In the present report it is not clear how well the patient's blood pressure was controlled after leflunomide was discontinued and cilazapril commenced. There is also no comment about whether haematological investigations were undertaken. As hypertension can lead to intracranial haemorrhage it is relevant to note that the literature database Drugdex on-line quotes product information (Humira solution for subcutaneous injection, 2007) indicating that in a placebo- controlled clinical study in which patients with RA were treated with adalimumab 40 mg subcutaneously alternate weeks (n=705) or placebo (n=690), hypertension was reported in 5% of the adalimumab group compared with 3% of the placebo group. The New Zealand data sheet for Humira (November 2007) lists hypertension as an uncommon adverse effect in clinical trials.

Discussion

The Committee noted the above.

2.1.8 Peginterferon Alfa 2a and pneumonia [death] (76001)
December 2007 minute item 4.1.1.4

Issue

In December 2007, the Committee recommended that NZPhvC change the causality from 'unclassified' to 'possible'.

Outcome

The NZPhvC has amended the database to reflect the change in causality.

Discussion

The Committee noted the above.

2.1.9 Clozapine and neutropenia, lymphopenia,anaemia [death] (76419)
December 2007 minute item 4.1.1.7

Issue

In December 2007, the Committee recommended that the College of Psychiatrists be contacted to determine how often clozapine is used to treat some of the features of dementia, and whether usage appears to be increasing.

Outcome

Prof Ellis has agreed to contact the College of Psychiatrists and obtain this information.

Discussion

Prof Ellis advised that the New Zealand members of the Faculty of Psychiatry of Old Age of the College of Psychiatrists had provided information regarding clozapine prescribing in the elderly. The College expressed the view that there was a place for the use of clozapine in the elderly, particularly in the treatment of dementia related psychosis in patients with Parkinson's disease. They provided an estimate of the number of patients aged 65 years or older currently receiving clozapine and noted that approximately half of these patients are being prescribed clozapine by members and associates of the Faculty of Psychiatry of Old Age (NZ). They considered that members were very aware of the adverse drug reactions that the elderly may be particularly vulnerable to. The College commented that a Prescriber Update article regarding the use of clozapine in the elderly, targeting those prescribers who are not prescribing under the Specialist Old Age service, would be of benefit, and offered assistance with this. The College also offered to conduct a more formal audit of the elderly patients in New Zealand who are receiving treatment with clozapine.

The Committee thanked the College for the comprehensive report. They agreed that a more formal audit would be of benefit, and that in the meantime, a short Prescriber Update article be published.

Recommendations

The Committee recommended that the College of Psychiatrists be approached to undertake a formal audit of the elderly patients in New Zealand who are receiving treatment with clozapine.

The Committee recommended that a short Prescriber Update article on the use of clozapine in the elderly be published.

2.1.10 Symbicort and exacerbation of asthma [death] (75986)
December 2007 minute item 4.1.1.12

Issue

In December 2007, the Committee recommended that the issue of the sharing of relevant information between the data collected by national mortality review process and CARM be further investigated.

Outcome

Dr Reith has agreed to investigate this issue.

Discussion

The Committee noted the above.

A member informed the Committee that the US FDA has recently requested manufacturers of some long acting beta agonists (LABAs) to provide information regarding controlled clinical studies conducted with these products in order to further evaluate the safety of LABAs when treating asthma. Following review of this information, the issue of the risk:benefit assessment of LABAs in adults and children was to be brought to a future FDA advisory committee.

2.1.11 Tramadol and drug dependence (narcotic) (75728)
December 2007 minute item 4.1.3.1

Issue

In December 2007, the Committee recommended that NZPhvC review the literature regarding the issue of tramadol and dependency, and report back to the MARC.

Outcome

The NZPhvC conducted a review and found no further information in the literature to add to that already noted. The incidence is approximately 2 per 100 000 patients and more often in patients with a history of opiate dependence.

Discussion

The Committee noted the above.

2.1.12 Influenza vaccine and myelitis transverse, encephalitis (76080)
December 2007 minute item 4.1.8.1

Issue

In December 2007, the Committee recommended that NZPhvC change the causality from 'unlikely' to 'possible'.

Outcome

The NZPhvC has amended the database to reflect the change in causality.

Discussion

The Committee noted the above.

2.1.13 Lipid-lowering agents and psychiatric adverse reactions: Active Monitoring Review
December 2007 minute item 2.1.3, September 2007 minute item 3.3

Issue

In September 2007, the Committee recommended that Medsafe contact the sponsors of all lipid-lowering agents and request datasheet changes regarding psychiatric adverse reactions.

Outcome

The sponsors have been contacted and requested to add memory loss and depression to the Adverse Effects section of their data sheets. With the following exceptions, the data sheets of all approved products in New Zealand have either been updated or are in the process of being updated as requested.

The exceptions are:

Lipitor (Pfizer), Lescol and Lescol XL (Novartis), Vytorin, Ezetrol and Lipex (MSD), Crestor (AstraZeneca).

The sponsors of the above products provided Medsafe with sufficient justification as to why they declined to list depression and memory loss in their data sheets, and have committed to informing Medsafe of any new information they obtain regarding the issue.

Discussion

The Committee noted that not all sponsors have amended their product datasheets as requested. They agreed it would be helpful if the changes were summarised and brought to the next MARC meeting.

The Committee considered that the exceptions are not necessarily reflecting the available evidence and expressed concern about the content of these datasheets in the context of public safety.

The Committee recommended that the issue of lipid-lowering agents and psychiatric adverse reactions be placed on the 'scheduled review' list for 12-monthly review in order to review the recent data and pursue the issue of datasheet changes further.

Recommendations

The Committee recommended that Medsafe provide a summary of the data sheet changes that have occurred to be brought to the next meeting.

The Committee recommended that the issue of lipid-lowering agents and psychiatric adverse reactions be placed on the 'scheduled review' list for 12-monthly review.

2.1.14 Oral terbinafine and serious adverse reactions (blood dyscrasias, heptatotoxicity and dermatological reactions ) -Active Monitoring Review
December 2007 minute item 2.1.5, September 2007 minute item 3.5

Issue

In September 2007, the Committee recommended that Medsafe contact the Best Practice Advocacy Centre (BPAC) and ask they include a paragraph in their publication regarding the appropriate prescribing of oral terbinafine.

The Committee recommended that NZPhvC bring back case reports to the MARC in six months time.

Outcome

BPAC published a paragraph in their publication regarding the appropriate prescribing of oral terbinafine in December 2007.

The NZPhvC will revisit this issue again in preparation for the December 2008 MARC meeting.

Discussion

The Committee noted the above.

2.1.15 Issues monitored by the MARC, Medsafe and NZPhvC as at June 2007
December 2007 minute item 2.1.7, September 2007 minute item 3.9, June 2007 minute item 1.6

Issue

In September 2007, the Committee recommended that Medsafe write to the sponsors of Amizide, asking them to justify why their product contains 50mg hydrochlorothiazide when similar medicines generally contain 12.5mg hydrochlorothiazide.

In December 2007, the Committee noted that this recommendation had been rejected by the Minister's Delegate on the advice of Medsafe.

Outcome

The Committee agreed to provide further information in support of this recommendation.

Discussion

The Committee noted the above.

Recommendation

The Committee recommended that the Chair write to BPAC on behalf of the MARC, highlighting the higher dose of hydrochlorothiazide contained in Amizide, and suggesting that they review the place of Amizide in the treatment of hypertension.

2.1.16 Diclofenac and duodenal ulcer haemorrhagic, oesophagitis [death] (74905)
December 2007 minute item 2.1.9, September 2007 minute item 4.1.1.3

Issue

In September 2007, the Committee recommended that NZPhvC should analyse the CARM reports of renal failure with diclofenac further, and that these should be included in the standing agenda item review of non-specific nonsteroidal anti-inflammatory medicines (NSAIDs) and cardiovascular adverse effects, including congestive heart failure, at the December 2007 MARC meeting.

Outcome

The report on renal failure with diclofenac and non-specific NSAIDs had been postponed to the March 2008 meeting.

A review of reports of acute renal failure with selected NSAIDs in the CARM database was included in the March 2008 dossier. Also included was an article regarding recent reports of acute renal failure in the CARM database published in Best Practice (BPAC) and an article regarding safer prescribing, including mention of diclofenac and acute renal failure, to be submitted to NZ Doctor.

Discussion

The Committee discussed the article to be submitted to NZ Doctor. A member noted that it would be helpful to clarify if aspirin, both high dose and low dose, was included in the paragraph headed "Concomitant use of similar medicines", as there was some uncertainty about this.

The Committee noted the NZPhvC report, which was an analysis of reports in the CARM database regarding acute renal failure and selected NSAIDs. This analysis showed that there were only an adequate number of reports regarding diclofenac in the database; however, these indicated a disproportionality high number of cases of acute renal failure with diclofenac, when compared with the other non-steroidal agents reviewed (ibuprofen, naproxen and piroxicam).

The Committee noted that the articles to be published in Best Practice and NZ Doctor will provide advice regarding risk factors for acute renal failure with NSAIDs to prescribers.

2.1.17 Salmeterol and bronchospasm aggravated (death) (75086)
December 2007 minute item 2.1.10, September 2007 minute item 4.1.1.11

Issue

In September 2007, the Committee recommended that NZPhvC should seek further information about this case and bring the information back to the MARC.

Outcome

The indirect route by which the report was made to CARM has delayed obtaining further information on other possible allergic factors. However these will be provided when they are received

Discussion

The Committee noted the above.

2.1.18 Lamotrigine and convulsion [death] (74826)
December 2007 minute item 2.1.17, September 2007 minute item 2.1.9, June 2007 minute item 4.1.1.3

Issue

In June 2007, the Committee recommended that NZPhvC should provide a follow up report to the MARC when the Coroner's report or further information that facilitates assessment becomes available.

Outcome

The NZPhvC will bring any further information to a future MARC when received.

Discussion

The Committee noted the above.

2.1.19 Quetiapine,paroxetine,and neuroleptic malignant syndrome,pneumonia inhalation[death] (74373)
December 2007 minute item 2.1.18, September 2007 minute item 2.1.10, June 2007 minute item 4.1.1.4

Issue

In June 2007, the Committee recommended that NZPhvC should seek further information about this case and bring the information back to the MARC.

Outcome

Further information has been requested and will be brought to a forthcoming MARC when received

Discussion

The Committee noted the above.

2.1.20 Clozapine and haematological malignancies
December 2007 minute item 2.1.20, September 2007 minute item 2.2.1, June 2007 minute item 2.1.1; March 2007 minute item 2.1.2; December 2006 minute item 2.2.3

Issue

In March 2007, the Committee recommended that Medsafe, in consultation with Assoc. Prof. Frampton, explore a protocol for obtaining age-standardised data on the frequency of haematological events with clozapine.

Outcome

Medsafe and Assoc. Prof. Frampton are developing a protocol for obtaining these data.

Discussion

The Committee noted the above.

2.1.21 Oral Terbinafine Serious Adverse Reactions
December 2007 minute item 2.1.21, September 2007 minute item 2.2.2, June 2007 minute item 2.1.2; March 2007 minute item 2.2.1; December 2006 minute item 2.1.1; September 2006 minute item; June 2006 minute item 9.2

Issue

In March 2007, 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.

Outcome

The Pharmaceutical Society published an article on their website in September 2007, which was also included in the next print version of their newsletter scheduled for November 2007. A response is still awaited from the Pharmacy Council.

Discussion

The Committee noted the above.

2.1.22 Tenecteplase and sudden death [death] (74192)
December 2007 minute item 2.1.23, September 2007 minute item 2.2.5, June 2007 minute item 2.1.8; March 2007 minute item 4.3.1.6

Issue

In March 2007, 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.

Outcome

The NZPhvC will bring further information to MARC when received.

Discussion

The Committee noted the above.

2.1.23 COX-2 Inhibitors: Active Monitoring Review
December 2007 minute item 2.1.24, September 2007 minute item 2.2.8, June 2007 minute item 2.2.2; March 2007 minute item 2.1.5; December 2006 minute item 3.1

Issue

In September 2007, Medsafe advised that the COX-2 inhibitor data sheets have been reviewed and the gastrointestinal safety warnings compared against those in the Australian Product Information (PI).

The Committee recommended that Medsafe write to sponsors to request the inclusion of the additional statements in the New Zealand data sheets.

Outcome

All data sheets for the COX-2 inhibitors have been updated with respect to gastrointestinal safety warnings and other information to ensure consistency with the Australian PIs and published on the Medsafe web site.

Discussion

The Committee noted the above.

2.1.24 Clozapine and myocarditis, heart failure, arrhythmia [death] (CARM case 66578)
December 2007 minute item 2.1.29, September 2007 minute item 2.2.17, June 2007 minute item 2.2.11; March 2007 minute item 2.2.6; 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 is awaiting a copy of the post mortem report and will bring the findings to a forthcoming MARC meeting when received.

Discussion

The Committee noted the above.

2.1.25 Clozapine and Myocarditis
December 2007 minute item 2.1.30, September 2007 minute item 2.2.18, June 2007 minute item 2.2.12; March 2007 minute item 2.2.7; 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.

In September 2007, the Committee noted the report from [..] and recommended that Medsafe contact [..] for further comment on the issues discussed.

Outcome

A draft Prescriber Update article was included in the March 2008 dossier. Members were invited to provide comment. The article will be forwarded to [..] for peer review.

Discussion

The Committee noted the above.

2.1.26 Influenza vaccine and sudden death (CARM case 71269)
December 2007 minute item 2.1.31, September 2007 minute item 2.2.19, June 2007 minute item 2.2.13; March 2007 minute item 2.2.8; 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 awaiting a copy of the post mortem report and will bring the findings to a forthcoming MARC meeting when received.

Discussion

The Committee noted the above.

2.1.27 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 January 2008, DHBNZ Safe Use of Medicines Group issued an alert entitled "Low Molecular Weight Heparin Treatment in Renal Impairment'.

A copy of this alert was included in the March 2008 dossier.

Discussion

The Committee noted the above.

3. Pharmacovigilance Issues

3.1 SSRI ANTIDEPRESSANTS AND THE RISK OF SUICIDALITY

References
Background

Medsafe and NZPhvC provided a report for the MARC on the issue of SSRI antidepressants and the risk of suicidality. In July 2005, the United States Food and Drug Administration (FDA) issued a Public Health Advisory to inform US prescribers that a review was being conducted to determine whether there was an increased risk of suicidal behaviour in adults taking antidepressants. In response to this, at its March 2006 meeting, the MARC reviewed a report on the issue of severe agitation, severe restlessness/akathisia and/or suicidality with selective serotonin re-uptake inhibitors (SSRIs). They agreed that the risk:benefit ratio for the SSRIs in the treatment of moderate to severe adult depression remained favourable and the datasheets adequately warned prescribers of the potential risks associated with these medicines and the need to monitor patients carefully, particularly during the early stages of treatment. They recommended that the issue of severe agitation, severe restlessness/akathisia and/or suicidality with selective serotonin re-uptake inhibitors (SSRIs) be placed on the watching brief list pending the outcome of the US FDA review.

In May 2007, as a result of the FDA's Psychopharmacologic Drugs Advisory Committee meeting, the FDA announced a request to manufacturers of all antidepressant medications to update the existing "black box" warning on their product labelling to include warnings about increased risks of suicidal thinking and behaviour (suicidality) in young adults aged 18 to 24 during initial treatment.

Additionally, the FDA requested that the labelling state that scientific data do not show an increased risk in adults older than 24 and that adults aged 65 and older taking antidepressants actually have a decreased risk of suicidality. It was also requested that warning statements emphasise that depression and certain other serious psychiatric disorders are themselves the most important causes of suicide.

At its June 2007 meeting, the MARC considered the outcome of the FDA's review. The Committee did not believe the new information altered the risk-benefit profile of SSRI antidepressant medicines. They agreed that the current New Zealand SSRI datasheets adequately warned prescribers of the potential risks associated with the use of these medicines, and the need to carefully monitor patients for the emergence or worsening of suicidal thoughts or behaviours, particularly during the initial stages of treatment. They did not consider it is necessary to revise the existing warnings to express the FDA findings that there is no evidence for an increased risk of suicidality in adults over 24 years, or that for those aged 65 years and older, suicidality risk is decreased. The Committee recommended that the issue of SSRIs antidepressants and severe agitation, severe restlessness/akathisia and increased suicidality should be removed from the 'watching brief' list.

At its December 2007 meeting, the Committee were advised of a recent analysis, which examined time trends in suicide attempts between 90 days prior and 180 days following treatment initiation with antidepressants or psychotherapy. This analysis found that the incidence of suicide attempts was highest in the month before treatment initiation and next highest in the month following treatment initiation. Another analysis showed that patients who received SSRIs alone or with other antidepressants had a significantly lower suicide attempt rate that those receiving other antidepressants or no antidepressants. The Committee agreed it would be useful to discuss these recent publications in more detail and recommended that the issue of SSRIs and suicidality be placed on the agenda for the next meeting of the MARC.

Discussion

The Committee noted the February 2008 Medsafe report.

The Committee discussed the Gibbons paper, which was referred to at its December 2007 meeting. This paper concluded that in both the United States and the Netherlands, SSRI prescriptions for children and adolescents decreased after U.S. and European regulatory agencies issued warnings about a possible suicide risk with antidepressant use in paediatric patients, and these decreases were associated with increases in suicide rates in children and adolescents. The Committee noted that this paper included only one year of data, and that these data were significantly flawed.

The Committee agreed that it was difficult to compare overseas data with the New Zealand situation. The risk of an increase in suicidality with the SSRIs is unlikely to be determined, as the small number of patients who are prescribed antidepressants, along with poor compliance, would not produce adequate numbers to allow for analysis.

The Committee noted the MARC advice issued to Health Professionals in October 2004.

"Monitor all patients with depression

The MARC considers that for all age groups worsening depression remains the most common reason for increased suicidality during treatment with any antidepressant. All patients with MDD should be monitored for the emergence or worsening of suicidal thoughts or behaviours regardless of whether they are taking an antidepressant medicine or not. Evidence suggests that the risk of suicidality may be especially increased during the first few weeks of treatment.

Finally, the MARC considers that the possible increased risk of suicidality in patients applies to all classes of antidepressant medicines, as available data are not adequate to exclude an increased risk of suicidality for any antidepressant (including SSRIs, TCAs and Monoamine Oxidase Inhibitors)."

They noted that this advice was not age specific and the information issued at that time also included more specific advice regarding the SSRI risk:benefit in childhood and adolescent major depressive disorder (MDD):

"For childhood and adolescent MDD, the possible risk of suicidal ideation and behaviours (suicidality) with SSRIs generally outweighs the possible benefits. However, there is some evidence of efficacy with fluoxetine and therefore it may have a favourable risk:benefit ratio. There is no evidence from clinical trials of an increased risk of completed suicide in any age group using SSRIs."

The Committee discussed the Wheeler et al paper and noted that it was an ecological study, and so could not demonstrate causality. This study was an attempt to determine whether there was a link between actual deaths when compared with suicidal ideation. They noted that in order to demonstrate causality, studies such as randomised controlled trials and meta-analyses were required. The Committee noted the difficulties in undertaking studies to demonstrate suicidal causality and agreed that the Wheeler study provided no further information.

The Committee agreed that there were many other factors, including social issues, which contribute to suicide and that it is difficult to compare different countries which each have their own issues. They agreed that it was important not to look at the use of SSRIs in isolation.

The Committee noted the usage data for New Zealand indicated that prescription numbers in young people under the age of 18 years for citalopram, paroxetine and venlafaxine appeared to be disproportionality high when compared with fluoxetine. However, it was not known if these patients had previously been prescribed fluoxetine. This was of concern as analyses from the FDA and MHRA showed venlafaxine had the highest risk of suicidal ideation and behaviour. The Committee considered that venlafaxine should be included in any new advice provided by the MARC.

The Committee noted the recently published meta-analysis by Kirsch et al. They noted that the analysis was undertaken on a collection of potentially biased, small-sample studies of short duration. They noted that the length of treatment was not adequate to show effectiveness in some patients. They noted that mean baseline severity was used as an outcome measure; however, they considered that this was not an appropriate measure of outcome. They noted that using individual patient data for the meta-analysis would have been preferable. They considered that the meta-analysis was flawed and did not alter the risk:benefit profile of the SSRIs.

The Committee agreed it was important to provide prescribers with a current summary of advice. They recommended that a Prescriber Update article be written, advising that the MARC advice issued in 2004 still remained valid in light of the recent/current evidence. The Committee recommended that the key messages to be contained in this article be discussed at the next meeting of the MARC.

The Committee did not believe the new information altered the risk:benefit profile of SSRI antidepressant medicines. They maintained that the current NZ SSRI datasheets adequately warn prescribers of the potential risks associated with the use of these medicines, and the need to carefully monitor patients for the emergence or worsening of suicidal thoughts or behaviours, particularly during the initial stages of treatment. The Committee considered the proposed Prescriber Update article would provide a summary of current advice.

Recommendations

The Committee recommended that the issue of SSRI antidepressants and the risk of suicidality be placed on the 'Scheduled Review' list for 12-monthly review.

The Committee recommended that a Prescriber Update article be written, advising that the MARC advice issued in 2004 still remained valid in light of the recent/current evidence. The Committee recommended that the key messages to be contained in this article be discussed at the next meeting of the MARC.

3.2 ALL ADVERSE REACTIONS TO ROSIGLITAZONE AND PIOGLITAZONE (ARCC*), PARTICULARLY FRACTURE/BONE DENSITY.

References
Bone
Other Adverse Effects
Other references
Issue

Medsafe and NZPhvC provided reports for the MARC's Scheduled Review on the issue of adverse effects to pioglitazone and rosiglitazone. This issue was placed on the active monitoring list for annual review in March 2006.

Since the last formal annual review of adverse reactions to pioglitazone and rosiglitazone in March 2007, these medicines have been discussed at the June, September and December 2007 MARC meetings.

At the June 2007 meeting, the Committee recommended that the issue of bone loss and fractures be reviewed as part of the March 2008 Scheduled Review. The Committee reviewed a draft Prescriber Update article about fluid retention, heart failure and macular oedema with glitazones. This article was subsequently published in November 2007. The Committee also discussed cardiovascular safety issues (in particular, heart failure and myocardial infarction) with rosiglitazone, noting that the Avandia data sheet was being updated to reflect this. The Committee asked Medsafe to contact the sponsors of Actos (pioglitazone) for comment on the cardiac safety of pioglitazone.

At the September 2007 meeting, the Committee was informed of proposed changes to the Actos data sheet, to manage the risk of heart failure and bone fracture.

At the December 2007 meeting, the Committee was informed that the Actos data sheet has been revised as part of the sponsor's response to Medsafe's request for comment on the cardiac safety of this medicine.

Since June 2006, pioglitazone and rosiglitazone have been on the list of Adverse Reactions of Current Concern. At that time, reports of adverse reactions published in the literature primarily involved rosiglitazone. However, emerging evidence has shown that the adverse reaction profile of pioglitazone is not dissimilar.

The purpose of the March 2008 review was to update the Committee on regulatory actions and new information regarding adverse reactions with pioglitazone and rosiglitazone that had arisen in the previous 12 months.

The Committee was asked to evaluate the information provided, and to determine whether the risk-benefit profile of pioglitazone or rosiglitazone has changed as a result of this new information; and if so, make recommendations about appropriate risk management.

Discussion

The MARC noted the February 2008 Medsafe and NZPhvC reports.

The Committee noted that, in the last 12 months, both the rosiglitazone and pioglitazone datasheets have undergone extensive updating with respect to safety issues. These changes have been consistent with the changes made to the Australian Product Information (PI) for these two medicines.

The Committee discussed if the New Zealand datasheet warnings adequately reflected the current state of knowledge, and were consistent with other jurisdictions, particularly with respect to heart failure, fracture risk and myocardial infarction.

The Committee reviewed the literature provided. They considered that the risk of heart failure appeared from the literature to be common to both medicines. The PROActive study suggested a number needed to harm (NNH) value of 50 for hospitalisations with heart failure, and therefore in the 3575 patients in NZ, 71 heart failure admissions would be expected with pioglitazone. The Committee noted that rosiglitazone is not subsidised in New Zealand. In order to obtain a subsidy for pioglitazone in NZ, an application for a Special Authority number is required. This application includes the patient's NHI number. The Committee asked if it would be possible to match Special Authority (and therefore NHI numbers) with admissions to hospitals of patients who had been coded with heart failure, in order to support this figure.

The Committee considered that the literature regarding myocardial infarction indicated a clear signal with rosiglitazone, but it was difficult to determine if this was common to both medicines due to the smaller amount of data available for pioglitazone.

The Committee considered that the fracture risk also appeared to be common to both medicines.

The Committee noted that the information included in the product datasheets for rosiglitazone and pioglitazone varied between countries. They noted, however, that the Contraindications / Precautions Sections in most datasheets included 'not to be used in heart failure, not recommended in people with ischaemic heart disease, acute coronary syndrome, post-myocardial infarction, angina and for people on nitrates', and (for rosiglitazone only) 'not recommended with insulin'.

The Committee noted that the number of patients receiving glitazones in New Zealand is low. They considered that the risk:benefit ratio appeared to be changing due to the increasing range and degree of risks and uncertainties. The Committee considered that the place of glitazones in therapy is uncertain, and long-term outcomes, mortality and morbidity have yet to be demonstrated.

NZPhvC analysis of the CARM data confirmed that these medicines should continue to be monitored on a 12-monthly basis, with particular focus on cardiovascular and bone events. The only new potential signals not previously presented to the MARC were hepatic and pancreatic malignancies, and bile duct disorders. The analysis of recent reports in the WHO database, Vigibase, showed these reactions had a positive IC value of between 2 & 4. 'Weight increased' and 'cardiac failure' both had strongly positive IC values of over 4. The Committee noted that these values applied to both rosiglitazone and pioglitazone.

The Committee agreed that the mechanism of action of both agents was thought to be similar and therefore it is possible that MI could be a risk associated with pioglitazone. The Committee recommended that an article be published in Prescriber Update, suggesting that the risk of myocardial infarction seen with rosiglitazone may also occur with pioglitazone, and the adverse effect profile should be considered before prescribing these medicines.

The Committee expressed concern that the adverse effects reported in association with rosiglitazone may also occur with pioglitazone. They considered it would be helpful if the IC values reported in the WHO database could be applied to each medicine separately. The Committee recommended that NZPhvC examine the Vigibase reports for rosiglitazone and pioglitazone in order determine individual IC values for the two medicines.

Recommendations

The Committee recommended that the issue of all adverse reactions to rosiglitazone and pioglitazone , particularly fracture/bone density remain on the 'Scheduled Review' list for 12-monthly review.

The Committee recommended that the NZ data sheet for Avandia (rosiglitazone) should be further updated to bring it in line with the information about ischaemic heart disease recently added to the Australian PI, i.e.:

The Committee recommended that an article be published in Prescriber Update, suggesting that the risk of myocardial infarction seen with rosiglitazone may also occur with pioglitazone, and the adverse effect profile should be considered before prescribing these medicines.

The Committee recommended that NZPhvC examine the Vigibase reports for rosiglitazone and pioglitazone in order determine individual IC values for the two medicines.

The Committee recommended that NZPhvC prepare a proposal for consideration for a NZ data-linkage study, to evaluate adverse events with the glitazones, with particular focus on cardiac events.

3.3 ALL ADVERSE REACTIONS TO COMPLEMENTARY AND ALTERNATIVE MEDICINES (ARCC*).

Issue

NZPhvC provided a report for the MARC on the issue of all adverse reactions to complementary and alternative medicines (CAMs). This issue was placed on the Adverse Reactions of Current Concern (ARCC) list in October 1996 when CARM received increasing numbers of reports of adverse reactions to CAMs. In March 2007, the Committee recommended that an annual report be provided. This report was the annual updated review and listing of abbreviated details of reports received in the period January to December 2007. Due to the large number of products available, often containing multiple active ingredients, NZPhvC advised 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.

Discussion

The Committee noted the March 2008 NZPhvC report. NZPhvC advised that there had been 20 reports received since the last review, of which three have been reviewed by the MARC. Most of the reports over this period described hypersensitivity-type reactions. Occasional other reactions were reported, such as hypoglycaemia (Chromium), myalgia and CPK elevated (Red Rice Yeast Extract/Saw Palmetto), hepatic function aberration (Saw Palmetto, 30 Plus, Herbal X, Glucosamine & Chondroitin, Bee Pollen), threatened abortion (Peppermint Gel), menstrual and mood disorder (Evening Primrose Oil) and a drug interaction (Glucosamine and warfarin) resulting in decreased prothrombin and a duodenal ulcer haemorrhage. The Committee noted that a Prescriber Update article is to be written describing adverse drug reactions with herbal medicines.

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/listing of all reports.

The Committee agreed 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/listing of all reports.

Recommendation

The Committee recommended that NZPhvC continue to report serious and/or unusual events to each MARC meeting, and provide an annual ARCC submission of a summary/listing of all reports.

3.4 ANTI-EPILEPTICS AND THE RISK OF SUICIDALITY.

References

Issue

Medsafe and NZPhvC provided the MARC with reports on anti-epileptics and the risk of suicidality. This followed a release on 31 January 2008 by the United States Food and Drug Administration (FDA) informing US healthcare professionals that the Agency had analysed reports of suicidality (suicidal behavior or ideation) from placebo-controlled clinical studies of eleven medicines used to treat epilepsy as well as psychiatric disorders, and other conditions. In the FDA's analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.

There were an estimated 2.1 per 1000 more patients in the anti-epileptic treatment groups who experienced suicidal behaviour or ideation than in the placebo groups.

US Healthcare professionals were advised to closely monitor all patients currently taking or starting any antiepileptic medicine for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression.

The FDA indicated that the medicines included in the analyses were: carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, the FDA expected that the increased risk of suicidality is shared by all antiepileptic medicines and anticipates that any regulatory action will be applied to all anti-epileptic drugs. This issue is to be further discussed at a meeting of the FDA's Expert Advisory Committee.

On 1 February 2008, Medsafe distributed a "Dear Health Professional" letter to all New Zealand prescribers informing them of the FDA's alert regarding the increased risk of suicidal thoughts and behaviours occurring in patients taking anti-epileptic medicines.

Prescribers were advised to follow the FDA's advice - notably:

Medsafe also contacted the sponsors of all anti-epileptic medicines approved for use in New Zealand, requiring them to update their data sheets to include the recent information.

Discussion

The Committee noted the March 2008 Medsafe and NZPhvC reports.

The Committee noted that the FDA's analysis suggested that the anti-epileptic medicines as a class may be associated with an increased risk of suicidal thoughts and behaviours compared with placebo. They agreed that more detail was required in order to determine if this information altered the overall risk profile of anti-epileptics and how the risk of suicide related to the other risks associated with these medicines.

The Committee noted that there were a large number of patients in New Zealand receiving these medications. They registered concern that if treatment was stopped suddenly, there was a greater risk from epilepsy-related adverse effects than from those relating to suicidality.

The Committee noted the advice issued by Medsafe in February 2008 to all New Zealand prescribers informing them of the FDA alert, and advising patients who are currently taking anti-epileptic medicines not to make any changes without first talking to their doctor.

The Committee noted that Medsafe will provide the MARC with a copy of the full results of the FDA's meta-analysis when it is available. At that time the MARC will be asked to consider whether any further regulatory action is required. The Committee agreed that the issue of Anti-Epileptic Medicines and the risk of Suicidality should be placed on the 12-monthly Scheduled Review list.

Recommendation

The Committee recommended that Medsafe provide the MARC with a copy of the full results of the FDA's meta-analysis when it is available.

The Committee recommended that the issue of anti-epileptic medicines and the risk of Suicidality be placed on the 'Scheduled Review' list for a 12-monthly review.

3.5 CARDIOVASCULAR RISKS OF CALCIUM SUPPLEMENTS IN WOMEN.

References
Issue

Medsafe provided information to the MARC following the publication of a paper in the British Medical Journal by Bolland et al entitled "Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial". The objective of the trial was to determine the effect of calcium supplementation on myocardial infarction, stroke, and sudden death in healthy postmenopausal women. The paper concluded that calcium supplementation in healthy postmenopausal women was associated with an increase in incidence of cardiovascular events, and this risk should be balanced against the likely benefits of calcium on bone.

Discussion

The Committee reviewed the Bolland study, which was a secondary analysis of a randomised controlled trial of calcium supplementation in healthy postmenopausal women, primarily designed to assess the effects of calcium on bone density and fracture incidence over five years.

They noted that the trial included approximately 730 women in each group - one group taking placebo and the other group calcium monotherapy. The age of participants was greater than had previously been studied in similar trials. After two years, the calcium group showed increased rates of myocardial infarction when compared with the group taking placebo.

The Committee noted that study participants received 1gram of calcium citrate salt, which has an increased bioavailability when compared to the carbonate salt. The recommended daily dose of calcium in older women is 1000mg to 1200mg. As an average diet provides approximately 500mg, participants received a total amount of calcium above the recommended daily dose. The Committee noted that following presentation of the data from the Bolland study, the Greenlane Bone Clinic issued advice regarding calcium supplementation and the risk of myocardial infarction. This advice suggested that calcium intake be maintained at a total of approximately one gram per day, including dietary intake and supplementation.

The Committee noted that it would have been helpful to see the original study protocol and original statistical analysis in conjunction with the results recorded. They noted that the baseline data in the calcium treated group showed a slightly higher rate of pre-existing heart disease, and after 60 months of treatment, this group showed an approximately 1.5% higher rate of verified myocardial infarction. When the Poisson regression model was applied to the data, it was shown that the history of cerebrovascular disease, history of ischaemic disease and compliance with study tablets were all more significant than the measurement for calcium or placebo.

The Committee noted that the primary end point of the study was unverified myocardial infarctions, rather than hospital reports. The result was not statistically significant, (p-value 0.16) when only hospital verified reports were included.

The Committee considered that the data presented in this paper were inconclusive and that the information provided does not alter the risk:benefit ratio of calcium supplementation.

The Committee considered that no further regulatory action was required at this time but would review further literature as it became available.

4. Matters arising from the New Zealand Pharmacovigilance Centre

4.1 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 website of the WHO Collaborating Centre http://www.who-umc.org/. These designations (certain, probable, possible, unlikely, unclassified and unclassifiable) refer to the degree of certainty about the relationship between the medicine and the adverse event. The terms should not be understood literally. For example, "certain" means that the appropriate elements are present to match the international definition. It does not mean there is absolute certainty that the medicine caused the adverse event. Explanations of the terms used by CARM and MARC can be accessed by hyperlink at each causality designation.

4.1.1 Deaths

4.1.1.1 Capecitabine and corneal disorder, xerophthalmia, disease progression [death] (77255)

Discussion

NZPhvC advised that the CARM database includes reports of visual disorders in association with capecitabine. The product datasheet includes reference to eye disorders.

The Committee noted that the patient's possible reaction was not related to the cause of death, which was disease progression.

The causal association with capecitabine was considered to be 'possible' for corneal disorder, 'possible' for xerophthalmia and 'unlikely' for disease progression.

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

4.1.1.2 Leuprolide and myocardial infarction, pancreatitis [death] (77280)

Discussion

NZPhvC advised that the CARM database includes a small number of reports for leuprolide, including cardiovascular events. The WHO database includes reports for both cardiovascular events and for pancreatitis.

The product datasheet includes reference to the possibility of cardiovascular events, including myocardial infarction and angina, but not pancreatitis. This is also reflected in the literature.

The Committee noted that the myocardial event may reflect a possible association with leuprolide, although the background history of ischaemic heart disease and hypertension may equally explain the outcome. There was little evidence to support an association with pancreatitis and leuprolide, and the patient had a background history of pancreatitis, which may have contributed.

The causal association with leuprolide was considered to be 'possible' for myocardial infarction, and 'unlikely' for pancreatitis.

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

4.1.1.3 TMC114 (darunavir), ritonavir, raltegravir and coronary artery disorder [death] (77238)

Discussion

NZPhvC advised that the CARM database includes no reports for darunavir, and the WHO database includes only one report describing an event, which is unrelated to this case. The product datasheet includes myocardial infarction as a possible adverse effect. There were no reports found in the literature.

The Committee noted that the patient's history was complex and documented multiple hospitalisations for his condition. They considered that there was insufficient detail to determine a casual association.

The causal association with TMC114 (darunavir), ritonavir, raltegravir was considered to be 'unclassified' for coronary artery disorder.

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

4.1.1.4 Lenalidomide, dexamethasone and fever, shock septic, immunosuppression [death] (76659)

Discussion

NZPhvC advised that further information received detailed a complex history suggesting previous periods of immunosuppression and compromise. This report concluded that the patient died of sepsis due to severe immunosuppression following progressive myeloma and its treatment.

NZPhvC advised that lenalidomide is an analogue of thalidomide and not yet approved in New Zealand. There are no reports regarding lenalidomide in the CARM database and only a small number in the WHO database.

The US Physicians Desk Reference (PDR) states that Revlimid (lenalidomide) is associated with significant neutropenia and thrombocytopenia.

The Committee noted that the dexamethasone may have also played a role and the patient's history was complex.

The Committee considered the causal association with lenalidomide, dexamethasone was 'possible' for fever, 'possible' for shock septic and 'possible' for immunosuppression.

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

4.1.1.5 Methotrexate, Propofol and pulmonary oedema, pneumonia [death] (76764)

Discussion

NZPhvC advised that the CARM database includes reports for pulmonary reactions with both medicines. The product datasheets for both medicines includes reference to respiratory effects.

The Committee noted that the patient's recent surgery and post-surgical complications may also have contributed. They noted that the features revealed on x-ray may have been part of the underlying (possibly drug-related) pathology, rather than due to pulmonary oedema.

The Committee considered the causal association with methotrexate was 'unclassified' for pulmonary oedema and 'possible' for pneumonia, whilst the association for both events for propofol was 'unclassified'.

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

4.1.1.6 Methotrexate and pneumonia, interstitial lung disease [death] (76765)

Discussion

See minute item 4.1.1.5.

The causal association with methotrexate was considered to be 'possible' for pneumonia and 'possible' for interstitial lung disease.

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

4.1.1.7 Clozapine and sudden death, cardiomyopathy, dyspnoea episodic [death] (76713)

Discussion

The Committee noted that the IMMP database contains reports of cardiomyopathy (including some of subsequent death) in association with clozapine. The IC value for cardiomyopathy in association with clozapine is strongly positive.

The New Zealand datasheets for clozapine include specific warnings regarding the risk of myocarditis and cardiomyopathy, and this is supported in the literature.

The causal association with clozapine was considered to be 'possible' for sudden death, 'possible' for cardiomyopathy and 'possible' for dyspnoea episodic.

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

4.1.1.8 Clozapine and sudden death, heart failure acute and flu-like illness [death] (76714)

Discussion

NZPhvC advised that the IMMP database includes reports of sudden cardiac death in association with clozapine, and there are also reports in the WHO database. The New Zealand datasheet for Clozaril (clozapine) lists sudden unexplained death as a very rare adverse effect. The issue of sudden death of patients taking atypical antipsychotics has been reported in the literature.

The causal association with clozapine was considered to be 'possible' for sudden death, heart failure acute and flu-like illness.

Recommendation

The Committee recommended that NZPhvC further study the causes of sudden death in young patients taking clozapine and other atypical antipsychotics.

4.1.1.9 Olanzapine and diabetic ketoacidosis [death] (77096)

Discussion

NZPhvC advised that the IMMP database includes reports of weight increase associated with olanzapine. There are also reports of diabetic ketoacidosis,new onset diabetes mellitus and hyperglycaemia. The product datasheet includes information about the risk of hyperglycaemia and diabetes mellitus (including ketoacidosis or hyperosmolar coma or death).

It is now well established in the literature that atypical antipsychotics, particularly olanazapine, cause weight gain in many patients. This is linked to a broader spectrum of adverse events, known as metabolic syndrome. The association of metabolic syndrome with atypical antipsychotics is now a recognised adverse effect of these medicines.

The Committee noted that although the report suggested that the antipsychotic treatment may have contributed to his death from diabetic ketoacidosis, further information was required to confirm causality.

The causal association with olanzapine was considered to be 'unclassified' for diabetic ketoacidosis.

4.1.1.10 Quetiapine, entacapone, pergolide and falls, neuroleptic malignant syndrome, rhabdomylosis, renal failure acute, haematuria [death] (76884)

Discussion

NZPhvC advised that further information obtained revealed a reasonably high creatine kinase although not as high as in some reports of rhabdomyolysis.

NZPhvC advised that the CARM database includes five reports of neuroleptic malignant syndrome associated with quetiapine, but none with entacapone or pergolide. There are no reports of rhabdomyolysis associated with any of these medicines. The WHO database includes reports of both NMS and rhabdomyolysis with all three medicines, but particularly associated with quetiapine.

The product datasheet for entacapone lists NMS including rhabdomyolysis associated with treatment. The quetiapine datasheet lists the risk of NMS, but does not include rhabdomyolysis. The Pergolide datasheet lists neither NMS nor rhabdomyolysis.

The literature includes some evidence for NMS associated with entacapone and quetiapine.

The causal association with quetiapine, entacapone, Pergolide was considered to be 'unlikely' for falls, 'possible' for neuroleptic malignant syndrome, rhabdomyolysis, renal failure acute, haematuria.

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

4.1.1.11 Paroxetine and suicide [death] (76968)
Case Report

Discussion

NZPhvC advised that the CARM database includes reports of suicide and suicide attempts associated with paroxetine. They advised that the details in this report are incomplete and it was not possible to determine whether there may be an association with paroxetine. However, the product datasheet draws attention to the potentially increased risk of suicidality in depressed patients and the need for closer monitoring.

The causal association with paroxetine was considered to be 'unclassified' for suicide.

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

4.1.1. 12 Venlafaxine and serotonin syndrome, rhabdomyolysis, multiple organ failure, drug interaction [death] (76686)

Discussion

NZPhvC advised that the CARM database contains reports of serotonin syndrome associated with both medicines. The IC value for serotonin syndrome with both medicines in the WHO database is positive.

The datasheets for both venlafaxine and paroxetine refer to the possibility of serotonin syndrome, particularly when given in combination with other serotonergic drugs.

The Committee noted that a drug interaction or possible synergistic effect had occurred between the two medications.

The Committee considered that it was important to obtain more details about this case.

The causal association with venlafaxine and paroxetine was considered to be 'possible' for serotonin syndrome, rhabdomyolysis, multiple organ failure, drug interaction.

Recommendation

The Committee recommended that NZPhvC seek further information about this case and report back to the MARC.

4.1.1.13 Flutamide and hepatic failure, renal failure [death] (76947)

Discussion

NZPhvC advised that the CARM database includes reports of hepatic reactions and renal failure associated with flutamide. The WHO database also includes reports of hepatic dysfunction associated with flutamide.

The product datasheets include reference to hepatic injury, which is supported in the published literature.

The Committee noted that this is a rare but recognised event associated with flutamide therapy, however, the disease progression resulting from metastatic spread may have also contributed.

The causal association with flutamide was considered to be 'possible' for hepatic failure and renal failure.

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

4.1.2 Alternative Medicines (CAM)

4.1.2.1 Eye Q and tics (77064)

Discussion

NZPhvC advised that there are no similar or related reports in the CARM database. The product is reported to contain "Natural fish oil" equivalent to Omega-3 marine triglicerides 120mg (containing EPA 92mg and DHA 29mg) and EPO 100mg (containing GLA 10mg and d-alpha-tocopherol acetate 1.6mg). There is no evidence for any of the constituents reported in the natural medicines databases or PubMed being implicated in tics.

The Committee noted that the evidence in this report provided convincing empirical evidence for an association of tics with the use of the product.

The causal association with Eye Q was considered to be 'certain' for tics.

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

4.1.3 Anti-epileptics

4.1.3.1 Sodium valproate, topiramate and hyperammonaemia, drug interaction (76527)

Discussion

NZPhvC advised that the CARM database includes reports involving valproate and topiramite combinations describing convulsions, hyperuricaemia, however, there are no reports specifically describing this presentation. The WHO database includes reports of hyperammoneamia.

The product datasheet for Topamax (topiramate) documents that the concomitant administration of valproic acid has been associated with hyperammonaemia with or without encephalopathy. The product datasheet for Epilim (sodium valproate) states that hyperammonaemia has been reported in association with valproate therapy, but it does not list a drug interaction with topiramate.

The Committee noted that the interaction is well documented in the literature with many recent reviews.

The Committee agreed that it was important that both datasheets contained information about this interaction and recommended that the Epilim datasheet be amended to include the same co-administration as the Topamax datasheet.

The causal association with sodium valproate, topiramate was considered to be 'probable' for hyperammonaemia, drug interaction.

Recommendation

The Committee recommended that the Epilim datasheet be amended to include the same advice about the co-administration of topiramate as the Topamax datasheet has for valproate.

4.1.3.2 Lamotrigine and mania (77337)

Discussion

NZPhvC advised that the CARM database includes one report of a manic reaction in an eight year old child associated with lamotrigine, which resolved on de-challenge. The WHO database includes reports of manic reactions associated with lamotrigine, including six reports in patients of 18 years of age or below. Of the reports in patients under 18, indications were both for bipolar disorder and for epilepsy.

The New Zealand datasheets do not include reference to mania as an adverse effect of lamotrigine treatment. In comparison, the Physicians Desk Reference for Lamictal includes reference to mania/hypomania/mixed episodes as adverse effects.

A member advised that clinical experience suggested that treating patients with bipolar depression with antidepressants may induce mania, or a rapid cycling process which may include a mixed mood status. This appeared to be seen with all antidepressants.

The Committee considered that there was sufficient evidence to request the product sponsors to amend the NZ datasheets for lamotrigine to include references to mania in the post-marketing reports of the Adverse Reactions section.

The causal association with lamotrigine was considered to be 'possible' for mania.

Recommendation

The Committee recommended that the NZ datasheets for lamotrigine be amended to include references to mania in the post-marketing reports of the Adverse Reactions section.

4.1.3.3 Lamotrigine and mania (77338)

Discussion

See minute item 4.1.3.2.

The causal association with lamotrigine was considered to be 'probable' for mania.

4.1.4 Diagnostic agent

4.1.4.1 Methylene Blue, Tramadol, Fentanyl, paroxetine and serotonin syndrome (77178)

Discussion

NZPhvC advised that there are no reports of serotonin syndrome with methylene blue in the CARM or WHO databases. The CARM database includes reports of serotonin syndrome associated with combinations and/or high doses of fentanyl, paroxetine and tramadol.

The product datasheet notes that Methylene Blue should be used with caution in patients with mild to moderate renal impairment, and is contra-indicated in patients with severe renal impairment.

The Committee agreed that there were other possible explanations for the patient's symptoms, including a possible hypersensitivity syndrome.

The causal association with Methylene Blue, Tramadol, Fentanyl, paroxetine was considered to be 'unlikely' rather that 'probable' for serotonin syndrome.

Recommendation

The Committee recommended that NZPhvC change the causality from 'probable' to 'unlikely'.

4.1.5 Immunosuppressants

4.1.5.1 Etanercept and uveitis (76978)

Discussion

Refer also to minute item 4.1.5.2,

NZPhvC advised that these are the first reports of uveitis in association with etanercept in the CARM database. The WHO database includes reports of uveitis, and other ophthalmic adverse effects, in association with etanercept. The product datasheet does not include information about ophthalmic adverse effects.

A recently published paper from the American College of Rheumatology found that etanercept therapy may be associated with a greater number of reports of uveitis when compared with Infliximab and adalimumab. The Committee noted that etanercept appeared to have a different mechanism of action from Infliximab and adalimumab which would therefore support the findings in the literature

The causal association with etanercept was considered to be 'probable' for uveitis.

Recommendations

The Committee recommended that Medsafe obtain international information regarding uveitis in association with etanercept.

The Committee recommended that NZPhvC analyse the reports of uveitis in association with etanercept in the WHO database, and bring this information back to the MARC.

4.1.5.2 Etanercept and uveitis (76980)

Discussion

Refer to minute item 4.1.5.1.

The causal association with etanercept was considered to be 'possible' for uveitis.

4.1.6 Psychiatric

4.1.6.1 Paroxetine and chromosome disorder (76892)

Discussion

NZPhvC advised that the CARM database includes reports of congenital abnormality in association with paroxetine. The WHO database includes reports of chromosome disorder in association with paroxetine.

The literature includes no published evidence to support an association of paroxetine or SSRIs with Turner's syndrome.

The Committee noted that epidemiological studies have shown an increased risk of cardiac malformations and pulmonary hypertension, and information regarding these has recently been included in the datasheets for the SSRI's.

The causal association with paroxetine was considered 'unclassifed' for chromosome disorder.

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

4.1.7 Other Reports

The Committee noted the following case reports:

4.1.71 Lumiracoxib (76577)

4.1.7.2 Pyrantel (76993)

4.1.7.3 Fluoxetine, pethidine, azathioprine, calcium carbonate, mulitivitamin, paracetamol, omeprazole, enoxaparin, fentanyl/clonidine (77067)

4.1.7.4 Pioglitazone (77078)

4.1.7.5 Pioglitazone (77289)

4.1.7.6 Leflunomide (77261)

4.2 Quarterly Reports from CARM as at 31 December 2007

Discussion

NZPhvC presented the report. They noted that the brand switch reports continue for methylphenidate and paroxetine. NZPhvC advised that reports had been received following changes in the brand of acetylsalicylic acid. These describe rash/urticaria/coughing and rectal bleeding.

The Committee noted the quarterly reports from CARM as at 31 December 2007.

4.3 Emerging Safety Issues with varenicline - early IMMP report

Discussion

NZPhvC presented the report. They advised that varenicline was added to the Intensive Medicines Monitoring Programme (IMMP) in July 2007. Data entry has now been completed for the period from April to November 2007.

There have been safety concerns which have emerged during post-marketing use of varenicline internationally, largely psychiatric reactions.

NZPhvC advised that NZ reports are primarily gastrointestinal effects (such as nausea and vomiting), followed by psychiatric effects. There have been no reports of suicidal ideation, which has been reported in Australia. There have been deaths in New Zealand in patients taking varenicline, however, further investigation is required in order to determine any association. NZPhvC recommended that varenicline continue to be monitored in the IMMP and advised that the next step in the study is to send out follow-up questionnaires to prescribers for varenicline patients, in order to identify any further adverse effects.

Medsafe advised that the New Zealand datasheet for Champix has recently been updated to reflect the latest changes required by the EMEA, and a "Dear Health Professional" letter was sent to New Zealand prescribers.

4.4 Nocturnal enuresis with atypical antipsychotic medicines - IMMP study

Discussion

The Committee noted the report, and noted that it was to be submitted for publication.

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. international pharmacovigilance-related Activities

6.1 United Kingdom

7. Summary listings of case reports considered by the MARC (1997- 2007)

8. OTHER BUSINESS

8.1 Australia and New Zealand Therapeutics Products Authority (ANZTPA) update

The Committee was advised that due to the postponement of the establishment of the Australia and New Zealand Therapeutics Products Authority, there may be a possible restructuring of Ministerial Committees. The MARC will convene at a later date to discuss possible options for the future operation of the Committee.

There being no further business, the acting Chair thanked members and the secretariat for their attendance and closed the meeting at 3.30pm.

Associate Professor T.J.B Maling
Chair
Medicines Adverse Reactions Committee

Professor P Ellis
Acting Chair
Medicines Adverse Reactions Committee

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