Revised: 21 May 2013

Committees

Minutes of the 115th Medicines Adverse Reactions Committee Meeting - 29 September 2003

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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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
Professor D.C.G. Skegg
Dr M. Rademaker
Dr F. McClure
Dr N. Rafter
Dr M. Tatley
Dr H. Kingston

marc secretariat present

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

Invited Experts

Dr M. Harrison-Woolrych (NZPhvC)

Visitors

Dr A. Roberts (Ministry of Health) (present for vaccine-related section of CARM Quarterly Report
Dr A. Lethaby (New Zealand Guidelines Group) (present for agenda item 3.1 - HRT, breast cancer and mammography).

1. MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed Mira Harrison-Woolrych of the NZPhvC to the meeting.

1.2 Minutes of the 114^th meeting

Members agreed that the minutes of the 114^th meeting are a true and accurate record of the meeting.

1.3 Date of next meeting

It was requested that the December MARC meeting be moved from the 4^th to the 10^th of December 2003.

1.4 Conflict of interest

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

1.5 Prescriber Update

Article

.., Thrombosis with Tranexamic for Menorrhagia (pre-peer review version).

Discussion

The Committee noted that this was a good and informative article. It was agreed that it should be made clear that the article is based on theoretical considerations and CARM case reports, rather than pharmacoepidemiological evidence.

2. MATTERS ARISING

2.1 Report on actions arising from the 114^th MARC meeting

2.1.1 Minute item 2.1.2 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.

Outcome

A letter, requesting that a Dear Healthcare Professional letter regarding the safety of leflunomide be issued to New Zealand prescribers, was sent to Aventis Pharma Ltd. Aventis has responded by telephone to say that a Dear Healthcare Professional letter will be drafted and provided to Medsafe.

Discussion

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

2.1.2 Minute item 2.1.8 Presentation on IC-values

Issue

The Committee recommended that .. liaise with an appropriate statistician to present both practical and technical issues around IC-values at a future MARC meeting.

Outcome

It is intended that this issue will be brought to the March 2004 MARC meeting. In addition, .. of the Uppsala Monitoring Centre has recently completed a PhD in the area of Bayesian Confidence Propagation Neural Networks (BCPNN). Medsafe holds a copy of Dr Bate's thesis, entitled The use of BCPNN in Pharmacovigilance, which can be made available to MARC members on request.

Discussion

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

2.1.3 June 2002 minute item 2.2.3 SSRIs and GI haemorrhage

Issue

The Committee recommended that Medsafe investigate whether the issue of SSRIs and GI bleeding is mentioned in international data sheets for Anafranil and Prozac. If so, the sponsor companies should be asked to include this information in the New Zealand product data sheets.

Action

Risk of GI bleeding is not mentioned in the Australian product information for Anafranil (clomipramine). ADRAC has received one report of 'peptic ulcer' out of 167 reports for clomipramine. Similarly, no reference to GI bleeding is made in the Australian product information for Prozac (fluoxetine).

Discussion

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

2.1.4 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 August, a letter requesting that the Fibro-Vein data sheet be updated to include current use of HRT as a contraindication was sent to New Zealand Medical and Scientific Ltd. A response to this letter has not yet been received.

A letter was also sent to the Secretary of the Appearance Medicine Society of Australasia, asking that they remind their members of the potential for the above interaction, and suggesting that they incorporate this contraindication into the AMSA's Guidelines.

Discussion

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

2.1.5 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, has been sent to Roche Products (NZ) Ltd and Douglas Pharmaceuticals Ltd, respectively. Responses to this request have not yet been received.

Discussion

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

2.1.6 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 have been 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 have been 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." Responses to these requests have not yet been received.

Discussion

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

2.1.7 Minute item 3.4.4.1 Brand-switch related reports

Issue

The Committee recommended that CARM forward their analysis of the clonazepam brand-switch reports to Medsafe.

The Committee also recommended that Medsafe write to the Pharmacy Guild, reminding pharmacists that they have an obligation not to dispense narrow therapeutic medications, such as clonazepam, without checking with the doctor as to which brand the patient is on.

Outcome

In June 2003, the Paxam brand of clonazepam became a sole subsidised supply product. GSK has since informed Medsafe that the Rivotril tablets will no longer be supplied to the New Zealand market.

Pharmacologically, Medsafe does not consider clonazepam to be a narrow therapeutic index medicine; however, the consequences of undermedicating in epilepsy can be serious. On enquiry, Pharmac has informed Medsafe that the Tender Medical Committee and Pharmac Board took this issue into account when the decision was made to make Paxam a sole supply product.

2.1.8 Item 3.5.2 Risperidone and epistaxis, bleeding disorders

Issue

The Committee recommended that Medsafe investigate references to thrombocytopenia in the international product information for risperidone, before deciding whether the current New Zealand data sheet statement ("a mild fall in thrombocyte count has been reported") should be strengthened.

Outcome

The Australian product information for risperidone states that, "a decrease in neutrophil and/or thrombocyte count has been reported". The FDA-approved data sheet states that thrombocytopenia was observed rarely (i.e., in <1/1000 patients) during pre-marketing evaluation of Risperdal. Janssen-Cilag has recently strengthened the New Zealand Risperdal data sheet with regard to thrombocytopenia - the statement is now identical to that in the Australian product information.

In addition, the IMMP has further analysed the WHO cases of epistaxis associated with risperidone. Of the original 56 reports of this association, 39 contained the minimum information required for assessment (i.e., a start date for risperidone treatment and an onset date for epistaxis). Two of these originated from New Zealand and were considered at the June 2003 MARC meeting. Of the remaining 37 reports, the outcome for 29 of the cases is unknown. In the 8 patients where outcome was known, 7 recovered and 1 died (the patient had a medical history of oesophageal carcinoma and other non-specified haemorrhage).

In 22 of the aforementioned 37 cases, epistaxis began within three weeks of starting risperidone. Of the 12 cases where dechallenge data were available, 10 showed evidence of a positive dechallenge. Rechallenge was carried out in three of these patients - in one case the rechallenge was positive, and in the other two it was negative.

In conclusion, while the WHO cases provide some additional information to the New Zealand cases, data are frequently missing or inadequate. The IMMP intends to publish the New Zealand case reports (with the WHO information as supporting data).

Discussion

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

2.1.9 Minute item 4.1 Paroxetine and Risk of Harmful Outcomes in Paediatric Patients

Reference material

Hazell, P (2003) Depression in children of primary school age - more common than may be expected. New Ethicals Journal, July, 41-43.

Therapeutic Guidelines: Psychotropic (2000 4^th ed.)

Issue

The Committee agreed that an article about the management of depression in children should be written for publication in Prescriber Update. The article should make particular reference to risk of harmful outcomes with paroxetine, and the fact that the FDA has approved fluoxetine for the treatment of depressive illness in children.

Outcome

Medsafe sought comment about the potential for such a Prescriber Update article from a number of experts in this area. One specialist in particular commented that the evidence base for the drug treatment of depressed children is not strong, with few randomised controlled trials. In his opinion, over-reactions to 'evidence' and uncertainties about the weight of the evidence would suggest the need for a cautious approach, and avoidance of knee-jerk reactions.

Medsafe also noted that the New Zealand College of Psychiatrists supports the 'Therapeutic Guidelines - Psychotropic' in relation to the treatment of major depressive disorder in children. Also, an article regarding depression in children of primary school age was published in the July 2003 issue of New Ethicals Journal.

In light of the above, Medsafe does not believe it is appropriate to publish a Prescriber Update article about the management of depression in children. The Committee was therefore asked to reconsider its June 2003 recommendation.

Discussion

Members believed that issuing MARC advice on the use of paroxetine for the treatment of depressive illness in children would be helpful to prescribers. It was agreed that a Prescriber Update article should be written, but the focus of the article should be to remind prescribers of concerns around an increased risk of suicidal thoughts and behaviour in children and adolescents treated with paroxetine. The article should also remind prescribers that a related Dear Healthcare Professional letter was issued by GSK to New Zealand prescribers in June 2003. The Committee also advised that, where possible, children suffering from depression should be referred to a specialist in psychiatry.

Recommendation

The Committee recommended that the focus of the Prescriber Update article be altered to remind 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.

2.1.10 Minute item 4.2 Combined Hormone Replacement Therapy and Dementia

Issue

The Committee recommended that product sponsors for combined HRT be asked to update their data sheets to include a statement about the possible increased risk of dementia.

Outcome

Medsafe will make this data sheet update request when the current section 36 action regarding HRT is complete.

Discussion

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

2.1.11 Minute item 4.3 Risperidone and Cerebrovascular Accidents in Elderly Patients with Dementia

Issue

The Committee recommended that Medsafe contact the product sponsor for risperidone, requesting that a Dear Healthcare Professional letter be issued to inform prescribers of the risk of cerebrovascular accidents in elderly patients with dementia. The letter should advise prescribers to reassess the use of Risperdal in elderly dementia patients, and inform patients/caregivers of the signs and symptoms of potential cerebrovascular adverse events.

Outcome

Janssen-Cilag issued a Dear Healthcare Professional letter, regarding Risperdal and cerebrovascular accidents, to New Zealand prescribers in June 2003.

As discussed at the June 2003 MARC meeting, Janssen-Cilag recently revised the Risperdal data sheet to include the risk of cerebrovascular adverse events in elderly patients with dementia-related psychosis. Given reports of thrombocytopenia with this product, the IMMP suggested that these cerebrovascular events might be related to an increased bleeding tendency. Medsafe has since received and reviewed the Janssen-Cilag Cerebrovascular Adverse Events (CAE) Clinical Expert Report, with regard to reports of haemorrhagic and thrombotic stroke. The term CAE included all adverse events within the WHO preferred term of cerebrovascular disorder (i.e., stroke, TIA, CVA, cerebral infarct, cerebral ischaemia, cerebrovascular disturbance, and cerebrovascular disorder - not cerebral haemorrhage).

Twenty-four serious CAEs were reported in the risperidone dementia studies. Of these, nineteen occurred in risperidone-treated patients, four in placebo-treated patients, and one in a patient receiving haloperidol. The mean age of the nineteen risperidone-treated patients was 82-years, and seven patients had a reported history of CVAs. Two of the nineteen patients underwent a CT scan but the case reports do not state whether the CVA was thought to be thrombotic or haemorrhagic.

Seven serious CAEs were reported in risperidone schizophrenia studies (all seven patients were being treated with risperidone). The case histories provided for these patients (mean age = 52-years) contain more detail than those from the dementia studies. One patient underwent an MRI, which showed multiple CVAs that were felt to be embolic, while another patient suffered a pulmonary embolus. Two other patients received CT scans but the case reports do not state whether the CVA was thought to be thrombotic or haemorrhagic (however, subsequent treatment of one patient with heparin and acetylsalicylic acid indicates a thrombotic event).

In conclusion, there is no evidence to indicate that the risk of cerebrovascular adverse events in elderly patients with dementia-related psychosis is related to an increased bleeding tendency.

Discussion

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

2.1.12 Minute Item 3.2.1 Influenza vaccine and Guillain Barre Syndrome

Issue

The Committee recommended that CARM write a letter to the Neurological Association of New Zealand to seek their views on the issue of influenza vaccine and GBS, and the need for epidemiological research in this area.

Outcome

CARM is currently awaiting a response from the Neurological Association.

Discussion

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

2.2 Report on actions outstanding

2.2.1 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.

2.2.2 March 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 and eformoterol to strengthen product data sheet advice, emphasising that the use of these medicines as maintenance therapy should be in addition to corticosteroid treatment of asthma.

Outcome

The above request was made in letters sent to GSK regarding Serevent, and Novartis regarding Foradil.

Novartis has declined to strengthen the Foradil data sheet advice regarding the use of eformoterol as maintenance therapy in addition to corticosteroids. Novartis believes this information is adequately covered in the Foradil data sheet and does not require further amendment. Medsafe has replied to say that the suggested changes were intended to improve the clarity of the information provided in the data sheet, and it is regrettable that Novartis does not wish to implement these improvements.

Medsafe is awaiting a response from GSK.

Discussion

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

2.2.3 December 2002 minute item 2.1.4 HRT and cancer/stroke/heart disease

Issue

The Committee recommended that Medsafe request a copy of the minutes of PTAC's osteoporosis and hormone sub-committee meeting. Following this, Medsafe should decide whether it is still necessary to convene an HRT/osteoporosis working party.

Outcome

Medsafe received and reviewed a copy of sub-committee minutes in July 2003, and a decision was made not to convene an HRT/osteoporosis working party. The NZGG, Osteoporosis New Zealand, and the Scottish Intercollegiate Guidelines Network (SIGN) all advocate bisphosphonates as first-line therapy for osteoporosis. In addition, PTAC's osteoporosis and hormone sub-committees have recommended that the current restriction on etidronate be removed from the Pharmaceutical Schedule to enable GP prescribing of this drug.

Discussion

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

2.2.4 December 2002 minute item 4.1 High-dose fluticasone and adrenal insufficiency

Issue

The Committee recommended that Medsafe write to product sponsors requesting that they review their product data sheets in light of the NZGG advice around appropriate daily doses of inhaled corticosteroids. If appropriate justification for the recommended doses in the data sheets cannot be provided, the data sheets should be suitably updated. Medsafe should determine whether this applies to all inhaled corticosteroids, or to fluticasone alone.

Dosage advice for adults and children over 16 years of age in the Flixotide data sheet:

Dosage advice for fluticasone in the NZGG Guidelines for the Diagnosis and Treatment of Adult Asthma:

Outcome

A letter was sent to GSK in March 2003 requesting that, in the event that they are unable to provide data to justify the discrepancies in dosage advice, the Flixotide product information be updated to reflect that of NZGG.

GSK has responded to say that the current posology in the Flixotide product information is supported by data in the original application dossier to Medsafe. In addition, GSK believes the posology section of the Flixotide data sheet is in line with international guidelines (e.g., British Thoracic Society Guidelines 2003, and the Global Initiative for Asthma Control Guidelines 2002). It is asserted that guidelines are attempts to reach consensus on best practice evidence-based application of treatments, and they do not override the submitted body of evidence supporting efficacy and safety of individual medications.

GSK notes that the meta-analysis cited by the NZGG (Holt et al, 2001) is limited by a lack of data for individual patients and a lack of dose-response studies that included doses of Flixotide greater than 500 micrograms/day. GSK also note that it is important to recognise that mean effective dose response data derived from large patient cohorts do not necessarily translate to the treatment of an individual patient. In this regard, GSK summarises other studies that have demonstrated improvements in asthma control with escalating doses of an inhaled corticosteroid.

In summary, GSK maintains that the posology section of the Flixotide data sheet is aligned with international best practice and should not be changed. Any further restrictions placed on prescribers in prescribing high doses may contribute to lack of asthma control.

Discussion

Members agreed that prescribers should be made aware that the MARC supports the dosage advice in the NZGG Guidelines for the Diagnosis and Treatment of Adult Asthma. It was also agreed that prescribers should be alerted to the fact that there is a discrepancy between the GSK dosing advice in the Flixotide data sheet and that supported by the MARC.

Recommendation

Members recommended that a paragraph, indicating to prescribers that the MARC supports the NZGG Guidelines for the Diagnosis and Treatment of Adult Asthma dosage advice, and that this advice is different from that in the Flixotide data sheet, be written for publication in Prescriber Update. This information should be published as MARC advice, and should accompany the general article about asthma therapy currently being prepared for Prescriber Update.

2.2.5 Sept 2002 minute item 3.3.1 COX-2 inhibitors

Issue

In view of a recent 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

In February 2003, Medsafe sent a letter to Pharmacia advising of discrepancies between the New Zealand, and Australia and American product information sheets for Celebrex. If Pharmacia is unable to justify these differences, the New Zealand Celebrex data sheet should be appropriately updated (requested changes are with regard to GI effects, anaphylactoid reactions, and serious adverse reactions that occur rarely (<0.1%)).

In addition, Pharmacia has been asked to provide comment on recent findings concerning limitations of the CLASS study.

Discussion

Members were extremely concerned that some companies were not responding, or were taking many months to respond, to pharmacovigilance requests made by Medsafe. It was suggested that New Zealand prescribers be informed when a company has been asked to address a medicines safety issue and has not responded. This could be communicated by way of Prescriber Update or the Medsafe website.

The Committee agreed that Medsafe should develop a process to ensure responses from product sponsors are timely. The drafted process should be brought to the December 2003 MARC meeting for discussion.

Recommendation

The Committee recommended that Medsafe develop a process to ensure responses from product sponsors are timely. The drafted process should be brought to the December 2003 MARC meeting for discussion.

2.2.6 December 2002 minute item 2.1.4 HRT and cancer/stroke/heart disease

Issue

The Committee recommended that Medsafe ask the product sponsor for Cerazette to change the missed-pill advice from 12 to 3 hours in the New Zealand datasheet, unless the company is able to provide evidence supporting the 12-hour rule.

Outcome

The above request has been made in a letter sent to the product sponsor, Pharmaco. Medsafe has since sent a letter of reminder to Pharmaco and is awaiting a response.

Discussion

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

3. Pharmacovigilance Issues

3.1 Hormone replacement therapy, breast cancer and mammography

Reference material

Medsafe report - HRT, breast cancer and mammography (September 2003)

Chlebowski et al (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the WHI randomised trial. JAMA, 289, 3243-3253.

Li et al (2003) Relationship between long duration and different regimens of hormone therapy and risk of breast cancer. JAMA, 289, 3254-3263.

Million Women Study Collaborators (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet, 362, 419-427.

Wyeth Dear Doctor Letter (June 2003) Updated report on breast cancer from the Women's Health Initiative.

UK CSM Dear Healthcare Professional Letter and Fact Sheet (August 2003) HRT and breast cancer - results of the UK Million Women Study.

ADEC media release and ADEC statement on use of HRT (August 2003).

New Zealand Guidelines Group draft of revised recommendations on hormone replacement therapy (2003).

Issue

The purpose of this agenda item was to inform the Committee about new evidence relating to HRT use, breast cancer, and mammography. The Committee's opinion on whether this issue requires further regulatory action in New Zealand was sought.

In September 2002, Medsafe issued the following MARC advice to New Zealand prescribers:

• Combined HRT should normally be used only where menopausal symptoms are disruptive to the quality of life of the woman;
• HRT should not be used for the primary or secondary prevention of coronary heart disease or stroke;
• In most circumstances, the risks of long-term treatment outweigh the benefits; and combined HRT should not be used for longer than 3-4 years;
• Oestrogen-only HRT increases the risk of breast cancer and venous thromboembolism to a similar extent as combined HRT;
• All prospective and current users of HRT should be advised of the risks and benefits of oestrogen and progestogens;
• The need for continued treatment with HRT should be reviewed at the woman's next visit to her General Practitioner and thereafter on a yearly basis.

In June 2003, an updated WHI report on the influence of combined HRT on breast cancer and mammography was published in JAMA. Also published in this issue was a study investigating the relationship between duration of HRT use and risk of breast cancer by histological type and hormone receptor status. In addition, results from the Million Women study, which was set up to investigate the effects of specific types of HRT (oestrogen-only, combined oestrogen-progestogen, and the synthetic sex steroid, tibolone) on incident and fatal breast cancer, were published in August 2003.

Key findings from the above three studies included:

• Current use of HRT increased the risk of incident and fatal breast cancer in a duration-dependent manner. The greatest increase in risk occurred with combined HRT.
• Ceasing HRT reversed the risk of breast cancer over time, and within five years had reached the same level as in women who had never taken HRT.
• Risk of breast cancer is not limited to oral HRT preparations (the risk was also shown with patches and implants).
• An increase in the risk of breast cancer becomes apparent within one to two years of starting treatment.
• Breast cancers in HRT-treated women were more likely to be larger and more advanced than in placebo-treated patients (but were of similar histology and grade).
• Mammography results showed a statistically significant increase in abnormal mammograms in the HRT-treated group from year one onwards.

In June 2001, companies marketing HRT products in New Zealand were issued a letter under section 36 of the Medicines Act. This section 36 notice concerned the safety of HRT products with respect to cerebrovascular and cardiovascular disease, and advised sponsors of data sheet changes recommended by the MARC. In February 2003, Medsafe issued an update to the June 2001 section 36 notice, which asked that HRT data sheets be further updated in light of significant hormonal therapy studies that had been published in the preceding eight months. Included amongst these changes was the request to "Delete from the data sheet any misleading statements (e.g. about lack of evidence of causality of breast cancer)".

With regard to breast cancer, typical data sheet statements at present include:

"….increase in the risk of having breast cancer diagnosed in women who have used HRT for more than five years. The findings may be due to an earlier diagnosis, the biological effects of HRT, or a combination of both."

"The relative risk increases with duration of treatment. This increased risk gradually disappears during the course of the first five years after cessation of HRT."

"Breast cancers found in women using HRT are more likely to be localised to the breast than those found in non-users."

Discussion

Members agreed that New Zealand prescribers should be informed of the key findings from the three recent HRT and breast cancer studies by way of a Prescriber Update article. In particular, the Committee agreed that prescribers should be made aware that, while the risk of breast cancer is increased with all types of HRT, the risk is greatest with combined preparations. Members noted that HRT is an effective short-term treatment option for menopausal symptoms, and agreed that the Million Women Study shows the absolute risk of breast cancer with HRT is not large, and some women may wish to take this risk.

Members noted that the Million Women Study shows an increase in the risk of breast cancer within one to two years of starting HRT. In light of this, members agreed the September 2002 MARC statement, "In most circumstances…combined HRT should not be used for longer than 3-4 years" is no longer appropriate. The Committee now advises that the risk of adverse effects increases with duration of HRT use, and that HRT should be used for as short a time as possible. In addition, the MARC now advises that the need for continued treatment with HRT should be reviewed on a six-monthly, rather than a yearly, basis. It was agreed that this new MARC advice should be communicated to prescribers in the aforementioned Prescriber Update article. The article should be combined with the HRT and dementia article currently being written for publication in Prescriber Update.

The Committee agreed that sponsors of all HRT products, including tibolone, should be asked to include statements that reflect the risk of breast cancer in their product data sheets. This request should be separate from the current section 36 notice that has been issued to HRT sponsors.

Members noted that an on-going WHI ancillary study is evaluating the relationship between breast density, mammographic interpretation, and breast cancer risk in a subgroup of patients. The Committee does not wish to provide advice regarding HRT and mammography until further data are available.

The Committee noted the draft of revised recommendations on HRT produced by the New Zealand Guidelines Group. Members did not believe these should be issued as they are, and agreed to provide comment to the NZGG outside of the meeting.

Recommendations

The Committee recommended that the key findings of the recent HRT and breast cancer studies be communicated to prescribers by way of a Prescriber Update article. In particular, this article should provide an indication of the absolute risk of breast cancer with HRT, and note that the risk is greatest with combined HRT preparations. The article should also inform prescribers that the MARC has altered its advice that, "in most circumstances…combined HRT should not be used for longer than 3-4 years", and now simply states that the risk of adverse effects increases with duration of HRT use, and should be used for as short a time as possible. In addition, the MARC now advises that the need for continued treatment with HRT should be reviewed on a six-monthly, rather than a yearly, basis.

The Committee recommended that Medsafe write to sponsors of all HRT products, including tibolone, requesting that statements that reflect the risk of breast cancer (and the potential delay in diagnosis through mammography) be included in HRT product data sheets. This request should be separate from the current section 36 notice that has been issued to HRT product sponsors.

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 Donepezil and syncope, concussion, sudden death (55732)

Discussion

Of 12 reports in the CARM database for donepezil, three are associated with sudden death, three with syncope, three with rhythm disorders, and one with a fall. In addition, three recent studies investigating the efficacy of donepezil report syncopal events as serious adverse events. Members noted that the product data sheet for donepezil lists syncope as occurring in 2% of patients in pre-marketing clinical trials. Due to incomplete case history details, the causal association for this case report was deemed to be "unclassified" for syncope, concussion, and sudden death.

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

Recommendation

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 ten CARM case reports for donepezil, to remind prescribers about the risk of syncope with this medicine.

4.1.1.2 Lorazepam, clonazepam, fluoxetine, zuclopenthixol, sodium valproate and suicide, irritability, memory impaired, headache, paraesthesia (55417)

Discussion

The Committee agreed that, while it is possible the adverse reactions reported occurred as a result of these medicines, it is not possible (due to the patient's underlying depression and psychiatric disorder) to determine whether any of the medications played a role in the patient's suicide. The causal association was deemed "possible" for irritability, memory impaired, headache, and paraesthesia, and "unclassified" for suicide.

4.1.1.3 Simvastatin and myalgia, creatine kinase elevated, renal failure acute, cardiac failure, death (56238)

Discussion

The Committee noted that CARM has received a cluster of reports of rhabdomyolysis associated with simvastatin. These reports were discussed further under section 4.2 of the meeting agenda.

The causal association was deemed "probable" for myalgia, creatine kinase elevated, renal failure acute, cardiac failure, and death.

4.1.2 Alternative medicine-related reports

4.1.2.1 Acetylsalicylic acid, Mega Potency Mens Multivitamin with Selenium - Natural Nutrition and toxic epidermal necrolysis, hepatitis (55698)

Discussion

Of 236 reports for acetylsalicylic acid received by CARM, 72 are associated with skin reactions (although none of these report toxic epidermal necrolysis). It was noted that Mega Potency Mens Multivitamin with Selenium contains vitamins, minerals, milk thistle, saw palmetto, epilobium, and panax ginseng. CARM has received three reports of angioedema with ginseng. In addition, literature reports have associated ginseng with Stevens Johnson Syndrome and cholestatic hepatitis.

The Committee agreed that it is more likely the patient had a viral infection, which gave rise to hepatitis and skin reaction. The causal association was deemed to be "possible" for toxic epidermal necrolysis and hepatitis. No further action was recommended.

4.1.2.2 Kordels Joint Pain Relief, Natural Nutrition Womens Mega Vitamin, Natural Nutrition Hair, Skin & Nails, Folic Acid, Healtheries Iron and Vitamin C and abortion spontaneous (56237)

Discussion

The Committee agreed that the causal association is "unclassified" for spontaneous abortion, and no further action was recommended.

4.1.2.3 Natural Way A Plus and hypertension aggravated, drug interaction (56297)

Discussion

CARM has received one other report of aggravated hypertension with ginseng. In addition, of 193 reactions associated with ginseng in the WHO database, there are seven reports of hypertension.

The Committee noted that the natural medicines database (www.naturaldatabase.com) states that Siberian ginseng has the potential to exacerbate hypertension and is contraindicated in individuals with blood pressures exceeding 180/90. Amongst its constituents are caffeic acid and phenylpropanoids - it may therefore have some alpha agonist properties. It was also noted that published case reports indicate ginseng is associated with clinically important elevations in blood pressure.

Members agreed that the possibility of hypertension with ginseng should be highlighted in the article on adverse reactions to herbal medicines currently being written for Prescriber Update. The causal association was deemed to be "possible" for hypertension aggravated and drug interaction.

Recommendation

The Committee recommended that the possibility of hypertension with ginseng be incorporated into the article about adverse reactions to herbal medicines currently being written for Prescriber Update.

4.1.2.4 Niacinol gg, Herbal preparation unclassified and rash, oedema face (56541)

Discussion

Niacinol gg is reported to contain inositol and guggul extract. The Committee noted a report in the literature that describes rash with guggulipids. The causal association was deemed to be "possible" for rash and facial oedema, and no further action was recommended.

4.1.2.5 Pregnacare, Evening Primrose oil and skeletal malformation (56337)

Discussion

Of seven reports for Evening Primrose oil received by CARM, none are associated with foetal effects. The Committee agreed that this is probably a coincidental occurrence, and the casual association was deemed to be "unlikely" for skeletal malformation. No further action was recommended.

4.1.3 Cardiovascular medication-related reports

4.1.3.1 Diltiazem and anaemia haemolytic, Coombs positive, bilirubinaemia (56528)

Discussion

The Committee noted the potential for drug interactions with cyclosporin and ranitidine, leading to elevated diltiazem levels. Members agreed, however, that this reaction was unlikely to be related to drug levels. The causal association was deemed "probable" for anaemia haemolytic, Coombs positive, and bilirubinemia, and no further action was recommended.

4.1.4 Musculoskeletal medication-related reports

4.1.4.1 Alendronate and headache, synovitis and stool black (55776)

Discussion

Of 52 reports for alendronate received by CARM, there is one other report of synovitis. The WHO database holds eight reports of synovitis with alendronate - one with a positive re-challenge. Members noted that the NZPhvC intends to publish the CARM case reports in collaboration with the Uppsala Monitoring Centre.

The causal association was deemed to be "certain" for headache and synovitis, and "probable" for black stools. No further action was recommended.

4.1.5 Psychiatric medicine-related reports

4.1.5.1 Fluoxetine and developmental delay, cognitive function abnormal (55992)

Discussion

Literature evidence suggests that this association is likely to be coincidental and this is supported by the absence of similar reports in the CARM and WHO databases. The Committee agreed that the casual association should be deemed "unlikely", and no further reaction was recommended.

4.1.5.2 Tramadol and hepatic enzymes elevated, pruritus, rash, jaundice (55370)

Discussion

CARM holds a total of 55 reports for tramadol, including one of elevated hepatic enzymes. Of 7271 reports for tramadol in the WHO database, 150 are associated with various hepatobiliary disorders, including fatal hepatic failure. A total of 354 reports for tramadol have been received in Australia - ten are associated with elevated hepatic enzymes, and one patient died after developing hepatic failure. Members noted that the New Zealand product data sheet indicates that tramadol may rarely cause elevations in hepatic enzymes. The Committee noted that the patient was also taking spironolactone, and agreed this could also cause toxic hepatitis. The causal association was deemed to be "probable" for hepatic enzymes elevated, pruritus, rash, and jaundice.

Given the reports in the WHO database and in Australia lend support to tramadol causing severe hepatic reactions, members agreed that New Zealand prescribers should be alerted to the possibility of tramadol-related hepatic reactions by way of a Prescriber Update article.

Recommendation

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

4.1.6 Urological medication-related reports

4.1.6.1 Sildenafil and chest pain, myocardial infarction (55594)

Discussion

Of 19 reports for sildenafil received by CARM, there is one other of myocardial infarction. This occurred in a 45-year-old male who developed chest pain 15 minutes after taking sildenafil and had a myocardial infarction after driving to hospital. There is also a report of cardiac failure occurring in a 48-year-old man who became short of breath after taking sildenfil and was found to have left ventricular failure on echocardiogram. Of 10553 reports for sildenafil in the WHO database, 625 are associated with myocardial infarction.

Members noted that the product data sheet for sildenafil makes reference to angina pectoris, AV block, myocardial ischemia, and heart failure as possible adverse effects. The causal association was deemed to be "possible" for chest pain and myocardial infarction, and no further action was recommended.

4.1.7 Vaccine-related reports

4.1.7.1 Influenza and Bells palsy, injection site reaction, hypoaesthesia, hearing impaired, dizziness (55905)

Discussion

Neurologic events following influenza virus vaccine now account for 224 reactions in the CARM database. There are five reports of Bells palsy, which have duration to onset between three and ten days.

It was noted that it is possible the vaccine potentiated an immune response that triggered Bells palsy. It is also possible that the patient had sub-clinical zoster and the influenza vaccine is unrelated. The causal association was deemed "possible" for Bells palsy, hypoaesthesia, hearing impaired, and dizziness, and "probable" for injection site reaction. No further action was recommended.

4.1.8 Reports of interest from section 5.6

Note: The following material was originally included in Section 5 (Pharmacovigilance Issues for Information only) of the meeting dossier. At the request of the Committee, it was brought forward into Section 4 (Matters arising from the New Zealand Pharmacovigilance Centre) of the dossier, in order for it to be discussed.

4.1.8.1 Postinor-2 and thrombosis venous deep (55546)

Discussion

Members noted this report and agreed there is a remote possibility the DVT was related to the use of the morning after pill. The causal association was deemed "unlikely" and no further action was recommended.

4.1.8.2 Menopro and sweating increased, flushing, headache (56562)

Discussion

Members noted the report and agreed the causal association is "probable". No further action was recommended.

4.2 Spontaneous reporting programme - signals

4.2.1 Simvastatin, diltiazem and rhabdomyolysis - an analysis of reports of rhabdomyolysis with simvastatin in the CARM database

Issue

From September 2002, five reports of rhabdomyolysis attributed to simvastatin have been received by CARM. Prior to this, there were no reports of rhabdomyolysis with this medicine, despite it having been monitored by the IMMP. There were, however, reports of myalgia, myopathy, myositis and elevated creatine kinase. The five case reports of rhabdomyolysis have been examined to assess the reliability of diagnosis, patient characteristics, the dose of simvastatin and any medicine interactions that may have contributed to this adverse reaction.

The patients ranged in age from 54 to 79 years, which is in keeping with the indication for this medicine. Where stated, duration to onset of the reaction was two to three years, six weeks, four weeks and "soon afterwards". In three patients, the symptoms commenced, or worsened, after a dose increase. Doses at the time of the reaction ranged from 20 to 80 mg daily. The patients who were taking 80 mg daily were females aged 73 and 79 years and one had chronic renal failure. Concomitant medicines were listed for four patients. Omeprazole was being taken by all of these patients. In addition, three patients were taking diltiazem and isosorbide mononitrate, and two patients were taking aspirin, a calcium preparation, and atenolol.

Discussion

The Committee noted that rhabdomyolysis is rare with simvastatin and is unlikely to be entirely attributable to high doses. However, it is known that high doses of simvastatin, and inhibition of its metabolism, increase the risk of rhabdomyolysis. Members noted that three patients were also taking diltiazem, which is a substrate and inhibitor of the CYP 3A4 iso-enzyme. As simvastatin is a substrate of CYP 3A4, concomitant diltiazem could result in elevated simvastatin levels. While four patients were also taking omeprazole, current knowledge is that omeprazole inhibits CYP 2C19 and 2C9, and simvastatin is not thought to be a substrate for these iso-enzymes.

The Committee noted that the New Zealand product data sheet for Lipex states that:

"Patients on diltiazem treated concomitantly with simvastatin 80 mg have a slightly increased risk of myopathy. The risk of myopathy is approximately 1% in these patients. In clinical studies, the risk of myopathy in patients taking simvastatin 40 mg with diltiazem was similar to that in patients taking simvastatin 40 mg without diltiazem."

" The risk of myopathy/rhabdomyolysis is dose related. The incidence in clinical trials, in which patients were carefully monitored and some interacting medicines were excluded, has been approximately 0.03% at 20 mg, 0.08% at 40 mg and 0.4% at 80 mg."

"Simvastatin has no significant renal excretion so modification of dose is not necessary in moderate renal insufficiency. If creatinine clearance < 30 mL/min caution with doses >10 mg daily and only if necessary."

Members agreed that the data sheets for preparations of simvastatin be amended to read, "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.

Members agreed that the possibility of an interaction between simvastatin and diltiazem, leading to severe myopathy and rhabdomyolysis, should be communicated to New Zealand prescribers. It was agreed that a paragraph about this interaction should be included in the article on myalgia with statins, currently being written for Prescriber Update.

Recommendations

The Committee recommended that presribers be reminded about the possibility of an interaction between simvastatin and diltiazem, leading to severe myopathy and rhabdomyolysis. A paragraph about this interaction should be included in the article on myalgia 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.

4.2.2 Patterns of vaccine adverse events following vaccine schedule changes in New Zealand

Issue

Recently in New Zealand, the whole cell pertussis vaccines were replaced with the acellular pertussis vaccines. Since this time, the percentage of CARM vaccine reports associated with prolonged crying, fever, and hypotonic hyporesponsive episodes has declined. However, injection site reactions to the fourth dose of the acellular pertussis-containing vaccines have increased. Typically, these reports describe massive injection site reactions, often involving the whole limb. Pain was reported in only 7% of the cases, and reporters were often surprised by the fact the child was undisturbed by the reaction. The dramatic appearance of these reactions occasionally resulted in them being confused with cellulitis, and a course of antibiotic therapy was initiated in some children. Health care providers and parents should be advised of the possibility of a significant injection site swelling with the fourth and possibly fifth doses of DTaP vaccines. Use of antibiotic therapy for local injection site swellings should be reserved for those cases that are bacterially infected.

Discussion

Members agreed that the possibility of injection site reactions with the fourth and perhaps the fifth dose of DTaP vaccines is an important issue for parents and healthcare professionals. Members also queried whether the massive limb swelling with the fifth dose is more likely to occur in the same child in which the reaction was experienced with the fourth dose. It was noted that the absence of denominator data does not enable the calculation of true incidence of injection site reactions. The NZPhvC is attempting to source the number of doses of vaccine administered to provide at least a proxy denominator, and enable an estimate of incidence.

The Committee noted that the NZPhvC will publish its observations about injection site reactions in a medium that is read widely by nurses and practitioners. Members recommended that the NZPhvC report 'Patterns of vaccine adverse events following vaccine schedule changes in New Zealand' be summarised for publication in Prescriber Update. If possible, the article should contain advice about whether it is safe and necessary to immunise children with the fifth dose of the acellular pertussis-containing vaccines.

Recommendation

The Committee recommended that the NZPhvC report 'Patterns of vaccine adverse events following vaccine schedule changes in New Zealand' be summarised for publication in Prescriber Update. If possible, the article should contain advice about whether it is safe and necessary to immunise children with the fifth dose of the acellular pertussis-containing vaccines. The article should also remind prescribers that use of antibiotic therapy for local injection site swellings should be reserved for those cases that are bacterially infected.

4.3 CARM Quarterly report (as at 30 June, 2003)

4.3.1 Multiple occurrence reaction reporting

≥ Three Reports in the Last Quarter

4.3.1.1 Brand-switch related reports

• Citalopram (switch from Cipramil to Celapram): 30 reports consistent with a reduced therapeutic effect have been received (these describe a return to depressive-like symptoms). Twelve reports indicate that these effects are manifest between one week and one month following the change of brand. The number of reports is now beginning to taper off in the expected brand-switch pattern.
• Dipyridamole (switch from Persantin to Ptyazen): 9 reports have been received. These reflect a diversity of reactions such as dizziness, headache, blurred vision, dyspepsia, and rash.
• Gliclazide (switch from Diamicron to Apo-gliclazide): 8 reports consistent with a reduced therapeutic effect have been received.

Discussion

Members noted that the return to depressive-like symptoms with Celapram may reflect a withdrawal reaction if there is altered bioavailability.

It was also noted that Persantin and Ptyazen have different drug delivery mechanisms that can be affected by gastric pH. In light of this, members questioned whether these patients were also on other medications, in particular H2 antagonists.

4.3.1.2 Other medicine-related reports

• Three or more reports have been received for amoxycillin, amoxycillin/clavulanic acid, X-ray contrast media, and infliximab - these reports have contained unremarkable reactions.

4.3.1.3 Vaccine-related reports

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

Discussion

The Committee noted that the Quarterly Report now contains a summary of serious adverse events following immunisation (AEFIs) reported in the last quarter. Case report details for these AEFIs are also provided.

≥ Six Reports in the Year-to-Date

There are no new medicines in this section, and the reports reflect reactions that are not unexpected or those that are reported with low frequency.

4.4 Intensive Medicines Monitoring Programme

4.4.1 Analysis of IMMP events reported for clozapine (August 2003)

Issue

IMMP monitoring of clozapine began in December 2000. To the period ending July 25 2003, 978 adverse events (229 incidents and 749 reactions) in 493 reports have been received. These events have come from spontaneous reports or from pharmaceutical companies as IMMP follow-up questionnaires regarding clozapine have yet to be sent.

A summary of the NZPhvC adverse event reports for clozapine was presented in order to identify the most frequently reported events, and unlabeled adverse events of potential significance.

Discussion

It was noted that many of the most frequently reported adverse events are known to occur, and most are included in the current clozapine data sheet. Some adverse events not included in the New Zealand data sheets are listed in the American clozapine product label. It was noted that Medsafe will request that these reactions also be included in the New Zealand data sheets for clozapine.

The Committee noted that the NZPhvC has received ten reports of lipid abnormalities with clozapine. It was agreed that the issue of hyperlipidemia with atypical antipsychotics should be further discussed at the December 2003 MARC meeting.

Recommendation

The Committee recommended that the issue of hyperlipidemia with atypical antipsychotics be placed on the agenda for the December 2003 MARC meeting.

4.4.2 Nocturnal enuresis associated with clozapine

Reference material

Kho & Nielsen (2001) Clozapine-induced nocturnal enuresis. Psychiatric Bulletin, 25, 232-233.

Issue

The IMMP database contains 11 reports of nocturnal enuresis associated with clozapine. Ten of these reports were forwarded to the IMMP by Novartis, the sponsor of Clozaril.

The majority of reports refer to enuresis in young men, receiving a daily dose of clozapine ranging from 125 to 700 mg. Information regarding the time to onset of enuresis was available for two patients - one developed enuresis after four weeks treatment and one after four months. The reports contained very little detailed information about the frequency of bedwetting. One report specified that enuresis occurred every night but others stated that it was 'troublesome'. Some evidence of causality comes from two cases in which there were positive dechallenge data.

Four of the 11 IMMP cases were also taking a SSRI at the time enuresis was experienced. It has been reported that fluoxetine (a potent inhibitor of CYP 1A4 and CYP 2D6) markedly increases plasma clozapine levels. This might increase the likelihood of adverse events, including enuresis, if such events are dose-dependent.

In the reporting of urinary adverse reactions (both to the WHO and Novartis) the term 'enuresis' has been included under the broader term 'urinary incontinence'. Perhaps because of this, the current New Zealand data sheets for clozapine do not specify enuresis as a recognised adverse effect. Instead, in the Adverse Effects section under 'Genitourinary system' it is stated that, "both urinary incontinence and urinary retention…have been reported".

Discussion

Members noted that enuresis with clozapine treatment is not a newly identified adverse reaction, but there is little published information available. However, the Committee advised against publishing the spontaneous case reports at this time, and recommended that the IMMP obtain an estimation of incidence by conducting a questionnaire-based study using a sample of the clozapine patient cohort. The IMMP believes it is appropriate to publish the case reports promptly, and intends to submit the New Zealand case reports of enuresis with clozapine for publication in an international journal.

Members agreed that enuresis is clinically distinct from other forms of incontinence, and recommended that Medsafe ask clozapine product sponsors to include nocturnal enuresis as an adverse effect in the New Zealand clozapine data sheets.

Recommendation

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.

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 Non-steroidal anti-inflammatory drugs and GI bleeding

References

Yong et al (2003) Do nonsteroidal anti-inflammatory drugs affect the outcome of patients admitted to hospital with lower gastrointestinal bleeding? NZMJ, 116(1178).

de Jong et al (2003) Combined use of SSRIs and NSAIDs increases the risk of gastrointestinal adverse effects. British Journal of Clinical Pharmacology, 55(6).

5.2 HRT and coronary heart disease, VTE

References

Hodis et al (2003) Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. NEJM, 349, 535-545.

Manson et al (2003) Estrogen plus progestin and the risk of coronary heart disease. NEJM, 349, 523-534.

Scarabin et al (2003) Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet, 362, 428-432.

5.3 Antiepileptic drugs and SUDEP

Reference

Walczak (2003) Do antiepileptic drugs play a role in sudden unexpected death in epilepsy? Drug Safety, 26(10), 673-683.

5.4 WHO drug safety signals

Reference

Stahl et al (2003) Assessing the impact of drug safety signals from the WHO database presented in 'SIGNAL': results from a questionnaire of national pharmacovigilance centres. Drug Safety, 26(10), 721-727.

5.5 General review articles

References

Stichtenoth & Frolich (2003) The second generation of COX-2 inhibitors: what advantages do the newest offer? Drugs, 63(1), 33-45.

Lee (2003) Drug-induced hepatotoxicity. NEJM, 349, 474-485.

Carey (2003) Drug-induced myelosuppression: diagnosis and management. Drug Safety, 26(10), 691-706.

5.6 CARM case reports

Black Cohosh, Vitamin C with Echinacea, Flaxomega (flaxseed oil) and rash erythematous (56165)

Clinicians Adrenal Support, Clinicians DHEA, Clinicians Mineral/Vitamin Boost, Healtheries odourless garlic, vitamin C, zinc and Echinacea with olive leaf and epistaxis (55160)

Menopro and sweating increased, flushing, headache (56562)

Red Seal Natural Health Executive Stress B High Potency Sustained Release Action Stress Reliever and erythema, pruritis (55613)

Weleda Hypercal and application site reaction, vulvitis (56579)

Diane-35 and thrombosis venous deep (55565)

Postinor-2 and thrombosis venous deep (55546)

6. New Zealand Activities

6.1 PHARMAC

Minutes of the Pharmacology and Therapeutics Advisory Committee Meeting, February 2003.

Minutes of the Pharmacology and Therapeutics Advisory Committee Meeting, May 2003.

7. international activities

7.1 Australia

Australian Adverse Drug Reactions Bulletin 22(4), August 2003

7.2 Ireland

Irish Medicines Board Drug Safety Newsletter 17, June 2003

7.3 Singapore

Health Sciences Authority Adverse Drug Reaction News 5(2), July 2003

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 3:00pm