Revised: 21 May 2013

Committees

Minutes of the 107th Medicines Adverse Reactions Committee Meeting - 5 September 2001

Held in Harbour Room Two, 20th Floor, Grand Plimmer Tower. Commenced at 9:30am.

Preface:

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Descriptions of unpublished case reports have not been included to protect the privacy of those involved.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

Minutes:

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:

• Cystitis with tiaprofenic acid will be considered for listing as an adverse reaction of current concern after the review of the safety of tiaprofenic acid under s.36 of the Medicines Act 1981 has been completed (section 4.2);
• Medsafe did not invoke s.36 of the Medicines Act concerning Zyban, but obtained agreement from the sponsor company that it would supply the requested information and comply with any restrictions imposed without the need to invoke the Act (section 12.5).

PRESENT

Associate Professor TJB Maling (Chairperson)
Dr M Tatley (Medical Assessor)
Dr R Savage (Medical Assessor)
Dr D Coulter (Director, IMMP)
Professor P Ellis
Dr J Goldsmith
Dr S Jessamine
Dr H Kingston
Dr F McClure
Dr N Rafter (Medical Advisor, Medsafe)
Dr K Ronaldson (Secretary)

IN ATTENDANCE

Ms S Von Afehlt (Editor, Prescriber Update)

1. WELCOME AND APOLOGIES

Apologies had been received from Dr Rademaker and Professor Skegg.

2. MINUTES OF THE 106^TH MEETING

The following corrections were made to the minutes of the 106^th meeting:

• change British Medical Journal on page 2 (item 4.2) to New Zealand Medical Journal;
• change the paragraph at the top of page 10 (item 6.5.3) to remove mention of CARM recommending progestogen-only pills and to state instead that CARM advises that women who develop venous thromboembolism (VTE) on combined oral contraceptives should avoid oestrogen-containing medication in the future;
• insert a comma after "discontinued" in the last line of paragraph 4 on page 24 (item 12.2.1);
• correct the spelling of embryopathy (item 12.6).

Regarding the case of flecainide and sudden death (case number 46833, item 6.4.1), the Committee asked that the relevant hospital be contacted for the coroner's report.

3. DATE OF THE NEXT MEETING

6 December 2001 was confirmed as the date of the next meeting.

4. MATTERS OF ADMINISTRATION

4.1 Conflict of interest

• Competing interests tables

4.2 Prescriber Update

• Schedule of Prescriber Update articles
• M Rademaker. Corticosteroids and risk of bone fracture. Draft Prescriber Update article
• Contents of Oct 2001 Prescriber Update
• M Tatley. Bupropion - an update on safety issues. Draft Prescriber Update article
• Medsafe Editorial Team. Growth retardation with inhaled intranasal corticosteroids. Draft Prescriber Update article
• Medsafe Editorial Team. Interaction between COX-2 inhibitors and warfarin. Draft Prescriber Update article
• Ruth Savage. Tiaprofenic acid-induced cystitis. Draft Prescriber Update article
• CARM. Your guide to adverse reaction reporting. Draft Prescriber Update article
• Medsafe Editorial Team. Adverse reactions of current concern. Draft Prescriber Update article
• Medsafe Editorial Team. Low dose aspirin and gastrointestinal haemorrhage. Draft Prescriber Update article

Members commented that many medical practitioners are not aware of Prescriber Update or have an appreciation of its value to them. Ms Von Afehlt explained that as editor of Prescriber Update she has worked to promote awareness of the publication. In addition, Medsafe has committed itself to publishing 3 issues per year, and editorial guidelines have been developed and implemented to limit the size and scope of articles.

It was noted that a review (by questionnaire to readers) had been conducted of the ADRAC bulletin. Readers liked the size of the bulletin and the length of articles. The ADRAC bulletin is only four A4 sides (1 page is title page), with most articles about half a page. In contrast Prescriber Update has much longer articles with a total length of > 40 pages.

The Committee asked that the promotion, profile (target reader awareness), frequency, length of articles and size of Prescriber Update be on the agenda of the next meeting.

Peer reviewers were proposed for the following articles:

• Interstitial pneumonitis with medicines: .., Wellington Hospital;
• Vascular effects with sumatriptan: .., .., Wellington Hospital;
• Fluoxetine and suicide/suicidal ideation: .., .., Auckland University;
• Oral corticosteroids and bone fracture risk: ..;
• Beta-agonists and tachyphylaxis: ...

Members expressed some concern at cystitis with tiaprofenic acid as described in the article by Dr Savage. The Committee recommended that the sponsor companies for medicines containing tiaprofenic acid (Surgam, Apo-Tiaprofenic) be sent a notice under section 36 of the Medicines Act 1981 asking that they justify their medicines remaining on the market in the light of the risk of cystitis, and complications from this adverse reaction, with these medicines.

The Committee also recommended that cystitis with tiaprofenic acid be an adverse reaction of current concern.

There was some discussion concerning the difficulty members have knowing whether it was worth their while to make editorial comments on draft Prescriber Update articles included on the agenda. Ms Von Afehlt advised that in this particular case the text for the articles was almost final because they are to be included in the October issue of Prescriber Update. However, she was happy to accept members' comments at this meeting. Most meetings will not have a publication date so soon afterwards, but in all cases it is likely that changes will have been made to articles subsequent to their inclusion in the dossier. Members asked that in future the stage of articles in the editorial process be made more clear to them. In addition, members considered that in some instances, the Committee peer reviewer may wish the entire Committee to formally review an article. Members asked that this possibility be incorporated into the guidelines for Prescriber Update articles.

5. MATTERS ARISING

5.1 Report on the recommendations

- K Ronaldson. Secretary's report to the members of the MARC for the 107^th meeting. 22 Aug 2001
- Minutes and recommendations of the 106^th meeting of MARC, 14 June 2001. Report for the Minister's Delegate. 13 Aug 2001
- Recommendations of the 106^th meeting of the MARC
- Recommendations tables
- Causality designations for the web site (to go with minutes)

5.1.1 Cross-communication between MARC and PTAC (5.1.1, June 2001)
The Committee noted that it is now receiving the minutes of PTAC meetings. Members expressed the need to see the agendas of PTAC meetings before the meeting occurs so that any safety concerns of the MARC could inform the PTAC discussion. If necessary, the MARC could hold out of session consultations on PTAC agendas.

The Committee recommended that Pharmac be approached to ask if the MARC could be supplied with the agendas of each PTAC meeting before the meeting occurs, and in time for comment to be obtained from MARC members.

5.1.2 Use of COCs and HRT in the perioperative period (5.1.2, June 2001)

- A Van Rij. Use of COCs and HRT in the perioperative period. Letter 31 July 2001
- M Insull. OCs and HRT in the perioperative period. Comment on behalf of RANZCOG. 27 Aug 2001

Members noted the responses received from Professor Van Rij and Dr Insull. Members expressed considerable reluctance to publish any sort of advice around the risk of VTE with COCs and HRT in the perioperative period and the need for measures to reduce the risk. The difficulty that concerned the Committee was the absence of data on which to base advice. The earlier intention had been to seek comment from the appropriate professional colleges and then prepare a brief Prescriber Update article based on these comments and the published literature, and with reference to the recommendations of the New Zealand Guidelines Group.

The Committee recommended that no Prescriber Update article be published, but that the matter be referred by the Ministry to the New Zealand Health Technology Assessment Group (NZHTA) in Christchurch for a comprehensive literature review. The Committee would reconsider action to be taken after completion of the review by the NZHTA.

The Committee also recommended writing to the orthopaedic surgeon, who had contacted Medsafe about the issue towards the end of 2000, to advise him of the action recommended by the Committee.

5.1.3 Propofol, dose for prolonged sedation (5.1.10, June 2001)

- K Ronaldson. Propofol (Diprivan) for infusion in prolonged sedation. Letter to AstraZeneca. 10 Aug 2001

The Secretary advised the Committee that an appropriate approach to the data about use of high dose propofol in prolonged sedation had been worked out in consultation with the College of Anaesthetists, Faculty of Intensive Care. The approach involved a data sheet update with the following additions:

To the dosage and administration section:
"There are limited data on propofol safety at high dosage (> 4 mg/kg/h) for extended periods of greater than 48 hours."

To the warnings and precautions section:
"Special caution should be exercised if infusion rates in prolonged sedation (> 48 hours) exceed 4 mg/kg/h. Infusion rates > 5 mg/kg/h for > 58 hours have been associated with fatal metabolic acidosis or cardiac failure. Review of the sedation regime should be conducted in the presence of unexplained acidosis or cardiovascular compromise."

To the adverse effects section:
Addition of metabolic acidosis and cardiac failure to the list of very rare adverse effects that may occur with prolonged sedation.

The Committee was in agreement with this action.

5.1.4 Safety of bupropion (12.1, June 2001)

The previous meeting had recommended that bupropion be considered for monitoring in the IMMP. The IMMP Sub-Committee had not met since that meeting, but would be meeting shortly to consider the monitoring of bupropion.

5.1.5 Hydroxyethylstarch in sepsis and renal function (12.5, June 2001)

- R Freebairn. Hydroxyethylstarch and renal failure. Letter 18 Aug 2001
- P Gosling, et al, G Godet, J Boldt, F Schortgen, L Brochard. Hydroxyethylstarch as a risk factor for acute renal failure in severe sepsis. Correspondence Lancet 358, 18 Aug 2001
- F Schortgen, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 357:911-6, 24 Mar 2001

A study had been considered at the last meeting which found a higher rate of renal failure with 6% hydroxyethylstarch (HES) in severe sepsis than with 3% gelatin. Advice on the relevance to the New Zealand situation of these results had been sought from the College of Anaesthetists, Faculty of Intensive Care. The following points had been made by the College:

• In the published study, there was a higher proportion of risk of renal failure in the HES group at recruitment than in those given gelatin.
• Gelatins have a shorter intra-vascular half-life than HES.
• The HES available in New Zealand (Pentastarch) has a higher molecular weight and a lower level of hydroxylation, and comes in a more concentrated solution (10% vs 6%) than the HES used in the study.
• With the lower level of hydroxylation, Pentastarch has a faster renal elimination rate (shorter intra-vascular half-life) than the HES in the study.
• Despite the difference in rate of renal failure in the study, there was no difference in mortality rate, suggesting that HES conveys some survival advantages (e.g. by reducing microvascular permeability).

The College concluded that "Although the paper is of scientific merit, and has interesting data, there is little direct implication for the New Zealand intensive care or resuscitation scene."

In addition, members commented that the study did not measure creatinine clearance, and although HES is dehydrating, patients in this group did not receive extra hydration.

The Committee agreed that, since the HES being used in New Zealand is different from that used in the study, there is no need to take any action on the basis of the results.

5.1.6 Consumer representative on MARC

The Secretary reported that nominations had been received from all of the three bodies approached (Ministries of Consumer Affairs and Women's Affairs and Te Puni Kokiri) for a consumer representative on the MARC.

5.2 Selective COX-2 inhibitors and cardiovascular events

- MI differences in the VIGOR study. Pharmaceutical J 264:835, 3 June 2000
- E Barr. Expert opinion report on the cardiovascular findings of the VIGOR study. Report for MSD. 21 Dec 2000.
- Rofecoxib tablets and oral suspension. Periodic Safety Update Report for 1 Aug 2000 to 31 Jan 2001. Merck Research Laboratories. Excerpts on cardiovascular disease and the overall conclusion
- D Mukherjee, et al. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954-9, 22/29 Aug 2001
- K Ronaldson. Selective COX-2 inhibitors and cardiovascular events. Report for MARC, 30 Aug 2001
- Merck Research Laboratories. Points to consider in review of Whelton, et al. 2 April 2001

5.2.1 The VIGOR study

The VIGOR study included 4047 rofecoxib (50mg once daily) and 4029 naproxen (500mg twice daily) recipients with rheumatoid arthritis. A surprise finding of the study was a higher rate of myocardial infarction (MI) with rofecoxib (22, 0.4%) than with naproxen (4, 0.1%).

Patients taking low dose aspirin were excluded from the study, but some of the participants were eligible for aspirin prophylaxis because of previous cardio-vascular events. A proposed reason for the difference in rate of MI was a protective effect by naproxen, similar to that conferred by aspirin, rather than any deleterious effect of rofecoxib. Those patients eligible for preventive therapy with aspirin accounted for 4% of the study population, but experienced 31% of the serious thrombotic cardiovascular events. For this group naproxen therapy was associated with a 43% reduction in risk of these events relative to rofecoxib.

5.2.2 Company data and comment

No other efficacy studies conducted by Merck Research Laboratories with rofecoxib have found evidence of a prothrombotic effect for rofecoxib.

At 13 March 2000, the company had received 78 reports of thrombotic cardio-vascular events with rofecoxib in patients not in clinical trials. The estimated rate of reporting of these events is similar to that for finasteride and alendronate, 2 other medicines marketed by MSD which are not thought to be associated with an increased risk of cardiovascular events.

The company report concluded that there is a biological basis for the difference in rate of cardiovascular events between rofecoxib and naproxen in the VIGOR study since naproxen is a potent inhibitor of platelet aggregation and rofecoxib has minimal effects on this process.

5.2.3 Analysis by Mukherjee et al

Mukherjee et al analysed the available evidence for an increased rate of cardiovascular events with rofecoxib and celecoxib. Their sources are the VIGOR and CLASS studies, 2 studies of rofecoxib submitted to the FDA (085 and 090), and a meta-analysis of 4 studies comparing aspirin with placebo in primary prevention of cardiovascular disease.

In the CLASS study, 3987 patients with rheumatoid arthritis received celecoxib, 1996 received ibuprofen and 1985 received diclofenac. Aspirin use (<325 mg/day) was permitted. Rates of MI were higher with celecoxib than with the non-selective NSAIAs for those who were receiving aspirin (1.5% vs 1.2%) and those who were not (0.2% vs 0.1%).

In Study 085 and Study 090, a total of 814 patients with osteoarthritis of the knee took rofecoxib, 802 took nabumetone and 404 took placebo. Use of low-dose aspirin was permitted. A total of 7 (0.9%) serious cardiovascular events were reported with rofecoxib, 4 (0.5%) with nabumetone and 1 (0.2%) with placebo.

The meta-analysis included 4 studies of primary prevention with a total of over 48,000 individuals taking aspirin or placebo. The subjects had similar cardiac risk factors to those in the VIGOR study. The annualised incidence rate of MI in those taking placebo was 0.52%, compared with 0.74% for rofecoxib in the VIGOR study (p = 0.04) and 0.80% with celecoxib in the CLASS study ( p = 0.02).

5.2.4 Comment on the Mukherjee et al analysis

The following comments apply:

• Between trial comparisons are problematic, especially as patient populations and selection criteria differ. In addition, rheumatoid arthritis is associated with an increased risk of MI.
• The dose of rofecoxib (50 mg daily; cf. approved dosage 12.5-25mg daily for osteoarthritis) in the VIGOR study may have been a factor - enhancing any prothrombotic potential.
• Naproxen offers a sustained inhibition of platelet aggregation throughout the dosage interval, which may account for the higher rate of MI with rofecoxib in the VIGOR study.
• Ibuprofen and diclofenac may not provide cardioprotection, and diclofenac may be somewhat prothrombotic by inhibition of vasodilatory PGI2. These effects may have masked the effects of celecoxib in the CLASS study. In addition, use of low-dose aspirin was permitted in this study.
• The rates of MI with rofecoxib and celecoxib in the VIGOR and CLASS studies, respectively, were similar and were significantly higher than that with placebo in the meta-analysis. These results suggest that selective COX-2 inhibitors may have a deleterious cardiac effect, but further investigation is required to confirm this.

Mukherjee et al went one step further than Merck Research Laboratories and proposed that celecoxib and rofecoxib may have a prothrombotic effect through inhibition of prostaglandin. However, the clinical evidence available so far is preliminary and needs further confirmation in studies designed to evaluate the presence of such an effect.

5.2.5 CARM data

CARM has received 30 reports of cardiovascular events in association with celecoxib and 9 with rofecoxib, representing a total of 20% and 32%, respectively, of reports received for these medicines. No reports of MI have been received for either medicine, but there had been 2 reports of angina with rofecoxib and 3 of chest pain with celecoxib. The mean rate of reporting of cardiovascular events with the non-selective NSAIAs is 8.2% of all reports. Although not too much weight can be put on data of this sort, members considered that it may be significant that selective COX-2 inhibitors were associated with a higher rate of reporting of cardiovascular events than the non-selective NSAIAs (note that celecoxib and rofecoxib are being monitored in the IMMP, but the data for the other NSAIAs was collected by spontaneous reporting).

5.2.5 Recommendations

Members noted that rofecoxib and celecoxib are already being monitored in the IMMP. Despite the lack of funding both medicines are being widely used in New Zealand.

It was noted that the article for Prescriber Update on the safety of rofecoxib and celecoxib, recommended at the meeting in June 2000 has now become two articles: one on gastrointestinal and liver effects and pancreatitis and the other on allergic reactions, cardiovascular effects and interactions.

In addition, the Committee recommended:

• writing to Pharmac to mention the concerns about the possible prothrombic effects of the COX-2 inhibitors; and
• making cardiovascular events with celecoxib and rofecoxib adverse reactions of current concern.

6. General Reporting

- Case reports considered since Nov 1997, by medicine class
- Case reports considered since Nov 1997, by recommendation
- Glossary of terms

Members commented that a survey conducted by ADRAC had obtained the result that many reporters would like to receive a personalised response to their adverse reaction reports. ADRAC sends responses that are somewhat personalised in a formalised way. It was noted that CARM sends detailed responses specific to each individual case (as outlined in the box below) and that reporters very much appreciate these helpful replies.

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.

6.1 CARM Quarterly report 6.2 Deaths

Note: These deaths were discussed under the therapeutic group of the medicine involved. Each of the deaths has an associated report number which is also a hyperlink to the comment on that case. To access the comment click on the hyperlink.

Ispaghula and choking, 47561
Lamivudine and hepatic necrosis, GI haemorrhage, confusion, cerebral oedema, INR increased, 47932
Dalteparin and haemorrhage intracranial, 47921
Felodopine and toxic epidermal necrolysis, 47567
Isotretinoin and suicide, 47802
Cyproterone acetate and pulmonary embolism, 47562
Bupropion and suicide, 47799
Gabapentin and neutropenia, pulmonary embolism, myocardial infarction, 47988
Allopurinol / bendrofluazide and toxic epidermal necrolysis, 47935

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:www.who-umc.org These designations, certain, probable, possible, unlikely, unclassified and unclassifiable, refer to the degree of certainty about the relationship between the medicine and the adverse event. The terms should not be understood literally. 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.

6.3 Alimentary

6.3.1 Ispaghula and choking (death), 47561

Comment: Members noted that the product information for Isogel (ispaghula) provides clear instructions that the substance should be mixed with water before ingestion. CARM has had no previous reports of such an event occurring with ispaghula. Members considered that the present tragic event was an isolated case. The causality designation given the event was "probable". The Committee recommended that no other action be taken.

6.4 Antiinfectives

6.4.1 Lamivudine and hepatic necrosis, GI haemorrhage, confusion, cerebral oedema, INR increased (death), 47932

Comment: Members considered the adverse events to be caused by the patient's hepatitis B infection rather than the lamivudine, or withdrawal of the lamivudine. It seemed that there had been an inadequate therapeutic response to lamivudine. Hence, members asked that the current reaction terms be dropped and the adverse reaction be entered as "therapeutic response inadequate" with a causality designation of "possible". No other action was recommended.

6.5 Analgesics

6.5.1 Paracetamol and anaphylactic reaction, 47949

Comment: The CARM database has 3 reports of anaphylactic shock, 1 of an anaphylactic reaction and 1 of an anaphylactoid reaction with paracetamol. The causality designation made in this case was "probable". There was some discussion over whether it would be appropriate to publish a Prescriber Update article about anaphylactic reactions occurring with paracetamol. Paracetamol is not usually thought to be associated with adverse reactions of this nature. However, members agreed that, with the vast amount of paracetamol used annually in New Zealand and the small number of cases reported, anaphylaxis must be very rare. Moreover, publishing an article would not be very useful in that a change in behaviour would not be the object. The Committee recommended that no other action be taken.

6.6 Antithrombotics

6.6.1 Dalteparin and intracranial haemorrhage (death), 47921

Comment: Members rated the causal association between the intracranial haemorrhage and use of dalteparin to be "possible". The Committee recommended no additional action.

6.7 Cardiovascular

6.7.1 Amiodarone and chromatopsia, scotoma, keratitis, 47655

Comment: The CARM database holds 18 reports of corneal deposits with amiodarone, 10 of keratitis and 7 of abnormal vision. The data sheets for Cordarone and Aratac (amiodarone-containing products) mention ocular effects, but not these specifically. Impairment in colour vision has been described in a small series of patients following long-term (16-72 months) amiodarone therapy. Members observed that impairment of colour vision is very rare with amiodarone; keratopathy occurs more frequently. The causal association between amiodarone and the adverse visual effects was designated "possible". No other action was deemed necessary.

6.7.2 Bezafibrate and rhabdomyolysis, acute renal failure, CK elevated, fatigue, dizziness, 47762

Comment: The CARM database holds 3 previous reports of rhabdomyolysis and 50 other reports of muscular reactions with bezafibrate which was monitored on the IMMP. It was considered, however, that in the present case renal failure may have been present prior to the development of rhabdomyolysis. Use of the combination of a diuretic, an ACE inhibitor and an NSAIA, plus the use of spironolactone would have contributed to this patient's renal failure. Each adverse reaction term was designated "probable" for association with bezafibrate in the present case. Rhabdomyolysis is mentioned in the data sheet for Bezalip, but not acute renal failure occurring as a result. No further action was recommended.

6.7.3 Felodipine and toxic epidermal necrolysis (death), 47567

Comment: The WHO database holds 2 reports of toxic epidermal necrolysis, 5 of erythema multiforme and 1 of Stevens Johnson syndrome with felodipine. Toxic epidermal necrolysis is not listed as an adverse reaction in the data sheets for either medicine containing felodipine (Plendil, Agon). If this is an adverse reaction of felodipine, it appears to occur very rarely. In the present case the event was given the designation "possible" for relationship to felodipine, because of rarity and the lack of precise details regarding time to onset and changes in medication. The committee recommended taking no further action.

6.7.4 Frusemide / Cilazapril / Indomethacin and acute renal failure, 47287

Comment: ADRAC has published an article which comments that > 50% of reports of acute renal failure are attributed to a diuretic, an NSAIA or an ACE inhibitor or combinations of two or three. Both NSAIAs and ACE inhibitors dilate the glomerular efferent arteriole, which is a problem if dehydration occurs such as with the diarrhoea and vomiting in this patient. Bezafibrate may also have contributed to the adverse reaction. It was noted that the possibility of an interaction between an NSAIA, an ACE inhibitor and a diuretic is not mentioned in the data sheets of these medicines. In the present case both of the reaction terms, acute renal failure and drug interaction, were given the designation "probable" for association with frusemide, cilazapril and indomethacin. Members observed that a similar interaction can occur with COX-2 inhibitors. The Committee asked that mention of the possible interaction between COX-2 inhibitors, diuretics and ACE inhibitors be included in one of the articles on COX-2 inhibitors which are currently in preparation (see 5.2.5).

6.8 Dermatologicals

6.8.1 Isotretinoin and suicide (death), 47802

Comment: In the professional experience of one member the effect of isotretinoin on mood resolves within 2-3 days of stopping the medication. Because of the lack of information on this case, including the fact that the suicide apparently occurred 5 months after cessation of isotretinoin, the causality designation was rated "unclassifiable" for relationship with isotretinoin. Further details had been requested without success. No further action was recommended by the Committee.

6.8.2 Mometasone furorate and peri-oral dermatitis, 47894

Comment: Peri-oral dermatitis is a known adverse reaction of use of topical corticosteroids on the face. The causality designation in the present case was "probable". The data sheet for Elocon lists peri-oral dermatitis as a contraindic-ation, and says that the product should not be used near or in the eyes, but there is no contraindication for use on the face. The data sheets for Betnovate and Dermovate state that the use of fluorinated corticosteroids is contraindicated on the face. The Committee recommended that the data sheet for the Elocon range of products (cream, ointment, lotion) be required to include a warning about use on the face:

Elocon (cream, ointment, lotion) should be used with caution on the face, and only for a short period. Use on the central part of the face can exacerbate rosacea and lead to peri-orificial dermatitis. Patients should be warned against use on the face except on medical advice.

This information should also be included in the CMI with suitable wording. The Regulatory Guidelines should include this as a requirement for the data sheets of potent topical corticosteroids.

6.8.3 Pimafucort and nerve deafness, 47907

Comment: The absorption of neomycin from topical preparations is minimal. The WHO database holds 70 reports of deafness and 8 of nerve deafness with neomycin; at least 10 of these cases were reported in association with topical use. CARM has recorded 4 previous cases of deafness with neomycin. Two of these cases were associated with topical use: on extensive burns in one case and in the ear in a child. In the present case the Committee considered the association with neomycin to be "unlikely". A genetic cause was considered more likely. The Committee recommended no additional action.

6.9 Hormones

6.9.1 Clomiphene and psychosis, insomnia, depression, self-mutilation, 47475

Comment: There are no reports of psychosis with clomiphene in the WHO database. However, clomiphene-induced psychosis has been reported in two published cases, also with no prior history. Generally drug-induced psychosis ceases soon after cessation of the medication and would be unlikely to persist or become more severe as in this case. The causal association with the medicine was designated "unlikely". No further action was recommended by the Committee.

6.9.2 Cyproterone acetate and pulmonary embolism (death), 47562

Comment: The CARM database holds 3 previous reports of deep vein thrombosis with cyproterone acetate (in 1 case the patient was also taking ethinyloestradiol) and 1 report of pulmonary embolism which was not thought to be causally related. The data sheet for Androcur notes that deep vein thrombosis and pulmonary embolism have occurred rarely with cyproterone acetate and a causal association has not been established. It was noted that the man's risk of VTE was increased by his cancer. The causal association with the use of cyproterone acetate was designated "possible". The Committee recommended no additional action.

6.9.3 Diane-35 and pulmonary embolism

6.9.3.1 Diane-35 and pulmonary embolism, pulmonary infarction, pleural effusion, cardiomegaly, 47893

6.9.3.2 Diane-35 and pulmonary embolism, pleural pain, 47537

6.9.3.3 Comment

Both cases of pulmonary embolism with Diane-35 were given the causality designation "possible". CARM has received 11 previous reports of pulmonary embolism with Diane-35 and 6 reports of deep vein thrombosis.

.. advised that the early results of a study by the group of R Farmer had been reported at the International Conference of Pharmacoepidemiologists in Toronto in August 2001. The results of this study found a rate of VTE with Diane-35 that was at least as great as that for the third generation oral contraceptives. Members observed that from anecdotal reports they understand that many medical practitioners believe Diane-35 to be associated with very little risk of VTE, less than that with second generation oral contraceptives. VTE with Diane-35 is an adverse reaction of current concern. The Secretary reported that a generic of Diane-35, Estelle-35, has now been approved. It will be fully funded from 1 October 2001. VTE with Estelle-35 has been added to the list of adverse reactions of current concern. The Committee recommended publishing a Prescriber Update article on the risk of VTE with Diane-35 and Estelle-35. The article is to be written by .. and to focus on the CARM data. The Committee also recommended writing to Pharmac to advise of the concerns of the Committee regarding the risk of VTE with Diane-35 and Estelle-35.

6.9.4 Other oral contraceptives and VTE

6.9.4.1 Marvelon and pulmonary embolism, 47289

Comment: There have been 14 previous reports of pulmonary embolism with Marvelon. The present case was given the causality designation "possible".

6.9.4.2 Microgynon 30ED and pulmonary embolism, DVT, 47609

Comment: There have been 14 previous reports of deep vein thrombosis with Microgynon or Monofeme (equivalent) and 2 reports of pulmonary embolism. The present case was given the causality designation of "possible" for association with Microgynon 30ED. It was noted that this young girl had a family history of deep vein thrombosis and thrombophilia. The problem of obtaining a family history of VTE from young girls was discussed by the Committee.

6.9.4.3 Comment

It was noted that VTE with oral contraceptives is an adverse reaction of current concern. The Committee recommended no additional action.

6.9.5 Mercilon and hemiplegia, 47662

Comment: CARM has received 1 previous report of arterial cerebellar thrombosis, 3 reports of cerebral thrombosis, 2 of cerebrovascular disorder, and 2 of transient ischaemic attack associated with third generation oral contraceptives. Because of the scarcity of data on this case, including details of the temporal relationship with use of the medicine, the causality designation was "unclassifiable". No additional action was recommended by the Committee.

6.9.6 Premarin / Climara and DVT, superficial leg thrombophlebitis, 48017

Comment: Members commented that oestrogen patches are assumed by some to be safer than oral oestrogens with regard to the risk of VTE, but this has not been substantiated. Since the switch from Premarin to Climara had occurred only a week before the event, the effects of Premarin were thought to be still persisting. CARM holds very few reports of VTE with oestrogen patches: 1 of deep vein thrombosis (DVT), 1 of retinal thrombosis and 1 of pulmonary embolism. With Premarin, 3 previous reports of DVT and 3 of pulmonary embolism have been received. For the present case, the causal association with Premarin and Climara was considered to be "possible". VTE with hormone replacement therapy is an adverse reaction of current concern. The Committee recommended that no further action be taken.

6.10 Psychiatric

6.10.1 Bupropion adverse reactions

6.10.1.1 Bupropion and suicide (death), 47799

Comment: CARM had received no previous reports of suicide or attempted suicide with bupropion, but these events have been reported in Australia. The WHO database holds 190 reports of attempted suicide. 28 reports of depressive-type reactions have been received by CARM. According to the data sheet, bupropion may adversely affect mood, particularly if these is a pre-existing psychiatric disorder. In the present case, the details had been received third hand, and CARM was not confident of their accuracy. Hence, the case was given the causality designation "unclassified" for association with the use of bupropion, pending receipt of further information.

6.10.1.2 Bupropion and aggravated hyperglycaemia, diabetic ketoacidosis, 48071

Comment: CARM had requested information about the diabetic status of the patient prior to the use of bupropion. These events or similar are not mentioned in the data sheet for Zyban (bupropion). CARM has no other reports of similar events. Nevertheless, the aggravated hyperglycaemia and diabetic ketoacidosis of this patient was designated "possible" for association with bupropion. The Committee recommended that no further action be taken at this time on this specific issue.

6.10.1.3 Comment

An article on the safety of bupropion is to be published in the next (October 2001) issue of Prescriber Update. For more on the safety of bupropion and for recommendations see section 12.5.

6.10.3 Gabapentin and neutropenia, pulmonary embolism, myocardial infarction (death), 47988

Comment: Leukopenia is listed in the data sheet as an adverse reaction of Neurontin (gabapentin). Granulocytopenia, leukopenia and sudden death have been reported to CARM in association with gabapentin. The adverse events in the present case were designated "unclassified" because of the paucity of data. CARM had requested further information. The Committee recommended taking no further action.

6.11 Immunosuppressive agents

6.11.1 Azathioprine and pancreatitis, dermatitis, 47788

Comment: Both pancreatitis (203) and dermatitis (19) have been recorded in the WHO database and these events are listed in the data sheet for Imuran (azathioprine). Members commented that dermatitis, but not pancreatitis, would be a hypersensitivity reaction. Both events were given the causality designation "possible" for association with azathioprine. The Committee recommended that no further action be taken.

6.12 Musculoskeletal

6.12.1 Allopurinol / bendrofluazide and toxic epidermal necrolysis (death), 47935

Comment: The WHO database holds 227 reports of toxic epidermal necrolysis with allopurinol and 27 with indomethacin, and 1 report of Stevens Johnson Syndrome with bendrofluazide. In the present case, the Committee gave the designation "possible" to the association between toxic epidermal necrolysis and each of the 2 medicines, allopurinol and bendrofluazide. The Committee recommended taking no additional action.

6.13 Vitamins

6.13.1 Vitamin K and hypotension, 47850

Comment: Members questioned whether the dose of 20mg given in this case may have been too high. The dose recommended in the data sheet for Konakion for severe coagulopathy is 10-20mg up to a maximum of 40mg in 24 hours. The Committee recommended that the appropriateness of the approved dosage recommendation be checked. The adverse event was given the causality designation, "probable" for association with vitamin K administration.

6.14 Alternative medicines

- Case reports for alternative therapies

6.14.1 Echinacea / sodium valproate and convulsions, 47991

Comment: CARM has received no previous reports of interaction between echinacea and sodium valproate. The reaction terms convulsions and drug interaction were given the causality designation "possible". The Committee recommended no additional action.

6.14.2 St Johns Wort and vomiting, headache, abdominal pain, rash, pruritus, 47754

Comment: Of these events, only headache (1 case) has been previously reported to CARM in association with St Johns wort. Members observed that these events might have been caused by St Johns wort alone or by an interaction between St Johns wort and citalopram. Each event was given the designation "possible" for association with St Johns wort, and interaction with citalopram was also designated "possible". The Committee recommended taking no other action.

6.14.3 Glucosamine and diarrhoea, vomiting, acute renal failure, 47348

Comment: This is the first report CARM has received for glucosamine. There are reports of nausea, vomiting and diarrhoea occurring with glucosamine published in the literature. In the present case, the diarrhoea was designated "probable" for association with glucosamine and vomiting and renal failure were designated "possible". No additional action was recommended by the Committee.

7. Vaccines

- Vaccine adverse reaction reports reviewed by MARC since Nov 97

7.1 New Zealand adverse reaction reports

7.1.1 Influenza vaccine and INR increased, 47711

Comment: The WHO database holds no reports of increased INR with influenza vaccine. Members considered it to be unlikely that influenza vaccine would influence INR (by interaction with warfarin or otherwise), but could not discount the possibility entirely. The present adverse reaction was given the designation "possible" for association with influenza vaccine. The Committee recommended contacting the companies marketing influenza vaccine to ask if they have any data or comment to make on the possible association between influenza vaccine and an increase in INR in patients taking warfarin.

7.1.2 Influenza vaccine and encephalopathy, 47957

Comment: The CARM database holds other previous reports of neurological adverse reactions, but this is the first report of encephalopathy. There are 102 reports of encephalopathy with influenza vaccine in the WHO database. Because of the lack of information, the present case was given the designation "unclassified" for association with the vaccine. Further information had been requested from the reporter. The Committee recommended that no additional action be taken.

7.2 Articles from the literature

7.2.1 Hepatitis B vaccine and thrombocytopenia

- C Pierfitte, M Ceuppens. Periodic Safety Update for Engerix B 1 July 1994 to 30 June 1999. p. 7,15, 42, 48-9.
- D Neau et al. Immune thrombocytopenic purpura after recombinant hepatitis B vaccine: retrospective study of seven cases. Scand J Infect Dis 30:115-118, 1998.
- P Finielz et al. Systematic lupus erythematosus and thrombocytopenic purpura in two members of the same family following hepatitis B vaccine. Nephrol Dial Transplant 13:2420-2421, 1998
- E Martinez, P Domingo. Evans's syndrome triggered by recombinant hepatitis B vaccine. Clinical infectious Diseases 15:1051, 1992
- V Conesa et al. Thrombocytopenic purpura after recombinant hepatitis B vaccine. A rare association. Haematologica 2001 86(e-letters):09
- P Poullin, B Gabriel. Thrombocytopenic purpura after recombinant hepatitis B vaccine. Lancet 344:1293, 5 November 1994
- F Ronchi et al. Thrombocytopenic purpura as adverse reaction to recombinant hepatitis B vaccine. Arch Dis Child 78:273-274, 1998
- RHB Meyboom, H Fucik, IR Edwards. Thrombocytopenia reported in association with hepatitis B and A vaccines. Lancet 345:1638, 24 June 1995
- K Ronaldson. Thrombocytopenia with hepatitis A and B vaccines. Report for MARC, 21 Aug 2001
- E Wilson, S Galea. Evaluation of reported thrombocytopenic purpura temporally association with the administration of Recombivax HB. Report prepared by MSD for MARC, Aug 2001

At the June 2001 meeting the Committee had asked that material on the possible association between hepatitis A & B vaccines and thrombocytopenia be presented to it.

Reports of 15 cases of thrombocytopenia in temporal association with hepatitis B vaccine have been published in the literature. Most cases occurred after the second or third dose. None of the patients died. In addition, the 33 reports held by WHO in association with hepatitis A (5 cases) and B (28 cases) vaccines have been analysed by Meyboom et al. For the WHO cases occurring following hepatitis B vaccination, the time to onset was a few days to about 2 months. The vaccination sequence was not given. In 8 cases the thrombocytopenia was said to be reversible.

Three of the cases associated with hepatitis A vaccine were difficult to assess. In 2 the time relationships were consistent with causality and one of these patients developed thrombocytopenia on 2 occasions after different doses of hepatitis A vaccine.

According to GlaxoSmithKline data the incidence of thrombocytopenia/thrombo-cytopenic purpura is 0.08 cases per million doses of hepatitis B vaccine. The PSU analysed 103 cases. In 36 cases the platelet count was < 20 x 109/L. The median time to onset was 18 days, range 2-360 days. In 56 of the 103 cases the causal association seemed unlikely, because of evidence of the presence of viral infection, concomitant systemic disease or medicine and "impossible" temporal relationship. In all cases the patient recovered, although some required corticosteroid or gammaglobulin therapy.

The report from Merck Sharp & Dohme (MSD) comments that thrombocytopenic purpura is not a clinical manifestation of hepatitis B virus (as it is of measles infection), and Recombivax HB is a non-infectious viral sub-unit vaccine. This does not exclude a causal relationship, however. The MSD report concludes that because the number of reports is very small (0.5/million persons vaccinated), it is unlikely that there is a causal relationship.

CARM holds 2 reports of thrombocytopenia and 2 of thrombocytopenic purpura with hepatitis B vaccine. No reports are held in association with hepatitis A vaccine although there is one report of splenomegaly which may be associated.

The Committee concluded that the evidence suggested that there may not a causal association between hepatitis B vaccine and thrombocytopenia. If there is a causal association, the occurrence is extremely rare. The evidence with hepatitis A vaccine was too scanty to comment. Members did not consider that the evidence supported asking companies to include mention of thrombocytopenia in the data sheets of hepatitis A or B vaccines. In addition, it was agreed that the cases of thrombocytopenia with hepatitis B vaccine that had been reported to CARM should have the causality designation changed from "probable" to "possible". (A designation of "probable" had been requested at the June 2001 meeting.)

7.2.2 Yellow fever vaccine and serious adverse reactions

- P Marianneau et al. Rarity of adverse effects after 17D yellow-fever vaccination. Lancet 358:84-85, 14 July 2001.
- P Vasconcelos et al. Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases. Lancet 358:91-97, 14 July 2001
- M Martin et al. Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases. Lancet 358:98-104, 14 July 2001.
- R Chan et al. Hepatitis and death following vaccination with 17D-204 yellow fever vaccine. Lancet 358:121-122, 14 July 2001

The articles describe 7 cases (2 Brazilian, 4 American and 1 Australian) of serious illness leading to death in 6 cases, following vaccination for yellow fever. There was evidence that the illness was caused by yellow fever virus in all cases and in some cases the same strain as in the vaccine was identified.

The Committee noted that this consequence of yellow fever virus vaccine is very rare and is probably associated with host factors leading to greater susceptibility. During the period that these cases cover, 400 million doses of yellow fever vaccine had been administered. It is important that persons travelling to areas where yellow fever is endemic be vaccinated.

The Committee recommended that no action be taken with regard to the overseas reports of serious illness occurring in association with yellow fever vaccine.

7.2.3 Vaccination and SJS/TEN

- R Ball et al. Stevens-Johnson syndrome and toxic epidermal necrolysis after vaccination: reports to the vaccine adverse event reporting system. Pediatric Infect Dis J 22:219-223, February 2001

Ball et al conducted a survey of reports of Stevens-Johnson syndrome and toxic epidermal necrolysis following vaccination (all vaccines) and reported to the US Vaccine Adverse Event Reporting System. Six cases with no other obvious triggering factors were identified, suggesting that these adverse events are very rare following vaccination, if they are indeed causally related.

7.2.4 MMR vaccine and allergic reaction

- A Patja et al. Allergic reactions to measles-mumps-rubella vaccination. Pediatrics 107:2, 1-7, February 2001

Patja et al reviewed 36 patients who had experienced anaphylaxis, urticaria, asthmatic symptoms or Henoch-Schonlein pupura following MMR vaccine and found 10 to be allergic to gelatin. Most patients had allergy to various foodstuffs, including egg and cows milk.

CARM has received 2 reports of allergic reactions with MMR vaccine.

7.2.5 Thiomersal in vaccines and autism

- UK DoH fears thiomersal autism scare. Scrip No.2655:8, 27 June 2001

The Committee considered that thiomersal was unlikely to be a causative agent of autism. In New Zealand only one hepatitis B vaccine contains thiomersal (mercury-containing substance). This vaccine will shortly be withdrawn.

7.3 Vaccine adverse reaction reporting in New Zealand

Dr Jessamine reported that IMAC (Immunisation Advisory Centre) which provides vaccine services to the community is interested in enhancing vaccine adverse reaction reporting and would like a sub-committee to be set up to bridge IMAC, MARC and the Immunisation Programme Advisory Committee. A primary purpose would be so that it could be seen that adverse reactions were being handled adequately. The Committee could see the merit in having such a sub-committee. It was agreed that Dr Jessamine and Dr Tatley would liaise with IMAC over this proposal, and keep the MARC informed.

8. IMMP

8.1 Selected reports

8.1.1 Clozapine and pulmonary embolism, 47228

Comment: The WHO database holds 167 reports of pulmonary embolism and 57 of deep vein thrombosis with clozapine. CARM holds 3 previous reports of pulmonary embolism with clozapine. There may be a causal association between clozapine and VTE and this possibility was the subject of a Prescriber Update published in February 2001. Members expressed concern at the number of serious adverse reactions with which clozapine is associated. However, it was noted that for many patients suffering from schizophrenia, it is the only medication which is effective, making it worthwhile to continue clozapine even after such a serious adverse reaction. The Committee recommended that no further action be taken.

8.1.2 Risperidone and exfoliative dermatitis, 47421

Comment: No previous reports of exfoliative dermatitis with risperidone have been received in New Zealand. Nine reports are held on the WHO database. The Committee recommended taking no additional action.

8.1.3 Celecoxib and bleeding, 47321

Comment: The WHO database holds 110 reports of coagulation disorder, 81 of haemorrhage (not otherwise specified), 150 of purpura and 116 of thrombocytopenia with celecoxib. The data sheet for Celebrex (celecoxib) states that it has no effect on platelet aggregation and bleeding time. Members wondered whether the current patient had received prophylaxis for clotting with warfarin. No further action was recommended by the Committee.

8.1.4 Celecoxib and coughing, 47388

Comment: One other similar case (also with positive rechallenge) has been reported since celecoxib has been monitored on the IMMP. The WHO database holds 58 reports of cough with celecoxib. Members commented that the cough may be prostaglandin mediated, and that the present patient may have been predisposed because of being on an ACE inhibitor. It was thought that this may be a signal of a previously unrecognised adverse reaction. The Committee recommended no additional action.

8.1.5 Rofecoxib and angina, 47350

Comment: Members noted that cardiovascular events may be an issue with rofecoxib and celecoxib. See item 5.2 for further discussion and recommendations on this issue.

8.2 Review of tolcapone monitoring

- Events listing
- Cohort data
- Most frequent events
- Review of hepatic events

At 31 March 2001, there were 386 patients on tolcapone in the IMMP cohort. Two-thirds of the group were men and 20% were aged <60 years. The system organ class with the most events were psychiatric (16% of reports), hepatobiliary (13%), death (13% - none attributable) and neurological (11%). Pneumonia (23 per 1000 patients) is a common event which probably reflects the frailty of the patients. To date 3 cases of intestinal obstruction have been reported.

Of the 17 adverse hepatic events reported, only one could involve hepatocellular damage. No dechallenge information is available for this case. An increase in ALP has been reported in 36 patients. However, rises in ALP are a common event in the elderly. In most of the tolcapone cases the rise was minor. In one case the event appeared to be dose-related. A rise in ALP was noted when the patient was taking double the recommended dose. When the dose was reduced, ALP fell to normal.

9. Other NZ activities

9.1 PTAC minutes

- Minutes of the Pharmacology and Therapeutics Advisory Committee meeting, 24 May 2001
- Minutes of the Pharmacology and Therapeutics Advisory Committee meeting, 15 February 2001
- Minutes of the Pharmacology and Therapeutics Advisory Committee meeting, 16 November 2000
- Minutes of the Pharmacology and Therapeutics Advisory Committee meeting, 17 August 2000

9.2 CIOMS report

- NJ Rafter. CIOMS IV. Benefit-risk balance for marketed drugs: evaluating safety signals, Geneva 1998. Report for MARC 20 Aug 2001

This item was held over until the December 2001 meeting.

9.3 Medical error

- Correspondence about medical error. BMJ 322:1423-7, 9 June 2001
- RA Hayward, TP Hofer. Estimating hospital deaths due to medical errors. Preventability is in the eye of the reviewer. JAMA 286:415-20, 25 July 2001
- P G Nightingale et al. Implementation of rules based computerised bedside prescribing and administration: intervention study. BMJ 320:750-753, 18 March 2000
- B Runciman, et al. Improving patients' safety by gathering information. BMJ 323:298, 11 Aug 2001

9.4 Causality definitions

- WHO causality definitions
- Explanations being used on the web site
- ADRAC working definitions

The Committee asked that the causality definition for adverse reaction reports to be used in New Zealand be finalised in consultation between CARM and Medsafe. The Committee asked to be advised if the working definitions are changed from the current WHO wording.

9.5 Adverse reactions of current concern

Members requested that the list of adverse reactions of current concern be reviewed at the next meeting, and that the review data include the numbers of reports of the listed adverse reactions received over the period of listing. In addition, they asked that the list of adverse reactions of current concern be included on the agenda of each meeting, with the number of reports received entered against adverse reaction.

10. Other countries

10.1 Australia

- Aust Adv Drug Reactions Bulletin 20(2):5-8, June 2001
- Aust Adv Drug Reactions Bulletin 20(3):9-12, Aug 2001

10.2 Canada

- Canadian Adv Drug React Newsletter 11(3):1-4, July 2001

10.3 WHO meeting in New Zealand

11. Publications

- ... Do women have more adverse drug reactions? To be published
- D M Coulter et al. Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study. BMJ 322:1207-1209, 19 May 2001

12 Current topics

12.1 Progestogen-only oral contraceptives and VTE

- N R Poulter, et al. Risk of cardiovascular diseases associated with oral progestagen preparations with therapeutic indications. Lancet 354:1610, 1999
- C Vasilakis, H Jick, and M del Mar Melero-Montes. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet 354:1610-1611, 1999
- WHO Collaborative Study of Cardiovascular Disease and steroid Hormone Contraception. Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives: results of an international, multicenter, case-control study. Contraception 57:315-324, 1998
- LA Heinemann et al. Oral progestogen-only contraceptives and cardiovascular risk: results from the Transnational Study on Oral Contraceptives and the Health of Young Women. Europ J Contraception & Reproductive Health Care. 4(2):67-73, Jun 1999
- Excerpts from data sheets of progestogen-only oral contraceptives
- K Ronaldson. Progestogen-only pills and risk of VTE. Report for MARC 20 Aug 2001

12.1.1 Background

The data sheets for some, but not all, progestogen-only oral contraceptives (POCs) list previous VTE as a contraindication. A review of the data was conducted to ascertain whether a contraindication was necessary and to try to achieve consistency for the New Zealand data sheets.

12.1.2 Published data - oral progestogens for contraception

The WHO Collaborative Study included 21 analysable cases who were current users of a continuous POC and 63 controls aged 15-49 years. The study was hospital-based and included 21 centres in 17 countries. Women with a history of VTE, who had died within 24 hours of admission, natural or surgical menopause, or a history within the last 6 weeks of pregnancy, surgery, or illness causing bed rest > 1 week were excluded. The adjusted relative risk of VTE in current users of POC versus non-users was 1.82 (95% CI 0.76-4.22).

The study by Heinemann et al included 9 cases of VTE and 54 controls in women aged 16-44 years who had used a POC. The odds ratio for VTE in users of POC was 0.68 (0.28-1.66).

The WHO asked the Boston group (Vasilakis et al) to conduct a study of the risk of VTE with progestogens alone. They did so using the General Practice Research Database. Women with risk factors predisposing them to VTE were excluded, as were those who had been included in other studies. There were 2 cases and 26 controls (aged < 50 years) who were using a progestogen without an oestrogen for contraception, giving an odds ratio of 1.3 (0.3-6.8) for VTE with use of progesto-gens for contraception (some may have been using injectable progestogen).

12.1.3 Published data - oral progestogens for therapeutic indications

For other indications of oral progestogens, Vasilakis et al found a relative risk of 5.3 (1.5-18.7) for VTE (5 cases and 10 controls). In these cases the daily dose would have been 5mg to 30mg compared with 0.5mg daily for oral contraception. Although the 95% confidence interval did not include 1.0, it was still very wide and, with the small numbers of cases and controls, random fluctuation could have artificially elevated the measured risk.

The WHO study (Poulter et al) included 7 cases with VTE, stroke or AMI and 12 controls aged 20-49 years who were using oral progestogens for therapeutic indications. The adjusted ("for BMI categories") odds ratio for VTE with therapeutic progestogens was 5.92 (1.16-30.1). The comment for the previous study applies.

The latter 2 studies were cautious about attributing the elevated risk of VTE with therapeutic progestogens to the use of the progestogen. The authors suggested there also may be an association with the gynaecological indication for which the progestogen is being used.

12.1.4 WHO guidelines, 2000

The newly released WHO guidelines advise for POCs with regard to the risk of VTE as follows:

Family history of DVT/PE: Use the method.
Personal history of DVT/PE: Generally use the method.
Current DVT/PE: Stop the method unless other methods are not available or are unacceptable.
Minor surgery/major surgery without immobilisation: Use the method.
Major surgery with immobilisation: Generally use the method.

12.1.5 Comment and recommendations

The Committee agreed that there is evidence that progestogens in doses several times greater than those used in oral contraceptives may be associated with VTE. It is generally recognised that most of the thomboembolic effect of COC comes from the oestrogen, but that the progestogen may contribute to some small degree. There may be a very small increase (odds ratio < 1.5) in the risk of VTE with the POC; studies conducted to date have not included a sufficiently large number of exposed cases for there to be confidence in the results. The risk of VTE with exposure to a POC in a woman with a previous DVT/PE during use of a COC has not been examined at all.

Members agreed that it was appropriate to follow the WHO guidelines.

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

Contraindications: Current thromboembolic process.

Warnings and precautions: There is evidence that doses of progestogen higher than those used for contraception (5-30mg daily vs 0.5mg daily) may be associated with an increased risk of venous thromboembolism. Progestogens at doses used for contraception do not appear to be associated with an increase in risk of venous thromboembolism. Progestogen-only contraceptive pills may be considered as an option for contraception in women who have experienced DVT or PE with a combined oral contraceptive, provided the thromboembolic process has resolved. In most cases a progestogen-only contraceptive pill need not be discontinued for major surgery whether it does or does not involve immobilisation.

The above information should be included in an appropriately modified form in the CMI for POCs.

In addition, the Committee recommended that a Prescriber Update article be published on the risk of VTE with POCs. The article is to be written by .. and peer reviewed by .. and ...

The Committee also asked that CARM data be checked for reports of VTE with the POCs.

12.2 The safety of combined oral contraceptives

12.2.1 Oral contraceptives and venous thromboembolism

- J M Kemmeren et al. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ 323:1-9, 21 July 2001
- J O Drife. The third generation pill controversy ("continued"): the risks are still small compared with those of pregnancy. BMJ 323:119-120, 21 July 2001

Kemmeren et al conducted a meta-analysis of studies comparing the risk of VTE with use of second and third generation oral contraceptives before October 1995. The overall adjusted odds ratio for the risk of VTE with third versus second generation combined oral contraceptives was 1.7 (1.4-2.0) for 7 eligible studies. Odds ratios were also calculated for first-time users (3.1; 2.0-4.6) and short-term users (2.0; 1.4-2.7). For studies funded by pharmaceutical companies the odds ratio was 1.3 (1.0-1.7) and for other studies it was 2.3 (1.7-3.2).

The authors concluded that their results support the view that there is a higher risk of VTE with third generation than with second generation oral contraceptives.

The Committee noted that this study further supported its contention that there is a higher risk of VTE with the newer third generation compared with second generation oral contraceptives, and its advice that the second generation oral contraceptives should be favoured in prescribing. The Committee did not wish any specific action to be taken on the basis of the study by Kemmeren et al.

12.2.2 Oral contraceptives and myocardial infarction

- L Rosenberg et al. Low-dose oral contraceptive use and the risk of myocardial infarction. Arch Intern Med 161:1065-1070, 23 April 2001
- N Dunn, A Arscott, M Thorogood. The relationship between use of oral contraceptives and myocardial infarction in young women with fatal outcome, compared to those who survive: results from the MICA case-control study. Contraception 63:65-69, 2001

12.2.3 Oral contraceptives in women with BRCA1 or BRCA2

- B Modan et al. Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. NEJM 345:235-240, 26 July 2001

12.2.4 WHO guidelines

Improving access to quality care in family planning. Medical eligibility criteria for contraceptive use. Second edition. WHO, Geneva, 2000:
- Executive summary and overview
- Low-dose combined oral contraceptives
- Progestogen-only contraceptives

- Requirements in NZ Regulatory Guidelines, 4^th Edn

12.2.5 Risk factors for venous thromboembolism

- ... Risk factors for venous thromboembolism in women using oral contraceptives. Report to Medsafe, Ministry of Health. October 1999, revised April & July 2001
- ... Peer review. 15 Aug 2001

Members noted the updated version of the report by .., and the peer review by ... The Secretary advised that .. have now revised their report as a result of the peer review by ...

Members noted the comments in the WHO guidelines with regard to non-breastfeeding women. Because of the high risk of thrombosis up to 3 weeks postpartum, COCs should not be used during this period. The Committee recommended that .. be asked to include this point in her summary. In addition, members found it hard to follow both the table in the .. report and the discussion of family history versus genetic factors under the heading "Family history of thrombosis". Members recommended that .. be asked to address these 2 issues.

The Committee recommended that after the report has been finalised, it be circulated with a summary for publication in Prescriber Update (approved by ..) to the four professional bodies (NZMA, RANZCOG, NZFPA, RNZCGP) for them to give their support. It was agreed that .. should be free to publish the report elsewhere if she wished, provided doing so did not put any restrictions on Medsafe which had commissioned the report.

12.3 The safety of hormone replacement therapy

12.3.1 Cardiovascular indication and contraindication for HRT(s.36 notice)

- N Rafter. HRT and cardiovascular and cerebrovascular disease. S.36 notice. Report for MARC, Sep 2001
- Requirements in NZ Regulatory Guidelines 4^th Edn
- The appropriate prescribing of HRT. NZGG, 2001. Pertinent summary guidelines.
- SJ Twigden, Pharmaco. Response to s.36 notice. 30 July 2001
- K James, Wyeth (NZ) Ltd. Response to s.36 notice. 16 July 2001
- Excerpts from the data sheet for Prempak-C/Premarin
- BW Hartmann, JC Huber. The mythology of hormone replacement therapy. Brit J Obstetrics & Gynaecology 104:163-8, 1997
- Novo Nordisk response to s.36 notice
- E Barrett-Connor, D Grady. Hormone replacement therapy, heart disease, and other considerations. Annual Rev Public Health 19:55-72, 1998
- DM Herrington, et al. Effects of estrogen replacement on the progression of coronary artery atherosclerosis. NEJM 343:522-9, 24 Aug 2000
- AP Spencer. Hormone replacement therapy should be administered as secondary prevention of coronary artery disease. Pharmacotherapy 20:1028-33, Sep 2000
- L Mosca, et al. Hormone replacement therapy and cardiovascular disease. A statement for healthcare professionals from the American Heart Association. Circulation 104:499-503, 24 July 2001
- LA Fitzpatrick, et al. The Women's Health Initiative: a heart-to-HRT conversation. Mayo Clin Proc 75:559-61, June 2000
- T Tolbert, S Oparil. Hormone replacement therapy and stroke. Are the results surprising? Circulation 103:620-22, Feb 2001
- JA Simon, et al. Postmenopausal hormone therapy and risk of stroke. The Heart and Estrogen-progestin Replacement Study (HERS). Circulation 103:638-42, Feb 2001
- FM North, K Sharples. Changes in the use of hormone replacement therapy in New Zealand from 1991-1997. NZMJ 114:250-3, 8 June 2001

12.3.1.1 Background

Recently the New Zealand Guidelines Group published recommendations concerning the use of hormone replacement therapy (HRT). Of relevance for this item are the recommendations concerning cardiovascular and cerebrovascular disease:

• HRT is not to be used for secondary prevention of coronary artery disease, because of lack of evidence of efficacy and evidence of an early excess of mortality.
• There is insufficient evidence of benefit or harm from HRT for the primary prevention of coronary artery disease.
• There is no evidence to justify prescribing HRT for the purpose of preventing stroke.
• The safety of HRT therapy given to women who have suffered a previous stroke is not known.

As a consequence of the release of these recommendations, the Delegate of the Director-General of Health had written, under section 36 of the Medicines Act, to the companies marketing hormone replacement therapies asking them:

• to justify, or remove, the indication for primary prevention of cardiovascular disease (2 product ranges only; 2 companies);
• to include the contraindications for cardiovascular and cerebrovascular disease required by the New Zealand Regulatory Guidelines ("contraindicated in cerebrovascular and coronary artery disease").

The s.36 notices had also asked for comment on the applicability of these contraindications to topical (vaginal) preparations.

The outcome of the review was as follows:

• One company had withdrawn its products with the primary prevention indication and the other had withdrawn the indication.
• Two companies agreed to include the contraindications and the others had refused.

The matter had been referred by the Delegate to the Committee under s.36(2) of the Medicines Act for an opinion on the contraindications in cardiovascular and cerebrovascular disease.

12.3.1.2 Evidence concerning coronary heart disease

Secondary prevention
The results of observational studies finding a significant cardioprotective effect with HRT were called into question by the HERS study. The HERS study was a randomised controlled trial of oestrogen plus progestogen therapy in postmenopausal women aged <80 years with coronary heart disease. Over the 5-year period of the study, there was no difference in rate of non-fatal MI or of death from coronary artery disease (CHD) between placebo and HRT. However, there was a significant time trend with a greater frequency of coronary heart disease events in the group receiving HRT than in those on placebo in the first year of the study.

The ERA (Herrington et al) studied 309 women over 3 years with angiographic evidence at baseline of CHD, who were given either unopposed oestrogen, oestrogen and methoxyprogesterone acetate (MPA), or placebo, and followed for angiographic evidence of progression. The study concluded that neither oestrogen alone nor oestrogen with MPA affected the progression of coronary atherosclerosis in women with established disease. This was despite reductions in LDL and increases in HDL cholesterol levels.

Primary prevention
A meta-analysis published in 1997 examined 22 randomised trials of over 3 months duration with 4124 women, for cardiovascular disease (CVD; includes coronary artery and cerebrovascular). Most of the data recording CVD events were given incidentally but the odds ratio for women taking hormones versus non-users was 1.39 (95% CI 0.48-3.95) for CVD events (without PE and DVT). Although the confidence interval includes 1.0 the authors thought that it was unlikely that such results would have occurred if the true odds ratio were 0.7 or less and hence concluded that the results of these pooled data do not support the notion that postmenopausal hormone therapy prevents cardiovascular events.

Although there is still much debate particularly around use of HRT for primary prevention, current consensus as expressed by the American Heart Association (Mosca et al) is that HRT should not be initiated for the secondary prevention of CVD and that the benefit:risk ratio for primary prevention is as yet unknown.

In the future, it is expected that the Women's Health Initiative (WHI) and the WISDOM study will provide further data on the value of HRT for CVD. Both are randomised controlled trials. Those eligible for inclusion in the WHI are postmenopausal women aged 50 to 79 years. Exclusions include acute MI/stroke/TIA in the previous 6 months. Hence, although it is mainly a study of primary prevention of CVD, some women with a previous cardiovascular event may be included. Scanty published data from WHI (Fitzpatrick et al) indicate an early excess of MI and stroke in the HRT treated group, but the difference in risk compared with placebo seemed to reduce over time.

New Zealand usage data
The study by North and Sharples showed that from 1991 to 1997 the proportion of New Zealand women aged 45-64 years starting HRT for CHD prevention increased from 13% to 25%. The HERS study was published in 1998.

12.3.1.3 Evidence concerning cerebrovascular disease

There are significantly less data available on the benefits and risks of HRT on cerebrovascular disease. The Nurse's Health Study (Tolbert, Oparil) of 59,000 women, found no difference in incidence or mortality from stroke between users and non-users of HRT. A case-control study of 349 ischaemic strokes in postmenopausal women found an odds ratio for ischaemic stroke in current hormone users of 1.03 (0.65-1.65). The HERS study (Simon et al) found odds ratios of 1.18 (0.73-3.55) and 1.61 (0.83-1.66) for nonfatal and fatal stroke, respectively, for users of HRT compared with users of placebo.

12.3.1.4 Conclusions

It seems that while some of the evidence may be contradictory (e.g. observational vs. randomised controlled trials) there is reason to suspect that HRT may not be beneficial in prevention of CHD, in particular in secondary prevention. Although there are only two randomised controlled trials for secondary prevention, these give clear evidence of no benefit and the HERS study found evidence of possible harm from HRT in the first year of use. The evidence is less certain for primary prevention; however, the early data from the WHI cause concern.

There is very little information regarding the effect of HRT on cerebrovascular disease.

12.3.1.5 Recommendations

The Committee made the following recommendations regarding CVD (coronary heart and cerebrovascular disease):

• HRT should not be initiated in women who have pre-existing CHD or cerebrovascular disease (a contraindication).
• For women with coronary heart disease who have been receiving HRT for ( 2 years, the decision to continue therapy should be for reasons other than prevention of coronary heart disease and should be based on patient preference.
• If a woman taking HRT develops an acute CVD event, HRT should be discontinued and not reinstated.
• There is insufficient evidence of benefit from HRT for the primary prevention of CHD, and HRT should not be used for this indication.
• There is no evidence to justify the prescribing of HRT for the prevention of stroke.
• The safety of HRT given to women who have suffered a previous stroke is unknown.
• Initiation and continuation of HRT should be for reasons other than prevention of CVD and should be based on patient preference.

These statements should be adapted and included in the Regulatory Guidelines as requirements for inclusion in the data sheets of HRT products, and the companies who were sent s.36 notices concerning their HRT products should be advised of these new requirements and asked to change the data sheets of their products.

The Committee asked Medsafe to do whatever was required to finalise the wording for the data sheets on the basis of these statements. The new wording would then be included in the Regulatory Guidelines as requirements for inclusion in the data sheets of HRT products, and the companies who were sent s.36 notices concerning their HRT products should be advised of these new requirements and asked to change the data sheets and CMI of their products. These recommended statements were shaped to be in line with the recommend-ations of the New Zealand Guidelines Group and the American Heart Association (AHA) with one exception. The AHA is less definite about discontinuation of HRT following an acute CVD event, and includes reinstatement as an option.

12.3.2 Relative contraindications (NZ regulatory guidelines)

- Requirements in NZ Regulatory Guidelines 4^th Edn

As part of the review of HRT and CVD, Dr Rafter had conducted an audit of data sheets for HRTs for compliance with all the required safety information, as specified in the NZ Regulatory Guidelines (Guidelines reference 9.2.5). Despite the fact that company personnel had signed a data sheet declaration form indicating compliance with the Guidelines, the vast majority of data sheets were deficient in some respect. However, also as part of the review, it was identified that the warnings and precautions required in the Regulatory Guidelines had been drafted some years ago, possibly 13 years, and they needed to be updated. The reasons for requiring some of the warnings and precautions were unclear. Dr Rafter advised that Medsafe would review the literature to find support for the existing statements and to ascertain whether other warnings and precautions were appropriate. The results of the review would be presented to the Committee for comment and recommendations.

12.3.3 HRT and coronary events

- S Heckbert et al. Risk of recurrent coronary events in relation to use and recent initiation of postmenopausal hormone therapy. Arch Intern Med. 161:1709-1713, 23 July 2001
- B M Psaty et al. Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women. JAMA 285 No 7:906-913, 21 February 2001

12.3.4 HRT and ovarian cancer

- C Rodriguez, et al. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 285:1460-5, 2001
- C Bosetti et al. E Hernadez et al. C Rodriguez et al. Relationship between postmenopausal hormone replacement therapy and ovarian cancer. JAMA 285:3089-90, 27 June 2001

12.4 Prescribing of adrenaline syringes

- .., Specialist in Clinical Immunology and Allergy. Comment on Unsworth article. 17 Aug 2001
- D J Unsworth. Adrenaline syringes are vastly over prescribed. Arch Dis Child 84: 410-411, May 2001
- H A Sampson et al. Fatal and near fatal anaphylactic reactions to food in children and adolescents. NEJM 327 No 6:380-384, 6 August 1992
- RSH Pumphrey. Lessons for management of anaphylaxis from a study of fatal reactions. Clinical & Experimental Allergy 30:1144-50, 2000
- SA Bock, et al. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 107:191-3, Jan 2001

Unsworth had argued that adrenaline syringes for self-administration are over-prescribed, putting patients at risk from adrenaline toxicity. Comment had been sought from a New Zealand allergist, ...

.. considered that the actual clinical problem is the converse, i.e. "that adrenaline syringes suitable for self use are not prescribed or are not available to patients." She noted that Unsworth has no prior publications in the allergy field.

Pumphrey's study of fatal anaphylactic reactions found that only 9 of 69 food and venom allergy patients who died had been prescribed adrenaline for self-administration. Two of these 9 died despite apparently using adrenaline appropriately, and the other 7 either did not use or have access to their adrenaline kits. He recommended that the need was for "more appropriate prescribing of self-treatment kit and improved training in its use; improved protocols for paramedics, and increased awareness of the correct dose of adrenaline used in treatment of anaphylactic reactions." .. agreed with this assessment, and in particular considered that the situation of individuals with allergies in New Zealand would be greatly improved by full funding of EpiPen under a special authority arrangement which includes an allowance of 2 syringes per patient.

The Committee recommended writing to Pharmac stating that the funding of adrenaline syringes for self-administration is a significant safety issue, and asking Pharmac to consider full funding of EpiPen under a special arrange-ment as suggested by ...

12.5 The safety of bupropion

- KJ Pederson, et al. acute myocardial ischemia associated with ingestion of bupropion and pseudoephedrine in a 21-year-old man. Can J Cardiol 17:599-601, May 2001
- Update on bupropion (Zyban SR) - 25 June 2001 ADRAC article 25 June 2001, www.health.gov.au/tga/docs/html/zyban.htm
- ... Zyban SR (buproprion). Review of selected safety issues for TGA. 10 July 2001. p.14-21 only
- Summary details of reports of fatal outcomes associated with Zyban. ADRAC data
- ... Report on bupropion for MAAC. 28 Feb 2000
- ... Report on bupropion for MAAC. 28 Feb 2001
- Zyban sales figures for NZ, x GlaxoSmithKline. CONFIDENTIAL
- M Tatley. Bupropion - an update on safety issues. Draft Prescriber Update article.
- M Tatley. Zyban (bupropion hydrochloride) - a review of safety issues in its use in smoking cessation. Report for MARC 29 May 2001
- M Tatley. Bupropion - update on analysis based on further reports received. Report for MARC 31 Aug 2001

CARM now has recorded 218 reports of adverse reactions occurring in association with bupropion, including 144 reports supplied by Glaxo SmithKline. Psychiatric (154 events), skin/hypersensitivity (130) and neurological (67) reactions predominated. There are now also significant numbers of nausea/vomiting (21) and dizziness (20). The most common psychiatric reaction is sleep disorder (35), followed by depressive-type reactions (28). In 70% of cases of depressive events, symptoms occurred on the low dose (150mg daily).

11% of all reports were rated serious, because treatment or hospitalisation was required. Most of these reactions were in the hypersensitivity group. Only 3 reports of convulsions, 1 poorly documented, and 1 report of non-fatal myocardial infarction have been received. To date only 1 death has been reported in New Zealand: the suicide discussed under 6.10.1.1, and for which there is insufficient data to assess whether there is a causal association to bupropion.

In 69% of reports, bupropion was the only medicine prescribed. In only one case was there evidence of known risk factors or use of interacting medicines. It appears that in New Zealand bupropion is generally being used according to the prescribing advice. The rate of reporting of adverse reactions is around 1% (216/23,000).

According to the latest communication from Australia, ADRAC has received 18 reports of death with bupropion. It was noted that there is international concern about the safety of bupropion.

The Committee recommended:

• making bupropion second-line therapy after other therapy including nicotine replacement therapy has failed;
• changing the Prescriber Update article to indicate that it should be second-line therapy; and
• writing to Pharmac to express the reservations of the Committee about the safety of bupropion and suggesting that it only be funded on a special authority basis (with two of the criteria including, after other therapy including nicotine replacement therapy has failed, and use as part of a comprehensive smoking cessation programme).

In addition, Dr Jessamine advised that Medsafe planned to invoke the provisions of s.36 of the Medicines Act in order to seek further information about bupropion from Glaxo SmithKline and to provide a route by which restrictive action could be taken, if this was considered necessary. Medsafe wished to obtain further information, particularly on the sudden unexplained deaths, and the cerebrovascular, cardiovascular and neuropsychiatric reactions. The Committee supported the intention to seek further information from the company.

12.6 NSAIAs in pregnancy and neonates

- M A Alano et al. Analysis of nonsteriodal anti-inflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics 107 No 3:519-523, March 2001
- L J Van Marter et al. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteriodal drug consumption during pregnancy. Pediatrics 97:658-663, May 1996

12.7 Mesalazine and olsalazine in pregnancy?

- I Wallace, Secretary NZ Society of Gastroenterology. Mesalazine, olsalazine in pregnancy. Letter 22 June 2001
- O Diav-Citrin, et al. The safety of mesalamine in human pregnancy: a prospective controlled study. Gastroenterology 114:23-8, Jan 1998
- CM Bell, et al. Safety of topical 5-aminosalicylic acid in pregnancy. Am J Gastroenterology 92:2201-2, 1997
- G Trallori, et al. 5-aminosalicylic acid in pregnancy: clinical report. Ital J Gastroenterol 26:75-8, 1994
- FM Habal, et al. Oral 5-aminosalicylic acid for inflammatory bowel disease in pregnancy: safety and clinical course. Gastroenterology 105:1057-60, 1993
- Mesalazine, olsalazine. Prescribing Medicines in Pregnancy 4^th edition. TGA, 1999
- Chemical structures of mesalazine and olsalazine
- Olsalazine, mesalazine. Martindale 32^nd Edn. 1999, p.1199-1200, 1204
- Pentasa (mesalamine). Physicians' Desk Reference 2001, p.3042-3
- K Ronaldson. Mesalazine and olsalazine - safety in pregnancy. Report for MARC, 27 Aug 2001
- I Boyd, ADRAC. Mesalazine and olsalazine in pregnancy. Email 28 Aug 2001.

12.7.1 Background

Dr Ian Wallace of the Society of Gastroenterology had objected to the entry in Prescribing Medicines in Pregnancy (a booklet prepared by the Australian Drugs Evaluation Committee [ADEC] and circulated to New Zealand medical practitioners by Medsafe) for mesalazine and olsalazine because:

• they have been classed differently to sulphasalazine;
• they have been classed as NSAIAs; and
• they have been given the classification C, meaning that harmful effects but not malformations may occur.

He was concerned that women who need this medication to control their inflammatory bowel disease (IBD) may stop it on the basis of this advice. He had provided several references in support of the safety of mesalazine in pregnancy.

12.7.2 Data from the literature

Habal et al, Trallori et al and Bell et al have conducted small uncontrolled prospective studies of mesalazine use in pregnancy in a total of 49 women. 32 of the women (Habal and Bell studies; 16 women in each study) had tried unsuccessfully to discontinue mesalazine before conception. The women in the study by Bell used topical (suppository or enema) mesalazine, but in Habal's study they were treated orally. No abnormalities were found in the Trallori study, although this was not a stated primary outcome. In the studies by Habal and Bell all neonates were examined at birth by a paediatrician and no foetal anomalies were found. One woman had a miscarriage, but she had miscarried previously and subsequently carried to term on mesalazine. All children were well at follow-up (≥1 year)

Diav-Citrin et al carried out a larger case-control study. Women taking mesalazine were identified through a teratogen helpline. They were matched to control women for cigarette smoking and alcohol consumption, and the groups did not differ significantly for age, gravidity, parity, pre-pregnancy weight and history of spontaneous and therapeutic abortions. The control women were taking known non-teratogens.

There was 1 major malformation in the mesalazine group (extra right thumb) and there were 5 in the control group (1/127 vs 5/131; p = 0.23). The rates of minor malformations were 8/127 vs 5/131 (p = 0.56). The malformations associated with exposure to mesalazine were hypospadias and umbilical hernia (n=1), umbilical hernia alone (2), congenital dislocation of the hips (1), skin discolouration on the back and varicose veins on the eyelids (1), cleft uvula, laryngotracheomalacia and bilateral hydrocele (1), sacral dimple (1) and Marcus Gunn's jaw-winking (1). The mean birth-weight was significantly lower in infants exposed to mesalazine (3253g vs 4361g; p = 0.0005). Women whose disease was in remission gave birth to infants of higher mean gestational age than those whose disease was active (39.6 weeks vs 38.8 weeks; p = 0.04).

12.7.3 Comment and recommendation

The US Physicians' Desk Reference 2001 places mesalazine in category B. There is no evidence of teratogenic effects or harm to the foetus in animal studies, but there are "no adequate and well-controlled studies in pregnant women." It also adds "Mesalamine [mesalazine] is known to cross the placenta." This designation would seem to be in accord with the data.

The Committee did not recommend that any action be taken to address this issue in New Zealand. Instead the Committee recommended that the suggestion be made to Dr Wallace that the New Zealand Society of Gastro-enterologists write to ADEC to address the issue.

12.8 Halothane, paediatric use

- J Holzki, H Wark, I Murat. Halothane: the last word? Paediatric Anaesthesia 11:249-56, 2001
- ... Comment re halothane use in children. 16 Aug 2001

Paediatric Anaesthesia had published some controversy about the safety of halothane in children. The strongest cases were for its safety. .., Starship Children's Hospital, had commented that he believed it to be safe, although agreement on this point was not unanimous. The Committee did not wish to add to the debate about the safety of halothane in paediatric use in any way or to pursue this matter any further at present.

12.9 Rofecoxib and celecoxib

- A Whelton et al. Cyclooxygenase-2-specific inhibitors and cardiorenal function: a randomised, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Amer J Therapeutics 8:85-95, 2001
- GA FitzGerald, C Patrono. The coxibs, selective inhibitors of cyclooxygenase-2. NEJM 345:433-43, 9 Aug 2001

See 5.2 for a discussion of cardiovascular effects of rofecoxib and celecoxib and 5.2.5 in particular for ongoing action and recommendations on the safety of the selective COX-2 inhibitors. See also 8.1.3 to 8.1.5 for results of IMMP monitoring of these medicines.

12.10 Items of interest

12.10.1 Reported fatalities with sildenafil and alprostadil

- J S Cohen. Comparison of FDA reports of patient deaths associated with sildenafil and with injectable alprostadil. Ann Pharmacotherapy 35:285-288, March 2001

12.10.2 Aspirin and Reyes syndrome

- MC McGovern, et al. Reye's syndrome and aspirin: lest we forget. BMJ 322:1591-2, 30 June 2001

12.10.3 Herbal medicines in the perioperative period

- M K Ang-Lee et al. Herbal Medicines and perioperative care. JAMA286:208-216, 11 July 2001

12.10.4 Nicotine patches and myocardial infarction

- S E Kimmel et al. Risk of acute first myocardial infarction and use of nicotine patches in a general population. J Amer Col Cardiology. 37 No. 5:1297-1302, April 2001

12.10.5 Inhaled corticosteroids and change in bone density

- A E Tattersfield et al. Bone mineral density in subjects with mild asthma random-ised to treatment with inhaled corticosteriods or non-corticosteriod treatment for two years. Thorax 56: 272-278, 2001

12.10.6 Clozapine and myocarditis

- L La Grenade et al. Myocarditis and Cardiomyopathy associated with clozapine use in the United States. NEJM 345:224-225, 19 July 2001
- D M Coulter et al. Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study. BMJ 322:1207-1209, 19 May 2001
- P Reid, S Pridmore. Clozapine rechallenge after myocarditis. Aust & NZ J Psychiatry 35:249, 2001

12.10.7 Determining QT-prolongation with medicines

- M Malik, A J Camm. Evaluation of drug-induced QT interval prolongation: implications for drug approval and labelling. Drug Safety 24:323-351, 2001

12.10.8 Result of limiting paracetamol and aspirin pack sizes in the UK

- K Hawton et al. Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom before and after study. BMJ 322:1-7, 19 May 2001

12.10.9 Withdrawal of cerivastatin

- Bayer voluntarily withdraws Baycol. FDA Talk Paper. 8 Aug 2001

12.10.10 IV amiodarone and paediatric use

- J Oakley, Sanofi-Synthelabo. Intravenous amiodarone and paediatric dosing. Letter 14 Aug 2001

The FDA had raised two issues with regard to the intravenous administration of amiodarone to infants and toddlers: leaching of the plasticiser di(2-diethylhexyl) phthalate (DEHP) from PVC tubing possibly affecting the development of the male reproductive tract and the potential for benzylalcohol preservative in solution with amiodarone to cause "gasping syndrome" in neonates. Sanofi-Synthelabo has proposed warning statements for the data sheet of Cordarone to cover both of these issues.

The Committee recommended liaising with .. over finalising the wording for the data sheets for IV amiodarone preparations. The companies should be reminded to update the CMI as well.

The meeting ended at 5pm.