Revised: 20 May 2013

Committees

Minutes of the 122nd Medicines Adverse Reactions Committee Meeting - 9 June 2005

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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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

1. Matters of Administration

1.1 Welcome and Apologies
1.1.1 MARC membership
1.2 Minutes of the 120^th MARC meeting
1.3 Minutes of the 121^st MARC meeting
1.3.1 Report to the Minister of Health
1.4 Dates of future MARC meetings
1.5 Potential conflicts of Interest

2. Actions Arising

2.1 Report on actions arising from the 121^st MARC meeting, March 2005
2.1.1 COX-2 inhibitors and cardiovascular safety.
2.1.2 Valdecoxib and cardiovascular safety.
2.1.3 Rofecoxib.
2.1.4 General recommendations regarding the cardiovascular safety of the COX-2 inhibitors - safety data.
2.1.5 General recommendations regarding the cardiovascular safety of the COX-2 inhibitors - IMMP studies.
2.1.6 General recommendations regarding the cardiovascular safety of the COX-2 inhibitors - perioperative use.
2.1.7 General recommendations regarding the cardiovascular safety of the COX-2 inhibitors - Direct-to-Consumer Advertising.
2.2 Report on actions arising from previous MARC meetings
2.2.1 Pharmacovigilance in New Zealand.
2.2.2 Atypical anti-psychotics and lipid abnormalities.
2.2.3 Tricyclic antidepressants in children and adolescents for treating major depressive disorder.
2.2.4 Atenolol in the treatment of hypertension (review of the literature).
2.2.5 Thioridazine and QT prolongation.
2.2.6 Pergolide and cardiac valvulopathy.
2.2.7 Domperidone and the risk of QT prolongation.
2.2.8 Review of the cardiovascular safety of the COX-2 inhibitors.
2.2.9 Alendronate and synovitis, carpal tunnel syndrome, ankle oedema and arthralgia (62186).
2.2.10 Adverse reactions to blood components 2003.
2.2.11 Low molecular weight heparins (LMWHs) in renal impairment.
2.2.12 Simvastatin, diltiazem and rhabdomyolysis.
2.2.13 COX-2 inhibitors.
2.2.14 Atypical antipsychotics and hyperglycaemia.

3. Pharmacovigilance Issues

3.1 Dextropropoxyphene/paracetamol combination products and the risk of overdose
3.2 The legacy of diethylstilboestrol (DES)
3.3 Valdecoxib and Serious Cutaneous Adverse Reactions (SCARs)
3.4 Atypical antipsychotics and increased mortality in elderly patients with dementia

4. Matters Arising From the New Zealand Pharmacovigilance Centre (NZPHVC)

4.1 Centre for Adverse Reactions Monitoring (CARM) case reports for the quarter to March 2005
4.1.1 Deaths
4.1.2 Alimentary
4.1.3 Alternative medications
4.1.4 Antiepileptics
4.1.5 Antithrombotics
4.1.6 Cardiovascular
4.1.7 Corticosteroids
4.1.8 Dermatological
4.1.9 Immunosuppressants
4.1.10 Psychiatric
4.1.11 Other reports
4.2 Centre for Adverse Reactions Monitoring (CARM) case reports for the quarter to June 2005
4.2.1 Deaths
4.2.2 Alternative Medicines
4.2.3 Anti-infectives
4.2.4 Cardiovascular
4.2.5 Contrast Media
4.2.6 Immunomodulators
4.2.7 Immunosuppressives
4.2.8 Musculoskeletal
4.2.9 Respiratory
4.2.10 Vaccines
4.2.11 Other reports
4.3 Pharmacovigilance issues arising from reports to CARM
4.3.1 Tramadol and Hepatic Disorders
4.3.2 Colchicine dosage
4.3.3 Salamol inhaler testing
4.4 Intensive Medicines Monitoring Programme (IMMP)
4.4.1 Summary of IMMP work on atypical antipsychotic medicines: Progress report to June 2005.
4.4.2 Analysis of IMMP events reported for risperidone
4.4.3 Deaths with atypical antipsychotics in elderly patients with dementia.
4.5 Intensive Vaccines Monitoring Programme (IVMP) - Meningococcal B vaccine
4.6 Adverse Reactions to Fractionated Blood Products
4.7 Quarterly reports from the Centre for Adverse Reactions Monitoring (CARM)

5 PHARMACOVIGILANCE issues for information only

5.1 Elidel (pimecrolimus)
5.2 Nitrous Oxide in Anaesthesia
5.3 COX-2 inhibitors and cardiovascular safety
5.4 SSRIs
5.5 HRT
5.6Atypical Antipsychotics and ischaemic stroke

6 New Zealand Pharmacovigilance-Related Activities

7 International Pharmacovigilance-Related Activities

7.1 Australia
7.2 Canada
7.3 Malaysia
7.4 Singapore
7.5 WHO

8 Summary of Case Reports Considered by MARC (1997 - 2004)

9 Other Business

9.1 Joint Trans-Tasman Therapeutic Products Agency (JTA)

MINUTES OF THE 122^ND MEDICINES ADVERSE REACTIONS COMMITTEE MEETING, 9 JUNE 2005.

The one hundred and twenty-second meeting of the Medicines Adverse Reactions Committee (MARC) was held on 9 June 2005 at the Sunderland room, Wellington Airport Conference Centre, Wellington, New Zealand. The meeting commenced at 0900 and closed at 1630.

marc members present

Associate Professor T.J.B Maling (Chair)
Professor P. Ellis
Dr H. Kingston
Dr M. Tatley
Dr F. McClure
Dr M. Rademaker
Dr S. Sime

marc secretariat present

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

invited experts

Dr R. Savage (New Zealand Pharmacovigilance Centre)
Mr D. Fitzgerald (Compliance Team Leader, Medsafe) attended by teleconference.

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed Dr Savage from the New Zealand Pharmacovigilance Centre.
Mr Fitzgerald was welcomed by teleconference for the discussion on Salamol inhaler testing.
Apologies had been received from Professor D. Skegg.

1.1.1 MARC membership

Discussion

Members discussed the need for consistent attendance from all members at MARC meetings to ensure that there is a quorum for decision-making. The Committee commented that it would be valuable to have two epidemiologists on the Committee in order to ensure that vital epidemiological skills are available at every meeting. The MARC recommended that Medsafe discuss the possible appointment of a second epidemiologist with Professor Skegg and ask if he could recommend a suitable candidate.

Members noted that there has been a delay in the establishment of the Joint Trans-Tasman Therapeutic Products Agency (JTA). In view of this delay, the Committee considered that it is important that these membership issues be addressed even though the JTA is soon to be established.

The Committee agreed that it is important that MARC members represent a variety of geographical areas from throughout New Zealand.

Recommendation

The Committee recommended that Medsafe should liaise with Prof Skegg regarding the need for the appointment of a second epidemiologist to the MARC.

The Committee recommended that Medsafe should investigate possible candidates for MARC membership, with expertise in pharmaco-epidemiology.

1.2 Minutes of the 120^th MARC meeting

The minutes of the 120^th MARC meeting were included for ratification due to other agenda items having higher priority at the 121^st MARC meeting.

Members discussed minute item 4.1.9.2, Rofecoxib and renal function abnormal, GI haemorrhage (62320). Members agreed that the minuted discussion on this item was too general and should read "The Committee commented that it was generally inappropriate to use any NSAID, including a COX-2 inhibitor, in a man of 80, in the peri-operative setting...". This change was made to the minutes, which were subsequently ratified by the Chair. The Secretary agreed to also make this change to the electronic minutes. The members agreed that the minutes of the 120^th MARC meeting are otherwise a true and accurate record of the meeting.

1.3 Minutes of the 121^st MARC meeting

The members agreed that the minutes of the 121^st MARC meeting are a true and accurate record of the meeting.

1.3.1 Report to the Minister of Health

Members noted that, regarding recommendations (c) and (d) re: Direct-to Consumer Advertising (DTCA), there is still a voluntary moratorium in place against DTCA for the COX-2 inhibitors, which the sponsors have agreed to maintain. There is no deadline for this voluntary moratorium. Medsafe has indicated to sponsors that, once the data sheets for the COX-2 inhibitors have been updated, consideration could be given to reinstating advertising to professionals. Members noted that the issue of DTCA is under review in the context of the establishment of the JTA. (See minute item 2.1.7 for further details).

1.4 Dates of future MARC meetings

The date for the next MARC meeting is Thursday 15 September 2005. This meeting is to be held at the Miramar Golf Club, due to lack of availability of the usual venue. The date for the subsequent MARC meeting will be Tuesday 29 November 2005.

1.5 Potential conflicts of Interest

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

The potential conflicts of interest were discussed and were not considered to influence the discussions or decisions of the Committee.

2. ACTIONS ARISING

2.1 Report on actions arising from the 121^st MARC meeting, March 2005

2.1.1 COX-2 inhibitors and cardiovascular safety.

March 2005 minute items 3.1.8.1, 2, 4, 5 and 6

Issue

The Committee recommended that the data sheet and consumer medicine information (CMI) for celecoxib, etoricoxib, parecoxib, lumiracoxib and meloxicam should be updated. (See the minutes of the 121^st MARC meeting for details).

Outcome

On 22 April 2005 the Director-General of Health informed each of the sponsors of the COX-2 inhibitors that, under Section 36(1) and (2) of the Medicines Act 1981, there is reason to believe that there are safety concerns with the COX-2 inhibitor medicines. These concerns relate primarily to the risk of cardiovascular adverse events.

In order to address these safety concerns, the Director-General required that detailed data sheet changes be made. In the interests of public safety, the Director-General required that this process be completed by 22 June 2005. If the sponsor wishes to provide justification as to why the sponsor believes the changes are not necessary, supporting evidence must be supplied to Medsafe as soon as possible to ensure that the data sheets are updated by 22 June 2005. If Medsafe is not satisfied with the evidence supplied, the issue will be referred to the MARC who may recommend that the sponsor be given notice that, under Section 36(3), either the supply of the product is prohibited (indefinitely or for a specified period) or conditions be imposed on the product.

It was additionally required of the product sponsors, pursuant to Section 36, to supply Medsafe with New Zealand usage data every six months.

Discussion

Members noted that three of the product sponsors have responded to Medsafe regarding the requested data sheet changes and have agreed to supply usage data to Medsafe every six months. Medsafe is awaiting a response from the fourth sponsor. Medsafe agreed to report back to the MARC at the September 2005 meeting on the progress that has been made regarding the requested data sheet changes.

2.1.2 Valdecoxib and cardiovascular safety.

March 2005 minute item 3.1.8.3

Issue

The Committee recommended that the data sheet and CMI for valdecoxib should be updated. (See the minutes of the 121^st MARC meeting for details).

Outcome

Subsequent to the MARC meeting, following a request from Medsafe on 8 April 2005, Pfizer voluntarily withdrew valdecoxib (Bextra) from the New Zealand market. This followed similar withdrawals in the US, Europe and Canada, due to increasing concerns about the risks of potentially life-threatening Serious Cutaneous Adverse Reactions (SCARs), as well as concerns regarding the cardiovascular safety of valdecoxib. The MARC recommendations with respect to valdecoxib were overtaken by events and, as a further safety review was required, Medsafe recommended that the Director-General of Health not accept the MARC recommendations for valdecoxib. Consequently, the MARC will be asked to undertake a further assessment of the risks associated with valdecoxib at the 122^nd MARC meeting on 9 June 2005.

Discussion

Members noted the above and agreed that this issue be discussed as agenda item 3.3. (See minute item 3.3 for discussion and recommendations on this issue.)

2.1.3 Rofecoxib.

March 2005 minute item 3.1.8.7

Issue

The Committee recommended that Medsafe should seek assurance from the sponsor of rofecoxib that if at any time the sponsor intends to re-introduce rofecoxib into the New Zealand market the MARC should be given the opportunity to review the available data and to make recommendations. If this does not occur, the MARC recommended that the approval of rofecoxib should be suspended, and the product only be allowed back on the market after it has satisfied both the MARC and the Medicines Assessment Advisory Committee (MAAC) of its cardiovascular safety.

Outcome

On 22 April 2005 the Director-General of Health contacted Merck Sharp & Dohme (MSD) requesting, under Section 36 of the Medicines Act 1981, that the above assurance be provided. MSD has responded that they agree to the requests as above.

Discussion

Members noted the above and agreed that no further action is required at this time.

2.1.4 General recommendations regarding the cardiovascular safety of the COX-2 inhibitors - safety data.

March 2005 minute item 3.1.8.8, dot point one.

Issue

The Committee recommended that, in order to improve risk-management decision-making in the future, the sponsors of all COX-2 inhibitors should be asked to supply Medsafe with further data on the gastrointestinal effects and cardiovascular risks of their products, as well as any adverse events that come to their attention, as a condition of continuing Ministerial consent for distribution.

Outcome

On 22 April 2005 the Director-General of Health contacted each of the sponsors of the COX-2 inhibitors informing them that, under Section 36 of the Medicines Act 1981, they are required to provide Medsafe with additional safety data, particularly on gastrointestinal effects (beneficial and harmful), cutaneous reactions and cardiovascular risks, as such data become available.

Discussion

Members noted that three of the product sponsors have responded agreeing with the request to supply further safety data to Medsafe as it becomes available. Medsafe is awaiting a response from the fourth sponsor.

2.1.5 General recommendations regarding the cardiovascular safety of the COX-2 inhibitors - IMMP studies.

March 2005 minute item 3.1.8.8, dot point three.

Issue

The Committee recommended that, as further studies into the cardiovascular adverse effects of COX-2 inhibitors would be of benefit, Medsafe should investigate if sponsors can be required to fund Intensive Medicines Monitoring Programme (IMMP) studies.

Outcome

Medsafe is in the process of investigating this issue.

Discussion

Medsafe's investigations have revealed that under current legislation there are no regulatory options for requiring product sponsors to fund or conduct post-marketing studies. The Committee considered it very important that the JTA legislation include provisions for post-marketing safety surveillance by the product sponsors and recommended that the proposed legislation should include this provision. Members noted that some sponsors are already funding large clinical trials.

Recommendation

The Committee recommended that the Joint Trans-Tasman Therapeutic Products Agency legislation should include provision that product sponsors be required to conduct post-marketing studies.

2.1.6 General recommendations regarding the cardiovascular safety of the COX-2 inhibitors - perioperative use.

March 2005 minute item 3.1.8.8, dot point four.

Issue

The Committee recommended that Medsafe should contact the New Zealand Society of Anaesthetists and the Royal Australasian College of Surgeons advising them that it is crucial that a full risk:benefit analysis is performed for all patients, and the patient fully informed before administering a COX-2 inhibitor in the peri-operative period.

Outcome

Medsafe has written to both the Australian and New Zealand College of Anaesthetists and the Royal Australasian College of Surgeons, to request that they disseminate to their members the MARC's advice on the peri-operative use of COX-2 inhibitors.

Discussion

Members discussed anecdotal reports that COX-2 inhibitors are not generally used peri-operatively in public hospitals. Members considered that the main use of these products peri-operatively may be in private practice.

Members agreed that no further action is required at this time.

2.1.7 General recommendations regarding the cardiovascular safety of the COX-2 inhibitors - Direct-to-Consumer Advertising.

March 2005 minute item 3.1.8.8, dot point five.

Issue

It is the MARCs opinion that, in order to decrease pressure on prescribers, and as the benefits of COX-2 inhibitor use outweigh the risks in only carefully selected patient groups, direct-to-consumer advertising (DTCA) of the COX-2 inhibitor class is not appropriate and therefore should cease if these products are to remain available in New Zealand.

Outcome

In consultation with Medsafe, the Director-General of Health did not accept the MARC's recommendation regarding DTCA, the justification being that:

• the Ministry of Health is reviewing DTCA as part of the programme for establishment of the JTA;
• the additional warnings on products and the release of advice to the public is sufficient to protect the public health in the interim;
• a voluntary moratorium on DTCA and advertising to health professionals for the COX-2 inhibitor class of medicines has been in place since requested by Medsafe in December 2004;
• the voluntary moratorium is more extensive than that requested by the MARC.

The Director-General of Health instead agreed that, in the first instance, the intent of the MARC could be bought into effect by asking the sponsors of the COX-2 inhibitors to continue their voluntary moratorium on DTCA and professional advertising, until further notice. This request was communicated to all COX-2 inhibitor product sponsors on 22 April 2005. (See the Health Report to the Minister's Delegate for the March 2005 meeting for more details)

Discussion

Please see minute item 1.3.1 for discussion on this issue.

2.2 Report on actions arising from previous MARC meetings

2.2.1 Pharmacovigilance in New Zealand.

December 2004 minute item 2.1.3; September 2004 minute item 2.1.19; June 2004 minute item 5

Issue

The Committee recommended that the working party minutes be made available to all Committee members.

Outcome

Members are asked to note that the working party minutes were forwarded to members in January 2005.

Discussion

Members noted the above and agreed that no further action is required at this time.

2.2.2 Atypical anti-psychotics and lipid abnormalities.

December 2004 minute item 2.1.4; September 2004 minute item 2.2.2; December 2003 minute item 3.1

Issue

The Committee did not agree that the evidence presented by Janssen-Cilag indicates that lipid abnormalities do not occur with risperidone. The Committee recommended that Medsafe investigate the options available under the Medicines Act 1981 for requiring Janssen-Cilag to update the risperidone data sheet.

Outcome

Medsafe is presently investigating the options available under the Medicines Act (1981).

Discussion

Members were informed that Medsafe has conducted a preliminary literature review of this topic but further research is required before proceeding on this issue. Members noted that although the US data sheet for risperidone indicates that hypertriglyceridaemia occurred rarely in the pre-marketing evaluation of risperidone, a statement that the adverse events reported are not necessarily related to risperidone use precedes this information. Members commented that although the US data sheets contain more information than the New Zealand data sheets, safety information is often very difficult to locate. Members noted that it is important that the New Zealand data sheets continue to provide adequate safety information whilst ensuring that the information is clear and succinct and therefore easy for prescribers to locate.

Members noted that the Australian data sheet for risperidone does not include lipid abnormalities as an adverse effect of risperidone use. In addition, the Therapeutic Goods Administration (TGA) in Australia is not planning any regulatory action on this issue. Members were also informed that a recent review of anti-psychotics, lipid abnormalities and hyperglycaemia had been published in the 'CNS Drugs' supplement. The details of this reference will be forwarded to Medsafe for review.

Recommendation

The Committee recommended that Medsafe should complete their review of lipid abnormalities associated with risperidone, including review of the CNS Drugs supplement outlined above, and report back to the Committee at the next meeting.

2.2.3 Tricyclic antidepressants in children and adolescents for treating major depressive disorder.

December 2004 minute item 2.1.5; September 2004 minute item 3.1

Issue

The Committee recommended that Medsafe contact New Zealand Doctor magazine to recommend that an article be written on the management of bedwetting in children.

Outcome

New Zealand Doctor magazine has agreed to write an article on bedwetting that incorporates the MARC advice that tricyclic antidepressants should not be used in this situation. The New Zealand Guidelines Group is in the process of developing guidelines for the management of nocturnal enuresis. They have been informed of the MARC's recommendations regarding the use of tricyclic antidepressants in children.

Discussion

Members noted the above and agreed that no further action is required at this time.

2.2.4 Atenolol in the treatment of hypertension (review of the literature).

December 2004 minute item 3.1

Issue

The Committee recommended that Medsafe liase with other international regulators on this issue. Members also recommended that an opinion be sought from the New Zealand Guidelines Group (NZGG) regarding advice to prescribers on the use of atenolol in blood pressure management.

Outcome

Medsafe has written to the NZGG on this issue and has received a response. The NZGG informed Medsafe that, based on current evidence, there is no need to update the guideline "The Assessment and Management of Cardiovascular Risk" (December, 2003). They concur with the MARC that further confirmation of the findings of the Carlberg et al (2004) meta-analysis is needed, and if the guideline advice were to be reviewed new evidence to support or refute the notion that atenolol is different from other beta-blockers for the primary prevention of myocardial infarction would need to be sought.

Discussion

Members noted that, at the December 2004 MARC meeting, it was considered that at present the data are insufficient to enable the Committee to offer definitive advice to prescribers on this issue. Members reiterated this opinion. Medsafe advised the Committee that no other international regulators have taken any action on this issue.

It was agreed that no further action is required at this time.

2.2.5 Thioridazine and QT prolongation.

December 2004 minute item 3.2; March 2001 minute item 12.1

Issue

The Committee recommended that, due to an unfavourable risk:benefit profile (in particular, the risk of QT prolongation), Medsafe should investigate the regulatory options for withdrawing the current approval of the only remaining available brand of thioridazine (i.e. Aldazine) and instead approve it under Section 23 of the Medicines Act (1981) as this would enable safety-related prescribing conditions to be imposed on the product.

The Committee recommended that Medsafe should reiterate the MARC's March 2001 advice in the next issue of Prescriber Update.

The Committee recommended that Medsafe should write to PHARMAC to request that the funding of thioridazine be restricted to Special Authority.

Outcome

Before commencing any regulatory action, Medsafe contacted Pacific Pharmaceuticals to ascertain whether the company intends to continue supplying Aldazine to the New Zealand market. The only other brand of thioridazine is Melleril, which has been discontinued worldwide as of June 2005.

Discussion

Medsafe advised the Committee that Pacific Pharmaceuticals has responded that they currently have a sole supply contract with PHARMAC to supply thioridazine tablets until September 2006. At this stage, it is their intention to supply until the end of this contractual period, and then discontinue the product. This decision may change depending on:

• If there is a significant decrease in the demand for the product following the proposed changes by Medsafe to limit prescribing.
• A marketing decision by Australia to discontinue the product (the product distributed in NZ has harmonised labelling with Australia).
• Continuity of supply of the active ingredient.
• Legislative changes related to the formation of the JTA.

Medsafe has replied to Pacific to advise that, because Aldazine will be discontinued in the near future, Medsafe does not believe it is necessary to impose further prescribing restrictions upon Aldazine to manage the risk of QT-prolongation. However, should the situation change (i.e. if Pacific decides to continue supplying Aldazine either beyond September 2006 or indefinitely), Pacific is asked to notify Medsafe immediately so that the safety issues of prescribing thioridazine can be re-assessed. With regard to the proposed September 2006 termination of Aldazine supply, Medsafe requested that Pacific provide prescribers with advance notice of this intention. This will enable prescribers to implement treatment changes for those patients using thioridazine. Medsafe recommended that Pacific contact all prescribers, as well as the Royal Australian and New Zealand College of Psychiatrists, at least six months prior to the market withdrawal of Aldazine. Medsafe asked to be kept informed of this process.

The June 2005 issue of Prescriber Update will include a reminder article about minimising the risk of QT-prolongation when treating with thioridazine.

The recommendation that Medsafe should write to PHARMAC to request that the funding of thioridazine be restricted to Special Authority has been superseded by the outcome of Medsafe's investigation of the regulatory options.

Members noted the above and agreed that no further action is required at this time.

2.2.6 Pergolide and cardiac valvulopathy.

December 2004 minute item 3.3

Issue

The Committee recommended that the product sponsor for pergolide be required to distribute the "Dear Doctor" letter as soon as possible, with particular emphasis on the new monitoring requirements that a baseline echocardiogram should be performed in all patients before initiating treatment with pergolide and that all patients should undergo a clinical cardiac review every 6 - 12 months after initiating treatment.

Members recommended that a Prescriber Update article should be written on pergolide and cardiac valvulopathy. The article should indicate that pergolide should not be used for the treatment of restless leg syndrome.

Medsafe should continue to monitor the literature on this issue and report back to the Committee if there are any new developments.

Outcome

A "Dear Doctor" letter regarding the risk of cardiac valvulopathy with pergolide use was distributed to New Zealand prescribers in January 2005. However, subsequent to this letter being distributed, the EMEA announced that the use of pergolide was to be restricted to "second line therapy in patients who are intolerant or fail treatment with a non-ergot compound". Following a request from Medsafe, the New Zealand data sheet for pergolide has been updated in line with the changes required by the EMEA.

Medsafe contacted PHARMAC in February 2005 to inform them that the MARC considers that cardiac valvulopathy is likely to be a class effect for all ergot-derivative dopamine agonists. PHARMAC was also informed that pergolide's use has been restricted to second line treatment in patients who have not responded to a non-ergot compound. PHARMAC was asked to consider this new safety information when the next review of the funding of a non-ergot derivative dopamine agonist in New Zealand is undertaken.

Discussion

Members noted that PHARMAC has yet to respond to Medsafe's letter. Members recommended that Medsafe write a further letter to PHARMAC requesting that the MARC be kept informed of any review of funding for a non-ergot derivative dopamine agonist.

Recommendation

The Committee recommended that Medsafe should write to PHARMAC again with a brief reminder of the previous request, and asking to be kept informed of any review of funding for a non-ergot derivative dopamine agonist.

2.2.7 Domperidone and the risk of QT prolongation.

December 2004 minute item 3.4

Issue

The Committee recommended that Medsafe write to the product sponsor of domperidone to request that the data sheet be updated to include the following statement: "Cases of QT prolongation, arrhythmia and sudden death have occurred with the intravenous form of domperidone. In most cases the serum domperidone concentration was well in excess of that achieved from maximal recommended oral dosing regimens. Domperidone should be used with caution in patients with risk factors for QT prolongation."

Members also recommended that the product sponsor be asked to supply Medsafe with evidence of the cardiovascular safety of domperidone when it is administered with other CYP3A4 inhibitors such as erythromycin. Alternatively the product sponsor should be asked to include the following statement included in the domperidone data sheet: "Domperidone should not be prescribed in combination with CYP3A4 inhibitors such as erythromycin"

Members also recommended that Medsafe write to the NZ College of Midwives to inform them of the MARC's recommendations.

The Committee recommended that a watching brief by maintained on domperidone and QT prolongation, arrhythmia or sudden death.

Outcome

Medsafe contacted Janssen-Cilag in January 2005 to inform them of the MARC's recommendations. Jansen-Cilag responded in May 2005 to inform the MARC that they did not consider that any data sheet changes were warranted with respect to a risk of QT prolongation with the use of oral domperidone. Janssen-Cilag stated that there was no evidence for an association between the use of oral domperidone and the development of QT prolongation. Janssen-Cilag also stated that post-marketing reviews do not suggest that there is a clinical risk associated with the concomitant use of domperidone and CYP3A4 inhibitors other than ketoconazole/itraconazole. However, Janssen-Cilag intends to conduct a clinical trial in healthy volunteers later this year, to investigate a possible interaction between domperidone and erythromycin. Janssen-Cilag asserts that no data sheet changes regarding the concomitant use of CYP3A4 inhibitors should be made prior to the completion of this study.

Medsafe has informed the New Zealand College of Midwives (NZCOM) of the MARC's advice. The NZCOM intends to disseminate this information to its members in its next national newsletter.

Discussion

Members reviewed a recently published population based case-control study that evaluated the risk of sudden cardiac death in patients taking non-cardiac QT prolonging medicines including domperidone¹. The authors reported that after adjustment for potential confounders there was a statistically significant odds ratio of 3.8 (95% CI 1.5-9.7) for the development of sudden cardiac death in users of domperidone compared to non-users.

Members expressed their extreme disappointment in Janssen-Cilag's response on this issue. The MARC considered it was inappropriate for the company to forward to Medsafe a response stating that there was no evidence of an association between oral domperidone use and the development of QT prolongation when the company was aware of the study published above.

The Committee recommended that Medsafe contact Janssen-Cilag again to request that the New Zealand data sheet for domperidone be updated to adequately inform prescribers of the risk of QT prolongation/sudden cardiac death in patients taking oral domperidone. However, the MARC is prepared to await the results of the clinical study on a domperidone/erythromycin interaction before making changes to the data sheet with respect to concomitant use of domperidone and CYP3A4 inhibitors other than ketoconazole/itraconazole.

Members were also informed that Janssen-Cilag has submitted an application to the Medicines Classification Committee (MCC) for domperidone to be reclassified to an over-the-counter (OTC) medicine. The MARC considers that it would be inappropriate to reclassify domperidone particularly as there are outstanding safety concerns, which the company seems to be unwilling to address. The MARC recommended that Medsafe contact the MCC to inform them that the MARC does not support the reclassification of oral domperidone to OTC status.

References: 1. Straus S et al. Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. European Heart Journal (2005) doi: 10.1093/eurheartj/ehi312

Recommendations

The Committee recommended that Medsafe should write to Janssen-Cilag again, to request that the New Zealand data sheet for domperidone be updated to adequately inform prescribers of the risk of QT prolongation and/or sudden cardiac death with oral domperidone.

The Committee also recommended that Medsafe should inform the Medicines Classification Committee that the MARC does not support the reclassification of oral domperidone to over-the-counter status.

2.2.8 Review of the cardiovascular safety of the COX-2 inhibitors.

December 2004 minute item 3.5

Issue

The Committee recommended that MARC advice and NICE guidance be disseminated to prescribers in the Prescriber Update article currently in progress. (Also see December 2004, minute item 1.5.2)

Members recommended that Medsafe should continue with the analysis of data submitted by the product sponsors of the COX-2 inhibitors available in New Zealand, and report back to the MARC when this is complete.

The MARC agreed that the NZPhvC should complete a preliminary analysis of the COX-2 inhibitor IMMP data (with an explanation of potential confounders). It was also agreed that no further follow-up data should be collected.

Outcome

A full assessment of the cardiovascular safety of the COX-2 inhibitors was conducted at the 121^st MARC meeting, 15 March 2005. See the minutes of that meeting for details.

Discussion

Members noted the above and agreed that no further action is required at this time.

2.2.9 Alendronate and synovitis, carpal tunnel syndrome, ankle oedema and arthralgia (62186).

December 2004 minute item 4.1.7.2

Issue

The Committee recommended that Medsafe review the literature to see if there is sufficient data to support publishing a Prescriber Update article on the pro-inflammatory adverse effects associated with alendronate use.

Outcome

Medsafe is in the process of reviewing the literature on this issue.

Discussion

Members noted the above and agreed that no additional action is required at this time.

2.2.10 Adverse reactions to blood components 2003.

December 2004 minute item 4.3

Issue

The Committee recommended that Medsafe write to the New Zealand Blood Service on the MARC's behalf to thank them for the report on adverse reactions to blood components 2003.

Outcome

Medsafe wrote to the New Zealand Blood Service in January 2005 to express the MARC's thanks for their report on Adverse Reactions to Blood Components. In May 2005 Medsafe received the 2004 report on Adverse Reactions to Fractionated Blood Products from the New Zealand Blood Service. A letter of thanks has been sent.

Discussion

Members noted the above and agreed that no further action is required at this time.

2.2.11 Low molecular weight heparins (LMWHs) in renal impairment.

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

The Committee agreed that Medsafe should write to the product sponsors of the low molecular weight heparins (LMWHs) requesting that the data sheets be amended to state that LMWHs should not be used in patients with a creatinine clearance <30ml/min unless anti-Xa monitoring is available.

The Committee also recommended that Medsafe should liase with the DHBNZ Safe Use of Medicines Group about developing a protocol for the safe use of LMWHs in patients with severe renal impairment. Medsafe should make the Safe Use of Medicines Group aware of any pertinent information from the recently published article on anti-Xa monitoring of enoxaparin.

Outcome

Medsafe has contacted the DHBNZ Safe Use of Medicines Group to suggest that they develop a protocol for the safe use of LMWHs in patients with severe renal impairment.

Medsafe has also contacted the product sponsors for the available LMWHs to recommend that data sheets be updated to state that unless evidence can be provided to the contrary: "LMWHs should not be used for more than 2 doses in patients with a creatinine clearance <30ml/min unless anti-Xa monitoring is available".

Pfizer (Fragmin) has responded that they are currently developing appropriate labelling for the use of Fragmin in renal impairment, which will be included in an application to Medsafe to revise the data sheet in due course.

CSL (Innohep) has responded that they will accept the text as above.

Aventis Pharma (Clexane) responded shortly before the MARC meeting that they believe that the current NZ data sheet, along with careful clinical monitoring, represent the most reliable method for the safe and effective use of enoxaparin sodium in this patient population.

Discussion

The Committee noted the responses from the sponsors of LMWHs as above. Members noted that the sponsors give contradictory opinions regarding the appropriateness of anti-Xa monitoring in this setting. It was noted that Pfizer asserts that anti-Xa levels may not correlate with haemorrhagic risk.

The members noted that the DHBNZ Safe Use of Medicines Group is currently developing a protocol for the safe use of LMWHs in patients with severe renal impairment, however it is unclear how the development of the protocol is progressing.

Recommendation

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.

2.2.12 Simvastatin, diltiazem and rhabdomyolysis.

September 2004 minute item 2.1.5; March 2004 minute item 2.2.5; September 2003 minute item 4.2.1

Issue

Members recommended that Medsafe write to MSD (the product sponsor for simvastatin), to indicate the MARC's disagreement with MSD's decision not to incorporate the MARC's recommendations into the simvastatin data sheet. Medsafe should repeat the request for inclusion of information on the simvastatin/diltiazem interaction in the simvastatin data sheet.

Another letter has been sent to MSD requesting that the following statement be added to the simvastatin (LIPEX) data sheet under the INTERACTIONS section for Diltiazem: "Treatment with simvastatin in a patient taking diltiazem should be started at the lowest possible dose and titrated upwards. If diltiazem treatment is to be added to patients already taking simvastatin, consider a reduction in statin dose and retitrate against serum cholesterol concentrations".

The New Zealand sponsors of diltiazem and verapamil products have all been requested to include a similar statement in their respective data sheets under the INTERACTIONS section for simvastatin.

Outcome

Medsafe has reviewed and accepted alternative wording proposed of similar intent by MSD for the simvastatin data sheet.

The data sheets for the following brands of diltiazem and verapamil have been updated as requested: Apo-Diltizem (Apotex NZ Ltd), Cardizem (Aventis Pharma), Dilcard (Pacific Pharmaceuticals Ltd), Dilzem (Douglas Pharmaceuticals), Isoptin (Abbott Laboratories (NZ) Ltd), Verpamil (Pacific Pharmaceuticals). Sanofi-Aventis has recently agreed to update the data sheet for Ziaxel (verapamil) as requested.

Medsafe has made a further request to the product sponsor for Diltahexal (diltiazem), as they have not yet updated their data sheet.

Discussion

Members noted the above and agreed that no further action is required at this time.

2.2.13 COX-2 inhibitors.

June 2004 minute item 2.2.10; September 2002 minute item 3.3.1

Issue

The Committee recommended that Pfizer amend or supply information supporting a statement that the risk of upper GI complications with celecoxib was "...approximately 8-fold less than with non-specific COX inhibitors". Pfizer declined this request to update the datasheet without adequate justification. A second letter was sent to Pfizer in July 2004 repeating this request.

Pfizer have responded again declining any changes to the datasheet, but this time have provided a published article that supports the above datasheet statement¹. The results of this study indicated an annual incidence of upper GI ulcer complications 8-fold higher for non-specific NSAIDs than for celecoxib (1.68% vs 0.20%; p=0.002).

The Committee recommended that Medsafe inform Pfizer that the MARC is prepared to accept the existing Celebrex data sheet statements in respect of upper gastrointestinal complications.

Reference

1. Goldstein et al. Reduced Risk of Upper Gastrointestinal Ulcer Complications With Celecoxib, A Novel COX-2 Inhibitor. The American Journal of Gastroenterology 2000; 95:1681-1690.

Outcome

Medsafe has informed Pfizer of the MARC's agreement to accept the existing Celebrex data sheet statements with respect to upper gastrointestinal complications.

Discussion

Members noted the above and agreed that no further action is required at this time.

2.2.14 Atypical antipsychotics and hyperglycaemia.

September 2004 minute item 2.1.13; June 2004 minute item 3.2

Issue

The Committee recommended that Medsafe write to the product sponsors of clozapine, olanzapine, risperidone and quetiapine requesting that the FDA warning statement relating to atypical antipsychotics and hyperglycaemia be included in the 'Warnings and Precautions' section of the New Zealand data sheets.

Outcome

Novartis (Clozaril), Douglas (Clopine), Eli Lilly (Zyprexa), Janssen-Cilag (Risperdal) and Astra Zeneca (Seroquel) have updated their data sheets as requested.

Discussion

Members noted the above and agreed that no further action is required at this time.

3. Pharmacovigilance Issues

3.1 Dextropropoxyphene/paracetamol combination products and the risk of overdose

References

Medsafe report: Dextropropoxyphene/paracetamol combination products. May 2005.

1. Report for CSM Subcommittee on Pharmacovigilance (2005). Risk:Benefit of Co-Proxamol products.
2. CSM. Co-Proxamol: Responses to request for evidence on risks and benefits.
3. Duff G (2005). "Dear Colleague" letter re: Withdrawal of co-proxamol products and interim updated prescribing information.
4. Press notice. MHRA withdraws the pain killer Co-proxamol. January 2005
5. Reith D, Fountain J, Tilyard M (2005). Opioid poisoning deaths in New Zealand (2001-2002). NZMJ 118(1209).
6. Submission from Healthcare Manufacturing Group and Apotex NZ Ltd. MARC Review of Dextropropoxyphene/paracetamol (Co-proxamol) Combination Products.
7. Submission from Sigma. Capadex (paracetamol and dextropropoxyphene). 11 March 2005.
8. Hawton K, Simkin S and Deeks J (2003). Co-proxamol and suicide: a story of national mortality statistics and local non-fatal self-poisonings. BMJ 326:1006-1008.
9. Prescrire Editorial Team (2004). Weak Opiate Analgesics. Prescrire International 13 (69): 22-25.
10. Jonasson B, Jonasson U, Saldeen T (2000). Middle-aged men - a risk category regarding fatal poisoning due to dextropropoxyphene and alcohol in combination. Preventive Medicine 31(2 Pt 1): 103-106.
11. Jonasson B, Jonasson U, Saldeen T (2000). Among fatal poisonings dextropropoxyphene predominates in younger people, antidepressants in the middle-aged and sedatives in the elderly. (Abstract only). J Forensic Sci 45(1): 7-10
12. Jonasson B, Jonasson U, Saldeen T (1999). Correlation between prescription of various dextropropoxyphene preparations and their involvement in fatal poisonings. (Abstract only). Forensic Sci Int 103(2): 125-32.
13. Jonasson B, Jonasson U, Saldeen T (1999). Suicides may be over-reported and accidents under-reported among fatalities due to dextropropoxyphene. (Abstract only). J Forensic Sci 44(2): 334-338.
14. Jonasson B, Jonasson U, Saldeen T (1998). The manner of death among fatalities where dextropropoxyphene caused or contributed to death. (Abstract only). Forensic Sci Int 96(2-3): 181-187.
15. Pharmaco (NZ) Ltd. Capadex data sheet (NZ) July 1999.
16. PSM Healthcare Ltd. Paradex data sheet (NZ) October 2002.
17. Apotex NZ Ltd. Apo-Paradex data sheet (NZ) June 1999.

Issue

In January 2005, the UK MHRA announced its decision to withdraw all dextropropoxyphene/paracetamol-containing products (Co-Proxamol is the main brand in the UK) from the UK over a period of 6-12 months. This decision was based on an assessment that the risk:benefit profile of these medicines is unfavourable due to inadequate evidence of efficacy and a significant risk of mortality from both intentional and accidental overdose.

In New Zealand, there are three dextropropoxyphene/paracetamol combination products available:

• Apo-paradex: 50mg Dextropropoxyphene napsylate + 325mg paracetamol
• Capadex: 32.5mg Dextropropoxyphene hydrochloride + 325mg paracetamol
• Paradex: 50mg Dextropropoxyphene napsylate + 325mg paracetamol

The New Zealand Poisons Centre recently performed an analysis of all opioid-related poisonings reported in New Zealand between 2001-2002. Dextropropoxyphene was assessed to be the primary cause of 8 overdose deaths and was implicated in another 8 overdose deaths. During that time period, dextropropoxyphene/paracetamol combination products accounted for almost 50% of all opioid prescriptions in New Zealand.

NEW ZEALAND DATA SHEETS:
Dosage:
Apo-Paradex: 2 tablets Q4H (maximum daily dose of dextropropoxyphene stated to be 600mg - equivalent to 12 tablets which would also provide 3.9g of paracetamol).
Capadex: 2 tablets QID (maximum daily dose of dextropropoxyphene stated to be 650mg - equivalent to 20 tablets which would also provide 6.5g of paracetamol).
Paradex: 2 tablets Q4H (maximum daily dose of dextropropoxyphene stated to be 600mg - equivalent to 12 tablets which would also provide 3.9g of paracetamol). However, the data sheet does not detail how much paracetamol or dextropropoxyphene is contained in each tablet.

Warnings/Precautions:
Although the data sheets differ in the detail provided on the risk of death with dextropropoxyphene, all data sheets advise the following:

• Do not prescribe dextropropoxyphene for patients who are suicidal or addiction-prone.
• Prescribe dextropropoxyphene with caution for patients taking tranquillisers or antidepressant medicines and patients who use alcohol in excess.
• Tell your patients not to exceed the recommended dose and to limit their intake of alcohol.
• In addition, the Capadex data sheet specifically contraindicates the use of alcohol.

INFORMATION FROM PRODUCT SPONSORS:
The sponsors for all dextropropoxyphene-containing medicines were asked to provide Medsafe with safety information and proposed risk-management plans for their products.

The sponsors of Paradex and Apo-Paradex accept that the risk:benefit equation for dextropropoxyphene/paracetamol combination products has become more negative but assert that these medicines still have a place in New Zealand for the treatment of pain. The sponsors have suggested the following plan to manage the risks associated with the use of their products:

1. Prescribers should be advised:
   • To restrict prescriptions to the smallest quantity necessary for the condition being treated.
   • To avoid prescribing to patients at risk of suicide or with a history of alcohol abuse.
   • To avoid prescribing to patients taking tranquillisers or antidepressant medicines.
   • To inform their patients of the risks of exceeding the maximum daily dose or taking Paradex or Apo-Paradex in combination with alcohol or tranquillisers.
2. The data sheets and consumer medicine information should be revised to include the following information:
   • Indications: restrict to the treatment of moderate to severe pain and/or restrict to chronic pain and/or restrict to second line therapy where first line analgesics have to proved to be ineffective or inappropriate
   • Dosage: Reduce maximum daily dose to 8 tablets
   • Strengthen the 'Warning and Precautions' section
3. Recommend to PHARMAC that dispensing of dextropropoxyphene-containing products be limited to 1 month at a time.

The sponsor for Capadex asserts that the risk of overdose in Australia and New Zealand may differ from that in the UK because pack sizes in Australia and New Zealand are smaller and the medicine can only be obtained through a prescription. The sponsor notes that Capadex has been contraindicated for use with alcohol since the 1990's in New Zealand but this has only recently occurred in the UK. The sponsor also asserts that Capadex offers advantages to patients who experience constipation with traditional opioid analgesics and therefore is still of significant value to New Zealand patients.

The MARC was asked to consider the following questions after reviewing the reference material provided by Medsafe:

1. Does the Committee consider the risk:benefit profile of dextropropoxyphene-containing products to be unfavourable in the New Zealand situation?
2. What risk-management plan does the Committee recommend to manage the risks associated with the use of dextropropoxyphene/paracetamol combination products?

Discussion

The Committee noted that the UK MHRA's decision to withdraw all dextropropoxyphene-containing products from the market was made only after alternative risk-management strategies had proven ineffective in reducing mortality from dextropropoxyphene-related overdoses. It was noted that no other international regulators have announced their intention to take similar action. Members commented that this brings up the issue of harmonisation between New Zealand and Australia in the run-up to the establishment of the JTA.

Members noted that there is currently no evidence that dextropropoxyphene/paracetamol combination products are more efficacious than paracetamol alone, particularly in the treatment of acute pain. Members commented that if dextropropoxyphene/paracetamol combination products were withdrawn, possible alternative analgesics could include codeine phosphate/paracetamol combination products.

Members discussed the evidence that dextropropoxyphene/paracetamol combination products are extremely toxic in overdose, and are more toxic than other weak opioids such as codeine. Members noted that death has occurred in patients taking as few as 15 tablets (2-3 tablets over the maximum daily dose), and that deterioration and death can occur very rapidly (in some cases within 15-30 minutes). It was noted that in some cases it would therefore be impossible to get medical attention in time to prevent death after an overdose. The Committee commented that although some overdoses with dextropropoxyphene/paracetamol combination products are intentional, accidental overdoses have occurred particularly when taken in combination with alcohol, which can potentiate the depressant effect of dextropropoxyphene.

Members noted that prescription medicine overdoses are responsible for a small proportion of completed suicides, but make up a much larger proportion of attempted suicides. This is likely to reflect the fact that medicines with a low level of toxicity are predominantly being used. Members commented that restricting supply of highly lethal medicines, such as barbiturates and tricyclic antidepressants, is likely to have limited deaths due to overdoses

The Committee noted that death can occur very quickly after an overdose of dextropropoxyphene. This may preclude effective medical intervention if help is sought after the overdose. They noted that dextropropoxyphene overdoses can cause severe cardiac arrhythmias in addition to the respiratory depression and coma that can occur with other opiates. Members noted that, as a result, it can very difficult to manage dextropropoxyphene overdoses and that, although naloxone is effective in reversing respiratory depression and coma, it does not reverse the cardiac adverse effects.

Members discussed that the available evidence that the risk of dose-related adverse effects is likely to be higher in patients taking dextropropoxyphene-containing products for the treatment of acute pain, rather than patients being treated for chronic pain who are likely to have developed some tolerance to dextropropoxyphene's effects. As there are limited treatment options available for the treatment of chronic pain any potential market withdrawal of the products would need to be undertaken over a significant period of time and carefully managed.

Members were concerned to note that the present Paradex, Apo-Paradex and Capadex data sheets contain some inconsistencies and that a maximum daily dose is not clearly stated. Furthermore, the data sheet for Paradex does not state the doses of active ingredients.

The Committee noted that, although usage data is not available for all products, the NZMJ study (Reith, 2005) indicates that prescriptions of dextropropoxyphene-containing products comprised 50% of all opioid prescriptions in 2002. Members noted that it is important to obtain further usage data in order to more clearly define the risk to the New Zealand population.

In response to the questions posed by Medsafe, the Committee considered that the presently available evidence suggests that dextropropoxyphene/paracetamol combination products have an unfavourable risk:benefit profile.

The Committee considered that the options to manage the risks associated with dextropropoxyphene/paracetamol combination products include removing the acute indications, limiting the funding to Special Authority, restricting supply to 30 days at a time, or withdrawal of Ministerial consent to market. However, the MARC considered it important that consultation with stakeholders occurs before any risk-management decisions are made. The Committee suggested that Medsafe seek submissions from The Royal New Zealand College of General Practitioners, The New Zealand Rheumatology Association, The New Zealand Pain Society, The Australian and New Zealand College of Anaesthetists, Arthritis New Zealand and Hospice New Zealand. The Committee will review these submissions before recommending the most appropriate risk-management plan.

Recommendations

The Committee recommended that the data sheets for Paradex, Capadex and Apo-paradex should be updated to remove inconsistencies between them and to state the dosages of active ingredients.

The Committee recommended that Medsafe should obtain usage data for dextropropoxyphene/paracetamol combination products.

The Committee recommended that Medsafe should investigate options for restricting the period for which dextropropoxyphene/paracetamol combination products can be dispensed to thirty days.

The Committee recommended that Medsafe should undertake a period of consultation with stakeholders and then report back to the MARC.

3.2 The legacy of diethylstilboestrol (DES)

Reference material

• Report for MARC. Diethylstilboestrol (DES) use in pregnancy in the 1940s to the 1960s. Prof. Charlotte Paul and Dr Mira Harrison-Woolrych. 13 May 2005.
• Paul C (2004). Personal correspondence to Medsafe re: the legacy of diethylstilboestrol from the 50s and 60s
• ADRAC Bulletin article. The Legacy of Diethylstilboestrol (DES) from the 1950s and 1960s. ADRAC Bulletin 23(3), June 2004
• Ministry of Health publication (1995). Information sheet on Stilboestrol use in pregnancy.
• Hatch E et al (1998). Cancer Risk in Women Exposed to Diethylstilboestrol In Utero. JAMA 280(7): 630-634
• Hanselaar A et al (1997). Clear Cell Adenocarcinoma of the Vagina and Cervix. An Update of the Central Netherlands Registry Showing Twin Age Incidence Peaks. Cancer 1997; 79:2229-2236.
• Klip H (2002). Hypospadias in sons of women exposed to diethylstilboestrol in utero: a cohort study. Lancet 359:1102-1107.
• Hernandez-Diaz S (2002). Commentary: Iatrogenic legacy from diethylstilboestrol exposure. Lancet 359:1081-1082.
• Kaufman R and Adam E (2002). Findings in Female Offspring of Women Exposed In Utero to Diethylstilboestrol. Obstetrics and Gynaecology 99:197-200.
• Verloop J, Rookus M and van Leeuen F (2000). Letter to the editor: Prevalence of Gynaecologic Cancer in Women Exposed to Diethylstilboestrol in Utero. New England Journal of Medicine 342 (24): 1838-1839.

Issue

A study published in the 1980s showed that approximately 1000 New Zealand women had received diethylstilboestrol (mainly to prevent miscarriage) in the 1940s, 1950s and 1960s. In 1989, the then Department of Health recommended that doctors should inform women whom they recalled prescribing stilboestrol to in pregnancy about the effects of exposure. In 1994/5 Jennie Connor and Charlotte Paul prepared an information sheet for exposed daughters, mothers and sons which was distributed by the Ministry of Health to all doctors. At that time the main recognised adverse effects were clear cell adenocarcinoma of the vagina, and histological and structural abnormalities of the genital tract, in exposed daughters. The former is rare but the latter is frequent and leads to high rates of pregnancy complications.

More information has become available in the last ten years (since 1994) including:

1. Timing of the risk of clear cell adenocarcinoma of the vagina in daughters:
   It is now clear that risk persists until at least 40-50 years of age and there is some evidence that there may be a second peak in incidence at 70-80 years of age;
2. Elevated risk of invasive cervical cancer:
   This has been observed despite increased surveillance of pre-cancerous abnormalities;
3. Possible third-generation effects have been reported.

Discussion

Members considered that the article 'The Legacy of Diethylstilboestrol (DES) from the 1950s and 1960s' (ADRAC Bulletin 23(3), June 2004) is a good summary of this issue. They noted that this had led to a number of enquiries from patients in New Zealand and that the Ministry of Health had last disseminated information on this issue in 1995.

Members noted the results of the Verloop et al study, showing a risk ratio of 5.4 (95% CI 2.8 - 9.5) for cervical carcinoma in intensively monitored DES daughters. Members discussed the evidence for adverse effects in the grandchildren of women who used DES in pregnancy, and concluded that third generational effects have not been clearly demonstrated. Members noted the evidence from the Klip et al study that there may be an increased risk of hypospadius in grandsons, however the numbers are very small. The concern for granddaughters remains based on animal studies, as the Kaufman et al study showed no increased risk. Members discussed the evidence from Hanselaar et al that there may be a twin peak of clear cell adenocarcinoma risk at 30-40 years of age and 70-80 years of age.

Members discussed whether the latest evidence warrants an update of the advice previously disseminated on this issue. Members considered that, as the last update was ten years ago, a Prescriber Update article is warranted.

Recommendation

The Committee recommended that a Prescriber Update article should be written updating prescribers about the current evidence and to remind them about monitoring recommendations.

3.3 Valdecoxib and Serious Cutaneous Adverse Reactions (SCARs)

Reference material

• Medsafe report: Bextra (valdecoxib), Dynastat (parecoxib) and serious cutaneous adverse reactions (SCARs). May 2005.
• Pfizer submission. Bextra/Valdyn (Valdecoxib): Analysis of Skin Reactions and Risk Management. 10 May 2005
• Pfizer submission. Dynastat (parecoxib): Skin reactions. November 2004.
• Report by R Savage. Extract from analysis of reports to Vigibase (WHO International Drug Monitoring Database) for COX-2 inhibitors compared with three standard NSAIDs, diclofenac, naproxen and ibuprofen. May 2005.

Issue

At the 121^st MARC meeting in March 2005 the Committee completed their review of the cardiovascular safety of the COX-2 inhibitor class of medicines. The MARC recommended that the data sheet and consumer medicine information (CMI) for all COX-2 inhibitors including valdecoxib should be updated in order to address the cardiovascular risks associated with their use, and hence to allow the medicines to remain available in New Zealand. However, prior to the recommendations regarding valdecoxib being accepted by the Director-General of Health, the FDA announced that they had asked Pfizer to voluntarily withdraw valdecoxib from the US market. This request was based on the FDAs assessment that the risk of Serious Cutaneous Adverse Reactions (SCARs) with valdecoxib, in addition to the cardiovascular risks identified with the whole COX-2 inhibitor class, rendered the risk:benefit ratio for valdecoxib unfavourable.

On 8 April 2005, Pfizer agreed to voluntarily withdraw valdecoxib from the New Zealand market pending a further safety review by Medsafe and the MARC. As a consequence of this withdrawal, the MARCs recommendations regarding the cardiovascular safety of valdecoxib were deferred pending completion of the review of SCARs and a final assessment of the overall risk:benefit ratio for valdecoxib. Consequently, the MARC was asked to undertake a further assessment of the risks of SCARs associated with valdecoxib at the 122^nd MARC meeting.

The New Zealand data sheet for valdecoxib was updated in December 2004 to include the following warning statements regarding the risk of SCARs:
PRECAUTIONS - SKIN EFFECTS:
Serious skin reactions, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported through postmarketing surveillance in patients receiving BEXTRA (see Adverse Reactions - Postmarketing Experience). Some of these reactions have resulted in death. Patients appear to be at highest risk for these events early in the course of therapy; the onset of the event occurring in the majority of cases within the first two weeks of treatment. Patients with a history of sulphonamide allergy may be at a greater risk for skin reactions, however, patients without a history of sulphonamide allergy may also be at risk. BEXTRA should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

ADVERSE REACTIONS: POST-MARKETING EXPERIENCE:
Skin and subcutaneous tissue disorders: erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis

The data sheet for parecoxib (the pro-drug of valdecoxib) includes the same information with a qualifying statement that SCARs have been reported with valdecoxib and cannot be ruled out for parecoxib.

VALDECOXIB SPONSOR INFORMATION:
Pfizer provided Medsafe with a copy of the report on the risk of SCARs associated with valdecoxib that was prepared for the EMEA. As of 31 March 2005, Pfizer had received 188 reports of SCARs associated with valdecoxib. Where duration of use was specified, 87% of cases occurred within the first month of treatment. An analysis of the WHO database by Pfizer indicated that SCARs are reported more commonly with valdecoxib than with any other COX-2 inhibitors but the rates are similar to other NSAIDs such as ibuprofen and piroxicam.

To manage the risk of SCARs, Pfizer proposes to add additional warning statements to the product information for valdecoxib as follows:

• Limit the indicated use of valdecoxib in OA and RA to patients who have failed to respond to or could not tolerate nonselective NSAIDs and other selective COX-2 inhibitors.
• Remove the indication for valdecoxib in primary dysmenorrhea.
• Mandate weekly visits for the first four weeks of each course of valdecoxib therapy.
• Data sheet and patient/physician education materials will stress the importance of immediate discontinuation of valdecoxib and notification to the treating physician at the first evidence of dermal and/or mucosal signs or symptoms, especially during the first month of therapy.

PARECOXIB SPONSOR INFORMATION:
There have been two post-marketing reports of "SCAR-like" events associated with parecoxib; there have not been any reports of Stevens-Johnson syndrome or toxic epidermal necrolysis reported with parecoxib.

Pfizer considers that, although the occurrence of SCARs with parecoxib is theoretically possible, this risk is likely to be substantially less than with valdecoxib because parecoxib is only available in a parenteral form and is only indicated for use in New Zealand as a single peri-operative dose; therefore patients receiving parecoxib are likely to be more closely monitored than patients receiving valdecoxib, and subsequently SCARs are likely to be detected earlier. If a case of SCARs occurs after discharge from hospital the patient should have already discontinued therapy with parecoxib "which is the first and most important step necessary to limit the severity of the episode".

NEW ZEALAND REPORTS:
There have been 2 reports of erythema multiforme and 1 report of Stevens-Johnson Syndrome associated with valdecoxib in New Zealand. There have been no reports of SCARs with parecoxib.

MEDSAFE SUMMARY AND QUESTIONS FOR THE MARC:
From the available evidence, it is clear that valdecoxib is more commonly associated with the development of serious skin reactions than the other COX-2 inhibitors, although the absolute risk of these events is very small. Serious skin reactions have very rarely been reported with the use of parecoxib.

1. Does the risk of serious skin reactions with valdecoxib alter its overall risk:benefit profile in comparison to other COX-2 inhibitors?
2. Does the MARC consider parecoxib to be associated with a similar risk of serious skin reactions as valdecoxib?
3. What does the MARC consider to be the most appropriate risk-management strategy for valdecoxib, taking into account the previously identified and discussed risk of cardiovascular adverse events?
4. Should the above (or any) risk-management strategy be applied to parecoxib?

Discussion

Members noted that valdecoxib was voluntarily withdrawn from the New Zealand market due to international safety concerns primarily related to the risk of Serious Cutaneous Adverse Reactions (SCARs) and cardiovascular adverse events.

Members discussed anecdotal reports that the use of parecoxib in the peri-operative setting has declined following the MARC's recommendations at the March 2005 meeting.

There was some discussion around the definition of SCARs and the difficulty of diagnosis. The acronym SCAR encompasses erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). There is a continuum between these three conditions, with erythema multiforme being at the lower end of morbidity and mortality (mortality approximately 1%), to the much more severe toxic epidermal necrolysis with a mortality of 35-45%. SCAR specifically excludes exfoliative dermatitis. Members commented that only about 50% of SCAR cases are seen in hospitals, and that SCARs are often misdiagnosed, even in hospitals.

Members noted that, worldwide, the incidence of SCARs ranges from 0.4 to 7.4 cases per million persons per year. Medicines most commonly implicated in case reports include sulfonamides, anticonvulsants and non-steroidal anti-inflammatory drugs (NSAIDs).

Members noted that risk factors for SCARs include both dosage and inherent patient factors. There appears to be an increased risk of SCARs with higher dosage, particularly with anti-epileptics such as lamotrigine. Early discontinuation of the offending medicine, particularly if it has a short half-life, may be associated with an improved prognosis. The majority of reactions occur early in the course of treatment. A member commented that it was his clinical experience that SCARs can be triggered by a single dose of a medicine.

Members noted the post-marketing reports of SCARs in the WHO database, expressed as a proportion of total reactions for each medicine, show that the proportion of SCAR reports for valdecoxib was higher than for other COX-2 inhibitors, but similar to piroxicam. Proportions for other non-selective NSAIDs were intermediate.

Members reviewed the points raised at the March 2005 MARC meeting that individual rheumatology patients respond differently to different anti-inflammatory agents, and that valdecoxib has potential benefit for some patients over other COX-2 inhibitors or non-selective NSAIDs. Members commented, however, that there are a variety of alternative treatment options available. Members considered that, should valdecoxib be returned to the NZ market, usage is likely to be low, due to the well-publicised adverse effects including cardiovascular and skin reactions.

Members indicated that a data-linkage study of NZ cases of SCARs with valdecoxib is unlikely to be helpful due to the problems with the diagnosis of SCARs, and the small numbers of events.

Members commented that although parecoxib, a pro-drug of valdecoxib, could theoretically be associated with an increased risk of SCARs, this risk is ameliorated by the fact that parecoxib is only indicated for a single dose. There is no current evidence of increased reporting of SCARs with parecoxib.

Members considered that the risk of SCARs with valdecoxib does not significantly alter its risk:benefit profile in comparison to other COX-2 inhibitors. However, in order to limit overall patient exposure and manage the cutaneous risks associated with valdecoxib, the Committee considered that Pfizer's proposed data sheet changes should be made, in addition to those cardiovascular risk-management changes recommended at the 121st MARC meeting.

Recommendations

The Committee recommended that the data sheet for valdecoxib should be updated to address its cardiovascular risks, as per the recommendations made at the 121^st MARC meeting in March 2005.

The Committee recommended that Medsafe should accept Pfizer's proposed data sheet changes for valdecoxib, in order to manage the risk of serious cutaneous adverse reactions, including:

• Limit the indicated use of valdecoxib in OA and RA to patients who have failed to respond to or could not tolerate non-selective NSAIDs and other selective COX-2 inhibitors.
• Remove the indication for valdecoxib in primary dysmenorrhea.
• Mandate weekly visits for the first four weeks of each course of valdecoxib therapy.
• Data sheet and patient/physician education materials will stress the importance of immediate discontinuation of valdecoxib and notification to the treating physician at the first evidence of dermal and/or mucosal signs or symptoms, especially during the first month of therapy.

3.4 Atypical antipsychotics and increased mortality in elderly patients with dementia

References

• Medsafe report: Atypical anti-psychotics and increased mortality in elderly patients with dementia. May 2005.
• M Harrison-Woolrych. Deaths with atypical antipsychotics in elderly patients with dementia: Briefing Report for MARC on recent FDA action.
• FDA Public Health Advisory. Deaths with Antipsychotics in Elderly Patients with Behavioural Disturbance. April 11 2005
• FDA Talk Paper. FDA Issues Public Health Advisory for Antipsychotic Drugs used for Treatment of Behavioral Disorders in Elderly Patients. 11 April 2005.
• Submission from Johnson and Johnson: Overview of mortality data for risperidone in elderly subjects with dementia supporting changes to the company core data sheet. 21 April 2005.
• Sink K, Holden K and Yaffe K. Pharmacological Treatment of Neuropsychiatric Symptoms of Dementia. A Review of the Evidence. JAMA 2005; 293:596-608.
• Gill S et al. Atypical antipsychotic drugs and risk of ischaemic stroke: population based retrospective cohort study. Accessed online 24 February 2005. BMJ, doi: 10.1136/bmj. 38330.470486.8F (published 24 January 2005)
• Johnson and Johnson. New Zealand Dear Health Professional letter for Risperdal.
• Johnson and Johnson. Hazard Ratios and Rate Ratios of Mortality with Risperidone in Elderly Patients with Dementia: Results of Seven Different Types of Analyses. 19 May 2005.

Issue

On 11 April 2005, the FDA released a Public Health Advisory informing US prescribers of an increased risk of mortality in elderly patients with dementia treated with atypical antipsychotic medicines. The FDA concluded that the increase in mortality was likely to be related to the pharmacologic effect of the atypical antipsychotics and not due to the individual chemical structures of the agents. As a consequence, the FDA intends to require a Black-Box warning in the data sheets of all atypical antipsychotics including those not specifically included in the FDA review. The FDA is also considering including this warning in the datasheets of all typical antipsychotics.

(NB: The FDA has not approved any atypical antipsychotics for use in the treatment of the behavioural or psychological symptoms of dementia. However, in New Zealand risperidone is indicated for this purpose.)

MANAGEMENT OF THE NEUROPSYCHIATRIC SYMPTOMS OF DEMENTIA:
A recently published review article evaluated the efficacy of typical and atypical antipsychotics, SSRI antidepressants, mood stabilisers (e.g. sodium valproate and carbamazepine), and cholinesterase inhibitors, in the treatment of the neuropsychiatric symptoms of dementia (Sink et al, JAMA, 2005). The authors concluded that although no medicine represents a "magic pill" for the treatment of these symptoms, there is clear evidence of efficacy for risperidone and olanzapine but not for quetiapine or the typical antipsychotics. In addition, the cholinesterase inhibitors showed statistically significant improvements in symptoms, although the clinical significance of this was unclear.

The authors recommend that management of all patients should begin with an evaluation of other causes of agitation (eg pain, infection etc), as well as initiation of non-pharmacologic treatments and caregiver education. If pharmacological therapy is required, the authors suggest using a cholinesterase inhibitor as first-line treatment (as they have less adverse effects compared to the atypical antipsychotics), with risperidone or olanzapine used as second-line treatment. The authors do not recommend using typical antipsychotics or benzodiazepines.

RISPERIDONE:
In New Zealand, risperidone is the only atypical antipsychotic approved for use in the treatment of the behavioural and psychological symptoms of dementia.

Janssen-Cilag, the product sponsor for risperidone, provided Medsafe with a review of mortality in the six placebo-controlled trials in dementia patients that were reviewed by the FDA. Janssen-Cilag calculated that the overall relative risk of mortality in patients taking risperidone was 1.14 (95% CI 0.67-1.92). The risk of death was higher in patients taking concomitant frusemide with a relative risk of 2.44 (95% CI 1.26-4.73). Janssen-Cilag concluded that there was a statistically and potentially clinically significant increased risk of mortality in patients with dementia treated with risperidone. However, Janssen-Cilag was unable to identify a pharmacologic or pathophysiologic basis for these findings.

The New Zealand risperidone data sheet has been updated to include this information.

OLANZAPINE:
Although olanzapine is not indicated for use in patients with dementia, the olanzapine data sheet includes extensive information on the increased risk of mortality observed in dementia patients.

QUETIAPINE:
The product sponsor for quetiapine has been asked to provide Medsafe with a review of mortality in placebo-controlled trials of dementia patients involving quetiapine. At present, the quetiapine data sheet does not include any information regarding an increased mortality in patients with dementia.

SUMMARY:
The MARC has previously considered the potential risks associated with the use of atypical antipsychotics in the treatment of the behavioural and psychological symptoms of dementia. At the September 2004 MARC meeting the issue of cerebrovascular adverse events associated with risperidone was discussed. After reviewing the available evidence the Committee supported the continued availability of risperidone for use in patients with dementia.

Medsafe considers that the current New Zealand data sheets for risperidone and olanzapine adequately inform prescribers of the mortality risk associated with the use of atypical antipsychotics in elderly patients with dementia. However, the quetiapine data sheet is presently inadequate.

Discussion

Members reviewed the FDA and the sponsor documents regarding the evidence for increased mortality in elderly patients with dementia-related psychosis.

Members noted that there is convincing evidence of efficacy for risperidone in dementia-related psychosis (Sink et al, 2005), and possibly for olanzapine, although the data are unclear for other atypical anti-psychotics. Members noted that efficacious treatment options for patients with neuropsychiatric symptoms of dementia are limited, and that in New Zealand risperidone is the only approved atypical antipsychotic medicine for use in this group of patients.

Members noted that Medsafe has received anecdotal reports that, in response to warnings about the risk of cerebrovascular adverse events associated with risperidone and olanzapine, quetiapine is increasingly being used as an alternative to treat the behavioural symptoms of dementia.

Members noted that there is evidence for an increased risk of death for risperidone, and that this risk is likely to be a class effect. Members noted that a multi-centre randomised controlled trial funded by the US National Institute of Mental Health, comparing risperidone, olanzapine, quetiapine, citalopram and placebo for up to 36 weeks for the treatment of psychosis and agitation in Alzheimer's disease, is due to be completed next year.

Members noted that in New Zealand Janssen-Cilag has sent a 'Dear Health Professional' letter to psycho-geriatricians, geriatricians and mental health pharmacists updating them on the risks associated with the use of risperidone in this setting.

Members considered that the current New Zealand data sheets for risperidone and olanzapine adequately inform prescribers of the increased risk of death associated with the use of atypical antipsychotics in elderly patients with dementia. However, they considered that the quetiapine data sheet does not address this risk and should therefore be updated.

Recommendations

The Committee recommended that the product sponsor for quetiapine should be required to update the New Zealand data sheet to include information on the increased risk of mortality associated with use of their product in elderly patients with dementia.

The Committee recommended that the NZPhvC should maintain a watching brief on risperidone and mortality in elderly patients (particularly those with dementia).

4. matters arising from the new zealand pharmacovigilance centre (NZpHVc)

Note: In the comment associated with each report, the case has been given a causality designation using terms and definitions developed by the WHO. The precise definitions are available on the website of the WHO Collaborating Centre http://www.who-umc.org. These designations (certain, probable, possible, unlikely, unclassified and unclassifiable) refer to the degree of certainty about the relationship between the medicine and the adverse event. The terms should not be understood literally. For example, "certain" means that the appropriate elements are present to match the international definition. It does not mean there is absolute certainty that the medicine caused the adverse event.

Explanations of the terms used by CARM and MARC can be accessed by hyperlink at each causality designation.

4.1 Centre for Adverse Reactions Monitoring (CARM) case reports for the quarter to March 2005

Please note that the CARM case reports for the quarter to March 2005 were not presented at the March 2005 MARC meeting due to other agenda items having higher priority.

4.1.1 Deaths

4.1.1.1 Cabergoline and antepartum haemorrhage, multiple malformations, respiratory disorder neonate (63154)

Discussion

Members noted that this case is of a woman taking cabergoline who became unintentionally pregnant, and that the outcome of the pregnancy was multiple foetal abnormalities and foetal death. The literature does not indicate an increase in incidence of such problems in those taking cabergoline over that in the general population. Cabergoline is classed as FDA category B (animal studies show no increased risk, but absence of adequately well controlled human studies). The NZ data sheet states that this product should be avoided in pregnancy. There are no foetal abnormality or pregnancy-related reports in the CARM database, and 43 in the WHO database.

Members commented that cabergoline is an ergot alkaloid, some of which are known to be teratogenic. Therefore, members considered that it may be valuable to investigate patterns of foetal abnormalities with other ergot derivatives. Members queried whether this particular combination of foetal abnormalities represents a known syndrome.

The causal association for cabergoline was deemed to be 'unlikely' for antepartum haemorrhage, malformations multiple and respiratory disorder - neonatal.

Recommendations

The Committee recommended that the NZPhvC should investigate patterns of foetal abnormalities with other ergot derivatives such as bromocriptine, ergotamine, lisuride, pergolide, and ropinirole, and report back to the MARC.

The Committee recommended that the NZPhvC should investigate whether the pattern of abnormalities that occurred in this neonate represents a known syndrome and report back to the MARC.

4.1.1.2 Streptokinase, anticoagulants, acetylsallicyclic acid, clopidogrel and haematoma, anaemia, cardiac arrest, myocardial infarction (62444)

References

• Cover note for MARC. R Savage. May 2005.
• Aventis Pharmaceuticals Inc. Amended Study Protocol 2 - EXTRACT - TIMI 25. 26 August 2004. CONFIDENTIAL.
• Interactive Q & A's with Dr Elliot Antman. October 5&6 2002.

Discussion

The Committee noted that there were two adverse reaction reports in the quarter to March 2005 for multiple anticoagulants and haemorrhage (also see minute item 4.1.5.1). Members noted that this case (62444) was in the context of a blinded, multinational, clinical trial. Members noted that clinical trials have internal safety monitoring in place, and are required to report serious adverse reactions that result in the study code being unblinded to the Standing Committee on Therapeutic Trials (SCOTT) in NZ. As a general rule, adverse reactions occurring in clinical trials are not reported to CARM, as they are managed by the trial Data Safety Monitoring Committee and are then published separately, after the study code is broken at the end of the trial, in the study report.

Members discussed the CARM report for the MARC. The CARM database shows disproportionately more reports of haemorrhage with the streptokinase, aspirin and unfractionated heparin combination than with streptokinase and aspirin without heparin. Members noted expert advice from a cardiologist that the protocol for this trial reflects standard clinical practice.

Members noted that the literature states that streptokinase is beneficial as a thrombolytic in myocardial infarction with ST elevation and that the risk of haemorrhage with streptokinase may be increased by co-administration of oral anticoagulants, heparin and/or antiplatelet drugs. Interactions with streptokinase are not well studied.

The Committee reviewed the relevant sections of the clinical trial protocol. Members commented that the protocol regarding the use of glycoprotein IIb/IIIa antagonists is not clear. Members noted that the use of clopidogrel is not addressed in the study protocol.

Members considered that, in this case, the underlying medical condition was probably the cause of death. The causal association for streptokinase, anticoagulants unclassified, acetylsalicylic acid and clopidogrel was deemed to be 'possible' for haematoma and anaemia, and 'unlikely' for cardiac arrest and myocardial infarction.

Recommendation

The Committee recommended that Medsafe should report back to the MARC on how adverse reaction reports are managed in the context of clinical trials.

4.1.1.3 Thalidomide and myelomatosis multiple, spinal cord compression (62790)

Discussion

Members noted that there have been 17 reports made to CARM considered at least possibly related to thalidomide, with 38 reactions. Members considered that these adverse reactions are consistent with the known adverse reaction profile for thalidomide.

The causal association for thalidomide was deemed to be 'unlikely' for myelomatosis multiple and spinal cord compression.

Recommendation

The Committee recommended that, as with other medicines, the NZPhvC should only bring reports of unexpected or serious reactions to thalidomide (including those suspected of causing death, admission to hospital, prolongation of hospitalisation or birth defects) to the attention of the MARC in the future.

4.1.2 Alimentary

4.1.2.1 Rosiglitazone and High Density Lipoprotein decrease (62760)

Discussion

Members noted that the datasheet for rosiglitazone states that hypercholesterolaemia is common. In this case there was a seemingly paradoxical decrease in HDLc. It was noted that this case report suggests that the mechanism may be similar to that involved with the adverse reaction of lowered HDLc with fibrates, as the patient had a similar adverse reaction to both medicines. The literature showed only one case of HDLc lowering with rosiglitazone alone. There is a small amount of evidence that this may be class effect of the glitazones.

Members noted that Dr Savage has authored an article on this topic based on the NZ, WHO and literature reports, which is to be published shortly in Signal.

The causal association for rosiglitazone was deemed to be 'probable' for high-density lipoprotein decrease.

Recommendation

The Committee recommended that the NZPhvC should keep a watching brief for rosiglitazone with regards to lowered high-density lipoprotein cholesterol and hypertriglyceridaemia.

4.1.3 Alternative medications

4.1.3.1 Euphoria, Voyager and haematemesis, abdominal pain, melaena (63265)

Discussion

Members noted that there are no reports in the CARM database for these specific products. There are reports for other "herbal party pills" which are cardiovascular and neurological in nature, but not gastrointestinal or haematological. Members noted that CARM was unable to determine the exact composition of these products.Members commented that there is very little known about the toxicology of these and related products, but that they are very commonly used.

The causal association for Euphoria and Voyager was deemed to be 'possible' for haematemesis, abdominal pain and melaena. No further action was recommended at this time.

4.1.4 Antiepileptics

4.1.4.1 Sodium valproate and pancreatitis (63175)

Discussion

Members noted that there are five reports in the CARM database of pancreatitis with sodium valproate, one other in a 10 year old, and 738 in the WHO database. Members noted that pancreatitis is a well documented, rare, life-threatening toxicity associated with valproic acid. The data sheet contains warnings of this adverse reaction.

Members considered that, although pancreatitis is a rare adverse effect, it would be of value to remind prescribers which medicines can cause it, through Prescriber Update.

The causal association for sodium valproate was deemed to be 'probable' for pancreatitis.

Recommendation

The Committee recommended that a brief Prescriber Update article should be written to highlight medicines that commonly cause pancreatitis.

4.1.5 Antithrombotics

4.1.5.1 Clopidogrel, enoxaparin, aspirin and haemorrhage intracranial (62982)

Discussion

Members noted the details of this case and no further action was recommended at this time. The causal association for clopidogrel, enoxaparin and aspirin was deemed to be 'probable' for haemorrhage intracranial.

4.1.6 Cardiovascular

4.1.6.1 Simvastatin and memory impairment (62686)

Discussion

Members noted that there are four reports of amnesia or memory impairment in the CARM database and 166 reports of amnesia in the WHO database for simvastatin. A literature search has revealed 60 cases in which statins were associated with short-term memory loss.

Members considered that the evidence for this adverse reaction is building, and noted that CARM is continuing to research this topic.

The causal association for simvastatin was deemed to be 'probable' for memory impairment. No further action was recommended at this time.

4.1.7 Corticosteroids

4.1.7.1 Mometasone and rosacea (62554)

Discussion

Members noted that there are 12 reports in the CARM database of telangiectasis, rosacea, skin atrophy or skin striae involving the face for mometasone, including three reports from this quarter (see minute items 4.1.7.2 and 3). These adverse reactions are well documented in the literature.

Members noted that the NZ data sheet was updated in 2001 to reflect the risks of using mometasone on the face, although a Prescriber Update article was not written at that time. Members discussed anecdotal reports that patients are prescribed mometasone for use on the body, but later use it on the face.

Members considered that it would be of value to remind prescribers about the risks of corticosteriod use on the face, through Prescriber Update.

The causal association for mometasone was deemed to be 'probable' for rosacea.

Recommendation

The Committee recommended that a brief Prescriber Update article should be written to remind prescribers about the risks associated with the use of corticosteroids on the face.

4.1.7.2 Mometasone and rosacea, telangiectasis, skin atrophy (62572)

Discussion

Please see minute item 4.1.7.1 for discussion and recommendations on this issue. The causal association for mometasone was deemed to be 'probable' for telangiectasis, erythema and skin atrophy.

4.1.7.3 Mometasone and telangiectasis, erythema, skin atrophy (62782)

Discussion

Please see minute item 4.1.7.1 for discussion and recommendations on this issue. The causal association for mometasone was deemed to be 'probable' for rosacea, telangiectasis and skin atrophy.

4.1.8 Dermatological

4.1.8.1 Isotretinoin and depression, suicidal tendency, behavioural change (63380)

Discussion

Members noted that there are 21 reports of depression, 8 of suicidality and one of personality disorder for isotretinoin in the CARM database. Members noted that the NZ data sheet addresses these adverse reactions in the 'Precautions' section. Regarding the case of personality disorder, members commented that a drug might cause a change in personality but not be a cause of personality disorder.

The causal association for isotretinoin was deemed to be 'possible' for depression, suicidal tendency and behavioural change. No further action was recommended at this time.

4.1.9 Immunosuppressants

4.1.9.1 Leflunomide and neutropenia, dyspnoea, fever, LFTs raised (63417)

Discussion

Members noted that all adverse reactions to leflunomide are 'Adverse Reactions of Current Concern'. They noted that data on CARM reports of abnormal hepatic function, neutoropenia and pneumonitis have been presented at previous MARC meetings.

The causal association for leflunomide was deemed to be 'possible' for neutropenia, dyspnoea, fever and LFTs raised. No further action was recommended at this time.

4.1.10 Psychiatric

4.1.10.1 Phenytoin, fluorouracil and ataxia, dizziness, drug level increased (62606)

Discussion

Members noted that there is a well-documented interaction between phenytoin and 5-fluorouracil resulting in a rise in phenytoin levels in patients who had previously been stable. There are two reports from CARM this quarter of this interaction (see minute item 4.1.10.2). Members noted that there are a total of four case reports in the literature of this interaction, and three reports of an interaction between capecitabine (an oral pro-drug of 5-fluorouracil) and phenytoin, the outcome in each case being elevated phenytoin levels and toxicity.

Members noted that the data sheet for 5-fluorouracil makes no mention of this interaction. The data sheet for phenytoin lists 'antineoplastic agents' under 'drugs that may increase plasma phenytoin levels' in the 'Interactions' section. The data sheet for capecitabine addresses this interaction fully.

Members considered that there is sufficient evidence to recommend that the data sheet for 5-fluorouracil be updated.

The causal association for phenytoin and fluorouracil was deemed to be 'possible' for drug interaction, ataxia, dizziness and drug level increased.

Recommendation

The Committee recommended that the data sheet for 5-fluorouracil should be updated to address the interaction with phenytoin.

4.1.10.2 Phenytoin, fluorouracil and drug level increased, dysarthria, nystagmus and ataxia (62607)

Discussion

Please see minute item 4.1.10.1 for discussion and recommendations on this interaction. The causal association for phenytoin and fluorouracil was deemed to be 'probable' for drug level increased, dysarthria, nystagmus, ataxia and drug interaction.

4.1.11 Other reports

4.1.11.1 Neonutrients Body Enhancer (62565)
4.1.11.2 Natures Own Fat Fighter (62610)
4.1.11.3 Spot Check (63301)
4.1.11.4 Pimecrolimus (62635)
4.1.11.5 Paroxetine (63429)

The Committee noted the above reports and agreed that no further action is required at this time.

4.2 Centre for Adverse Reactions Monitoring (CARM) case reports for the quarter to June 2005

4.2.1 Deaths

4.2.1.1 Flucloxacillin and renal failure acute, rash maculopapular, pruritus (63623)

Discussion

Members commented that they cannot be sure that the renal failure was caused by the flucloxacillin, and that if so, the concomitant diuretics and captopril would have exacerbated the situation. Members considered that there could be a number of causes of renal failure in this patient, and therefore it would be of value for CARM to review the post-mortem report.

The causal association for flucloxacillin was deemed to be 'possible' for renal failure-acute, rash-maculopapular and pruritis.

Recommendation

The Committee recommended that CARM should review the post-mortem report for this case and report back to MARC.

4.2.1.2 Capecitabine and diarrhoea, intestinal perforation, pancytopaenia, stomatitis (63868)

Discussion

Members noted that this patient died while taking capecitabine as part of a clinical trial, and as such the trial Data Safety Monitoring Committee (DSMC) have assessed this report. The DSMC made the following recommendations to investigators:

• Recommend a general staff in-service reminder of the perils and management of this problem.
• Recommend emphasis on patient education with respect to possible toxicities and early reporting.
• There is a potential role for patient selection and dihydropyrimidine dehydrogenase testing, however it is not routinely performed in New Zealand for patients on 5-flurouracil and its pro-drug capecitabine.

The recommendations above were sent to the Standing Committee on Therapeutic Trials (SCOTT), through Medsafe, for comment. The SCOTT considered the recommendations to be appropriate.

Members noted that QTc prolongation due to hypokalaemia and domperidone could be an alternative cause of death in this case, however, the most likely cause is intestinal perforation.

The causal association for capecitabine was deemed to be 'probable' for diarrhoea, intestinal perforation, pancytopaenia, stomatitis and death. No further action was recommended at this time.

4.2.1.3 Interferon alpha and suicide, anxiety, concentration impaired, diarrhoea, rash pruritic (64261)

Discussion

Members noted that this case is one of two reports related to suicide/suicide attempt with interferon alpha this quarter (see minute item 4.2.6.1). In this case, members considered that the prescriber was mindful of this possible adverse reaction.

Members noted that depression and suicide are well-known adverse reactions to interferon alpha that are documented in the literature and in the product data sheet. Members noted that there have been 9 previous 'psychiatric' reports to CARM, and 45 fatal suicides in the WHO database.

The causal association for interferon alpha was deemed to be 'possible' for suicide, anxiety, concentration impaired, diarrhoea and rash pruritic. No further action was recommended at this time.

4.2.1.4 Citalopram, dihydrocodeine interaction and cardiac arrest, respiratory arrest, suicide, stupor (63701)

Discussion

Members noted that the ESR toxicology analysis concluded that the level of citalopram in the blood was consistent with a fatal citalopram overdose "however the central nervous system depressive effects of the citalopram would have been further enhanced by the dihydrocodeine that was probably present." Members noted that dihydrocodeine is a slow-release formulation with similar analgesic effects to codeine.

Members considered that it is not possible to determine if this is an adverse reaction, as there is no description of the patient's behaviour after starting citalopram or any evidence that it was taken in therapeutic doses.

The causal association for citalopram and dihydrocodeine was deemed to be 'unclassifiable' for cardiac arrest, respiratory arrest, drug interaction, suicide and stupor. No further action was recommended at this time.

4.2.1.5 Haloperidol and neuroleptic malignant syndrome (63848)

Discussion

Members noted that this adverse reaction is well documented in the literature and the product data sheet. It was noted that in this case the patient was taking variable doses of haloperidol, and that NMS developed slowly. In addition, citalopram and/or fluoxetine may have interacted with haloperidol to increase the risk of NMS.

The causal association for haloperidol was deemed to be 'probable' for neuroleptic malignant syndrome. No further action was recommended at this time.

4.2.1.6 MeNZB and demyelination (64359)

Discussion

Members noted that this is the first of two reports of death in patients who had received the MeNZB vaccine in this quarter (see minute item 4.2.1.7).

Members reviewed the details of this case. It was noted that both the MeNZB Clinical Review Committee and the Independent Safety Monitoring Board (ISMB) extensively reviewed this case and determined that this event is unrelated to the MeNZB vaccine.

The causal association for MeNZB vaccine was deemed to be 'unlikely' for demyelination. No further action was recommended at this time.

See minute item 4.5 for general discussion on adverse reactions to the MeNZB vaccine to date.

4.2.1.7 MeNZB and pneumonia (64403)

Discussion

Members noted that this is the second of two reports of death in patients who had received the MeNZB vaccine in this quarter (see minute item 4.2.1.6).

Members noted that this patient had a long-standing medical condition, and died within four days of MeNZB vaccination. They noted that the post-mortem findings supported the pneumonic process. It was noted that both the MeNZB Clinical Review Committee and the ISMB extensively reviewed this case and determined that this event is unrelated to the MeNZB vaccine.

The causal association for MeNZB vaccine was deemed to be 'unlikely' for pneumonia. No further action was recommended at this time.

See minute item 4.5 for general discussion on adverse reactions to the MeNZB vaccine to date.

4.2.2 Alternative Medicines

4.2.2.1 Adulterated medication, Multistress vitamins and Cushings syndrome, adrenal suppression (64520)

Discussion

Members commented that this case is of a complex clinical situation. The circumstances of this history and the reason for discovery are unclear.

The causal association for adulterated medication-?Multistress vitamins was deemed to be 'unclassifiable' for Cushings syndrome and adrenal suppression. No further action was recommended at this time.

4.2.3 Anti-infectives

4.2.3.1 Doxycycline and foetal abnormality, pregnancy exposure (64189)

Discussion

Members noted that the data sheet for doxycycline states that "animal studies indicate that tetracyclines cross the placenta, are found in foetal tissues and have toxic effects on the developing foetus manifested by retardation of skeletal development", which is inconsistent with axial mesodermal dysplasia spectrum displayed in this case.

Members noted that there have been three reports in the WHO database of 'malformations multiple' and four reports of 'malformation hand'.

The causal association for doxycycline was deemed to be 'possible' for foetal abnormality and pregnancy exposure. No further action was recommended at this time.

4.2.3.2 Miconazole, warfarin interaction and haematuria, prothrombin increased (63753)

Discussion

Members noted that a Prescriber Update article was written on the interaction between miconazole and warfarin in 2003, and that there have been three reports to CARM since that time (see minute item 4.2.3.3).

Members noted that miconazole oral gel is classified as a restricted medicine (e.g. must be dispensed by a pharmacist), and that the creams and lotions are pharmacy only. Members expressed concern that, as it is a topical agent available in pharmacies, patients do not appreciate the risks associated with this product.

Members considered that it would be valuable to remind prescribers and dispensers of this interaction through a brief Prescriber Update article, and by contacting stakeholders such as dentists, the Pharmaceutical Society and the DHBNZ Safe Use of Medicines Group.

The causal association for miconazole and warfarin was deemed to be 'probable' for haematuria, prothrombin increased and drug interaction.

Recommendations

The Committee recommended that there should be a short article published in Prescriber Update reminding prescribers of the interaction between miconazole and warfarin.

The Committee recommended that Medsafe should write to the DHBNZ Safe Use of Medicines Group, the New Zealand Dental Association and the Pharmaceutical Society of New Zealand asking them to remind members of the interaction between miconazole and warfarin.

4.2.3.3 Miconazole, warfarin, diclofenac interaction and INR increased, haemorrhage subarachnoid (63181)

Discussion

Please see minute item 4.2.3.2 for discussion and recommendations on this issue.

The causal association for miconazole, warfarin and diclofenac was deemed to be 'possible' for INR increased, haemorrhage subarachnoid and drug interaction.

4.2.4 Cardiovascular

4.2.4.1 Quinapril and diarrhoea, vomiting, dehydration, delirium, oedema intestinal (64548)

Discussion

Members noted that intestinal angioedema is a recognised adverse reaction to ACE-inhibitors, and is well documented in the data sheets.

The causal association for quinapril was deemed to be 'possible' for diarrhoea, vomiting, dehydration, delirium and oedema intestinal. No further action was recommended at this time.

4.2.4.2 Simvastatin and rhabdomyolysis, acute renal failure, fever, hyperosmolar state, hepatic enzymes increased (63998)

Discussion

Members noted that a Prescriber Update article was published in 2004 reminding prescribers of the risk of myopathy/rhabdomyolysis with statins.

The causal association for simvastatin was deemed to be 'probable' for rhabdomyolysis, acute renal failure, fever, hyperosmolar state and hepatic enzymes raised. No further action was recommended at this time.

4.2.5 Contrast Media

4.2.5.1 Iodixanol and arteriospasm, CVA (64501)

Discussion

Members noted that this case has a positive re-challenge. Members noted that this is the first report of this nature to CARM and is one of the very few severe events recorded to date with contrast media. Members considered that this is probably a very rare occurrence.

The causal association for iodixanol was deemed to be 'certain' for arteriospasm and CVA. No further action was recommended at this time.

4.2.6 Immunomodulators

4.2.6.1 Interferon alpha and suicide attempt (64504)

Discussion

Please see minute item 4.2.1.3 for further discussion on this issue.

The causal association for interferon alpha was deemed to be 'possible' for suicide attempt. No further action was recommended at this time.

4.2.7 Immunosuppressives

4.2.7.1 Leflunomide and peripheral neuropathy (64385)

Discussion

Members noted that all adverse reactions to leflunomide are 'Adverse Reactions of Current Concern'. They noted that there have been case reports of peripheral neuropathy with leflunomide in the literature, and the data sheet states that peripheral neuropathy occurs very rarely.

The causal association for leflunomide was deemed to be 'possible' for neuropathy peripheral. No further action was recommended at this time.

4.2.8 Musculoskeletal

4.2.8.1 Colchicine, flucloxacillin and diarrhoea, haemorrhage rectum, anorexia, nausea (63707)

Discussion

Members noted that this patient was 98 years old and the dose of colchicine was less than that recommended for acute episodes but greater than that recommended for prophylaxis.

The causal association for colchicine and flucloxacillin was deemed to be 'probable' for diarrhoea, haemorrhage rectum, anorexia and nausea.

Please see minute item 4.3.2 for further discussion and recommendations on this issue.

4.2.9 Respiratory

4.2.9.1 Montelukast and eosinophilia, Churg Strauss syndrome, dyspnoea, weight loss, pericardial effusion (63626)

Discussion

Members noted that this case is brought to MARC in order to raise awareness as the disorder is very rare and this is the second report in 12 months.

The causal association for montelukast was deemed to be 'possible' for eosinophilia, Churg Strauss Syndrome, dyspnoea, weight loss and pericardial infusion. No further action was recommended at this time.

4.2.10 Vaccines

4.2.10.1 MMR and encepahlomyelitis, optic neuritis (63618)

Discussion

Members noted that this case is one of two this quarter presenting with encephalitis following MMR vaccination (see minute item 4.2.10.3, in which 'encephalitis' was subsequently removed as a possible reaction). Members noted that there is one other case in the CARM database.

The causal association for MMR vaccine was deemed to be 'possible' for encephalomyelitis and optic neuritis. No further action was recommended at this time.

4.2.10.2 MMR and Guillain Barre syndrome (63724)

Discussion

Members noted that Guillain-Barre syndrome (GBS) is a very rare adverse reaction to the MMR vaccine, which is identified in the product data sheet. Members noted that the literature does not indicate an increased risk over the background rate of GBS.

The causal association for MMR vaccine was deemed to be 'possible' for Guillain Barre Syndrome. No further action was recommended at this time.

4.2.10.3 MMR, DTaP/Hib and fever, ataxia, pupils dilated, encephalitis (64230)

Discussion

Members noted that follow-up information on this case is now available. The patient has been seen by an ophthalmologist, and was diagnosed with physiological unequal pupils. Therefore, as the dilated pupils were thought to support the encephalitis hypothesis in the added presence of ataxia, 'encephalitis' is to be removed as a possible reaction.

The causal association for MMR vaccine and DTaP-Hib vaccine was deemed to be 'possible' for fever and ataxia, and 'unlikely' for pupils dilated. No further action was recommended at this time.

Please see minute item 4.2.10.1 for further discussion.

4.2.11 Other reports

4.2.11.1 Clopidogrel (64549)
4.2.11.2 Methotrexate, leflunomide (63532)
4.2.11.3 Methotrexate, leflunomide (64391)

Discussion

The Committee noted the above two reports regarding methotrexate and leflunomide. Members noted that the previous Prescriber Update article on leflunomide included a brief section describing respiratory adverse effects. They noted that the respiratory adverse effects may also be attributable to methotrexate in these cases, and that concomitant use may have cumulative adverse effects. Members considered that a brief reminder to prescribers in Prescriber Update would be of value.

Members considered that it is imperative that there be dialogue between respiratory physicians and rheumatologists on this issue.

Recommendations

The Committee recommended that a brief Prescriber Update article should be written to update prescribers on the respiratory adverse effects of leflunomide.

The Committee recommended that CARM should investigate how best to initiate dialogue between respiratory physicians and rheumatologists on this issue.

4.2.11.4 Simvastatin (63537)
4.2.11.5 Personal Care Moisturising Baby Oil (64475)
4.2.11.6 Anti-Flamme Crème (64568)
4.2.11.7 Linseed (64636)

The Committee noted the above reports and agreed that no further action is required at this time.

4.3 Pharmacovigilance issues arising from reports to CARM

4.3.1 Tramadol and Hepatic Disorders

Reference

• Savage, R (2005). Tramadol and Hepatic Disorders. (Not yet published).

Issue

There have been two case reports to the New Zealand Pharmacovigilance Centre of hepatic disorders in patients taking tramadol, one case with a positive re-challenge. There has been one case reported in Australia. An interrogation of WHO's Vigibase, using a variety of search terms related to hepatic disorders, found 62 reports from 12 countries. However, none of these reports had positive IC values. The majority of patients were taking other medicines, particularly analgesics, and these were often reported as co-suspect medicines with tramadol. Although NSAIDs and paracetamol were not recorded as co-suspect medicines, they could be considered as a possible cause of hepatic disorders in some cases. Of the 32 cases with no co-suspect medicines eight were poorly documented, six were taking NSAIDs and five were taking paracetamol. Of the remaining 13 cases, five had a good recovery.

Of the 62 reports, there were 17 cases of life-threatening and fatal suspected hepatic reactions. There does not appear to be a specific pattern of hepatic disorders among these cases. There is one case report in the literature of fatal fulminant hepatic necrosis following an accidental overdose of tramadol, which had been taken over eight days. It is likely that the patient took almost three times the maximum recommended daily dose of 400 mg, however, there are no literature reports suggesting hepatic failure as the cause of death in fatal tramadol overdoses.

One of the most striking features of these reports is the short duration of tramadol use prior to the onset of the suspected reaction. Of the 36 patients for whom this information was provided nine reactions occurred within 24 hours of the first dose and 14 occurred between one day and one week after the first dose. Hepatic adverse reactions usually present within one month, often within one week and occasionally within a few days of beginning treatment.

Discussion

Members noted that the above report was generated at the request of the MARC at the September 2004 meeting, and is to be published in the Signal.

After reviewing the Signal report, members considered that these cases represent good evidence for a signal for tramadol and hepatic disorders and supported the publication of the report. No further action was recommended at this time.

4.3.2 Colchicine dosage

References

• Cover note for MARC. R Savage. May 2005.
• NZ Rheumatology Association. NZRA Consensus Statement on the use of Colchicine in the Treatment of Gout. March 2005.
• Morris I et al. Colchicine in Acute Gout. BMJ 2003;327;1275-1276
• Clinical Presentation of Rheumatic Disease - Gout. Oxford Textbook of Rheumatology 2004
• P Gow et al. Gout-an Update on a Deadly Disease. NZ Pharmacy Journ 2005;25;4:21-24.
• Colchicine NZ data sheet. September 1998.

Discussion

Please see minute item 4.2.8.1 for the case history (63707) that prompted this report.

The New Zealand Rheumatology Association (NZRA) had asked that Medsafe consider publishing in Prescriber Update the NZRA Consensus Statement regarding the recommended doses of colchicine to be used in the treatment of acute gout.

Members noted that the current NZ data sheet states, in the 'Dosage and Administration' section: It is usual to start with a dose of 1.2mg (two 0.6mg tablets). This dose may be followed by one tablet 2-hourly until the pain is relieved or diarrhoea, or other gastrointestinal symptoms develop. The total dose in an acute attack should not exceed 6mg (10 tablets total). It is important to observe this maximum because of the toxicity of colchicine, and the risk of serious prolonged diarrhoea. In elderly patients, those who are small and slight (<50kg) and those with renal or hepatic impairment, other treatments should be considered. If colchicine is used in these patients a lower maximum dose (3mg) should be observed.

Members noted that the NZRA Consensus Statement states: The use of large doses of colchicine to treat acute gout is no longer appropriate, especially in older patients, because of the serious adverse effects arising from large doses. The recommended dose for colchicine in the treatment of acute gout is 1.2mg stat, followed by 0.6mg six hourly, up to a maximum dose of 2.4mg per 24 hours.

Members commented that in elderly patients the tolerable dose of colchicine is much lower than in other adults. Members considered that a total daily dose of 2.4mg may be too high for many elderly patients. The BMJ article (Morris et al, 2005) backs this opinion up by suggesting that 500 micrograms three times daily or less frequently should be used in acute gouty arthritis. Members discussed anecdotal reports that general physicians rarely use doses this high in the elderly. One member suggested that, based on his own clinical experience, a dosage regimen in the elderly of 1.2mg stat and nothing further in 24 hours may be more appropriate than that recommended by the NZRA. Therefore, the Committee recommended that the NZRA should be asked to review their Consensus Statement with regards to colchicine doses to be used in the elderly.

Members considered that the current advice on dosage in the NZ data sheet for colchicine does not reflect doses used in practice, and that, in the first instance, the sponsor should be asked to review the current dosage advice for this product.

Recommendations

The Committee recommended that Medsafe should ask the sponsor for colchicine to review the dosage advice in the current data sheet.

The Committee recommended that the NZPhvC should liaise with the NZRA and communicate the Committee's position regarding colchicine dosage in the elderly.

4.3.3 Salamol inhaler testing

References

• Summary of reports to the NZPhvC of problems arising in patients transferring from Ventolin to Salamol inhalers. 4 May 2005.
• D Fitzgerald, Medsafe. Preliminary report on test results for Salamol inhalers. 2 June 2005. (emailed to members 7 June 2005)

Issue

In late December 2004 PHARMAC announced that there would be a brand-switch for the sole supply of salbutamol inhalers from Ventolin to Salamol, to be effective on 1 July 2005. Following this announcement patients were gradually switched from Ventolin to Salamol, which resulted in considerable numbers of adverse reaction reports to CARM for the Salamol inhaler.

Reports to CARM began in late March 2005, and there have been 773 reports to date. The usual rate for brand-switch related reports is about 40 per 3 months. The majority of the Salamol reports are of reduced therapeutic effect, clogging or blocking of the device, poor spray delivery, device emptying quickly, taste unpleasant/persistent and vomiting. 6 reports have been of serious loss of therapeutic effectiveness requiring nebulisers, steroids or hospitalisation. The majority of the reports have been from pharmacies, with some from GPs or patients. In addition, there had been concerns raised regarding the anhydrous ethanol content of the inhaler (0.97g/inhaler) and how this may affect patient populations such as children, alcoholics or Muslims.

In response to these concerns, Medsafe initiated testing of Salamol inhalers. The Committee was provided with the preliminary results of this testing.

The day before the MARC meeting, 8 June 2005, PHARMAC announced their decision to revise the funding of salbutamol inhalers, and to fund both Ventolin and Salamol at the same subsidy level for the next 2 years.

Discussion

Mr Fitzgerald, the Compliance Team Leader at Medsafe, joined the meeting by teleconference for the discussion on Salamol inhaler testing. He talked through the preliminary test results with the Committee. The Committee were satisfied that the testing strategy was appropriate for the problem identified.

Members discussed anecdotal reports that the appearance of the spray for the two inhalers is quite different; Ventolin has a strong, dry spray that can be easily seen and heard, whereas Salamol has a gentle, wet spray that spreads more widely at a slower speed. Mr Fitzgerald suspected that device blockage may be due to the wet spray (consisting of salbutamol in an anhydrous ethanol suspension) forming droplets on the actuator, which block the device as it dries. Members commented that Ventolin is a very well known brand that has been used in NZ for a long time, and that some patient concerns may be due to the differences in the physical characteristics of the inhalers.

Mr Fitzgerald explained that the Salamol inhaler currently has about 23% of the salbutamol inhaler market in the UK. However, Air Flow Products has reported that there were similar device problems when Salamol was introduced in the UK in 2000. In their application for funding to PHARMAC the sponsor provided information regarding how this issue was resolved in the UK. This information has been supplied to Medsafe for assessment.

Members considered that the main issue appears to be the cleaning of the device, and patient education around cleaning. The patient instructions for Salamol state that the device should be cleaned with water and air-dried once a week. Members noted that the cleaning instructions in the patient information for Ventolin are very similar to those for Salamol, however anecdotal reports are that patients have not had to clean their Ventolin inhalers in the past. Members noted that the data sheet for Ventolin makes no mention of cleaning the device. They noted that problems such as device blocking have been reported for Ventolin in the past, but not on the same scale as for Salamol.

Members considered that the nature of acute asthma attacks is such that patients may not be able to clean the inhaler if it blocks in an emergency. Acute asthma attacks may occur in isolated locations, or in other locations where cleaning the inhaler is not practical. In addition, members commented that patients commonly keep multiple inhalers in multiple locations, and therefore that weekly cleaning of all of these inhalers is not realistic.

Members considered that this is an issue of effectiveness rather than efficacy, and may represent a significant safety issue. Preliminary testing indicates that the Salamol inhaler is satisfactory from a technical perspective, however there are serious concerns around the maintenance of the device. Members considered that adequate device maintenance relies on good patient information in the package insert, and alerting patients to look for this information. Patient education was considered to be paramount in overcoming these issues. The sponsor has written to prescribers, pharmacists and asthma educators regarding this issue, and that patient cleaning information leaflets have been sent to asthma educators. Medsafe commented that the sponsor has communicated their intention to disseminate further patient information in the near future. Members commented that it is unclear whether pharmacists are providing adequate information around device cleaning when dispensing Salamol, but that this is likely to be improving.

Recommendations

The Committee recommended that Medsafe should identify the issues that have occurred with the Salamol inhaler in the UK and how these issues were resolved, and report back to the MARC at the next meeting.

The Committee recommended that Medsafe should assess the results of the further tests of Salamol inhalers and report back to the MARC at the next meeting.

The Committee recommended that Medsafe should ask the product sponsor to update the information in the package insert of Salamol inhalers, in order to provide clear instructions about cleaning the inhaler device once weekly.

The Committee recommended that Medsafe should convey updated information to prescribers and pharmacists through a 'red Dear Health Professional' letter.

4.4 Intensive Medicines Monitoring Programme (IMMP)

4.4.1 Summary of IMMP work on atypical antipsychotic medicines: Progress report to June 2005.

Issue

The atypical antipsychotic medicines clozapine, olanzapine, risperidone and quetiapine are currently monitored by the IMMP. This report describes the work performed to date, including specific projects currently in progress for these medicines.

Discussion

Members noted the progress report on IMMP. Members noted that three specific studies are underway. These studies are a paediatric study, a nocturnal enuresis study and a data linkage study. No further action was recommended at this time.

4.4.2 Analysis of IMMP events reported for risperidone

Issue

A summary of the IMMP adverse event reports for risperidone was provided. Many of the most frequently reported adverse events are well documented and some of these have been previously reported to the MARC, including hyperprolactinaemia, male sexual dysfunction, hypertension, hyperglycaemia/diabetes and oedema.

The IMMP events listing for risperidone was also reviewed for adverse events (occurring more than once), which are not identified in the product data sheet. These events include:

Seizure risk: The IMMP has had eight reports of seizures in patients treated with risperidone. Of these reports, six occurred in patients without a history of epilepsy and three patients experienced a grand-mal seizure within 48 hours of commencing risperidone. At present the New Zealand data sheet states "Caution is recommended when treating patients with epilepsy".

Epistaxis: The IMMP identified epistaxis as a potential signal for risperidone and published this in the BMJ in 2004. Recently the Netherlands Pharmacovigilance Centre has confirmed this signal and has recommended that epistaxis be included in the European SPC.

Nocturnal enuresis: There are 3 reports of nocturnal enuresis associated with risperidone in the IMMP database. For all three causality was deemed to be 'probable' or 'possible'.

Dysphagia: Dysphagia is listed in the US product information and there have been 2 reports to CARM in New Zealand.

Discussion

Members noted the above. There was some discussion regarding the adverse reactions of epistaxis, nocturnal enuresis and dysphagia which are not included in the current data sheet. Members noted that a potential signal for epistaxis has been identified. Members commented that there is a plausible mechanism for the class of products that cause tardive dyskinesia to also cause dysphagia, and therefore aspiration pneumonia. The MARC considered that the following statement or one of similar intent should be added to the data sheet: "Seizures have occurred in patients without a history of epilepsy".

Members considered that this is sufficient evidence to request that the data sheet for risperidone be updated for all of these issues.

Recommendation

The Committee recommended that the data sheet for risperidone should be updated to include reference to the adverse reactions of seizures, epistaxis, nocturnal enuresis and dysphagia.

4.4.3 Deaths with atypical antipsychotics in elderly patients with dementia.

Briefing Report for MARC on recent FDA action

Please see minute item 3.4 for discussion and recommendations on this issue.

4.5 Intensive Vaccines Monitoring Programme (IVMP) - Meningococcal B vaccine

References

• Summary of findings of reactions to the MeNZB vaccine as observed by the New Zealand Pharmacovigilance Centre's CARM and IVMP monitoring programmes - spontaneous reports following MeNZB vaccination received at the CARM to 31 December 2004.
• Summary of spontaneous reports following MeNZB vaccination received by CARM for the period 19 July 2004 to 27 May 2005. (Tabled at the meeting).

Issue

For the 19 July 2004 to 27 May 2005 period, almost 950,000 doses of MeNZB vaccine were administered, with approximately 187,000 individuals having received three doses of vaccine. For the same period, 780 spontaneous reports of events following MeNZB vaccination were received by CARM. Although the number of reports has averaged around 18 per week, it has increased in the weeks immediately following commencement of vaccination in a new area.

Overall, the main pattern of reactions observed is that of local reactions (injection site/limb pain, injection site inflammation, injection site erythema); somatic immune responses (fever, headache, gastrointestinal and musculoskeletal symptoms) and hypersensitivity (skin reactions - mostly rashes, anaphylactoid-like events and breathing disorders).

There were ten febrile seizures, one of which had evidence of a concurrent infection (tonsillitis) and another two possibly had an upper respiratory tract infection at the time. All of the febrile seizures reported occurred within 48 hours of immunisation. There were seven non-febrile seizures, four of which had a history of epilepsy or predisposing factors. All of the non-febrile seizures occurred within 24 hours of immunisation. There have been very few reports of anaphylactic-type reactions, all of which had negative serum tryptase levels.

CARM data are reviewed weekly by the Independent Safety Monitoring Board (ISMB), which has expressed no concerns regarding safety of the MeNZB vaccine. Serious adverse reactions are fully evaluated and followed up.

The Intensive Vaccine Monitoring Programme (IVMP) has a patient cohort of 12,000 with a total of 25,000 vaccine exposures. The analysis of this cohort will be brought to the MARC in due course.

Discussion

Members noted the data regarding adverse event reports for the MeNZB vaccine, as detailed above. Members considered that the patterns of adverse events have been predictable, with no particular reactions being of clinical concern. Members commented that reports of adverse reactions have been lower than expected, based on reports from other countries. In particular, injection site reaction reports have been lower than expected, possibly due to prescribers being forewarned of the likelihood of local reactions and therefore a low reporting rate.

The Committee asked to be kept informed of issues related to MeNZB as they arise.

4.6 Adverse Reactions to Fractionated Blood Products

Reference

• Faed J et al. Adverse Reactions to Fractionated Blood Products reported to NZ Blood Service during 2004. 26 April 2005.

Discussion

Members noted the report and expressed the Committee's thanks to the New Zealand Blood Service.

4.7 Quarterly reports from the Centre for Adverse Reactions Monitoring (CARM)

Members noted the quarterly reports as at 31 December 2004 and 31 March 2005.

5 PHARMACOVIGILANCE issues for information only

The Committee did not discuss the majority of this material. It includes 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.

5.1 Elidel (pimecrolimus)

References

• Cover note from Medsafe
• Novartis "Dear Health Professional" letter. 12 May 2005
• FDA Public Health Advisory. 10 March 2005

Issue

An EMEA-commissioned review of pimecrolimus is currently being undertaken and the results should be available in approximately six months. At that time, a report will be provided to the MARC. The NZ Dermatological Society will also be asked for their view at that time. In the interim, a data sheet update is not being pursued.

Discussion

Members noted the above and expressed concern that the Novartis "Dear Health Professional" letter was distributed only to prescribers who requested updated information. Members considered that there are not currently sufficient data to warrant updating all prescribers on this issue.

Recommendation

The Committee recommended that Medsafe should ask Novartis to supply information, at the time of the release of the results of the EMEA-commissioned review, regarding the number of patients using Elidel in New Zealand.

5.2 Nitrous Oxide in Anaesthesia

• Cover note from Medsafe
• J Robotham. Patients wake in fright after anaesthetic gas. Sydney Morning Herald. 5 May 2005.
• Media statement from Medsafe. 5 May 2005.
• Press Release. New Zealand Society of Anaesthetists. Future Limits on use of Nitrous Oxide in Anaesthesia Possible.
• Press Release. New Zealand Society of Anaesthetists. It's No Laughing Matter. 6 May 2005.
• Email from L Petrov. Nitrous Oxide Statement Update. Australia New Zealand College of Anaesthetists. 13 May 2005.

5.3 COX-2 inhibitors and cardiovascular safety

• Medsafe Dear Health Professional letter. Prescribing restrictions for all COX-2 inhibitors. 29 April 2005.
• Medsafe Media Release. Stringent conditions for COX-2 inihibitors. 29 April 2005.
• M Weatherall et al. COX-2 inhibitors - first do no harm. New Zealand Medical Journal. 11 March 2005, Vol 118 No 1211.
• A Harrison. COX-2 inhibitors - second, do some good. New Zealand Medical Journal 1 April 2005, Vol 118 No 1212.
• bpac^nz. NSAIDs - Your questions answered.
• M Harrison-Woolrych et al. Incidence of Thrombotic Cardiovascular Events in Patients Taking Celecoxib Compared with Those Taking Rofecoxib. Interim results from the New Zealand Intensive Medicines Monitoring Programme. Drug Safety 2005; 28(5): 435-442.
• TGA Media Centre. Status of action on products containing meloxicam. 15 April 2005. Accessed online 21 April 2005. http://www.tga.gov.au/media/2005/050415-meloxicam.htm
• FDA Regulatory Actions for the COX-2 Selective and Non-Selective Non-Steroidal Anti-inflammatory drugs (NSAIDs). Questions and Answers. 7 April 2005. Accessed online 8 April 2005 http://www.fda.gov/cder/drug/infopage/COX2/COX2qa.htm
• Health Sciences Authority - Drug Safety Information No. 12. Dear Healthcare Professional - HSA's Expert Advisory Committee's Recommendations on Cyclo-oxygenase-2 (COX-2) Selective and Non-selective Non-steroidal Anti-inflammatory Drugs (NSAIDs). 28 April 2005.

5.4 SSRIs

• News release from The Royal Australian and New Zealand College of Psychiatrists. SSRI guide released by Australia's leading medical colleges. 22 April 2005.
• Press release from EMEA. European Medicines Agency finalises review of antidepressants in children and adolescents. 25 April 2005.
• E J Sanz et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 2005; 365: 482-87.

5.5 HRT

• L A Brinton et al. Hormones and endometrial cancer - new data from the Million Woman Study. Lancet 2005; 365: 1517-18.
• Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 2005; 365: 1543-51.
• Press Release from MHRA. Latest data on HRT from the UK Million Women Study. 29 April 2005.

5.6 Atypical Antipsychotics and ischaemic stroke

• S S Gill et al. Atypical antipsychotic drugs and risk of ischaemic stroke: population based retrospective cohort study. Accessed online 11 April 2005. BMJ, doi:10.1136/bmj. 38330.470486.8F (published 24 January 2005).

6 NEW ZEALAND PHARMACOVIGILANCE-RELATED ACTIVITIES

• M Harrison-Woolrych et al. Unintended pregnancies with the etonogestrel implant (Implanon): a case series from postmarketing experience in Australia. Contraception 71 (2005) 306-308.

7 INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

7.1 Australia

• Minutes of the December 2004 meeting of the Adverse Drug Reactions Advisory Committee
• Minutes of the February 2005 meeting of the Adverse Drug Reactions Advisory Committee
• Australian Adverse Drug Reactions Bulletin 24 (2), April 2005
• Australian Prescriber 28 (2), April 2005

7.2 Canada

• Canadian Adverse Reaction Newsletter 15(2), April 2005

7.3 Malaysia

• Malaysian Adverse Drug Reactions Newsletter. January 2005

7.4 Singapore

• Adverse Drug Reactions News. 7(1), March 2005

7.5 WHO

• WHO Pharmaceuticals Newsletter No 1 2005
• WHO Pharmaceuticals Newsletter No 2 2005
• MUR 29: Uppsala Reports April 2005

8 SUMMARY OF CASE REPORTS CONSIDERED BY MARC (1997 - 2004)

• CARM case reports considered by the MARC
• Vaccine adverse reaction reports considered by MARC
• Complementary and alternative medicine case reports considered by the MARC

9 Other business

9.1 Joint Trans-Tasman Therapeutic Products Agency (JTA)

Discussion

Medsafe updated members on the progress of the establishment of the Australia/New Zealand JTA, which is scheduled to commence operations on 1 July 2006. Drafting of the proposed legislation is underway. Drafts of the proposed Ministerial Council Rules will be released in the future at which time stakeholder and Committee consultation will be sought. The framework for Pharmacovigilance services is currently being refined. It is considered imperative that there be a separation between pre- and post-marketing services within the JTA.

Members considered that it would be of value for members of the MARC and the Medsafe secretariat to re-establish cross-attendance at the Australian Adverse Drug Reactions Advisory Committee (ADRAC), and vice versa.

Recommendation

The Committee recommended that Medsafe should disseminate the dates of future Australian Adverse Drug Reactions Advisory Committee (ADRAC) meetings to MARC members.

The Committee recommended that Medsafe should invite members of the Australian Adverse Drug Reactions Advisory Committee (ADRAC) to attend future meetings of the MARC.

There being no further business, the Chair thanked members for their attendance and closed the meeting at 16:30.