Revised: 20 May 2013

Committees

Minutes of the 117th Medicines Adverse Reactions Committee Meeting - 10 March 2004

At the Sunderland Room, Wellington Airport Conference Centre, commencing at 9:00am

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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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

MARC MEMBERS PRESENT

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

MARC Secretariat Present

Dr K. Maclennan (Pharmacovigilance Advisor/MARC Secretary, Medsafe)
Ms S. Von Afehlt (Senior Pharmacy Advisor/Editor of Prescriber Update, Medsafe)
Dr Stewart Jessamine (Principal Technical Specialist, Medsafe)

Invited Experts

Dr P. Graham (Department of Public Health and General Practice, Christchurch School of Medicine)
Dr R. Savage (New Zealand Pharmacovigilance Centre)
Dr M. Harrison-Woolrych (New Zealand Pharmacovigilance Centre)

1. MATTERS OF ADMINISTRATION

1.1 Welcome and apologies

The Chair welcomed Drs Ruth Savage and Mira Harrison-Woolrych from the New Zealand Pharmacovigilance Centre (NZPhvC). Dr Patrick Graham, a biostatistician from the Christchurch School of Medicine and Health Sciences, was welcomed to the early afternoon session of the meeting. Apologies had been received from Professor David Skegg.

1.2 Minutes of the 116^th meeting

Members agreed that the minutes of the 116^th meeting are a true and accurate record of the meeting.

1.3 Dates of 2004 MARC meetings

The Committee noted that the remaining 2004 MARC meetings are to be held on Tuesday 22 June, Thursday 23 September, and Wednesday 1 December.

1.4 Conflicts of interest

Committee members with undeclared conflicts of interest submitted these to the Secretary.

1.5 Prescriber Update

Article

.., Diarrhoea with beta blockers - blast from the past (pre-peer review version).

Discussion

The Committee agreed that this is a well-written and informative article.

Article

Medsafe Editorial Team, Potential for influenza vaccine interaction exists (pre-peer review version).

Discussion

The Committee questioned whether the sentence stating that, "Toxic elevations in levels of concurrent medicines have been known to occur up to 28 days post-vaccination" is supported by the half-life of the influenza vaccine. Members also agreed that New Zealand case reports of influenza vaccine interaction should be included in the article. Aside from this, members agreed this is a well-written and informative article.

Article

The salmeterol multicentre asthma research trial (SMART) and asthma management

Discussion

Medsafe proposed to reprint the aforementioned article from Adverse Drug Reactions News (November 2003), which was published by the pharmacovigilance section of the Singaporean Health Sciences Authority. Some members expressed concern about publishing an article based on unpublished pharmaceutical company data - the quality of which has not been evaluated by the Committee. It was noted, however, that the study was carried out at the request of the US Food and Drug Administration.

The Committee noted that, given it is New Zealand practice to prescribe salmeterol with an inhaled corticosteroid, there is no urgency to publish an article about the SMART study. It was agreed that the Committee should await peer-reviewed publication of the SMART study, or an assessment of the data by the US Food and Drug Administration.

Recommendation

The Committee recommended that the Singaporean article on the SMART study and asthma management should not be reprinted in Prescriber Update at this time. The Committee agreed that Medsafe should await peer-reviewed publication of the study, or an assessment of the data by the US Food and Drug Administration.

Article

Acne, isotretinoin and depression

Discussion

Medsafe is seeking permission from the UK Drug and Therapeutics Bulletin (DTB) to reprint their article on acne, isotretinoin, and depression, published in October 2003. The Committee agreed this is a very informative article that should be disseminated to New Zealand prescribers.

Recommendation

The Committee recommended that the DTB article on acne, isotretinoin, and depression should be reprinted in Prescriber Update.

Article

Medsafe Editorial Team, Leflunomide: serious multi-system adverse effects (pre-peer review version).

Discussion

The Committee agreed this is a well-written and informative article.

Article

.., Myopathy with statins: check CK levels and interactions (pre-peer review version).

Discussion

Please refer to section 2.2.5 of these minutes for discussion relating to this article.

2. MATTERS ARISING

2.1 Report on actions arising from the 116^th MARC meeting

2.1.1 Minute item 2.2.1 (December 2002 minute item 4.1) High-dose fluticasone and adrenal insufficiency

Issue

The Committee recommended that a review of evidence underlying fluticasone dosage advice be prepared for discussion at the March 2004 MARC meeting. A representative from the New Zealand Guidelines Group should be invited to attend this part of the MARC meeting.

Outcome

The dosage advice contained in the New Zealand Flixotide data sheet is in concordance with that accepted by the US Food and Drug Administration, the Australian Therapeutic Goods Administration, and the British National Formulary. Medsafe is of the view that evidence of harm is required to overturn these dosage recommendations. If there were reports or signals of harm occurring in adult patients at these doses, Medsafe would certainly alert the MARC, and request advice as needed. However, in the absence of any such signal, it is neither appropriate nor efficient for Medsafe to conduct a review of evidence underlying fluticasone dosage advice for MARC discussion.

Discussion

While the Committee noted that it does not have clinical evidence that suggests the dosage recommendations in the New Zealand Flixotide data sheet are inappropriate, it wished to support the dosage advice in the New Zealand Guidelines Group Guidelines for the Diagnosis and Treatment of Adult Asthma. Members also acknowledged that it might be inappropriate to compare dosage advice for inhaled corticosteroids as a group, with advice for individual products.

The Committee agreed that a general article about asthma therapy should be written for publication in Prescriber Update. The article should make reference to the New Zealand Guidelines Group Guidelines for the Diagnosis and Treatment of Adult Asthma, and provide dosage advice about starting low and titrating up as necessary. In addition, the article should note the difference in potency between fluticasone and other inhaled corticosteroids.

Recommendation

The Committee recommended that a general article about asthma therapy should be written for publication in Prescriber Update. The article should make reference to the New Zealand Guidelines Group Guidelines for the Diagnosis and Treatment of Adult Asthma, and provide dosage advice about starting low and titrating up as necessary. In addition, the article should note the difference in potency between fluticasone and other inhaled corticosteroids.

2.1.2 Minute item 3.1 Atypical antipsychotics and lipid abnormalities

Issue

The Committee recommended that prescribers be informed about the potential association between atypical antipsychotics and lipid abnormalities through an article or paragraph in Prescriber Update. Baseline and follow-up lipid monitoring should be encouraged.

The Committee also recommended that product sponsors for clozapine and risperidone be asked to include data sheet statements to say that there are post-marketing reports of a possible association between their product and lipid abnormalities. In addition, product sponsors for all four of the atypical antipsychotics available in New Zealand should be asked to comment on the issue of lipid abnormalities.

Outcome

The aforementioned requests were made to the respective product sponsors in February 2004.

Douglas Pharmaceuticals has responded to say that Clopine is not currently marketed in New Zealand; however, the requested data sheet changes will be incorporated into a clozapine New Medicine Application (presently submitted to Medsafe), or the request for renewal of provisional consent for the 25 mg and 100 mg clozapine tablets. Medsafe is agreeable to this action.

Janssen (Risperdal) and Eli Lilly (Zyprexa) have referred the matter to Head Office. Responses from Novartis (Clozaril) and Astra Zeneca (Seroquel) are yet to be received.

Discussion

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

2.1.3 Minute item 4.2.1 Intramuscular gold, ACE inhibitors, and nitritoid reactions

Issue

The Committee recommended that the New Zealand sponsor for aurothiomalate sodium be asked to update the product data sheet to include a more detailed description of nitritoid reaction symptoms, and the potential for interaction with ACE inhibitors.

The Committee also recommended that prescribers be reminded about the potential for nitritoid reactions with gold injections by way of an article in Prescriber Update. The article should provide advice to prescribers about reintroducing gold injections at a lower dose, and a reminder about the potential interaction with ACE inhibitors.

Outcome

Aventis Pharma provided Medsafe with an updated Myocrisin data sheet in March 2004. .. has agreed to author the Prescriber Update article.

Discussion

Members noted the above and agreed that no further action is necessary.

2.1.4 Minute item 4.2.2 Summary of leflunomide reports to CARM to 30 September 2003 (regardless of causality).

Issue

The Committee recommended that pulmonary infiltration be included in the respiratory disorders section of the leflunomide article, which is planned for publication in Prescriber Update.

Members also recommended that CARM continue to inform the MARC about significant adverse reaction reports to leflunomide.

Outcome

Please refer to section 1.5 of these minutes for discussion regarding the draft leflunomide Prescriber Update article.

2.1.5 Minute item 4.3.1.1 Brand-switch related reports

Issue

The Committee recommended that Medsafe and CARM further investigate brand-switch issues with citalopram.

Outcome

It was reported that CARM has received 68 reports of adverse events occurring after patients had changed from the Cipramil to the Celapram brand of citalopram. As has been observed with previous brand-switch issues, the number of reports tapered off within three to six months.

Of the 68 reports received by CARM, 70% described reduced therapeutic effect on changing to Celapram. Of particular concern, was the early receipt of two reports associated with suicidal ideation. The duration to onset of symptoms was indicated in 21 reports - symptoms typically occurred within three days, with most occurring in less than 10 days. Of the 65 reports where outcome was known, 43% showed definite improvement on dechallenge.

Discussion

Members agreed that the citalopram brand-switch issue does not appear to be a major concern at this time. It was noted that the pattern of reporting might be explained, at least in part, by individual versus population pharmacokinetics (i.e., a shift in those who respond or react within a normal distribution curve is not unexpected).

The Committee expressed concern at the lack of standardised criteria to determine the clinical significance of brand-switch reactions. Given the increasing use of generic medicines, the development of such criteria was considered extremely important. The Committee agreed that the CARM citalopram brand-switch report, and the MARC's concern regarding the lack of criteria to determine the clinical significance of brand-switch issues, should be brought to the attention of PHARMAC and the Generics Sub-Committee of the Medicines Assessment Advisory Committee.

Recommendation

The Committee recommended that the CARM citalopram brand-switch report, together with the MARC's concern regarding the need for criteria to determine the clinical significance of brand-switch issues, be brought to the attention of PHARMAC and the Generics Sub-Committee of the Medicines Assessment Advisory Committee.

2.1.6 Minute item 4.3 Adverse Reactions of Current Concern

Issue

The Committee recommended that the list of Adverse Reactions of Current Concern be reviewed at the March 2004 MARC meeting.

The Committee recommended that Medsafe explore options for displaying MARC information or advice at weekly Grand Rounds.

Outcome

Medsafe is in the process of exploring options for displaying MARC advice at weekly Grand Rounds.

Discussion

Please refer to section 4.3 of these minutes for discussion regarding Adverse Reactions of Current Concern.

2.1.7 Minute item 6.1 PHARMAC reference pricing of isotretinoin

Issue

The Committee recommended that Medsafe draft a letter to PHARMAC for the MARC Chair's comment and signature. The letter should seek to ensure there is an adequate isotretinoin education strategy in place for prescribers.

The Committee also recommended that Medsafe investigate the possibility of monitoring GP prescribing of isotretinoin using the RNZCGP research unit database at Otago University.

Outcome

Medsafe is in the process of preparing a draft letter to PHARMAC for the MARC Chair's comment and signature.

Medsafe has contacted the RNZCGP research unit, which has since provided isotretinoin GP prescription data for 2002 (the Unit's database is complete up to the end of 2002; the data for 2003 will be available later in 2004).

The search for isotretinoin prescriptions involved the records from 63 general practices distributed throughout New Zealand, with a total of 1.4 million patients on their registers, 350,000 consulting patients, and a total of approximately 1,770,000 prescriptions. Of the 1,770,000 prescriptions, 26 are for isotretinoin and these were prescribed to 24 different patients.

Due to the lag time between the prescribing of a medicine and data collection/entry, it is unlikely that the RNZCGP research unit can provide timely data to enable the monitoring of GP isotretinoin prescribing. However, the Unit's database could be used retrospectively, which may be useful if other sources (such as adverse reaction reports) indicate increasing prescribing of isotretinoin by GPs.

Discussion

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

2.1.8 Minute item 4.1.1.5 Enoxaparin and haemorrhage (57708)

Issue

The Committee recommended that CARM conduct an assessment of the 33 reports of enoxaparin and bleeding or haemorrhage in the CARM database. The findings of this analysis should be reported to the MARC at a future meeting.

Outcome

Of the 33 reports of enoxaparin and bleeding or haemorrhage reported to CARM, 17 were assessed as serious. These include five reports of death, and four reports of life-threatening haemorrhagic reactions. Six of these nine patients had renal impairment, and one had a serious pre-disposing condition. There is no evidence of dose adjustment for renal impairment amongst those who died.

Seven of the nine patients who died or had a life-threatening reaction were receiving enoxaparin for unstable coronary artery disease (UCAD) or myocardial infarction (MI). This compares with three of the eight patients who experienced less severe reactions. All but one of the patients with UCAD or MI were aged between 72 and 87 years.

Discussion

Members questioned whether the cases in elderly patients could have been prevented if the dose of enoxaparin was reduced. It was noted that District Health Boards New Zealand (DHBNZ) has recently produced a 'tool-kit' regarding dosage adjustment of medicines in patients with renal impairment. The Committee suggested that expert advice about the use of enoxaparin in the elderly be sought from a haematologist. In addition, members agreed the issue should be discussed with the DHBNZ Quality Use of Medicines team to ensure that any potential MARC advice concurs with the recently developed 'tool-kit'.

Recommendation

The Committee recommended that expert advice about the use of enoxaparin in the elderly be sought from a haematologist. In addition, members recommended that the issue be discussed with the DHBNZ Quality Use of Medicines team to ensure that any potential MARC advice concurs with the recently developed 'tool-kit' for dosage adjustment of medicines in patients with renal impairment.

2.2 Report on actions outstanding

2.2.1 September 2003 minute item 4.1 Safety information from the Salmeterol Multi-centre Asthma Research Trial

Issue

The Committee recommended that, as appropriate, Medsafe ask New Zealand product sponsors for salmeterol to strengthen product data sheet advice, emphasising that the use of this medicine as maintenance therapy should be in addition to corticosteroid treatment of asthma.

Outcome

The salmeterol data sheet advice has been strengthened, as requested. In addition, GSK has provided Medsafe with a further three volumes of data containing analyses from the Salmeterol Multi-centre Asthma Research Trial. A confidential GSK synopsis of this information was provided to MARC members for their information.

Discussion

Please refer to section 1.5 of these minutes for discussion regarding the Salmeterol Multi-centre Asthma Research Trial.

2.2.2 September 2003 minute item 4.1.1.1 Donepezil and syncope, concussion, sudden death (55732)

Issue

The Committee recommended that the NZPhvC seek advice from .. about how well recognised syncope with donepezil is amongst prescribers. Following this, Medsafe should consider publishing a Prescriber Update article, based on the CARM case reports for donepezil, to remind prescribers about the risk of syncope with this medicine.

Outcome

Due to the unavailability of .., Medsafe contacted .. (a psychogeriatrician at ..). .. is of the opinion that specialists who work in psychogeriatrics and prescribe acetylcholinesterase inhibitors are aware that syncope can occur with donepezil. However, .. commented that it would be worthwhile bringing this issue to the attention of GPs as they may also prescribe these medicines. .. believes it is more usual that a GP would prescribe on-going therapy, rather than initiating treatment with an acetylcholinesterase inhibitor. In addition, .. made the following comments:

• If a Prescriber Update article were written, it should explain that syncope might occur with any of the acetylcholinesterase inhibitors (not only donepezil), as these agents all have a similar mechanism of action.
• Acetylcholinesterase inhibitors are used primarily in three different patient groups: those with early dementia where the acetylcholinesterase inhibitor is used to improve cognitive function; those with more advanced dementia +/- psychiatric or behavioural disorders; and those with Lewy body dementia. Of particular note is that syncope is a core feature of Lewy body dementia, therefore it is possible the syncope is not due to the acetylcholinesterase inhibitor.
• Syncope has occurred in only one of .. patients. This patient was also taking a beta-blocker, therefore it was difficult to identify the causal agent. The Prescriber Update article should mention that concomitant use of acetylcholinesterase inhibitors and medicines known to cause syncope may further increase the risk of this adverse effect occurring.

As a result of these discussions, Medsafe has agreed that a Prescriber Update article should be published. The brief of this article should be extended to syncope with all acetylcholinesterase inhibitors, and include the possibility of synergistic interactions. Medsafe will author the article, and .. has agreed to provide external peer review. Medsafe asks for one MARC member to volunteer as the internal peer reviewer of the article.

Discussion

Members noted the above and agreed that the brief of the Prescriber Update should be extended to syncope with all acetylcholinesterase inhibitors, and should include the possibility of synergistic interactions. .. agreed to act as the internal peer reviewer of this article.

2.2.3 September 2003 minute item 4.1.5.2 Tramadol and hepatic enzymes elevated, pruritus, rash, jaundice (55370)

Issue

The Committee recommended that New Zealand prescribers be alerted to the risk of hepatic reactions with tramadol by way of a Prescriber Update article.

Outcome

Drs .. and .. of the NZPhvC searched the WHO database for case reports of tramadol and hepatic reactions. Of 7812 reports for tramadol, 163 involved some form of hepatic reaction; in 22 of these cases, the outcome was fatal. Review of these case reports revealed that the evidence for an association between tramadol and various hepatic reactions is weak. The IC-values indicated that none of the associations with tramadol stood out significantly from the background incidence; in most cases, the IC-value was negative. In many of the 163 WHO case reports, patients were on concomitant medications that are also potentially hepatotoxic. Very few of the reports had sufficient data to enable any conclusion regarding causality. In the literature, there is very little relevant published data linking tramadol with liver enzyme abnormalities.

In the February 2003 ADRAC bulletin article on tramadol, there are 10 reports of hepatic reactions from 354 tramadol reports received in the past four years. Over one million dispensings of oral tramadol were recorded in Australia in 2002.

If an article were published in Prescriber Update, it could say only that it is possible tramadol may cause hepatic disorders, although there are no published data to support this. The New Zealand and Australian cases could be cited, but it would need to be explained that for many of the WHO cases, there are alternative explanations for the reaction.

As the evidence for an association between tramadol and hepatic reactions is weak (due to confounders such as concomitant hepatotoxic medicines), Medsafe believes a Prescriber Update article should not be published at this time. Instead, a watching brief should be implemented, with CARM advising MARC if further reports are received.

Discussion

The Committee agreed with Medsafe's proposal not to publish a Prescriber Update article at this time. Members also agreed that there should be a watching brief on the issue of tramadol and hepatic reactions, with CARM advising the MARC if further reports are received.

Recommendation

The Committee agreed that a Prescriber Update article about tramadol and hepatic reactions should not be published at this time. Members also agreed that there should be a watching brief on the issue of tramadol and hepatic reactions, with CARM advising the MARC if further such reports are received.

2.2.4 September 2003 minute item 2.2.5 Timely responses from industry

Issue

Medsafe will review and develop processes around industry response, and will present these to the MARC for the Committee's information.

Outcome

This will be developed and presented to the Committee at a future MARC meeting.

Discussion

Given that Medsafe and the Australian Therapeutic Goods Administration (TGA) will merge to form a joint trans-Tasman medicines regulatory agency in 2005, the Committee agreed that processes around timely responses from industry should be developed in conjunction with the TGA.

Recommendation

The Committee recommended that Medsafe develop processes around timely responses from industry in conjunction with the TGA.

2.2.5 September 2003 minute item 4.2.1 Simvastatin, diltiazem and rhabdomyolysis - an analysis of reports of rhabdomyolysis with simvastatin in the CARM database

Issue

The Committee recommended that prescribers be reminded about the possibility of an interaction between simvastatin and diltiazem, which may lead to severe myopathy and rhabdomyolysis. A paragraph about this interaction should be included in the article about myopathy with statins, currently being written for Prescriber Update.

The Committee also recommended that simvastatin product sponsors be asked to amend their New Zealand data sheets to state that, "Treatment with simvastatin in a patient taking diltiazem should be started at the lowest possible dose and titrated upwards. For patients already taking simvastatin, the dose should be considerably reduced if calcium channel blockers are prescribed". Medsafe should decide whether this information should be cross-referenced in data sheets for calcium channel blockers.

Outcome

During the editing of the resultant Prescriber Update article, it became apparent that the above advice from the Committee might not be particularly helpful for prescribers due to lack of specificity. Medsafe sought clarity from the Committee about what is meant by "lowest possible dose" and "considerably reduced". In addition, Medsafe asked the Committee to provide more definitive advice for prescribers (e.g., if doses of statins are reduced due to concurrent calcium channel blocker therapy, should prescribers be advised to measure serum cholesterol levels to determine whether therapeutic efficacy of the statin has been maintained?).

In January 2004, a letter was sent to Merck Sharp & Dohme (NZ) requesting that the simvastatin data sheet be updated to include the aforementioned MARC recommendations. A response from MSD is yet to be received.

Discussion

Members agreed that the Prescriber Update article should refer only to simvastatin and diltiazem, as the Committee does not have evidence to extrapolate these findings to other statins or calcium channel blockers. It was agreed that the article should remind prescribers about the possibility of an interaction between simvastatin and diltiazem, which may lead to severe myopathy and rhabdomyolysis. In addition, the need to monitor such patients for symptoms of rhabdomyolysis should be emphasised. .. and .. agreed to liaise regarding the amendments to the draft article.

Recommendation

The Committee recommended that the Prescriber Update article should refer only to simvastatin and diltiazem. The article should remind prescribers about the possibility of an interaction between simvastatin and diltiazem, which may lead to severe myopathy and rhabdomyolysis. In addition, the article should emphasise the need to monitor such patients for symptoms of rhabdomyolysis.

2.2.6 September 2003 minute item 4.4.2 Nocturnal enuresis associated with clozapine

Issue

The Committee recommended that Medsafe write to product sponsors of clozapine, requesting that nocturnal enuresis be included as an adverse effect in the New Zealand clozapine data sheets.

Outcome

The aforementioned request was made in a letter to clozapine product sponsors in January 2004.

Douglas Pharmaceuticals has responded to say that Clopine is not currently marketed in NZ, however, the requested data sheet change will be incorporated into a clozapine New Medicine Application (presently submitted to Medsafe), or the request for renewal of provisional consent for the 25 mg and 100 mg clozapine tablets. Medsafe is agreeable to this action.

A response from Novartis is yet to be received.

Discussion

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

2.2.7 September 2003 minute item 2.1.1 Leflunomide/methotrexate/ketoprofen/triamcinolone and septic shock/septic arthritis/multiple organ failure/infection streptococcal/vomiting - CARM case report 52507

Issue

The Committee recommended that Medsafe ask the product sponsor for leflunomide to issue a Dear Healthcare Professional letter to New Zealand prescribers. The letter should convey information about serious reactions to leflunomide, and the importance of patient review and monitoring. In addition, a related article should be published in Prescriber Update.

The Committee recommended that the product sponsor for Arava be asked to remove the words "first-line" from the data sheet statement, "Arava may be used as a first-line treatment in patients who have failed to respond to other treatments".

Outcome

Aventis is currently reviewing the issue of interstitial pneumonia with leflunomide. As this may need to be addressed in the New Zealand Dear Healthcare Professional letter, Aventis will finalise the letter when the outcome of their review is known.

Aventis has informed Medsafe that the sentence, "Arava may be used as a first-line treatment in patients who have failed to respond to other treatments" erroneously came about when a previous data sheet change was made. Aventis will amend this sentence and submit an updated data sheet to Medsafe.

Discussion

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

A draft Prescriber Update article regarding adverse reactions to leflunomide has been prepared. Please refer to section 1.5 of these minutes for the MARC review of this article.

2.2.8 September 2003 minute item 4.1 Paroxetine and Risk of Harmful Outcomes in Paediatric Patients

Issue

The Committee recommended that the focus of the Prescriber Update article be altered to inform prescribers of concerns around an increased risk of suicidal thoughts and behaviour in paediatric patients receiving paroxetine treatment for depression. The article should refer to the related Dear Healthcare Professional letter issued to New Zealand prescribers in June 2003, and advise that specialist input be sought for children suffering from depressive illness.

Outcome

The Committee further considered the issue of SSRI antidepressant use for the treatment of paediatric depression at the March 2004 meeting. Please refer to section 3.1 of these minutes for associated discussion.

2.2.9 June 2003 minute item 3.1.3.1 Sodium tetradecyl sulphate/Premia 5 and DVT, drug interaction (54298)

Issue

The Committee recommended that the sponsor company for sodium tetradecyl sulphate be asked to update the product information to include current use of HRT as a contraindication. A letter should be sent to the Appearance Medicine Society of Australasia to inform them of this data sheet update, and to suggest that they incorporate this information into their Guidelines.

Outcome

In October 2003, New Zealand Medical and Scientific Ltd updated their Fibro-Vein data sheet to include current use of HRT as a contraindication.

Discussion

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

2.2.10 June 2003 minute item 3.1.4.1 Isotretinoin and dry skin/photosensitivity/flushing/vulval vaginitis/vulval discomfort (54986)

Issue

The Committee recommended that the sponsor companies for isotretinoin be asked to specify the possibility of vaginal and anal drying in the product data sheets.

Outcome

A letter, requesting that the product data sheets for Roaccutane and Oratane be updated to include drying of the vagina and anus as adverse effects, was sent to Roche Products (NZ) Ltd and Douglas Pharmaceuticals Ltd, respectively.

Douglas Pharmaceuticals Ltd updated the Oratane data sheet as requested in November 2003. A letter has been sent to Pacific Pharmaceuticals asking that the Isotane data sheet be similarly updated. Roche has not yet responded to this request; however, it has informed Medsafe that, due to lack of PHARMAC funding, Roaccutane will be discontinued in New Zealand in the very near future.

Discussion

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

2.2.11 June 2003 minute item 3.1.4.2 Itraconazole/budesonide/diltiazem and Cushing's syndrome/drug interaction (54458)

Issue

The Committee recommended that product sponsors for budesonide be asked to include the risk of Cushing's syndrome in the 'Interactions' section of budesonide data sheets.

Outcome

Astra Zeneca Ltd, Pacific Pharmaceuticals, and Douglas Pharmaceuticals were asked to add a statement about the risk of Cushing's syndrome, as a result of CYP3A4 inhibition, to the 'Interactions' section of their budesonide data sheets. In addition, Douglas and Pacific were asked to include the statement "The metabolism of budesonide is primarily mediated by CYP3A4, a subfamily of cytochrome P450. Inhibitors of this enzyme may therefore increase systemic exposure to budesonide."

Douglas and Pacific updated their data sheets as requested in December 2003 and September 2003, respectively.

Astra Zeneca Ltd has not yet responded to this request, and a follow-up letter has recently been sent.

Discussion

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

2.2.12 March 2003 minute item 3.1.2.1 Thyroguard and back pain/TSH decreased/fatigue (53598)

Issue

The Committee recommended that the above CARM case report be passed to the Compliance section of Medsafe for investigation and potential testing of Thyroguard.

Outcome

The Compliance section of Medsafe will test Thyroguard for the presence of thyroxine. Thyroguard is a Nutra-life product and was affected by the Pan Pharmaceuticals product recalls, so there may be some delay before a sample is obtained.

Discussion

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

2.2.13 September 2002 minute item 3.3.1 COX-2 inhibitors

Issue

In view of a BMJ editorial concerning limitations of the CLASS study, members recommended the sponsor company be asked to revise the Celebrex data sheet. The Committee advised that Medsafe compose appropriate data sheet statements to be presented to the company.

Outcome

The Celebrex data sheet update request was not actioned by the Pfizer office in New Zealand. The New Zealand office has since merged with the Pfizer office in Sydney, where the Celebrex data sheet update request is apparently under urgent review. A further follow-up letter has recently been sent.

Discussion

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

3. Pharmacovigilance Issues

3.1 SSRIs in child and adolescent Major Depressive Disorder

Reference Material

SSRIs in child and adolescent Major Depressive Disorder (Medsafe report - .., February 2004)

CSM Expert Working Group (December 2003) SSRIs: overview of regulatory status and CSM advice relating to Major Depressive Disorder in children and adolescents, including a summary of available safety and efficacy data.

American College of Neuropsychopharmacology (January 2004) Executive summary: preliminary report of the task force on SSRIs and suicidal behavior in youth.

Faculty of Child and Adolescent Psychiatry - Royal Australian and New Zealand College of Psychiatrists (28 January 2004) Official correspondence with the Australian Therapeutic Goods Administration re SSRIs in the treatment of MDD in children and adolescents.

Food and Drugs Administration (5 January 2004) Memo to the Psychopharmacologic drugs advisory committee and the Paediatric subcommittee of the of the anti-infective drugs advisory committee: Background on suicidality associated with antidepressant drug treatment.

Drug Information Dispatch (February 2004) Committee supports added warning for antidepressant use in pediatric patients.

Australian Therapeutic Goods Administration (March 2004) ADRAC statement on the use of SSRI antidepressants in children and adolescents.

Issue

The purpose of this agenda item was to inform the Committee about recent international regulatory activity regarding the use of SSRI antidepressants in the treatment of Major Depressive Disorder in children and adolescents. The Committee was asked to review the safety and efficacy of SSRIs when used to treat paediatric patients with depression, and to comment on what regulatory action, if any, should be taken in New Zealand.

Discussion

The Committee noted that in December 2003, the UK Committee on Safety of Medicines (CSM) issued a letter to UK health professionals informing them that a CSM Expert Working Group had completed a review of the clinical trial data regarding the safety and efficacy of SSRIs in the treatment of paediatric depression. On the basis of this review, the CSM advised prescribers that paroxetine, citalopram, escitalopram, sertraline, and venlafaxine should not be used for the treatment of depression in children less than 18 years of age. The CSM deemed the balance of risks and benefits of fluoxetine in these patients to be favourable.

The MARC examined reports from the UK CSM, the American College of Neuropsychopharmacology, US Food and Drug Administration (FDA) advisory committees, and the Royal Australian and New Zealand College of Psychiatrists.

Members agreed the studies regarding the safety and efficacy of SSRIs for the treatment of paediatric depression are small in size and are confounded by inconsistencies in how safety and efficacy are defined. Without additional information, the Committee could not accurately determine the risk:benefit ratio for the use of these medicines in treating children and adolescents with depression. The Committee noted that, in order to resolve some of the confounding factors in these studies, the FDA has commissioned a further analysis of the raw data. Members agreed to await the outcome of this FDA analysis before making a definitive statement about the use of SSRI antidepressants in children and adolescents.

The Committee noted that, in New Zealand, none of the SSRIs are approved for use in the treatment of depression in those under the age of 18 years. In addition, the New Zealand data sheets for SSRIs reflect the fact that safety and effectiveness in children has not been established. Members also noted that tricyclic antidepressants have poor safety and marginal efficacy when used to treat depressed children and adolescents.

Members agreed that Medsafe should issue a Dear Health Professional letter containing MARC advice about the use of SSRI antidepressants in children and adolescents. The letter should emphasise the need to seek specialist advice before prescribing any antidepressant to children under the age of 18 years, and to monitor all patients with depression for the emergence or worsening of suicidal thoughts and behaviours.

Recommendation

The Committee recommended that Medsafe issue a Dear Health Professional letter containing MARC advice about the use of SSRI antidepressants in children and adolescents with depression. The letter should emphasise the need to seek specialist advice before prescribing any antidepressant to children under the age of 18 years, and to monitor all patients with depression for the emergence or worsening of suicidal thoughts and behaviours.

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 CARM Case Reports

4.1.1 Reports in which death occurred

4.1.1.1 Risperidone and hypertension worse, stroke, osteoarthritis (57383)

Discussion

The Committee agreed that this case is complicated by the patient's pre-existing hypertension, and the fact that one or more of the other medications she was taking could have contributed to the CVA. The causal association was deemed "possible" for hypertension worse and stroke, and "unlikely" for osteoarthritis.

It was noted that the NZPhvC has received three other reports of hypertension with risperidone (in one, the causal relationship was considered unlikely), and one report of stroke in an 82-year-old man with multi-infarct dementia.

Members were informed that the UK Committee on Safety of Medicines (CSM) has recently considered the issue of atypical antipsychotics and CVA. The CSM intends to issue a letter to UK health professionals, primarily regarding an increased risk of stroke in elderly patients with dementia who are treated with risperidone or olanzapine. The Committee agreed that a watching brief should be placed on risperidone and CVA. In addition, Medsafe should review the aforementioned CSM advice and seek further information from the product sponsor, as is deemed necessary.

Recommendation

The Committee recommended that a watching brief should be placed on risperidone and CVA. In addition, Medsafe should review the recent CSM advice on atypical antipsychotic medicines and stroke, and seek further information from the product sponsor, as is deemed necessary.

4.1.1.2 Clozapine and congestive cardiac failure, myocarditis, cardiomegaly (58718)

Discussion

The Committee agreed that this patient had several risk factors for the cardiac failure that led to his death. Members questioned whether the hospital had conducted a mortality review for this patient, and speculated that withdrawal of his medications on admission to hospital may have contributed to his death. The causal association was deemed "possible" for myocarditis, congestive cardiac failure, and cardiomegaly.

4.1.1.3 Docetaxel and neutropenia, pneumonia, hypotension, abdominal pain, tachycardia (58691)

Discussion

The CARM database holds six reports for docetaxel - one each is associated with neutropenia, pancytopenia, agranulocytosis, death, and hypotension, and two are associated with agranulocytosis. The causal association was deemed "probable" for neutropenia, pneumonia, hypotension, abdominal pain, and tachycardia. No further action was recommended.

4.1.1.4 Flucloxacillin and rash erythematous, diarrhoea (58505)

Discussion

The CARM database holds 264 reports for flucloxacillin - 162 are associated with skin reactions, four with morbilliform rash, and seven with diarrhoea. The causal relationship was deemed "probable" for rash erythematous and diarrhoea. No further action was recommended.

4.1.1.5 Phenytoin and hepatic enzymes elevated (58230)

Discussion

Of 204 reports for phenytoin received by CARM, 19 are associated with hepatic disorders. The causal association was deemed "possible" for hepatic enzymes elevated, and no further action was recommended.

4.1.1.6 Rosiglitazone and pulmonary oedema, pleural effusion, oedema peripheral, renal failure, cardiovascular disorder (58230)

Discussion

Of 4834 reports for rosiglitazone in the WHO database, 390 are associated with cardiac failure, 57 with abnormal renal function, and 31 with cerebrovascular disorder. It was noted that the New Zealand data sheet for Avandia states that thiazolidinediones can cause fluid retention, which can exacerbate congestive heart failure. It also states that patients at risk of heart failure (particularly those on insulin) should be monitored for signs and symptoms of heart failure.

The causal association was deemed "possible" for pulmonary oedema, pleural effusion, oedema peripheral, renal failure, and cerebrovascular disorder. The Committee agreed that a watching brief should be placed on rosiglitazone and cardiac failure.

Recommendation

The Committee recommended that a watching brief be placed on rosiglitazone and cardiac failure.

4.1.1.7 Simvastatin, diltiazem and rhabdomyolysis, renal failure, drug interaction (58560)

Discussion

The CARM database holds five reports of rhabdomyolysis with statins. The Committee noted that an interaction between simvastatin and diltiazem was discussed at the December 2003 MARC meeting, and a related Prescriber Update article is in press. The causal association was deemed "probable" for rhabdomyolysis, renal failure, and drug interaction.

4.1.1.8 Tacrolimus and thrombocytopoenic purpura, haemolysis, drug level increased (58460)

Discussion

The CARM database holds 12 reports for tacrolimus (two of haemolysis, and one of Haemolytic-Uremic Syndrome) and one report for sirolimus, which is not associated with a haematological reaction. The Committee agreed that thrombocytopenia is a well-recognised event with tacrolimus. The causal association was deemed "possible" for thrombocytopenic purpura, haemolysis, drug level increased, and death. No further action was recommended.

4.1.1.9 Tiotropium, warfarin, colchicine and GI haemorrhage (58183)

Discussion

The Committee agreed that this elderly and unwell patient was at risk of gastrointestinal haemorrhage. This risk may have been increased by the concomitant administration of warfarin and colchicine; however, there is no evidence at present to implicate tiotropium. The causal association was deemed "possible" for gastrointestinal haemorrhage. No further action was recommended.

4.1.1.10 Tiotropium and cardiac arrest (58229)

Discussion

Of 247 reports for tiotropium held in the WHO database, there are seven reports of sudden death and no reports of cardiac arrest or arrhythmia. The causal association for the above case report was deemed "unlikely" for cardiac arrest.

4.1.2 Alternative medicine-related reports

4.1.2.1 Choline bitartrate, paroxetine and aggression aggravated (58116)

Discussion

Of 282 reports for paroxetine held in the CARM database, four are associated with an aggressive reaction. CARM has received no other adverse reaction reports for choline bitartrate. The Committee agreed that the presence of evidence for paroxetine-associated aggression, and the absence of other reports for choline bitartrate, suggests there is not an interaction between these two products. The causal association was deemed "possible" for paroxetine and aggression aggravated. No further action was recommended.

4.1.2.2 Thyrogen, Womens Tonic and weight loss, palpitations, T4 increased, thyrotoxicosis aggravated (58434)

Discussion

The Committee noted that Thyrogen 2000 contains potassium iodide, licorice root, bladderwrack, and zinc. Womens Tonic 2000 is reported to contain black cohosh, chaste tree, don quai, red raspberry, and licorice root. The CARM database holds no reports for either of these products; however there is one report of hyperthyroidism with Thyroguard, which also contains iodine. A search of the Natural Medicines Database revealed that bladderwrack has been reported to exacerbate hyperthyroidism, and chaste tree has been associated with agitation, anxiety, and tachycardia.

The causal association was deemed "possible" for weight loss, anxiety, palpitations, thyroxine (T4) increased, and thyrotoxicosis aggravated. No further action was recommended.

4.1.3 Psychiatric medication-related reports

4.1.3.1 Citalopram, prostaglandin, Syntometrine and abruptio placentae, foetal death (58196)

Discussion

The Committee noted there are multiple risk factors present for PROM. The causal association was deemed "possible" for abruptio placentae and foetal death. No further action was recommended.

4.1.4 Anticonvulsant medication-related reports

4.1.4.1 Topiramate and depression, thoughts of self-harm, suicidal tendency (57886)

Discussion

Of 17 reports for topiramate held in the CARM database, four are associated with psychiatric adverse events. The causal association for the above case report was deemed "probable" for depression, thoughts of self-harm, and suicidal tendency. The Committee noted that, in New Zealand, topiramate is not indicated for migraine prophylaxis, and members queried how common this off-label use might be. The Committee recommended that a watching brief be placed on reports of topiramate and severe psychiatric reactions.

Recommendation

The Committee recommended that a watching brief be placed on reports of topiramate and severe psychiatric reactions.

4.1.5 Antiinfective medication-related reports

4.1.5.1 Mebendazole and foetal death (58348)

Discussion

Of seven reports for mebendazole in the CARM database, there are none associated with foetal abnormalities or death. Given that mebendazole is poorly absorbed from the gastrointestinal tract, members questioned a possible mechanism of action in this case. The causal association was deemed "possible" for foetal death. No further action was recommended.

4.1.6 Cardiovascular medication-related reports

4.1.6.1 Simvastatin and vasculitis (58127)

Discussion

The Committee noted that Zocor and Lipex differ only in their name and packaging. In light of this, it was agreed that the development of vasculitis after the brand change is likely to have been a coincidental event. The causal association was deemed "possible" for vasculitis and brand-switch. No further action was recommended.

4.1.7 Hormone-related reports

4.1.7.1 DHEA and blurred vision, diplopia, nausea, weight gain, benign intracranial hypertension (58198)

Discussion

The causal association was deemed "probable" for vision blurred, diplopia, nausea, weight gain, and benign intracranial hypertension. No further action was recommended.

4.1.7.2 Estelle 35, clozapine and DVT, pulmonary embolism, drug interaction (58330)

Discussion

The causal association was deemed "possible" for thrombosis venous deep, embolism pulmonary, and drug interaction. No further action was recommended.

4.1.8 Musculoskeletal medication-related reports

4.1.8.1 Leflunomide and fever, bullous eruption, diarrhoea, MI, PE, UTI, hypothyroidism (58289)

Discussion

The causal association was deemed "probable" for fever, bullous eruption, and diarrhoea, "possible" for myocardial infarction, pulmonary oedema, and urinary tract infection, and "unlikely" for hypothyroidism. The Committee agreed that leflunomide and all adverse reactions should be made Adverse Reactions of Current Concern.

The Committee discussed the issue of leflunomide and interstitial pneumonia, which is currently being discussed and investigated internationally by Aventis Pharma and a number of medicines regulatory agencies. Members agreed that Medsafe should obtain the most recent Periodic Safety Update Report for this medicine, along with any relevant communications between Aventis Pharma Head Office and the European Agency for the Evaluation of Medicinal Products (EMEA) on this issue. The Committee requested that Medsafe report back on the issue of leflunomide and interstitial pneumonia at the June 2004 MARC meeting.

Recommendations

The Committee recommended that leflunomide and all adverse reactions should be made Adverse Reactions of Current Concern.

The Committee also recommended that Medsafe obtain the most recent Periodic Safety Update Report for leflunomide, along with any relevant communications between Aventis Pharma Head Office and the European Agency for the Evaluation of Medicinal Products (EMEA) regarding leflunomide and interstitial pneumonia. The Committee requested that Medsafe report back any significant findings at the June 2004 MARC meeting.

4.2 Spontaneous reporting programme - signals

4.2.1 Severe application site reactions with pimecrolimus (Elidel)

Issue

As at December 2003, CARM had received 30 reports of adverse reactions to pimecrolimus - of these, 24 are associated with application site reactions. Ten of these reports are for reactions described as severe, with eight occurring in children. The reactions include bullous eruption, oedema, severe burning sensation, application site pain, severe erythema, dermatitis, and desquamation.

Discussion

The Committee noted that, while the New Zealand data sheet for Elidel indicates that various application site reactions can occur with this product, it does not reflect the potential for severe reactions. Members agreed that Medsafe should inform the New Zealand sponsor for Elidel about the CARM case reports, and request that the data sheet be amended to reflect the potential for severe local reactions. The Committee also agreed that prescribers should be informed about the possibility of severe application site reactions with pimecrolimus by way of an article in Prescriber Update.

Recommendation

The Committee recommended that the New Zealand sponsor for Elidel should be informed of CARM case reports regarding severe application site reactions with this product. The sponsor should be asked to amend the Elidel data sheet to reflect the potential for severe local reactions. The Committee also recommended that prescribers be informed about the possibility of severe application site reactions with pimecrolimus by way of an article in Prescriber Update.

4.2.2 IC-values presentation

Issue

In order to further inform the Committee about the use of IC-values in pharmacovigilance, members requested that Ruth Savage liaise with a statistician to present both practical and technical issues around IC-values. Drs Patrick Graham and Ruth Savage gave a joint presentation to the Committee entitled 'Signal detection in the WHO spontaneous reporting database via a Bayesian neural network: some Bayesian background'.

Discussion

The Committee noted a number of points regarding neural network architecture, Frequentist and Bayesian logic, and the mechanics of Bayesian inference for IC-values. Dr Graham concluded that IC-values are useful screening tools for the WHO spontaneous reporting database. It was noted, however, that alternative Bayesian data-mining methods should be considered and compared with the IC-value approach, and that substantial precision gains would be possible if more use was made of prior information (e.g., similarities and differences between medicines).

Members were extremely grateful to hear an independent opinion about the use of Bayesian Confidence Propagation Neural Network methodology in pharmacovigilance. The Committee thanked Drs Graham and Savage for their highly informative presentation.

4.3 CARM Quarterly report (as at 31 December, 2003)

4.3.1 Multiple occurrence reaction reporting

≥ Three Reports in the Last Quarter

4.3.1.1 Brand-switch related reports

Paracetamol + codeine phosphate (switch from Panadeine to Codalgin): 1 report of reduced therapeutic effect has been received.

Morphine sulphate (switch from MST to Kapanol): 1 report of disorientation and agitation has been received.

Benztropine mesylate (switch from Cogentin to Benztrop): 1 report of increased therapeutic effect has been received.

Citalopram (switch from Cipramil to Celapram): 8 reports have been received this quarter (a drop from 30 in the previous quarter).

No further reports of brand-switch reactions were reported with clonazepam, dipyridamole, or gliclazide.

4.3.1.2 Other medicine-related reports

Three reports of vomiting with rivastigmine have been received this quarter. In addition, there are nine reports of application site reactions with pimecrolimus in this quarter. Three or more reports have also been received for carbamazepine, rocuronium, simvastatin, flucloxacillin, and amoxycillin/clavulanic acid. A background level of X-ray contrast media hypersensitivity reactions is once again reflected.

4.3.1.3 Vaccine-related reports

The pattern of adverse events following immunisation is largely unremarkable with typical expected events. Vaccines with three or more specific events are DT, MMR, DTaP/HiB, ADT, DTaP/IPV, HepB, HiB/HepB, and IPV.

≥ Six Reports in the Year-to-Date

There are two new medicines in this section (enalapril brand-switch reports, and amoxycillin/clavulanic acid hypersensitivity reaction reports). The reports reflect reactions that are not unexpected, or those that are reported with low frequency.

Adverse Reactions of Current Concern

Recommendations

The Committee recommended that the following reactions be removed from the list of Adverse Reactions of Current Concern.

• Celecoxib and cardiovascular events
• Rofecoxib and cardiovascular events
• Atypical antipsychotics and hyperglycaemia
• Fluticasone (inhaled) and adrenal insufficiency, hypoglycaemia, seizure
• Oral contraceptives and venous thromboembolism
• HRT and venous thromboembolism

The Committee recommended that all adverse reactions to complementary and alternative medicines (CAMs), and SSRIs and agitation, restlessness/akathisia, suicidality should remain adverse reactions of current concern.

4.4 Intensive Medicines Monitoring Programme

4.4.1 Review of the Intensive Medicines Monitoring Programme (IMMP report - ..)

Issue

.. of the IMMP conducted this review in order to determine whether the current work of the IMMP is sustainable with the available resource. In addition, the review provided a base from which to plan and prioritise the future work of the IMMP. The review concluded that, overall, the IMMP was attempting to perform too large an amount of work for the resource available. The high number of medicines on the IMMP, and the monitoring of two very large cohorts, resulted in an overloading of the system. It was concluded that it might be necessary to adapt the current IMMP methodology in order to perform studies within a shorter time frame.

The IMMP review identified changes that need to be made to make the programme more effective, focused, and resource-efficient. Such changes include removing some medicines from the IMMP and restricting the amount of follow-up performed on the remaining medicines.

Discussion

The Committee noted the IMMP review. Members agreed that Medsafe should provide the MARC with details of how pharmacovigilance might be managed in the upcoming Joint Trans-Tasman Agency, for discussion at the June 2004 MARC meeting. Such a document may stimulate useful discussion about possibilities and improvements in the post-marketing surveillance of medicines in the future.

Recommendation

The Committee recommended that Medsafe provide members with details of how pharmacovigilance might be managed in the upcoming Joint Trans-Tasman Agency, for discussion at the June 2004 MARC meeting.

5. PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

The Committee did not discuss 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 Antibiotics and breast cancer

References

Ness & Cauley (2004) Antibiotics and breast cancer - what's the meaning of this? JAMA, 291(7), 880-881.

Velicer et al (2004) Antibiotic use in relation to the risk of breast cancer. JAMA, 291(7), 827-835.

5.2 New antiepileptic medications

References

LaRoche & Helmers (2004) The new antiepileptic drugs: Scientific review. JAMA, 291(5), 605-614.

LaRoche & Helmers (2004) The new antiepileptic drugs: Clinical applications. JAMA, 291(5), 615-620.

5.3 HRT

References

Holmberg & Anderson (2004) HABITS (hormonal replacement after breast cancer - is it safe?), a randomised comparison: trial stopped. Lancet, 363, 453-455.

Chlebowski (2004) Menopausal hormone therapy after breast cancer - commentary. Lancet, 363, 410-411.

McPherson (2004) Where are we now with hormone replacement therapy? BMJ, 328, 357-358.

Minelli et al (2004) Benefits and harms associated with hormone replacement therapy: clinical decision analysis. BMJ, 328, 371-376.

5.4 Statins

References

Yang et al (2003) Lipid-lowering drugs and the risk of depression and suicidal behaviour. Archives of Internal Medicine, 163, 1926-1932.

Young-Xu et al (2003) Long-term statin use and psychological well-being. Journal of American College of Cardiology, 42, 690-697.

5.5 Vaccines

References

Kissam et al (2004) Is signed consent for influenza or pneumococcal polysaccharide vaccination required? Archives of Internal Medicine, 164, 13-16.

Jefferson et al (2003) Unintended events following immunization with MMR: a systematic review. Vaccine, 21, 3954-3960.

5.6 Medical device surveillance

References

Samore et al (2004) Surveillance of medical device-related hazards and adverse events in hospitalised patients. JAMA, 291(3) 325-334.

Small (2004) Medical device-associated safety and risk. JAMA, 291(3) 367-370.

5.7 Warfarin interactions and ADRs

References

Suvarna et al (2003) Possible interaction between warfarin and cranberry juice. BMJ, 327, 1454.

Srinivasan et al (2004) Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Archives of Internal Medicine, 164, 66-70.

5.8 Dietary supplements

References

McBride et al (2004) Electrocardiographic and hemodynamic effects of a multicomponent dietary supplement containing ephedra and caffeine: a randomised controlled trial. JAMA, 291(2), 216-221.

5.9 Miscellaneous case series

References

Bolland et al (2003) Cushing's syndrome due to interaction between inhaled corticosteroids and itraconazole. Annals of Pharmacotherapy, 38.

Veitch & Clifton-Bligh (2004) Long-acting sulfonylureas - long-acting hypoglycaemia. MJA, 180, 84-85.

Peter et al (2004) Severe hypoglycaemia after being given intravenous bisphosphonate. BMJ, 328, 335-336.

Morton et al (2004) Rash and acute nephritic syndrome due to candesartan. BMJ, 328, 25.

Nisbet et al (2004) Metformin and serious adverse effects. MJA, 180, 53-54.

5.10 CARM case reports

Premarin and DVT (57799)

Amiodarone and back pain (57899)

Starch buster and abdominal pain, hepatic enzymes raised (58193)

Nicotinic acid and flushing, dysaesthesiae (58279)

Healtheries Immunity Boost and rash purpuric, urticaria (58355)

Thermotrim, Reviva and hepatic function abnormal (58605)

Good Health Body Burn Activator and anxiety, paraesthesiae, dizziness, diarrhoea (58671)

Citrimax and hypertension (58701)

Nature Bee Potentiated Pollen and hypoaesthesiae, paraesthesiae (58757)

6. New Zealand Activities

6.1 Publications

Skegg, D.C.G. (2003) Autism and measles-mumps-rubella (MMR) vaccination: a challenge for pharmacoepidemiology. Pharmacotherapy, 23(12), 1521-1523.

Gladding, P (in press) Potentially lethal interaction between diltiazem and statins. Annals of Internal Medicine.

7. International Activities

7.1 WHO

WHO Pharmaceuticals Newsletter No. 1, 2004

7.2 Canada

Canadian Adverse Reaction Newsletter 14(1), January 2004

Health Canada - It's Your Health. Safe use of natural health products. January 2004

Health Canada - It's Your Health. Benefits and risks of combined HRT. January 2004

7.3 USA

FDA - Safety concerns associated with OTC products containing analgesic/antipyretic active ingredients for internal use (Science Background, Letter, and Press Release). January 22, 2004.

7.4 Australia

Australian Adverse Drug Reactions Bulletin 22(6), December 2003

Australian Adverse Drug Reactions Bulletin 23(1), February 2004

Minutes of the October 2003 meeting of the Adverse Drug Reactions Advisory Committee

8. summary of case reports considered by marc (1997 to 2003)

CARM case reports considered by the MARC

Vaccine adverse reaction reports considered by the MARC

Complementary and alternative medicine case reports considered by the MARC

The meeting ended at 5:00pm