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Updated 31 December 2012

Minutes of the 108th Medicines Adverse Reactions Committee Meeting - 11 December 2001

Held in Harbour Room One, 20th Floor, Grand Plimmer Tower, commenced at 9:15am.


The material listed as being considered on an issue is not intended to be exhaustive.

Descriptions of unpublished case reports have not been included to protect the privacy of those involved.

Names of individuals have been deleted where the contribution is not in the public domain and will not shortly be so. For example the names of those to be approached to write an article are deleted, but not usually the names of those who have contributed a draft article. Names are not usually deleted when a contribution has been made in an official capacity.

The recommendations of the committee are in bold type face.


Note relevant to these minutes: All of the recommendations of this meeting were accepted by the Delegate of the Minister of Health with the following exceptions:


Associate Professor TJB Maling (Chairperson)
Dr M Tatley
Dr R Savage
Dr D Coulter
Professor P Ellis
Dr H Kingston
Dr F McClure
Dr M Rademaker
Dr N Rafter
Professor DCG Skegg
Dr K Ronaldson (Secretary)


All day
Ms S Von Afehlt (Editor, Prescriber Update)
Dr M Harrison-Woolrych (Visiting Medical Specialist, IMMP)

Part of the day
Dr S Jessamine (Principal Technical Specialist, Medsafe)
Dr S Alder (Principal Medical Officer, TGA)
Mrs C Smith (Secretary, MCC)


1.1 Welcome and apologies

The Chair welcomed Dr Harrison-Woolrych, who is a specialist in obstetrics and gynaecology from the UK Medicines Control Agency and is visiting CARM for 6 months. It was also noted that Dr Rafter had now been officially appointed as Medsafe's representative to the Committee and Dr Jessamine had resigned.

Apologies had been received from Dr Goldsmith.

1.2 Minutes of the 107th meeting

The minutes of the 107th meeting were signed by the Chair as a true and accurate record of the meeting.

Members noted that for some items the comment was made that the Committee recommended no action. Members argued that having the item on the agenda and discussing it was action. Members asked that in future the wording not be "no action" but "no further action" or words of similar meaning.

1.3 Dates of the meetings for 2002

The following dates were set for the 2002 meetings:

1.4 Conflict of interest

1.5 Prescriber Update

1.5.1 New format of Prescriber Update

Ms Von Afehlt circulated to members copies of a mock up of an A4 presentation of Prescriber Update. She advised that it was intended to use this format from 2002 onwards. Most medical journals, including Australian Prescriber and Australian Adverse Drug Reactions Bulletin, are in A4 format. Using this format improves the status of Prescriber Update. Other changes to be made at the same time were using the volume number issue number system (recommended at the June 2001 MARC meeting), and placing the contents on the front page (to entice readers into the issue).

Members preferred the new format to the old A5 size and commented in particular that it was advantageous that the volume was less thick and the font size was larger. Members suggested that in order to increase the profile of the publication itself (for branding purposes) it would be better to have the title of the publication, rather than the Ministry of Health logo, at the top of the cover sheet.

Ms Von Afehlt advised that Medsafe was not financially able to conduct market research on the revised format. However, she and Dr Rafter had discussed the A4 format with medical doctors and pharmacists known to them. Ms Von Afehlt advised that comment was also to be invited from the professional bodies such as the Pharmaceutical Society and the Royal New Zealand College of General Practitioners.

Those with whom Ms Von Afehlt and Dr Rafter had consulted favoured having articles restricted to a single page or two facing pages. This suggestion required care with the length of articles and/or the use of fillers to complete pages. Fillers could include single paragraphs on a subject or artwork. Members suggested using the list of medicines in the IMMP or the adverse reactions of current concern as fillers, but Ms Von Afehlt advised that she had adopted the policy of having these items at the end of each issue with the advertisement for CARM so that people will know where to look for them when required. Members suggested considering the use of single paragraph articles as fillers to complete pages where articles were short.

She also mentioned that different ways of including the adverse reaction reporting card were being explored, including having it on the outside of the back cover.

Members considered that it would be advantageous to have sequential page numbering for each volume, rather than starting each issue at page one and asked that this arrangement be considered. It was pointed out that the adverse drug reactions bulletins from Australia, the United Kingdom and Canada are all numbered sequentially. Numbering sequentially conveys the signal that citation of articles is expected.

1.5.2 Circulation

Members also asked about distribution of Prescriber Update. There was some discussion of how to ensured that junior doctors receive Prescriber Update. First year doctors are currently sent the publication, but they move rather frequently, and hence it is difficult to maintain an up-to-date mailing list. Final year medical students do not currently receive it. Members considered it to be desirable that this group receive the publication. In addition, Ms Afehlt advised that Prescriber Update was not being sent to midwives, nurses or dentists. Midwives and dentists used to receive copies, but they were dropped from circulation for cost reasons. At that time, an arrangement was made that relevant articles could be published in the professional bulletin of these bodies. Members noted that in future when nurses are able to prescribe, it would be useful for them also to receive Prescriber Update. Members suggested that an advertisement be published in the professional bulletins of midwives, dentists and nurses offering a free subscription to Prescriber Update. With regard to junior doctors, members suggested contacting clinical training co-ordinators, sending a copy of Prescriber Update and asking them to promote it to final year medical students and first year doctors and to advise them that they can be put on the mailing list if they are not currently receiving it.

1.5.3 Authors' guidelines

Ms Von Afehlt mentioned changes that had been made to the guidelines for authors:

In addition, Ms Von Afehlt reminded members of the need to write succinctly so that articles did not become too long.

Members suggested that it would be useful to have a model text for an article to send to authors. The model text would illustrate abstract, subheadings, style of article, style of referencing, etc.

With regard to authors of articles, members agreed that it was not necessary to list their qualifications, but job titles and affiliations should be mentioned.

Members objected to the editorial team making changes to articles according to the comments of peer reviewers rather than the author. Members mentioned that editors of most peer reviewed journals send the comments of peer reviewers to the author and the author is responsible for making changes according to these comments. The author knows far more about the material in the article than the editor and is in a better position to modify the article appropriately. Also it is the author who must take ultimate responsibility for the content of the article. It was acknowledged that Prescriber Update is different from other publications in that its focus is to provide evidence-based practical clinical advice. Its purpose is not to air controversial opinions. If the editor was not happy with changes made by an author and a compromise could not be reached, the article could be scrapped. Ms Von Afehlt indicated that one reason she makes the changes to articles based on peer reviewers' comments is because of the time constraints. She also advised that most articles received for Prescriber Update are substantially rewritten in order to conform to the Prescriber Update style.

The Committee asked that authors be given the right to make changes based on peer reviewers' comments, but agreed that the editor should be free to apply the necessary time constraints to authors in order for publication deadlines to be met.

Members indicated that they appreciated the way that the editorial team had tightened up articles to make them briefer and more succinct.

1.6 Agenda presentation

In consultation with the Chair, Medsafe had changed the presentation of agenda material, so that items were prioritised with high priority issues at the beginning of the agenda (sections 3 and 4), and material of lesser importance included later in the agenda (section 5), and some material being included as abstract or reference only (section 9). In addition, the agenda material was being presented in a ring binder so that late material could be included where it belonged on the agenda. A letter had explained the new presentation to members. There was no discussion of the new presentation, but members expressed their approval of the changes.

Another innovation was a single page document listing the "Tools available to MARC", in other words possible recommendations or outcomes that the Committee could consider for each issue on the agenda. The list was not intended to be exhaustive, but it was intended to assist.


2.1 Report on the recommendations

2.1.1 Use of combined oral contraceptives and hormone replacement therapy in the perioperative period (5.1.2, Sep 2001)

At the recommendation of the Committee, Medsafe had requested from New Zealand Health Technology Assessment (NZHTA) a review of the literature around the management of women taking combined oral contraceptives (COCs) or hormone replacement therapy (HRT) and undergoing surgery. Dr Rafter advised that the result showed that there are not sufficient data in the literature on the issues around this question on which to base definitive advice. Several bodies have produced recommendations, some suggesting withholding COCs or HRT for several weeks. Medsafe had discussed with NZHTA the possibility of preparing an executive review (about 6 pages) of the material obtained. In view of the lack of pertinent information in the literature, the Committee considered it would not be worthwhile to obtain a review of the material.

The Committee recommended publishing a brief Prescriber Update article advising that it is not possible to develop evidence-based guidelines on the management in the perioperative period of women taking COCs or HRT.

2.1.2 Intravenous vitamin K dosage instructions (6.13.1, Sep 2001)

The Committee had asked that the dosage instructions for intravenous vitamin K be checked to see whether the maximum dose may be too high. Dr Rafter reported that the approved dosage is 0.5-20mg slowly. She commented that clinical practice may be evolving towards use of lower dosages, but at present the approved dosage instructions for Konakion are consistent with international guidelines.

2.1.3 The safety of bupropion (12.5, Sep 2001)

Glaxo SmithKline (GSK) at first agreed to the recommendation of the last meeting that bupropion be second line therapy, but then the company reversed its agreement. Medsafe had intended to write to GSK under section 36 of the Medicines Act 1981 to obtain data from them on:

Using s.36 also provided a route for possible restrictive action. The company's legal advisor had requested that s.36 not be invoked. However, the company agreed to the terms of s.36 being applied (supply of data in response to a concern, 60-day response time, referral to a Committee, possible restrictive action, etc) and hence these terms had been used in the letter. A comprehensive reply was expected from the company in mid January 2002.

2.1.4 Mesalazine and olsalazine in pregnancy? (12.7, Sep 2001)

… had prepared a comment on the safety of the use of mesalazine and olsalazine in pregnancy. He considered that mesalazine should be pregnancy category B, but olsalazine category C because of the lesser amount of data related to pregnancy with this medicine. His comments and references had been passed on to the Australian Drug Evaluation Committee (ADEC) and to the New Zealand Society of Gastroenterology.

2.1.5 MARC letters to Pharmac - K Ronaldson. Bupropion. Letter to Pharmac, 28 Sep 2001

The Chair pointed out that 4 letters to Pharmac highlighting issues the Committee considered to be important and/or of concern had been recommended at the previous meeting. He considered that it was good to be raising issues with Pharmac in this manner. However, it was noted that no replies had been received. The Committee asked that a letter be sent to Mr Wayne McNee, Manager, Pharmac and to Dr John Hedley, Chair of PTAC, expressing concern at the lack of response from Pharmac. The letter is to be signed by Associate Professor Maling.

2.1.6 Prescribing of adrenaline syringes (12.4, Sep 2001)

A letter had been written to Pharmac (see previous item) asking that Pharmac consider funding 2 adrenaline syringes for self-administration per year for eligible patients, as recommended by …. Members were concerned that this recommendation be implemented, but were uncertain what further action could be taken to ensure it happens. The Committee asked that its concerns about adrenaline syringes be mentioned in the letter requested in the previous item (2.1.5).

2.1.7 Minutes on the web site

At 23 November 2001, the number of hits on the minutes on the web site had been as follows:

Members were interested to see the number of hits continuing to increase for the minutes which had been published for some time.

Members were interested in seeing a breakdown of the hits on the minutes by country of origin, and suggested that this possibility be investigated.

2.2 CIOMS IV report

The method attempts to make the evaluation quantitative, or at least semi-quantitative.

Dr Rafter's report provided a lead into the material for members.

A member commented that he had been part of a working group which had conducted this sort of analysis of bee products. It took the group of 7 people 3 days to complete the evaluation with the help of a facilitator. He considered that this sort of evaluation process would become faster with experience. Members realised that there were not sufficient time or resources for a CIOMS IV evaluation to be conducted on each issue that comes before the Committee.

Members agreed that the CIOMS IV report presented fundamental principles to keep in mind and a structure within which to work when evaluating safety issues. It was observed that CARM would be in a position to produce quantitative data a CIOMS IV assessment

The assessment of thioridazine in relation to arrhythmias from QT-prolongation conducted by the UK Medicines Control Agency was noted. The analysis achieved was semiquantitative.

The Committee asked that Medsafe in consultation with the Chair arrange a one-day or half-day workshop with a selected safety issue to analyse using the CIOMS IV approach to be attended by Committee members. It was suggested that … (FDA) be approached to be facilitator at the meeting.


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:

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 web site of the WHO Collaborating Centre http: 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. So "certain" means 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, certain, probable, possible, unlikely, unclassified and unclassifiable.

3.1 Spontaneous reporting programme

3.1.1 Deaths Enalapril and malaise, palpitations, 48722

Comment: CARM staff advised that a copy of the post-mortem report had been requested. CARM has received 13 previous reports of palpitations and 2 of MI with enalapril. Members considered that the palpitations and death in the present case might have been coincidental with the switch to the generic brand and then back to the innovative enalapril. However, the case was difficult to interpret and it was agreed that a causality designation of "unclassifiable" was appropriate for palpitations and malaise. The death was recorded as "cause unknown". No additional action was recommended by the Committee. Enoxaparin and intracerebral haemorrhage, 48656

Comment: CARM has received 18 reports associated with enoxaparin, including 13 of haematoma and 2 of non-specific haemorrhage. Members agreed that a causality designation of "possible" was appropriate for this case, and that the death should be recorded as "medicine may be contributory." The Committee recommended no further action. Flecainide and ventricular arrhythmia, 48644

Comment: CARM has received 3 previous reports of sudden death with flecainide and 1 of arrhythmia. A review indicated the arrhythmia occurs in 4-8% of patients taking flecainide. Members agreed with the assessment of the reporter in this case, and considered that ventricular arrhythmia should be given the designation "possible", and the death recorded, "medicine may be contributory". The Committee recommended that no additional action be taken. Atorvastatin and myositis, increased creatine kinase, 48774

Comment: Myositis with increased creatine kinase is a known adverse reaction of atorvastatin. CARM has received 15 previous reports of myalgia, 2 of myopathy, 1 of myositis and 5 of creatine kinase increase with atorvastatin. In the present case members considered the appropriate causality designations for myositis and increased creatine kinase to be "probable", but considered the patient's death to be unrelated to the medicine. No additional action was recommended by the Committee.

3.1.2 Dermatologicals Isotretinoin and multiple malformations, 48737

Comment: Isotretinoin is a known teratogen with 691 cases of foetal disorders recorded in the WHO database. This is the first such case to be reported to CARM. The Committee considered that the causal designation for the present case should be "possible".

The Committee recommended taking the following action:

In addition the Committee recommended publishing a paragraph (or "filler" article) in Prescriber Update on this case, making the following points:

The Committee also recommended sending a letter to all dermatol-ogists in a similar vein to the article.

3.1.3 Hormones Diane 35 and pulmonary embolism, 48120

Comment: CARM has 12 previous reports of pulmonary embolism with Diane-35. The causality designation in the present case was "possible". Members discussed whether there may be a need to provide stronger advice regarding the choice of contraceptive in women who are immobile. No resolution was reached. Members also raised the need for Diane-35 to be discontinued despite continued use of warfarin. CARM staff believed this would have been advised in the response letter, but members asked that the letter be checked.

3.1.4 Musculoskeletal NSAIAs and post-operative haemorrhage, 48527, 48528

Comment: CARM has no reports of post-operative haemorrhage with NSAIAs. There are 12 reports of this event with ketorolac in the WHO database, and several cases with some of the other NSAIAs. The present cases were given the causality designation, "possible". The Committee asked that a literature review of the safety of post-operative NSAIAs in relation to haemorrhage (especially gynaecological and ear, nose and throat procedures) be conducted and the results brought to the next meeting.

3.1.5 Psychiatric Gabapentin and multiple malformations, abortion, 48796

Comments: Gabapentin is designated category B1 in the ADEC booklet Prescribing Medicines in Pregnancy meaning that animal studies have shown no evidence of foetal damage, and in experience with a limited number of pregnant women no increase in frequency of malformations or harmful effects has been noted. The comments in the data sheet for Neurontin (gabapentin) are in line with this. Members considered that the association with use of gabapentin was coincidential, and hence, the causality was designated "unlikely". Members recommended consulting the Anti-Epileptic Drug Pregnancy Registry in the US for other cases of malformation with gabapentin. Paroxetine and haemorrhage, 48294

Comment: Details of other medications had been requested by CARM staff. CARM holds no reports of haemorrhage with paroxetine, but there have been several such reports with fluoxetine (1 epistaxis, 1 haematoma, 2 thrombocytopenia, 2 anaemia, 3 menorrhagia). The WHO database holds 4 reports of postoperative haemorrhage with fluoxetine. A case of neonatal intracranial bleeding following delivery to a woman taking paroxetine had been reported at the WHO conference in Dunedin in November. The possible association of SSRIs with haemorrhage was discussed at item 4.3. For the present case, a causality designation of "possible" was made. The Committee recommended that no further action be taken.

3.1.6 Vaccines MMR vaccine and rash, conjunctivitis, cough, abnormal behaviour, fever, 48597

Comment: CARM holds one report of meningoencephalitis and one of meningitis with MMR vaccine. CARM sought comment from a paediatrician who advised that the girl may have had measles-related encephalitis even though it did not progress to convulsions and decerebration. The symptoms of measles, rash, conjunctivitis and fever were given the designation "possible", meningoencephalitis was designated "unclassifiable" because the diagnosis was made in retrospect, and abnormal behaviour was designated "unclassifiable" because of a lack of epidemiological evidence. The paediatrician had recommended contacting the Centers for Disease Control in Atlanta for comment on this case. Members concurred with this recommendation.

3.1.7 Alternative medicines Royal jelly/Ginseng Peking and asthma, 48729

Comment: The CARM database holds 3 reports of asthma attacks with royal jelly, all of which involved bronchospasm. The event was given the causality designation "probable." No other action was recommended. St Johns wort and disassociative reaction, suicidal tendency, 48735

Comment: This is the first report of this type of psychiatric reaction with St Johns wort in the CARM database. Other reports of suicide or suicide attempt (total of 2 cases) with St Johns wort in the WHO database involve patients also taking an SSRI. Because of the close temporal relationship of the event to the use of St Johns wort, the causality designation made was "probable". The Committee recommended that no other action be taken.

3.2 IMMP

3.2.1 Clozapine and omeprazole interaction Clozapine and omeprazole interaction with clozapine level increased, 48858 Clozapine and omeprazole interaction with clozapine level increased and seizure, 48914 Clozapine and omeprazole interaction with seizure and CPK increased, 40510 Clozapine and omeprazole interaction with neuroleptic malignant syndrome, death, 29452 Comment

Regarding the first case, it was considered unlikely that clozapine had interacted with rofecoxib, since there is no common metabolic pathway. In addition, there are no reports of interaction between clozapine and rofecoxib in the WHO database. Both clozapine and omeprazole are metabolised by multiple enzymes in the CYP450 system, and both to some extent by CYP3A4. It is possible that with genetic variations CYP3A4 or other relevant factors may be more important in some people.

The WHO database has 6 reports associated with the combined use of omeprazole and clozapine: neutropenia, grand mal convulsions with clozapine level increased, and NMS. Members questioned whether NMS and neutropenia may have been occurring as a result of an interaction, since both events are considered to be idiosyncratic. In the view of the Committee the cases of seizure probably were caused by the interaction.

The Committee recommended publishing a note on the possibility of an interaction occurring between clozapine and omeprazole in the publication of the Australian and New Zealand College of Psychiatrists and a short article in Prescriber Update. Both items would invite reports and would be written by Dr Coulter.

3.2.2 Hyperglycaemia and olanzapine Olanzapine and diabetes mellitus, 48860 Olanzapine and diabetes mellitus, renal impairment, increased plasma osmolality, LFTs increased, 48645 Comment

The CARM database holds 1 report of diabetes mellitus and 4 of hyperglycaemia with clozapine, 1 report of diabetes mellitus with olanzapine and 1 report of hyperglycaemia with risperidone. In the WHO database there are 597 reports of diabetes mellitus or hyperglycaemia with clozapine, 375 with olanzapine, 16 with quetiapine and 139 with risperidone.

It was noted that a Prescriber Update article had been published in June 1999 about hyperglycaemia with clozapine. The article had also mention-ed a possible association with olanzapine. Hyperglycaemia with clozapine had been listed as an adverse reaction of current concern at that time.

The Committee recommended:

3.3 Adverse reactions of current concern

Members recommended removing from the list of adverse reactions of current concern neutropenia and thrombocytopenia with ticlopidine (in prescribing practice ticlopidine has largely been replaced by clopidogrel) and cardiac arrhythmias with cisapride (cisapride use is greatly reduced, and the approved indication permits prescription only by specialists).

There was some discussion whether venous thromboembolism with oral contraceptives should remain on the list. However, members agreed they did still wish this adverse reaction to be brought to prescribers' attention, and for all cases to be reported.


4.1 Diane-35/Estelle-35 and venous thromboembolism

Vasilakis-Scaramozza and Jick had conducted a case-control study using the General Practice Research Database (GPRD) in the UK on the risk of VTE with low dose combined oral contraceptives containing cyproterone or levonorgestrel. The study included 14 cases and 114 matched controls taking levonorgestrel-containing OCs and 12 cases and 30 controls taking cyproterone-containing OCs. After adjustment for body mass index, smoking status, history of hirsutism, acne, polycystic ovary disease and asthma the relative risk of VTE with OCs containing cyproterone was 3.9 (95% CI 1.1-13.4). Since the relative risk compared with non-users for the levonorgestrel-containing OCs is around 4, the relative risk compared with background for cyproterone-containing OCs is around 16 (a similar figure to those found in the NZ and WHO studies - see below).

Seaman and Farmer, also using the GPRD, found a relative risk of VTE with OCs containing cyproterone compared with other combined oral contraceptives of 1.75 (1.17-2.63). However, these results were not adjusted for confounding factors including age and indication for use.

Other studies (discussed at earlier meetings by MARC) have also found elevated relative risks for combined oral contraceptives containing cyproterone:

All of these studies point to the risk of VTE with OCs containing cyproterone being greater than that for the second generation OCs, and some suggest that the risk may be greater than that for the third generation OCs. All of the studies had small case and control numbers, but the consistency of results suggests that this is a real effect. Members concluded that the risk of VTE with cyproterone-containing OCs is similar to that with the third generation products.

Members noted that CARM has now received 14 reports of pulmonary embolism with Diane-35 (cyproterone-containing OC).

It was also noted that a letter had been sent to Pharmac expressing concern at the full funding of Estelle-35 (generic of Diane-35) in the light of the risk of VTE. No reply had been received. None of the third generation OCs are fully funded. Members considered that the funding arrangement sent out an unfortunate signal about the safety of Estelle-35. In addition, the listing in the Pharmaceutical Schedule advises prescribers to code the prescription "contraceptive" (code "O") when Estelle-35 is indicated for contraception. Contraception is a secondary indication for Estelle-35 and Diane-35 and should not be the primary purpose for use.

The Committee recommended:

Publication of a Prescriber Update article on VTE with Diane-35 and Estelle-35 had been recommended at the September meeting. Members recommended that the article include mention of the CARM case reports of pulmonary embolism with Diane-35 and provide the advice that these medicines should not be the first choice of OC in women wanting contraception.

4.2 HRT and cardiovascular and cerebrovascular disease

At the previous meeting members had discussed advice that should be required for the data sheets of HRTs with regard to cardiovascular disease. This was following on from the sponsor companies being sent notices under s.36 of the Medicines Act concerning non-compliance with the current requirements in the Regulatory Guidelines. A questionnaire was sent to members to seek their agreement with a series of statements. The responses had been formulated into a draft statement for the data sheets of HRTs for Committee consideration.

Alexander et al conducted a reanalysis of the Coumadin Aspirin Reinfarction Study data for post-menopausal women with recent myocardial infarction (MI) comparing users and non-users of HRT. 21% (111) began HRT after MI. Compared with never users, new users had a higher incidence of death/MI/unstable angina (41% vs 28%, p=0.001) largely due to a higher incidence of unstable angina (39% vs 20%, p=0.001).

Viscoli et al conducted a randomised double-blind placebo controlled trial of the use of oestrogen-replacement therapy in 664 postmenopausal women with a recent ischaemic stroke or transient ischaemic attack. Oestrogen therapy was not associated with a reduced rate of stroke or death (relative risk in oestrogen group 1.1; 95% CI 0.8-1.4). However, there was a higher risk of fatal stroke with oestrogen (2.9; 0.9-9.0; RR for ischaemic stroke 4.4; 0.9-20.2), and non-fatal strokes in this group were associated with slightly worse neurological and functional deficits.

Mendelsohn and Karas were commenting on cardiovascular disease and HRT, and questioning the fact that the results of the HERS study have overridden previous epidemiological evidence of a cardiovascular benefit of HRT. These authors argued that the HERS study applies to women around 20 years past menopause. However, members observed that the women included in the HERS study were aged 44-79 years, with a mean age of 66.7 years. The comments of Mendelsohn and Karas were published alongside a study by Shlipak et al which, in a retrospective review of the National Registry of Myocardial Infarction (US), found a 35% reduction in mortality with use of HRT after MI in postmenopausal women. This study was not available to the Committee at the time of the meeting.

The Committee recommended that the following wording be adopted for the data sheets of HRTs:

For systemic therapies (e.g. oral tablets and transdermal patches)

Delete current: "Contraindicated in cerebrovascular or coronary artery disease."

Add: "HRT should not be initiated in women who have pre-existing coronary artery disease or cerebrovascular disease."

Add: "There is insufficient evidence to support the prescribing of HRT for the primary prevention of coronary artery disease. Initiation and continuation of HRT should be for reasons other than prevention of coronary artery disease.

"For women with coronary artery disease who have been taking HRT for at least 2 years, the decision to continue therapy should be made in discussion with the woman and used for the approved indications (see Indications).

"Women with coronary artery disease who have been taking HRT for less than 2 years should discontinue HRT and use other treatments. This advice is based on a randomised controlled trial of HRT use in women with pre-existing coronary disease (the Heart and Estrogen-progestin Replacement Study, HERS) that found an increased risk of coronary heart disease events in the first year of HRT use.

"If a woman taking HRT develops an acute cardiovascular event, HRT should be discontinued and not reinstated.

"There is no evidence to justify the prescribing of HRT for the prevention of stroke. The safety of HRT in women with a past history of stroke is unknown."

For topical (vaginal) oestrogen therapy

Delete current: "Contraindicated in cerebrovascular or coronary artery disease."

Add: "There is evidence from a randomised controlled trial (the Heart and Estrogen-progestin Replacement Study, HERS) that during the first year of systemic HRT use, there is increased risk of coronary heart disease events in women with pre-existing coronary disease. Systemic HRT (e.g. oral or patches) should not be initiated in women with coronary artery disease or cerebrovascular disease. However there are no data on the effects of topical (vaginal) oestrogens on the risk of coronary artery disease or cerebrovascular disease events."

With regard to the statement about the HERS study required with the primary prevention indication (no longer current) in the Regulatory Guidelines, members asked that this statement be dropped altogether.

Members recommended that the above statements (including mention that any contraindication statement for cerebrovascular or coronary artery disease should be deleted) be required for the data sheets for HRTs (systemic and topical, respectively, as specified), by the Regulatory Guidelines, and that the companies sent notices under s.36 be advised of this outcome of the review and required to make the necessary changes to the data sheets and CMI for their HRT products.

4.3 SSRIs and haemorrhage

In a retrospective cohort study of elderly people conducted in Ontario, van Walraven et al found 974 gastrointestinal bleeds in > 130,000 person-years use of an SSRI with an overall bleeding rate of 7.3 per 1000 person-years. The rate of bleeding increased with increasing degrees of serotonin re-uptake inhibition. Differences in bleeding rates between low and high inhibitors of serotonin reuptake were greatest in those > 80 years and in those with previous upper gastrointestinal bleeding. In this study the number needed to harm was 85, and if the patient was > 80 years the number was smaller.

Layton et al used the Southampton Drug Safety Research Unit's prescription event monitoring database to examine the rate of gastrointestinal haemorrhage with SSRIs. Comparison of the cohort exposed to SSRIs during the first month and months 2-6 of treatment with the unexposed cohort showed small non-significant increases in rates of bleeding in the SSRI cohort. The numbers in this study were not sufficient to show an effect.

In an earlier population-based case-control study conducted in Spain, Jose de Abajo et al found an adjusted odds ratio of 3.0 (2.1-4.4) for risk of upper gastrointestinal bleeding with SSRIs compared with non-use. The relative risk with an SSRI plus an NSAIA was 15.6 (6.6-36.6). This study was discussed at the MARC meeting in March 2000 (item 12.10.2).

Members noted that there is a pharmacological basis for this possible effect of SSRIs, in particular serotonin is a weak agonist in platelet aggregation.

Dr Coulter advised that the incidence of abnormal bleeding reported while fluoxetine was monitored in the IMMP was 1.6/1000, including 2 cases of purpura, and one case each of bleeding time increased, bruising, pulmonary bleeding and thrombocytopenia. There were no reports of gastrointestinal bleeding.

The Committee recommended publishing a brief Prescriber Update article on SSRIs and gastrointestinal bleeding with mention of age and use with NSAIAs and aspirin as risk factors. The central message is to be that if a patient has a gastrointestinal bleed, consider that SSRI use is a potential causative factor. The article is to be written by ….

The Committee also recommended:

4.4 Anticonvulsants and reduced bone mineral density

Valmadrid et al conducted a survey of neurologists in the US concerning their practice regarding the effects of antiepileptic therapy on bone and mineral effects. Only 28% of neurologists evaluated adult patients for bone and mineral disease and only 7% prescribed prophylactic calcium or vitamin D for patients on antiepileptic medication. These results were despite the fact that loss of bone mineral density is a known effect of anticonvulsants.

The Committee recommended writing to … to ask whether prophylaxis for bone mineral loss with anticonvulsants should be prescribed for all or some of those taking these medicines, and whether he considered that Medsafe should draw this issue to the attention of prescribers.

4.5 Steroid hormone contraception and bone mineral density

D B Petitti, et al. Steroid hormone contraception and bone mineral density: A cross-sectional study in an international population. Obstet Gynaecol 95:736-744, May 2000

Reduction in bone mineral density with depot medroxyprogesterone acetate. Item 11.1, Minutes of the Sep 1999 meeting of MARC

Petitti et al examined bone mineral density (BMD) in 2474 women aged 30-34 years attending family planning clinics in the developing world. BMD was significantly higher in short term, current users of OCs compared with women who had never used hormonal contraception. BMD was significantly lower in short term, current users of depot medroxyprogesterone acetate and levonorgestrel implants compared with women who had never used hormonal contraception. However, for all types there were no significant differences in BMD between past users and never users, even for those who had used a method ( 4 years. Hence the study found that there were small changes in BMD which were reversible in these young women. The study was conducted for the WHO Study of Hormonal Contraception and Bone Health.

… advised that the WHO was conducting another study of hormone contraception and BMD in teenagers and women in their forties.

The Committee recommended that the actions (Prescriber Update article and data sheet updates) on this topic recommended at the meeting in September 1999 wait until publication of the next WHO study. The actions recommended in September 1999 had been put on hold at the time pending publication of the WHO studies.

4.6 NSAIAs and COX-2 inhibitors and infertility

Smith, Akil and Mendonca et al describe cases of women who were infertile while taking NSAIAs, but who returned to fertility after withdrawal of the medication. Pall et al conducted a randomised double-blind trial in 13 women using rofecoxib. Compared with the placebo group, 4 of the 6 women taking rofecoxib had delayed follicle rupture > 48 hours after the luteinising hormone peak. In his commentary, Norman proposed that COX-2 inhibitors may interfere with fertility by inhibition of prostaglandin synthesis since ovulation, fertilisation, implantation, decidualisation and parturition depend on prostaglandin activity.

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. Dr Rademaker is to write the article and Dr Kingston is to peer review it.

4.7 Once daily dosing of quinapril

… was concerned that the sponsor company for quinapril is marketing it as a medicine which is effective in most individuals if administered once daily. However, a significant proportion (possibly as many as 50%) of individuals need twice daily administration for adequate blood pressure control. The approved dosage information gives twice daily administration as an option, but the primary recommendation is for once daily use.

The Committee recommended:

4.8 Paracetamol and peptic ulcer

García Rodríguez and Hernández-Díaz in a nested case-control study of 2105 cases and 11,500 controls found that use of paracetamol at >2g daily was associated with an increased risk of upper gastrointestinal complications (relative risk 3.6; 2-6-5.1). For the combination of paracetamol (> 2 g/day) and an NSAIA, the relative risk was 13.2 (9.2-18.9).

… had conducted an unpublished case-control study with 494 cases and 972 matched controls and found a relative risk of haemorrhage or perforation of peptic ulcer with paracetamol >1g daily compared with non-use of 3.6 (1.9-5.0). When a reanalysis was conducted using cases and controls (16 each) who had taken paracetamol alone rather than in combination with codeine or dextropropoxyphene the adjusted relative risk was 1.4 (0.6-3.4).

… had suggested that the association with use of > 1 analgesic may be because their use "indicates a degree of pain which might predispose to more severe peptic ulceration or because they mask ulcer symptoms more effectively so that patients finally present with haemorrhage or perforation." However, the new study suggested an association with paracetamol alone. Members considered that the quality of the study was such that, although confirmation was required, the result appeared to be convincing.

The Committee asked that further articles on the possible association between paracetamol and gastrointestinal complications be brought to its attention.

4.9 Safety of bupropion

The update from the CSM together with the reports of serum sickness (2 cases) and overdose (1case) were noted.

It was noted also that Medsafe is awaiting a substantial submission of data concerning the safety of bupropion from GSK to be considered at the next meeting (see 2.1.3).

5 Issues for Information Only

- usually 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, in which case it would be moved to section 3 or 4, as appropriate.

5.1 Spontaneous reporting programme - more case reports

5.1.1 Antithrombotics

5.1.2 Hormones

5.1.3 Psychiatric

5.1.4 Vaccines

5.1.5 Alternative medicines

5.2 CARM Quarterly Report

5.3 IMMP

5.4 NSAIA use and group A streptococcal infection

5.5 Selective COX-2 inhibitors and nephrotoxicity

5.6 Roaccutane and birth defects

5.7 Vaccine articles from the literature

5.8 Cerivastatin and rhabdomyolysis

5.9 Prescriber Update


6.1 PTAC minutes

6.2 Publications

7 Other Countries

7.1 Australia

7.2 Canada

7.3 United Kingdom

7.4 EMEA (Europe)

7.5 Overseas conference attendance report

7.6 24th Annual meeting of the WHO Drug Monitoring Programme


9 Issues for Interest Only - abstract or reference only

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 being of more peripheral relevance or importance. The material was provided for the interest of the members. Reading it was optional. Members were able to request that the material be discussed at the present or subsequent meeting. Items discussed were moved to section 4.

9.1 Abstract only

9.2 Reference only - brief description of content supplied

The meeting ended at 5 pm.

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