Revised: 21 May 2013


Minutes of the 111th Medicines Adverse Reactions Committee Meeting - 11 September 2002

At the De Havilland Room, Wellington Airport Conference Centre, commencing at 9:00am.


In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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



Associate Professor T.J.B. Maling (Chair)
Professor P. Ellis
Dr J. Goldsmith
Dr H. Kingston
Dr F. McClure
Dr M. Rademaker
Dr N. Rafter
Dr D. Coulter
Professor D.C.G. Skegg


Ms S. Von Afehlt (Senior Pharmacy Advisor/Editor of Prescriber Update, Medsafe)
Dr K. Maclennan (MARC Secretary/Pharmacovigilance Advisor, Medsafe)
Dr M. Tatley (Director of CARM)
Dr M. Harrison-Woolrych (IMMP Senior Research Fellow, CARM)
Dr R. Savage (Medical Assessor, CARM)
Dr S. Jessamine (Principal Technical Specialist, Medsafe)
Dr B. Boyd (Principal Advisor, Public Health Medicine, NZ Food Safety Authority) (morning only)


Dr I. Boyd (Adverse Drug Reactions Unit, TGA, Australia)
Mrs C. Smith (Analyst/MCC Secretary, Medsafe)


1.1 Welcome and apologies

The Chair welcomed Dr Ian Boyd from the Adverse Drug Reactions Unit in Australia, Dr Bob Boyd from the NZ Food Safety Authority, and Mrs Carol Smith from Medsafe to the meeting.

1.2 Minutes of the 110th meeting

Members agreed that the minutes of the 110th meeting are a true and accurate record of the meeting.

1.3 Date of the next meeting

Wednesday 4th December was confirmed as the date of the next meeting.

1.4 Conflict of interest

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

1.5 Prescriber Update

Upcoming articles
  • M. Harrison-Woolrych. Progestogen-only oral contraceptives and risk of ectopic pregnancy (pre-peer review version of article).
  • N. Rafter. HPV, OC's and risk of cervical cancer (pre-peer review version of article).
  • D. Coulter Omeprazole may elevate clozapine levels (pre-publication version of article).
  • P. Ellis. Reports of agitation, restlessness and suicidal behaviour with fluoxetine, paroxetine and sertraline (post-peer review version of article).

Members were requested to provide any comment on the above articles to S. Von Afehlt outside of the meeting. .. suggested that Prescriber Update articles include the primary indication of the medicine under consideration in the introduction.


2.1 Report on actions arising from the 110th MARC meeting

2.1.1 Clozapine and fever (agenda item 3.3.2, MARC June 2002)

A literature search conducted by Medsafe revealed a small number of articles relating to clozapine-induced fever.

Tremeau et al. (1997) Spiking fevers with clozapine treatment. Clinical Neuropharmacology, 20(2), 168-170.

Patterson and Jennings (1993) Spiking fever and profuse diarrhea with clozapine treatment. American Journal of Psychiatry, 150(7), 1126.

Jeong et al. (2002) The characteristics of clozapine-induced fever. Schizophrenia Research, 56, 191-193.

These articles suggest that spiking fever with GI/respiratory symptoms is an adverse effect of clozapine therapy, possibly caused by excessive release of cytokines (in particular tumour necrosis factor-α and interleukin-1).


Members noted the above articles and agreed that CARM should keep a watching brief on this issue.

2.1.2 ECP and risk of ectopic pregnancy (agenda item 4.1, MARC June 2002)


At the June MARC meeting, the Committee was informed that the CARM has received three case reports of ectopic pregnancy associated with the use of Postinor-2. Members recommended that, after checking whether the CMI for ECPs contains warnings for ectopic pregnancy, Medsafe contact the sponsor company with regard to what data or reports it may have on this issue.

In addition to the Levonelle patient booklet, the data sheets and CMI for Postinor-2 and Levonelle make suitable reference to the risk of ectopic pregnancy. In a letter to Medsafe, Schering (NZ) Ltd states that their international safety database holds 14 reports of ectopic pregnancy with Postinor-2/Levonelle. In New Zealand, Schering has sold 244,000 packs of this product since its launch in June 2000. A PSUR for Postinor-2 is currently being produced, however it is not expected to be available until late 2002. Schering (NZ) Ltd has also provided comment on M Harrison-Woolrych's intended Prescriber Update article entitled 'Progestogen-only oral contraceptives and risk of ectopic pregnancy'.


The Committee acknowledged Schering NZ Ltd's response but considered the content of the Prescriber Update to be largely satisfactory. Members noted that M. Harrison-Woolrych is writing an editorial on the progestogen-only ECP and ectopic pregnancy for the British Journal of Family Planning.


M. Harrison-Woolrych is to revise the Prescriber Update article, taking into account the peer reviewers comments and considering the comments made by Schering NZ Ltd.

2.1.3 Tiaprofenic acid (s.36 notice for Surgam tablets) (agenda item 4.2, MARC June 2002)


Sponsor companies for tiaprofenic acid have been asked to justify their medicines remaining on the market. The Committee also requested that Aventis propose potential initiatives to minimise the risk of untreated/unrecognised tiaprofenic acid-induced cystitis. The New Zealand office of Aventis Pharma Ltd is still waiting to receive a risk/benefit report for tiaprofenic acid from their head office. In the interim, they have proposed the following list of options for minimising the risk of cystitis going untreated.

Place a note in the Pharmacy Guild's publication "Dispensary Topics", to remind all pharmacies of this adverse reaction.

Contact the companies that produce dispensing software and ask them about the possibility of including a note to remind pharmacists to ask about cystitis when dispensing tiaprofenic acid.

Send a letter to all pharmacies reminding them of this adverse reaction.

Get a patient information leaflet printed. This could be sent to all pharmacies to be given out when dispensing tiaprofenic acid.


Members considered the above options and agreed that while Option 2 was favoured, it would not be implemented quickly enough. The Committee did not think Options 1 and 3 would be particularly effective in communicating the risk to the patient, and agreed that a sticker on the product container is preferable.


The Committee recommended that Medsafe consult the Pharmaceutical Society to discuss a suitable warning sticker. Medsafe will then take the resultant proposal to Aventis Pharma Ltd.

2.1.4 Categorisation of Estelle-35 in the Pharmaceutical Schedule (agenda item 2.1.3, June 2002)


The entry for Estelle-35 in the Pharmaceutical Schedule was discussed at the Medsafe/Pharmac liaison meeting on 6 June. Pharmac indicated that it would consider Medsafe's comments and recognised that, with the change to the indications, it would not be appropriate to suggest that Estelle-35 could be regarded primarily as a contraceptive. Medsafe asked Pharmac to consider putting Estelle-35 under the "dermatologicals" section in the Pharmaceutical Schedule.


Dr Peter Moodie of Pharmac was present at the MARC meeting to discuss this issue. It is the view of Pharmac that the logical place for Estelle-35 in the Schedule is under 'Hormone Preparations - Systemic, excluding contraceptive hormones (Other Progestogen Preparations)". The MARC was not against this view and Dr Moodie agreed to progress this issue with Pharmac.

2.1.5 Amoxycillin + Clavulanic acid/Erythromycin and colitis pseudomembranous - CARM case report (49802) (agenda item, June 2002)


The Committee recommended that erythromycin data sheets that do not already include pseudomembranous colitis as a potential adverse effect be updated to do so.

A review of the data sheets for erythromycin-based products in New Zealand revealed that Pacific Pharmaceuticals Ltd is the only company not to warn against the potential for pseudomembranous colitis with erythromycin. In light of this, Pacific Pharmaceuticals have added the following statement to the Warnings and Precautions section of their E-mycin data sheet

"Pseudomembranous colitis has been reported with most antibacterial agents, including erythromycin. Therefore, it is important to consider this diagnosis in patients who develop diarrhoea in association with antibiotic use."


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

2.1.6 Sibutramine and manic reaction (agenda item 3.3.3, June 2002)


The Committee recommended that Medsafe contact PreMeC with regard to writing a bulletin on sibutramine. It was recommended that PreMeC liaise with CARM about potential adverse reactions with sibutramine.


PreMeC is willing to publish a bulletin on sibutramine; however, it cannot confirm its ability to do so until November 2002.


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

2.1.7 Desogestrel and VTE (agenda item 4.5, June 2002)


Pharmac asked for MARC comment regarding the safety profile of Cerazette, specifically with regard to the risk of VTE. Members agreed that the MARC Chair would contact Pharmac in order to determine the issues behind their request. He will then meet with Medsafe to discuss what advice should be given. The outcome of this will be reported at the September 2002 MARC meeting.


In July 2002, a letter was sent to Pharmac informing them that the MARC believes that there is no evidence to indicate Cerazette is better, or is more of a problem, than any other progestogen-only contraceptive.


While the New Zealand data sheet for Cerazette gives 12-hour missed-pill advice, it was brought to the attention of the Committee that the UK has 3-hour missed-pill advice for this product. The Committee requested that Medsafe investigate this discrepancy and report back at the September 2002 meeting.


The New Zealand data sheet (along with the pharmaceutical company information) gives 12 hour missed pill advice for this product. .. of Pharmaco is following up this discrepancy with the company's head office in Holland.


The Committee recommended that Organon be asked to update the Cerazette data sheet to reflect the fact that the risk of VTE with Cerazette is unknown.


Organon has agreed to add the following statement to the Warnings and Precautions section of the Cerazette data sheet.

"Epidemiological investigations have associated the use of combined OCs with an increased incidence of venous thromboembolism (VTE, deep venous thrombosis and pulmonary embolism). Although the clinical relevance of this finding for desogestrel used as a contraceptive in the absence of an estrogenic component is unknown, Cerazette should be discontinued in the event of a thrombosis. Discontinuation of Cerazette should also be considered in case of long-term immobilisation due to surgery or illness. Women with a history of thrombo-embolic disorders should be made aware of the possibility of a recurrence."


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

2.1.8 Enalapril / Insulin and hyperglycaemia - CARM case report (50442)(agenda item, June 2002)


On considering the case report, members questioned whether the patient's blood sugar levels normalised upon return to Renitec. CARM has requested this information from the case reporter but has not yet received a reply. The Committee requested that CARM obtain this information. If a difference between Renitec and the generic is apparent, members recommended that Pharmac be directly informed of this issue.


CARM has received a reply stating that the patient's blood sugar levels normalised on return to Renitec. CARM has since informed Pharmac of this issue.


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

2.1.9 Flecainide and sudden death - CARM case report (46833)(agenda item, June 2002)


The Committee requested that CARM write to the National Poisons Centre (NPC), asking if they have further information regarding flecainide toxicology.


The NPC has no reports of sudden death with flecainide, nor does it have reports that could aid in interpreting the findings of the above case.


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

2.2 Report on actions outstanding

2.2.1 Funding for third generation oral contraceptives (agenda item 4.4.3, March 2002)


At the March 2002 MARC meeting, members requested that a letter be sent to Pharmac expressing the Committee's concern regarding the intention to fully-fund a third generation OC. The MARC suggested that the third generation OCs be funded only where a woman, without contraindications, has difficulties with a second generation OC (the script would be endorsed "certified condition").


Dr Peter Moodie of Pharmac was present at the meeting to discuss this issue. He commented that it is Pharmac's view that if there is a need for third generation contraceptives, they should be fully funded where possible. The MARC commented that fully funding third generation contraceptives might encourage their use - an unwanted outcome given the increased risk of VTE associated with these products.


The Committee requested that Medsafe send a letter to Pharmac which outlines the risk and benefit issues, highlights the need to take action, and requests that, on a safety basis, Pharmac considers funding third generation OCs only when a script is endorsed with 'certified condition'. This letter should also state that the MARC does not advocate Special Authority restrictions on third generation contraceptives.

2.2.2 NSAIAs/COX-2 inhibitors and infertility (agenda item 4.6, December 2001)

At the Dec 2001 MARC meeting, the Committee recommended publishing a brief Prescriber Update article on the possibility that selective COX-2 inhibitors and NSAIAs may cause infertility. The article would give no advice, only present the possibility.

.. was originally nominated as the author but Medsafe thought this area would be of more interest to ... .. voiced some uncertainty as to whether this was a significant enough issue to warrant a Prescriber Update article. Consequently, S. Von Afehlt contacted .. at Fertility Associates in Wellington. .. sees 10 new patients each week, and very few are on NSAIAs or COX-2s (and if they are, it is usually for endometriosis). .. doesn't feel there is a big problem with NSAIA/COX-2 induced infertility in NZ, either as an association of questionable causality or as an adverse reaction that is not being recognised by GPs. .. is more concerned about the 50% of .. patients who are taking herbal-type supplements. As a result of this opinion, Medsafe and the MARC Chair jointly agreed that a Prescriber Update article on infertility with NSAIAs/COX-2s was not necessary.


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

2.2.3 Hyperglycaemia and atypical antipsychotics (agenda item 3.2.2, December 2001)


In February, 2001, Medsafe wrote to companies marketing atypical antipsychotics (clozapine, olanzapine, quetiapine and risperidone) in New Zealand. The companies were asked to update the data sheet for their product with regard to the available data on impaired glucose metabolism.

Satisfactory data sheet updates have been received for risperidone, quetiapine and clozapine (both Clopine and Clozaril). Eli Lilly is prepared to update the olanzapine data sheet as requested, with additional statements regarding the incidence of diabetes mellitus in schizophrenics, and the atypical antipsychotic class effect. Medsafe is currently awaiting a proposed statement from Eli-Lilly.


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

3. matters arising from carm

3.1 Spontaneous reporting programme

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

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

Note: In the comment associated with each report, the case has been given a causality designation using terms and definitions developed by the WHO. The precise definitions are available on the website of the WHO Collaborating Centre 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.

3.1.1 Reports in which death occurred Amantadine and myocardial ischaemia/hallucinations, 51852


Of a total of 18 reports involving amantadine in the CARM database, there has been one report of tachycardia. The product data sheet advises caution and dose-adjustment in patients with impaired renal function. The data sheet also states that cardiac insufficiency/failure has been reported. For this case report, the causal association was deemed to be "possible" for myocardial ischemia and increased drug level, and "probable" for hallucinations. No further action was recommended. Amoxycillin + Clavulanic acid and interstitial nephritis, 51066


The CARM database holds 609 reports for amoxycillin/clavulanic acid, two of which involve acute renal failure. It has been reported in the literature that amoxycillin/clavulanic acid can cause increased serum creatinine and blood urea nitrogen. The product data sheet makes reference to rare cases of interstitial nephritis and haematuria. Members commented that this patient might have had acute renal failure on top of pre-existing diabetic nephropathy. For this case report, the causal association was designated "possible" and no further action was recommended. Citalopram and sudden death, 51989


Members agreed that more information is required for a complete assessment and considered the report to be "unclassified". No further action was recommended. Clarithromycin/Ceftriaxone/Cefuroxime and hepatic necrosis/cardiac arrest/hepato-renal syndrome, 51198


The CARM database holds 20 reports for Clarithromycin. Of these, there is one associated with cholestatic hepatitis and one that reports hepatocellular damage. Of 59 reports for Ceftriaxone, there are three associated with abnormal hepatic function, and two reporting increased hepatic enzyme levels. The WHO database holds 457 reports of hepatic dysfunction with Clarithromycin, and 108 reports of hepatic function abnormalities with Ceftriaxone. The product data sheets for all three suspected medicines make reference to mild, transient hepatic function abnormalities, and advise care in the presence of renal dysfunction. For this case report, the causal association was deemed to be "possible" for hepatic necrosis and hepato-renal syndrome, and "unclassified" for the cardiac arrest. No further action was recommended. Fluoxetine and alveolitis, 50993


The WHO database holds four reports of alveolitis, 12 of pulmonary infiltration and 628 of dyspnoea for fluoxetine. CARM has received 571 reports for fluoxetine, two of dyspnoea and one of pulmonary fibrosis. Cough and dyspnoea after four months fluoxetine therapy (with a positive rechallenge) has been reported in the literature. The causal association was designated "possible" and no further action was recommended. Methylphenidate and sudden death, 51605


Of 46 reports for methylphenidate in the CARM database, none are associated with death or cardiac events. The causal association was designated "unclassified" and no further action was recommended. Itraconazole/Prednisone and exfoliative dermatitis/pruritus/leg oedema/pneumonia/hip fracture/confusion, 49818/49865


The causal association was designated "possible" for pneumonia and hip fracture, and "probable" for exfoliative dermatitis, pruritis, oedema and confusion. No further action was recommended. Azathioprine/Prednisone and agranulocytosis/sepsis/leukopenia, 51035


The CARM database holds three reports of leukopenia associated with azathioprine and one report of leukopenia with prednisone. Of 3422 reports for azathioprine in the WHO database, 184 are related to leukopenia (IC-2SD = 2.25) with 10 fatal. The WHO database holds 5408 reports for prednisone, 111 of which are associated with leukopenia (27 fatal). The product data sheets for azathioprine make reference to leukopenia and some advise complete blood count and platelet counts at regular intervals. The causal association was designated "probable" and no further action was recommended. Tranexamic acid and deep venous thrombosis/superficial thrombophlebitis/pulmonary embolism, 51372


The CARM database holds six reports for tranexamic acid - nil associated with DVT but one associated with cerebral thrombosis. Of 775 reports for tranexamic acid in the WHO database, there are 22 associated with pulmonary embolism. The causal association was designated "possible".


The Committee recommended that, as tranexamic acid is now available on GP prescription (with specialist recommendation no longer required), CARM write a short Prescriber Update article to remind prescribers about the risk of thromboembolism with tranexamic acid. Tramadol/morphine/warfarin and increased INR/cardiac arrest, 51199


Of 49 reports for tramadol in the CARM database, 10 are of cardiovascular origin. The database holds 77 reports for morphine, of which one is associated with cardiac arrest. The causal association was designated "unclassified" and no further action was recommended.

3.1.2 Alternative medicine-related reports Aloe vera juice and periorbital oedema/conjunctivitis, 51126


This is the first report to CARM of this kind. In the literature, the only adverse effects related to aloe vera are laxative-like effects. The causal association was designated "possible" and no further action was recommended. Cell Tech (ascorbic acid?)/Warfarin and decreased INR, 51713


Amongst other components (incl. Mg, Na, K, creatine, taurine), Cell Tech contains 250 mg vitamin C. High dose ascorbic acid has been shown to reduce PT in patients on warfarin therapy. The causal association was designated "possible" and no further action was recommended. Chamomile and facial oedema/pruritus, 51145


This is the first report to CARM of this kind. The Natural Medicines Database however, advises against applying chamomile to the eyelids. The causal association was designated "possible" and no further action was recommended. Cheng Kum and skin atrophy/adrenal insufficiency, 51366


The Committee noted that recent testing of Cheng Kum has shown it to contain betamethasone. The CARM database holds one other report of skin fragility and adrenal cortical insufficiency with Cheng Kum. The causal association was designated "possible" and no further action was recommended. Grapeseed and pruritic rash, 51121


The causal association was designated "probable" and no further action was recommended. Thermogenic weight control and nausea/abdominal pain/pruritic rash/dizziness/tremor, 51374


The CARM database holds no reports for this product, however, it does contain reports of dizziness, chest pain, depression, and abnormal LFTs with other 'fat burning' products. The causal association was designated "probable" and no further action was recommended.

3.1.3 Cardiovascular medication-related reports Felodipine and vasculitis, 50980


Of 118 reports for felodipine in the CARM database, none are associated with vasculitis. Of 11939 reports for felodipine in the WHO database, 18 are associated with vasculitis (four showed definite improvement on withdrawal, and two showed positive re-challenge). The causal association was designated "probable" and no further action was recommended.

3.1.4 Hormone-related reports Diane-35 and deep vein thrombosis, 51263


The CARM database holds 15 reports of pulmonary embolism and six reports of deep vein thrombosis with Diane-35. The causal association was designated "possible" and no further action was recommended. Estelle-35 and cerebral infarction/dysphasia, 51802


The CARM database holds no reports of aphasia for either Estelle-35 or Diane-35 (however there is one report of transient ischaemic attack with Diane-35). The causal association was designated "possible" and no further action was recommended. Mercilon and deep vein thrombosis, 51709


Of 46 reports for Mercilon held in the CARM database, 11 are associated with venous thrombosis. The causal association was designated "probable" and no further action was recommended. Microgynon 30 and arterial thrombosis, 51163


Further clarification of the patient's symptoms has been requested. Of 29 reports for Microgynon 30 in the CARM database, none are associated with arterial thromboembolism. The causal association was designated "possible" and no further action was recommended. Progesterone cream and headache, 51106


This is the first report to CARM for this product. The causal association was designated "probable" and no further action was recommended.

3.1.5 Urological medication-related reports Tamsulosin and abortion, 51172


Tamulosin is not indicated for use in females. This is the first report to CARM for this medicine. The causal association was designated "unclassified" and no further action was recommended.

3.2 Quarterly report (as at 30 June, 2002)

3.2.1 Multiple occurrence reaction reporting Brand-switch related reports

M. Tatley presented a report on the patterns of brand-switching of medications reported to CARM. For medicines that have more than 10 cumulative reports, the following specific observations were made.

Two peaks of reporting were noted for fluoxetine. These appear to reflect the two PHARMAC changes, initially from Prozac to Plinzene and later from Plinzene to Fluox. In both instances there has been an apparent return almost to baseline.

Enalapril (switch from Renitec to Enahexal) was a focus of brand-switch reporting concerns from September 2001 to March 2002. Despite the continued use of Enahexal, reports have all but ceased.

Estelle-35 (switch from Diane-35) reports have described breakthrough-bleeding events, suggestive of bioavailability issues. The numbers of reports are not large enough to determine any trend to the typical pattern of tail-off.

Felodipine (switch from Plendil to Felo) reports continue to be received. The pattern of reporting suggests a tail-off of reports, however, the numbers are too small to confirm this.

Reports for methylphenidate (Ritalin to Rubifen) have documented a profound reduction of therapeutic effect. Similarly to other medicines, the pattern of reporting is characterised largely by single reports each month which have largely ceased.

It was noted that while the size of the brand-switching problem is small in national terms, it could have significant individual clinical implications. Members agreed that evaluation of brand-switch patterns and problems should continue as part of the pharmacovigilance strategies in New Zealand. The Committee noted that the next issue of Prescriber Update contains a paragraph aimed to encourage healthcare professionals to report brand-switch issues. Bupropion

After a general drop in reports of reactions with bupropion, there has recently been a small influx of reports (the majority regarding hypersensitivity reactions and three associated with depression). Vaccine-related reactions

Atypical reports for the influenza vaccine include seven associated with paraesthesias and three with pericarditis. The parathesias, which typically involve the arm (distal to the injection site) and sometimes the neck, have tended to persist for days to weeks. Dr Ian Boyd informed the Committee that of 900 reports for the influenza vaccine in Australia, three describe pericarditis.

3.3.3 Pharmacovigilance literature of interest

The Committee noted the list of pharmacovigilance-related references.

3.3 IMMP

3.3.1 COX-2 inhibitors COX-2 inhibitors and liver damage

The Committee noted that the IMMP has received six adverse event reports related to liver injury for celecoxib, and two for rofecoxib. While four of the six reports had a strong relationship, one was ascribed to alcohol and one was part of multi-organ failure following a staphylococcal infection. COX-2 inhibitors and urinary retention

Members noted a single adverse event report describing a strong association between rofecoxib and acute urinary retention. COX-2 inhibitors and suicide

The Committee noted two case reports for celecoxib, one associated with suicide and the other with suicidal ideation. COX-2 inhibitors and pancreatitis

The IMMP has received three adverse event reports for Celecoxib and pancreatitis. COX-2 inhibitors - reports of death where relationship may be causal

Eleven of the 14 reports of death for Celecoxib were associated with heart and/or liver failure. The remaining three deaths were associated with upper gastrointestinal complications. Five of the six reports of death for Rofecoxib included cardiac events; one was associated with gastrointestinal complications. COX-2 inhibitors and cardiovascular events

Reference material

Merck Frosst Canada Dear Health Care Professional Letter, Important VIOXX safety information. April 2002

Vioxx data sheet (Canada)

Vioxx data sheet (USA)

Vioxx data sheet (NZ)

Celebrex data sheet (NZ)


D. Coulter provided a commentary on issues related to the cardiovascular effects of COX-2s arising from the International Society of Pharmacoepidemiology Conference (August, 2002). Points of note included:

There is a plausible pharmacological mechanism for a prothrombotic action

The VIGOR study showed a higher rate of cardiovascular deaths with rofecoxib, compared with naproxen.

The fact that traditional NSAIDs have varying degrees of COX-2 specificity may confound studies in which they are compared with COX-2 inhibitors.

Rofecoxib is significantly more COX-2 specific than celecoxib, and at high doses, COX-2s lose their specificity.

Rofecoxib (50 mg daily) should not be used for more than five days. There is a dose-response relationship for hypertension, oedema and rise in serum creatinine.

D. Coulter reported that preliminary analysis of IMMP data shows that when the combined COX-2 incident profile is compared with omeprazole and all other medicines (other than COX-2s), there is a statistically significant increase in the proportion of circulatory events (principally myocardial infarction and stroke) for COX-2s. It should be noted that the incident profile excludes heart failure and related problems. Overall, the duration to onset of death for the COX-2 inhibitors was found to be shorter than for patients taking moclobemide and omeprazole. However, when these data are stratified by age (<65 and = 65 years), this effect is seen only in patients older than 65 years. It is possible these data may be confounded by the underlying conditions being treated. Ideally, the data should also be stratified by indication, however patient numbers are not high enough for this to be practical at present. While the above findings are not evidence of a prothrombotic effect of COX-2s, they are perhaps suggestive of a problem. N. Rafter informed the Committee that the American and Canadian data sheets for rofecoxib contain data from the VIGOR study showing an increased risk of myocardial infarction with rofecoxib compared to naproxen. A Dear Healthcare Professional letter informing prescribers of GI and cardiovascular risks with rofecoxib has also been issued in these countries.


Members agreed that .. should write a short article regarding COX-2 inhibitors and hepatotoxicity/pancreatitis, to be published in Prescriber Update.
Members expressed concern at the inadequacy of the information regarding gastrointestinal effects in the New Zealand data sheet for Celebrex. In light of current evidence regarding the limitations of the CLASS study (see Section 5.7), members recommended the sponsor company be asked to revise the Celebrex data sheet. The Committee requested that Medsafe compose appropriate data sheet statements to be presented to the company. Medsafe should note the Australian data sheet for this product, in order to ensure there is some consistency between the two countries. The Committee recommended that CARM keep a watching brief on cardiovascular effects with COX-2s. Members also requested that Medsafe negotiate with the New Zealand sponsor companies for Celebrex and Vioxx, in order to effect appropriate data sheet updates with regard to cardiovascular effects. Data sheets should also be updated with regard to renal effects if Medsafe deems this to be necessary.

3.3.2 Atypical antipsychotics Hyperglycaemia and clozapine

Reference material

Wang et al. (2002) Clozapine use and risk of diabetes mellitus. Journal of Clinical Psychopharmacology, 22(3), 236-243.

Members agreed that while the Wang et al (2002) case control study did not find an association between clozapine and risk of diabetes mellitus, this seems to be inconsistent with other evidence. The IMMP has 13 reports of hyperglycaemia associated with clozapine - two of these had a positive rechallenge. CARM will keep a watching brief on clozapine and hyperglycaemia.

4. Pharmacovigilance issues

4.1 HRT and cancer/stroke/heart disease

Reference material
Minutes of the NZGG meeting held on August 16th 2002.

Nelson et al. (2002) Postmenopausal hormone replacement therapy - Scientific review. JAMA, 288(7), 872-881. (+ associated Clinical Applications article and Patient page).

Women's Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the WHI randomised controlled trial. JAMA, 288(3), 321-333.(+ editorial pp.366-368).

Wyeth Dear Doctor Letter. July 10, 2002.

TGA - Report of Expert Committee. July 11, 2002.

FDA statement on the results of the WHI. August 13, 2002.

Grady et al. (2002) Cardiovascular disease outcomes during 6.8 years of hormone therapy: HERSII. JAMA, 288(1), 49-57.

Hulley et al. (2002) Noncardiovascular disease outcomes during 6.8 years of hormone therapy: HERSII. JAMA, 288(1), 58-66.

Hulley et al. (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women (HERS). JAMA, 280(7), 605-613.

Lacey et al. (2002) Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA, 288(3), 334-341. (+ editorial pp. 368-369).

Collaborative Group on Hormonal Factors in Breast Cancer (1997) Breast cancer and HRT: collaborative reanalysis of data from 51 epidemiological studies of 52705 women with breast cancer and 108411 women without breast cancer. Lancet, 350, 1047-1059.

Cadarette et al. (2001) Evaluation of decision rules for referring women for bone densitometry by dual-energy x-ray absorptiometry. JAMA, 286(1), 57-63.

Barrett-Connor et al. (2002) Raloxifene and cardiovascular events in osteoporotic postmenopausal women. JAMA, 287(7), 847-857.

Hlatky et al (2002) Quality of life and depressive symptoms in postmenopausal women after receiving hormone therapy. JAMA, 287(5), 591-597.

HRT and fracture risk. Bandolier - Evidence based health care, (2002).

Viscoli et al. (2002) Oestrogen did not prevent death or non-fatal stroke in postmenopausal women with ischaemic stroke or transient ischaemic attack. N Engl J Med, 345, 1243-1249.

Stewart (2002) Hormone replacement therapy and cardiac risk. New Ethicals Journal, August, 43-46.

Simon et al (2001) Postmenopausal hormone therapy and risk of stroke (HERS). Circulation, 103, 638-642.

Daly et al. (1996) Risk of venous thromboembolism in users of hormone replacement therapy. Lancet, 348, 977-980.

Gutthann et al. (1997) Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ, 314, 796-800.

Beresford et al. (1997) Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet, 349, 458-461.

Wells et al. (2002) Effect on endometrium of long-term treatment with continuous combined oestrogen-progestogen replacement therapy: follow up study. BMJ, 325, 239-243.

NZGG (May 2001) The appropriate prescribing of HRT (Guideline Summary).

Medsafe Recommendation re HRT data sheet changes (July 2002).

Wyeth's proposed data sheet update for Premia, August 2002.

Regulators discourage long-term HRT use. Scrip, August 7 2002.

Sumner-Burstyn (2002) HRT - Point of View. Beral et al. (2002) Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet, (to be published).


Recent publications on HRT have offered further information about the risks and benefits of this therapy. Medsafe requested that the MARC provide comment on:

  1. Appropriate indications for use of HRT
  2. Appropriate duration of use of HRT
  3. Management advice for prescribers
  4. Key messages to consumers

.. commented that it is important to consider new data in the context of previous randomised trials and observational studies. .. also noted that all of the randomised trials suffer from a lack of statistical power, therefore it is wise to consider the combined estimates of risk from all trials. Members commented on the excellent summary of apparent HRT risks and benefits reported in the Lancet article by Beral et al. (2002). .. commented that evidence to date indicates a small increase in the risk of breast cancer, stroke, and possibly cardiovascular heart disease, and an increased risk of VTE. These risks appear to increase with age and duration of use and members believed it should be made clear that the risks from short-term use for the treatment of menopausal symptoms are very small indeed. Members also agreed that, as some women participating in the Women's Health Initiative study had been on HRT before entering the study, it would not be advisable to recommend a specific duration of use. The Committee discussed the key messages from the New Zealand Guidelines Group's draft recommendations regarding appropriate prescribing of HRT. To a large extent, members agreed with what the New Zealand Guidelines Group has proposed and this is reflected in the following recommendations. It was also agreed that, in light of these new data, the recommendations made at the December 2001 MARC meeting (regarding the section 36 notice for HRT) are superseded by these more recent recommendations.

  1. Appropriate indications for use of HRT
    The Committee agreed on the following:
    1. Combined HRT is indicated for the control of menopausal symptoms due to oestrogen deficiency. However, even short-term use is associated with increased risk of venous thromboembolism, stroke, and possibly coronary heart disease. HRT may only be used where menopausal symptoms are troublesome and women are fully informed of the risks.
    2. Combined HRT should not be used long-term in most women because the risks of breast cancer, venous thromboembolism, stroke, and possibly coronary heart disease outweigh the benefits of fracture reduction and reduced risk of colorectal cancer in most women. iii. Combined HRT should not be used for the prevention or treatment of coronary heart disease or stroke.
    The Committee agreed that these data cast significant doubt on the validity of HRT for the prevention/treatment of osteoporosis. Members did not feel they had enough information to make a recommendation on this issue and therefore proposed that Medsafe convene a working party to examine the risks and benefits of HRT and osteoporosis. It was noted that it would be favourable for the PTAC osteoporosis sub-committee to also reconvene at this time.
  2. Appropriate duration of use of HRT
    The Committee recommended that HRT should not normally be used for more than three to four years.
  3. Management advice for prescribers
    The Committee agreed that the continued use of HRT should be reviewed by women and their doctors at the time of their next prescription, or within three months (whichever is sooner). Following this, a patient's use of HRT should be reviewed yearly. In order for women to make a fully informed decision, review should include discussion of indications for HRT use, duration of treatment, risks/benefits of treatment, and other prevention/treatment/management options. Women who decide to stop HRT may need to gradually reduce the dose over several months to avoid rebound symptoms.

The MARC did not review evidence for unopposed oestrogens or topical/vaginal preparations. As a result, members requested that Medsafe resolve whether the above recommendations should apply to HRT in general, or to specific types of HRT. The Committee requested that Medsafe communicate all of the above advice to prescribers in the form of a Prescriber Update article (November issue) and a Dear Healthcare Professional letter. The exact content of this letter should be discussed with a sub-committee of the MARC by teleconference. Members agreed that Medsafe should negotiate with sponsors of HRT products with regard to the appropriate updating of data sheets.

4.2 Kava and liver toxicity

Reference material
  • German Federal Institute for Drugs and Medical Devices (June, 2002) Kava Assessment Report.
  • Campo et al. (2002) Kava-induced fulminant hepatic failure. J Am Acad Child Adolesc Psychiatry, 41(6), 631.
  • Escher et al. (2001) Hepatitis associated with kava, a herbal remedy for anxiety. BMJ, 322, 139.
  • TGA Media Release (August, 2002) Recall of kava-containing OTCs.
  • ADRU (February, 2002) Review of 'Report on kava and liver damage'.
  • MCA (July 2002) Consultation document on prohibition of kava in unlicensed medicines.
  • WHO Information Exchange (June, 2002) Kava-containing products withdrawn in Germany.
  • FDA Consumer Advisory (March, 2002) Kava-containing dietary supplements may be associated with severe liver injury.
  • FDA Letter to Health Care Professionals (March, 2002)
  • Fast News (July 2002) Singapore joins growing list banning South Pacific herb, kava.
  • Health & Herbs International (August 2002) Kava.
  • Medsafe (drafted March, 2002) Possible consumer advice on kava-containing dietary supplements.
  • Waller, D (2002) Report on kava and liver damage. (including the following case reports: ARMS# 13198, ARMS# 14538, ARMS# 14723, ARMS# 15035, ARMS# 15267).
  • Schmidt, M (2001) Analysis of kava side effect reports concerning the liver (translation of German to English).
  • MCA (2002) Data relating to case reports of suspected hepatotoxicity associated with kava-kava.
  • Traditional Medicines Evaluation Committee (2002) Response to concerns
    about Piper methysticum Forst. F., Kava.
  • Health Canada - Advice regarding products containing kava (January/August, 2002).
  • Ovid bibliographic records search for 'Kava'. Abstracts regarding efficacy and adverse effects. Pittler & Ernst (2002) Kava extract for treating anxiety. The Cochrane database of systematic reviews, Issue 3. Natural Products Industry Centre News Release, No basis for stop-sale order for Kava products. August 2002 American Herbal Products Association, Kava product warning label. March 2002.

The recent association of kava and serious hepatotoxicity (primarily based on case reports from Germany) has prompted some regulatory agencies (Germany, Switzerland, France, Portugal, UK, USA, Canada, Australia and Singapore) to warn consumers and/or take action to remove kava-containing products from the market.

The New Zealand Food Safety Authority requested that the MARC provide advice on the following:

Are there enough data available to enable the safety of kava-containing products to be determined?

If a significant safety issue is deemed to be apparent, what action (if any) does the MARC recommend in order to reduce the risk of adverse events?


Members took note of the fact that Medsafe has kept a watching brief on kava-associated liver damage since the reporting of the German case-reports in 2001. The Committee noted that no cases of hepatic injury associated with kava have been reported in New Zealand. Members also noted that, while it is not known in detail which formulations of kava-containing products are available in New Zealand, hepatotoxicity has been reported with ethanolic, methanolic, acetone, and concentrated aqueous extracts. Members noted that in many of the case reports from other countries, patients were concomitantly taking other medications that could in themselves lead to liver toxicity. In general, members agreed that on the basis of the available case reports, the association between kava-containing extracts and hepatotoxicity is not strong. It was also noted that there is some evidence for the efficacy of kava as an anxiolytic.


The Committee recommended to the New Zealand Food Safety Authority that labels, warning against the possibility of serious liver damage, should be required for kava-containing products.
Members also requested that the CARM keep a watching brief on this issue and that Medsafe provide comment in a Prescriber Update issue, reminding prescribers to consider herbal medicines as a possible cause of adverse effects.

4.3 Propofol and paediatric sedation

Reference material
  • Bray (2002) The propofol infusion syndrome in infants and children: can we predict the risk? Current Opinion in Anaesthesiology, 15, 339-342
  • Health Canada - Update on the use of propofol (July 10, 2002)
  • AstraZeneca USA Dear Healthcare Provider Letter (March 26, 2001)
  • AstraZeneca-Medsafe correspondence - propofol paediatric ICU sedation indication

In 2001, propofol was approved for 24 hour ICU paediatric sedation in New Zealand. Since this time, both the USA and Canada have advised that propofol should not be used for paediatric sedation (on the basis that sedation with propofol results in a higher death rate than with other agents).

Medsafe requested that the MARC provide comment on the following:

Is the approved indication for propofol in New Zealand still acceptable?


Members agreed that while the exact mechanism of propofol-infusion syndrome is not known, the evidence for its existence appears convincing. Dr Ian Boyd advised the Committee that propofol is contraindicated for the sedation of paediatrics receiving intensive care in Australia.


The Committee recommended that Medsafe consult the New Zealand Committee of the Australian and New Zealand College of Anaesthetists, with regard to their opinion on:

  • propofol being contraindicated for the sedation of children 18 years or younger receiving intensive care;
  • the availability of suitable alternatives for sedation;
  • any additional information that should be considered

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

4.4 COX-2 function and bone fracture healing

Reference material

Simon et al. (2002) Cyclo-oxygenase 2 function is essential for bone fracture healing. Journal of Bone and Mineral Research, 17(6), 963-976.


The Committee was informed that there is concern amongst some orthopaedists about the use of even traditional NSAIDs after major fracture.


The Committee requested that .. seek an expert opinion on this issue and Medsafe conduct a literature search for further information. Findings should be reported back to the MARC at the December meeting.

4.5 High dose fluticasone and adrenal insufficiency

Reference material
  • Drake et al. (2002) Symptomatic adrenal insufficiency presenting with hypoglycaemia in children with asthma receiving high dose inhaled fluticasone propionate. BMJ, 324, 1081-1083.
  • Patel et al. (2002) Symptomatic adrenal insufficiency during inhaled corticosteroid treatment. Arch Dis Child, 85, 330-334.
  • Wong et al. (2002) Growth and adrenal suppression in asthmatic children on moderate to high doses of fluticasone propionate. J Paediatr Child Health, 38, 59-62.
  • Todd et al. (2002) Acute adrenal crisis in asthmatics treated with high-dose fluticasone propionate. Eur Respir J, 19, 1207-1209.

.. expressed concern at GlaxoSmithKline's marketing of Flixotide, and the fact that Asthma New Zealand has sent a letter to GPs inferring that Flixotide is safer than beclomethasone in children. .. also expressed concern that prescribers may overlook advice to halve the total daily dose, when switching patients from beclomethasone to fluticasone. Because of a lack of time, the aforementioned articles on high-dose fluticasone and adrenal suppression in children were not discussed.


The Chair requested that .. clarify the issues of concern for possible presentation at the December meeting. The Chair also requested that Medsafe obtain background information with regard to the Asthma New Zealand letter, to aid MARC discussion.

5. ISSUES FOR INFORMATION ONLY - full text supplied

This material was not discussed by the Committee. 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 Sildenafil and aggressive behaviour

  • Milman & Arnold (2002) Neurologic, psychological, and aggressive disturbances with sildenafil. The Annals of Pharmacotherapy, 36, 1129-1134.

5.2 Oral contraceptives and cancer

  • Marchbanks et al. (2002) Oral contraceptives and the risk of breast cancer. NEJM 346(26), 2025-2032.
  • Letters to the Lancet (2002) OCs and cervical cancer. Lancet 360, 409-410.

5.3 SSRIs and withdrawal syndrome

  • Trenque et al. (2002) Reports of withdrawal syndrome with the use of SSRIs: a case/non-case study in the French Pharmacovigilance database. Pharm & Drug Safety, 11, 281-283.

5.4 Contraceptives and thrombosis

  • Lidegaard & Kreiner (2002) Contraceptives and cerebral thrombosis: a five-year national case-control study. Contraception, 65, 197-205.
  • Heinemann et al. (2002) Case-control studies on VTE: bias due to design? Contraception, 65, 207-214.
  • Kemmeren et al. (2002) Risk of arterial thrombosis in relation to oral contraceptives (RATIO) study. Stroke, 33, 1202-1208.

5.5 Interaction with dihydrocodeine and sildenafil

  • Goldmeier & Lamba (2002) Prolonged erection produced by dihydrocodeine and sildenafil. BMJ, 324, 1555.

5.6 HRT, VTE and surgery

  • McLintock (2002) HRT, VTE and surgery: what is best practice? NZMJ, 115(1157)
  • Arden et al. (2002) Peri-operative use of oestrogen containing medication and deep vein thrombosis - a national survey. NZMJ, 115(1157)

5.7 Re-analysis of the CLASS trial

  • Juni et al. (2002) Are selective COX-2 inhibitors superior to traditional non-steroidal anti-inflammatory drugs? Adequate analysis of the CLASS trial indicates that this may not be the case. BMJ, 324, 1287-1288.
  • Letters to the BMJ (2002) Are selective COX-2 inhibitors superior to traditional NSAIDs? BMJ, 325, 161-164.

5.8 OCs and VTE - UK court decision

  • News Article (2002) UK high court dismisses risk of VTE in "pill" test case. Lancet, 360, 391.
  • Editorial (2002) Epidemiology on trial. Lancet, 360, 421.

5.9 Olanzapine/Risperidone and diabetes

  • Koro et al. (2002) Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: a population based nest case-control study. BMJ, 325, 243-247.

5.10 SSRIs and growth suppression

  • Weintrob et al. (2002) Decreased growth during therapy with selective serotonin reuptake inhibitors. Arch Pediatr Adolesc Med, 156, 696-701.

5.11 CARM case reports

  • Ranitidine, glipizide, metformin, warfarin and hyperglycaemia (51260)
  • Carbamazepine and pneumonitis (51232)
  • Isotretinoin and unexpected therapeutic effect (51367)
  • Pamidronate and iritis, optic neuritis (51094)
  • Influenza vaccine and pericarditis (51175)
  • Influenza vaccine and INR decreased (51722)

6. Other New Zealand activities


Minutes of the Pharmacology and Therapeutics Advisory Committee Meeting, May 2002.

6.2 Publications

  • Coulter, D.M. (2002) Signal generation in the NZ IMMP. A combined clinical and statistical approach. Drug Safety, 25(6), 433-439.

6.3 Ministry of Health Meningococcal Vaccine Strategy Team

Summary of systems proposed to monitor adverse events following immunisation

7. International Activities

7.1 Australia

Minutes of the 10th May meeting of the Adverse Drug Reactions Advisory Committee

Australian Adverse Drug Reactions Bulletin 21(3), August 2002.

7.2 Canada

Canadian Adverse Reaction Newsletter 12(3), July 2002.

7.3 International Symposium on the Evaluation of Safety of Human Vaccines (Rome, May 2002)

Conference report by Dr M. Tatley.

8. general reporting

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

9. ISSUES FOR INTEREST ONLY - abstract supplied

This material was not discussed by the Committee. It includes updates on issues already known to the Committee and preliminary information on emerging issues. This material differs from that in section 5 in that it is of more peripheral relevance or importance. The material was provided for the interest of the members, and reading it was optional. Members were able to request that the material be discussed at the present, or at a future, meeting.

9.1 Anticonvulsants and cancer

  • Lamminpaa et al. (2002) Cancer incidence among patients using antiepileptic drugs: a long-term follow-up of 28,000 patients. Eur J Clin Pharmacol, 58, 137-141.

9.2 Warfarin and mango fruit interaction

  • Monterrey-Rodriguez et al. (2002) Interaction between warfarin and mango fruit. The Annals of Pharmacotherapy, 36, 940-941.

9.3 SSRIs and hyponatraemia in the elderly

  • Movig et al. (2002) Serotonergic antidepressants associated with an increased risk for hyponatraemia in the elderly. European Journal of Clinical Pharmacology, 58, 143-148.

9.4 Nefazodone discontinued in Sweden

  • Letter from Bristol-Myers Squibb to Kathlyn Ronaldson, 26 July 2002.

9.5 Erythromycin and hypertrophic pyloric stenosis

  • Cooper et al. (2002) Very early exposure to erythromycin and infantile hypertrophic pyloric stenosis. Arch Pediatr Adolesc Med, 156, 647-650.

9.6 Cisapride safety alerts changes prescribing

  • de la Porte et al. (2002) Impact of safety alerts upon prescribing of cisapride to children in NZ. NZMJ, 115 (1157).

9.7 Antiepileptic drug exposure in utero

  • Dean et al. (2002) Long-term health and neurodevelopment in children exposed to antiepileptic drugs before birth. Journal of Medical Genetics, 39, 251-259.

The meeting ended at 5pm.

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