Revised: 20 May 2013

Committees

Minutes of the 130^th Medicines Adverse Reactions Committee Meeting - 14 June 2007

Preface:

In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.

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

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

The recommendations of the Committee are in bold typeface.

Minutes:

TABLE OF CONTENTS

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

INVITED GUESTS AND EXPERTS

1. MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

1.1.1 MARC membership

1.2 Minutes of the 129^th MARC Meeting

1.2.1 Report to the Minister's Delegate

1.3 Dates of Future MARC Meetings
1.4 Potential Conflicts of Interest
1.5 Prescriber Update

1.5.1 Schedule of Planned Prescriber Update Articles

1.6 Issues Monitored by the MARC, Medsafe and the NZPHVC as at June 2007

2. ACTIONS ARISING

2.1 Report on Actions Arising from the 129^th MARC Meeting, 15 March 2007

2.1.1 Clozapine and haematological malignancies
2.1.2 Oral Terbinafine Serious Adverse Reactions
2.1.3 Aprotinin and cardiovascular, renal & cerebrovascular adverse reactions: watching brief review
2.1.4 Venlafaxine and pancreatitis – watching brief review
2.1.5 Adverse reactions to rosiglitazone & pioglitazone: regulatory review
2.1.6 Adverse Reactions of Current Concern (ARCC) Review
2.1.7 Golimumab, amoxycillin/clavulanic acid, isoniazid, and diarrhoea, vomiting, colitis, septic shock, cardiac arrest [death] (73358)
2.1.8 Tenecteplase and sudden death [death] (74192)
2.1.9 Tamoxifen and retinal deposits (73804)
2.1.10 Lumiracoxib and dyspnoea, orthopnoea (74295)

2.2 REPORT ON ACTIONS ARISING FROM PREVIOUS MEETINGS OF THE MEDICINES ADVERSE REACTIONS COMMITTEE

2.2.1 Infliximab/methotrexate/prednisone and secondary sepsis, dural abscess, tooth abscess, headache, coma [death] (CARM case 72110)
2.2.2 COX-2 Inhibitors: Active Monitoring Review
2.2.3 Non-selective NSAIDs: Active Monitoring Review
2.2.4 Omeprazole and headache (72715)
2.2.5 Roxithromycin, warfarin, and decreased prothrombin (73165)
2.2.6 Sodium valproate and foetal valproate syndrome (73289)
2.2.7 Candesartan and palpitations (73162)
2.2.8 Quinine, Nocturnal Leg Cramps, and Thrombocytopenia
2.2.9 Inhaled Long-Acting Beta-Adrenoceptor Agonists (LABAs) and the Risk of Fatal and Non-Fatal Asthma Exacerbations
2.2.10 SSRIs and Use in Pregnancy: Watching Brief Review
2.2.11 Clozapine and myocarditis, heart failure, arrhythmia [death] (CARM case 66578)
2.2.12 Clozapine and Myocarditis
2.2.13 Influenza vaccine and sudden death (CARM case 71269)
2.2.14 Diclofenac/ibuprofen/prednisone and gastric ulcer, duodenal ulcer, intestinal ulceration, haematemesis, hypoproteinaemia (CARM case 71906)
2.2.15 Tramadol-Drug Interactions and Serious Reactions

2.3 REPORT ON UNRESOLVED ACTIONS ARISING FROM RECOMMENDATIONS OF THE MARC

2.3.1 Low Molecular Weight Heparins (LMWHs) in Renal Impairment

3. PHARMACOVIGILANCE ISSUES

3.1 ADVERSE REACTIONS TO LEFLUNOMIDE: ACTIVE MONITORING REVIEW
3.2 BISPHOSPHONATES AND OSTEONECROSIS OF THE JAW: ACTIVE MONITORING REVIEW
3.3 SSRI ANTIDEPRESSANTS AND SEVERE AGITATION, SEVERE RESTLESSNESS/AKATHISIA, AND/OR INCREASED SUICIDALITY; WATCHING BRIEF REVIEW
3.4 TOPICAL PIMECROLIMUS AND THE RISK OF MALIGNANCY: WATCHING BRIEF REVIEW

4. MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 CENTRE FOR ADVERSE REACTIONS MONITORING (CARM) SPONTANEOUS CASE REPORTS

4.1.1 Deaths
4.1.2 Antihistamine
4.1.3 Cardiovascular
4.1.4 Complementary and Alternative Medicine
4.1.5 Dermatological
4.1.6 Endocrine
4.1.7 Psychiatric
4.1.8 Other Reports

4.2 QUARTERLY REPORTS FROM CARM AS AT 31 MARCH 2007
 

5. PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

6. NEW ZEALAND PHARMACOVIGILANCE-RELATED ACTIVITIES

7. INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

7.1 AUSTRALIA
7.2 CANADA

8. SUMMARY LISTINGS OF CASE REPORTS CONSIDERED BY MARC (1997-2006)

9. OTHER BUSINESS

9.1 CLOZAPINE AND SEVERE GASTROINTESTINAL EFFECTS
9.2 APPOINTMENT TO THE HONORARY EDITORIAL COMMITTEE OF DRUG SAFETY BULLETIN 9.3 VACCINE SAFETY EVALUATION: POST MARKETING SURVEILLANCE CONFERENCE – REPORT ON CONFERENCE

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MINUTES OF THE 130^th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING,
14 JUNE 2007.

The one hundred and thirtieth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 14 June 2007 at the De Havilland room, Wellington Airport Conference Centre, Wellington, New Zealand. The meeting commenced at 9:00 am and closed at 3:00 pm.

marc members present

Professor T Maling (Chair)
Dr H Kingston
Professor P Ellis
Dr D Reith
Ms L Bryant
Associate Professor C Frampton
Dr M Tatley
Dr S Jessamine

marc secretariat present

Ms S Von Afehlt (Senior Pharmacy Advisor/Editor of Prescriber Update, Medsafe)
Dr K Maclennan (Senior Pharmacovigilance Advisor, Medsafe)
Ms J McNee (MARC Secretary)

invited guests and experts

Dr R Savage (New Zealand Pharmacovigilance Centre) attended the meeting to provide expert advice on items related to the Centre for Adverse Reactions Monitoring (CARM).

Dr S Reid (general practitioner) and Dr A Roberts (Ministry of Health) attended the meeting from 11:00 am to 12:00 am.

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Dr F McClure, Honorary Associate Professor M Rademaker and Dr S Sime.

1.1.1 MARC membership

Discussion

The Committee commented that it would be valuable to have two representatives from the New Zealand Pharmacovigilance Centre on the Committee in order to ensure that expert comment is available at every meeting. The MARC recommended that Dr Ruth Savage be appointed as an alternate member to Dr Michael Tatley.

1.2 Minutes of the 129^th MARC Meeting

Members agreed that the minutes of the 129^th MARC meeting were a true and accurate record of the meeting. The Chair subsequently ratified the minutes.

1.2.1 Report to the Minister's Delegate

Members noted that all of the recommendations made at the 129^th MARC meeting had been accepted by the Minister's Delegate.

1.3 Dates of Future MARC Meetings

The date for the next MARC meeting was confirmed as being Thursday 13 September 2007. The subsequent MARC meeting was scheduled for 13 December 2007.

1.4 Potential Conflicts of Interest

Committee members submitted their Conflict of Interest Declaration forms to the Secretary. The Chair reminded the MARC members that, in addition to conflicts disclosed in the declaration forms, members should declare conflicts of interest at the commencement of discussion of any relevant agenda item.

One member declared a potential conflict of interest. The Committee considered that this potential conflict of interest would not influence the discussions or decisions of the Committee.

1.5 Prescriber Update

1.5.1 Schedule of Planned Prescriber Update Articles

Discussion

The Committee was asked to review three draft Prescriber Update articles.

LABAs - Reminder About Safe Prescribing.

The Committee had previously recommended that an article on inhaled long-acting beta agonists (LABAs) be written following the publication of papers suggesting that inhaled long-acting beta agonists might increase the risk of serious asthma exacerbations, particularly in patients who do not use a concomitant inhaled corticosteroid.

The Committee reviewed the draft Prescriber Update article and noted that combination inhalers containing a LABA and a glucocorticoid are available. In particular, Symbicort in two strengths, 100/6 and 200/6, is now indicated under the SMART (Symbicort Maintenance and Reliever Therapy) regimen for both maintenance and reliever therapy in patients with asthma. The data sheet specifically states that a separate inhaler for rescue use is not necessary. The Committee asked that Medsafe review the draft article to take this into consideration.

Serious Adverse Reactions and Interactions with Tramadol: Convulsions and Serotonin Syndrome

The Committee had previously recommended that an article on serious adverse effects of tramadol, specifically serotonin syndrome and convulsions be written following reports in the CARM database.

The Committee reviewed the draft article and suggested changes, with an emphasis on shortening the article to make it more succinct. It was agreed to remove the references to general anaesthesia and focus the article on the message originally proposed - to give the lowest effective dose of tramadol, especially when given close to antiemetics and high dose opioids, particularly pethidine.

Glitazones: Fluid Retention, Cardiac Failure, and Macular Oedema

The revised draft of the Prescriber Update article on Glitazones: Fluid Retention, Cardiac Failure, and Macular Oedema was discussed. The Committee made several suggestions for improvements to the article. Due to the emergence of further issues around the use of glitazones and their place in treatment the Committee discussed the need for an additional article about other emerging adverse drug reactions with the glitazones.

Recommendation

The Committee recommended that an additional, separate Prescriber Update article should be written to focus on the other side effects of the glitazones.

1.6 Issues monitored by the MARC, Medsafe and NZPhvC as at June 2007

The Chairman raised the issue of the continued use of Amizide (hydrochlorothiazide 50 mg and amiloride 5 mg). It was suggested that the use of Amizide is a common cause of hyponatraemia, while it could cause hyperkalaemia in patients with renal failure. The Committee noted that the dose of hydrochlorothiazide contained in Amizide is 50 mg, while the majority of the combinations products available currently contain only 12.5 mg. The New Zealand Guidelines Group is not currently recommending its use. The Committee asked that more information be sought and the issue brought back to the MARC as an agenda item at its next meeting.

Recommendations

The Committee recommended that NZPhvC review the reports in the CARM and WHO databases regarding Amizide, and bring these back to the MARC.

The Committee recommended that Medsafe seek information on the current usage of Amizide in New Zealand.

The Committee recommended that the issue of Amizide, hyponatraemia, and hyperkalaemia be placed on the Agenda for the next MARC meeting.

2. actions arising

The Committee considered the list of issues monitored by MARC, Medsafe and NZPhvC.

2.1 Report on Actions Arising from the 129^th MARC Meeting, 15 March 2007

Please refer to the minutes of the 129^th MARC meeting, held on 15 March 2007, available on the Medsafe web site at www.medsafe.govt.nz/profs/adverse/Minutes129.htm for background information on these issues.

2.1.1 Clozapine and haematological malignancies

March 2007 minute item 2.1.2; December 2006 minute item 2.2.3

Issue

In March 2007, the Committee recommended that Medsafe in consultation with Associate Professor Frampton, explore a protocol for obtaining age-standardised data on the frequency of haematological events with clozapine.

Outcome

Medsafe and Associate Professor Frampton are considering possible methods for obtaining these data.

Discussion

The Committee noted the above and asked to be kept informed of the outcome.

2.1.2 Oral Terbinafine Serious Adverse Reactions

March 2007 minute item 2.2.1; December 2006 minute item 2.1.1; September 2006 minute item; June 2006 minute item 9.2

Issue

In March 2007, the Committee recommended that Medsafe write to the Pharmacy Council of New Zealand and the Pharmaceutical Society of New Zealand (Inc) asking that they remind pharmacists about the adverse reactions of oral terbinafine.

Outcome

A draft letter is being prepared by Medsafe.

Discussion

The Committee noted the above.

2.1.3 Aprotinin and cardiovascular, renal & cerebrovascular adverse reactions: watching brief review

March 2007 minute item 3.1

Issue

In March 2007, the Committee recommended that the issue of aprotinin and cardiovascular, renal and cerebrovascular adverse reactions should remain on the watching brief list.

In March 2007, the Committee recommended that Medsafe bring back to the MARC any data that arises from the BART study, and continue to monitor international regulatory activity and report back to the MARC as appropriate.

In March 2007, the Committee agreed with Medsafe's suggested revisions for the NZ Trasylol data sheet.

Outcome

A letter requesting amendments to the NZ datasheet for Trasylol was sent to Bayer in May 2007. Medsafe is awaiting a response.

Discussion

The Committee noted the above.

2.1.4 Venlafaxine and pancreatitis - watching brief review

March 2007 minute item 3.2

Issue

In March 2007, the Committee recommended that the issue of venlafaxine and pancreatitis should be removed from the 'watching brief' list.

Outcome

This issue has been removed from the watching brief list.

Discussion

The Committee noted the above.

2.1.5 Adverse reactions to rosiglitazone & pioglitazone: regulatory review

March 2007 minute item 4.1

References

• Medsafe report for the MARC, May 2007
• Nissen, S.E. & Wolski, K. (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. NEJM. 356
• FDA Alert (May 2007) Information for healthcare professionals: Potential safety issues related to rosiglitazone
• Home, P.D.et al (2007) Rosiglitazone evaluated for cardiovascular outcomes- An interim analysis, NEJM, 357
• New Zealand Guidelines Group, Prevention of hip fracture amongst people aged 65 years and over, June 2003.

Issue

In March 2007, the Committee recommended that Medsafe seek an expert opinion on an appropriate measure of bone turnover that might indicate reduced bone density in thiazolidinedione (TD) treated patients.

In March 2007, the Committee recommended that all adverse reactions to rosiglitazone and pioglitazone should remain on the active monitoring list for annual review.

In March 2007, the Committee recommended that Medsafe contact the sponsors of rosiglitazone and pioglitazone to request datasheet revisions.

Outcome

A letter requesting amendments to the NZ datasheet for rosiglitazone (Avandia) was sent to GSK in May 2007. Medsafe is awaiting a response.

Discussion

The Committee discussed the expert opinion received from Dr Andrew Grey on an appropriate measure of bone turnover which might indicate reduced bone density in thiazolidinedione (TD) treated patients. It was noted that his opinion was there was no adequate biochemical way of measuring bone formation and the available options were limited to clinical risk factors and bone density measurement. In his opinion, fracture risk should be considered in all patients for whom TD therapy is contemplated and bone density measurements should be obtained in patients who have clinical risk factors. The Committee noted that the issue of adverse reactions to rosiglitazone and pioglitazone is included on the active monitoring list and will be reviewed in March 2008. The Committee agreed that a particular point should be made to review the information around fractures and bone loss at this time.

The Committee discussed the Medsafe briefing regarding the cardiac safety of rosiglitazone. This was provided in response to a recently published meta-analysis regarding rosiglitazone and cardiovascular events, and subsequent communications from international regulators and GSK. Medsafe advised that GSK had recently provided data providing further analysis of the integrated data sheet, which looked at different cardiac endpoints and also included data from the recently completed long term ADOPT study and the DREAM study, another long term study which is investigating the ability of rosiglitazone to prevent diabetes developing in a prediabetic population.

The Committee discussed the article by Nissen and Wolski and noted that despite its limitations, it contained some well-made points.

The Committee discussed the Home et al interim analysis of the RECORD study due to be completed in 2009. They noted that the findings were inconclusive, other than indicating that rosiglitazone increased the risk of heart failure. It appeared that rosiglitazone may increase the risk of myocardial infarction, however there was not enough statistical evidence to draw any firm conclusions. The Committee noted that GSK had been requested to update the data sheet for Avandia to state that it was not recommended for use in patients with any grade of heart failure, but, if the potential benefit was thought to outweigh the risks in patients with mild-moderate heart failure, the medicine should be initiated at the lowest possible dose. They noted that the use of rosiglitazone has been contraindicated in patients with any degree of heart failure and in patients on insulin therapy in Europe since its introduction, but this is not the case in New Zealand.

The Committee noted that while these studies focused on rosiglitazone, it is not currently funded in New Zealand. The Committee considered that there was no evidence to suggest that the funded option, pioglitazone, did not have similar cardiac effects and asked that Medsafe contact the sponsor of pioglitazone (Actos) for comment.

Recommendations

The Committee recommended that the issue of the effects of the glitazones on bone density be included in the Active Monitoring review to be discussed at the March 2008 MARC meeting.

The Committee recommended that Medsafe contact the sponsors of Actos for comment on the cardiac safety of pioglitazone.

2.1.6 Adverse Reactions of Current Concern (ARCC) Review

March 2007 minute item 4.2

Issue

In March 2007, the Committee recommended that complementary and alternative medicines (CAMs) remain as Adverse Reactions of Current Concern on the active monitoring list.

In March 2007, the Committee recommended that NZPhvC report serious and/or unusual events to each MARC meeting and provide an annual ARCC submission.

Outcome

NZPhvC has implemented the above system.

Discussion

The Committee noted the above.

2.1.7 Golimumab, amoxycillin/clavulanic acid, isoniazid, and diarrhoea, vomiting, colitis, septic shock, cardiac arrest [death] (73358)

March 2007 minute item 4.3.1.2

Issue

In March 2007, the Committee recommended that NZPhvC should obtain a copy of the post-mortem report on this case and bring the results back to the MARC if warranted.

Outcome

The NZPhvC reports:

The report states that no autopsy was performed.

Further information:

The patient was also taking methotrexate. She had also taken diclofenac on unknown dates. After she developed diarrhoea she was given metronidazole.

The patient was given isoniazid because she was Mantoux positive, (chest x-ray clear) and commencing golimumab. There was no history of TB exposure although she was a nurse. She developed abnormal hepatic function. Two weeks later she developed a chest infection and amoxycillin/clavulanic acid was commenced, two days later she developed nausea and severe diarrhoea, the following day isoniazid was discontinued because of the abnormal hepatic function. She was admitted approximately 11 days later because of dehydration, diarrhoea persisted, blood cultures were negative. A colonoscopy 11 days later showed ulcerated mucopurulent haemorrhagic colitis, no C difficile was grown. She developed severe vomiting and a chest x-ray was suggestive of aspiration pneumonia, although there was a suggestion of a more chronic component. The following day CXR showed disseminated infection. On that day she collapsed due to severe sepsis and subsequently died. The company noted that there has been one blinded golimumab trial report of colitis which was attributed to recent surgery.

The NZPhvC considers that this information does not alter the initial assessment of the report by the NZPhvC.

Discussion

The Committee discussed the referral of cases to ACC. NZPhvC advised that it is difficult to determine if patients who have suffered a treatment injury have been referred to ACC, as this information is not always provided. The Committee suggested ways of making the reporters of adverse events aware that if someone has a serious or ongoing problem as a result of a drug side effect, they may be eligible to make a claim under ACC. The Committee suggested that a statement could be included on the NZPhvC letter sent back to reporters drawing their attention to the issue, or alternatively a more generic letter could be written to reporters.

Recommendation

The Committee recommended that NZPhvC discuss the issue of making reporters aware of patient's rights with respect to ACC and report back to the Committee.

2.1.8 Tenecteplase and sudden death [death] (74192)

March 2007 minute item 4.3.1.6

Issue

In March 2007, the Committee recommended that NZPhvC should await more information from the reporter on the cause of death in this case (74192) and bring the results back to the MARC.

Outcome

The NZPhVC will bring the report back in the event that further information on the cause of death is received.

Discussion

The Committee noted the above.

2.1.9 Tamoxifen and retinal deposits (73804)

March 2007 minute item 4.3.4.1

Issue

In March 2007, the Committee recommended that a reminder article is published in Prescriber Update informing prescribers of retinopathy with tamoxifen.

Outcome

Medsafe will author this article.

Discussion

The Committee noted the above.

2.1.10 Lumiracoxib and dyspnoea, orthopnoea (74295)

March 2007 minute item 4.3.5.5

Issue

In March 2007, the Committee recommended that the NZPhvC should change the causality from 'probable' to 'possible' for lumiracoxib and dyspnoea and orthopnoea.

Outcome

The NZPhVC has made the appropriate adjustment to the database.

Discussion

The Committee noted the above.

2.2 Report on Actions Arising from Previous Meetings of the Medicines Adverse Reactions Committee (MARC)

2.2.1 Infliximab/methotrexate/prednisone and secondary sepsis, dural abscess, tooth abscess, headache, coma [death] (CARM case 72110)

March 2007 minute item 2.1.1; December 2006 minute item 2.1.9; September 2006 minute item 4.1.1.5

Issue

In December 2006, the Committee recommended that an article be written for publication in Prescriber Update, raising the awareness of a possible association between anti-TNF agents and dental cavity abscess, and describing the CARM case reports.

Outcome

A Prescriber Update article, including information about the possibility of infection in general with anti-TNF agents will be authored by [..]

A Signal article authored by [..] entitled "Tumour Necrosis Factor Inhibitors and Oral Cavity Abscess" was included in Section 4 of the MARC dossier.

Discussion

Please refer to minute item 3.1 for discussion on the topic of this article.

2.2.2 COX-2 Inhibitors: Active Monitoring Review

March 2007 minute item 2.1.5; December 2006 minute item 3.1

Issue

In December 2006, the Committee recommended that the issue of COX-2 Inhibitors should be removed from the active monitoring list.

In December 2006, the Committee recommended that Medsafe review the data sheets for all of the COX-2 inhibitors for GI risks and report back to the Committee at the next meeting.

Outcome

This issue has been removed from the active monitoring list.

Medsafe is in the process of comparing the New Zealand and Australian data sheets for the COX-2 inhibitors with respect to GI safety. Following a review of the data sheets, Medsafe will contact the sponsors to request data sheet changes in line with the Australian data sheets, as appropriate.

Discussion

The Committee noted the above.

2.2.3 Non-selective NSAIDs: Active Monitoring Review

March 2007 minute item 2.1.6; December 2006 minute item 3.2

Issue

In December 2006, the Committee recommended non-selective NSAID product information [..] that should be adopted in New Zealand.

In December 2006, the Committee recommended that an article is written for publication in Prescriber Update to inform prescribers of current evidence regarding the safety of NSAIDs and to provide advice for the safe use of these agents.

The Committee recommended that the information in Prescriber Update form the basis of a Dear Healthcare Professional letter.

Outcome

In Australia, all non-selective NSAIDs PIs have been updated with the new information on cardiovascular, gastrointestinal, and skin reactions. Most innovator sponsors individualised the information or added extra information in addition to the standard text. Following liaison with the TGA to ensure consistency of product information updates between the two countries, letters were sent to NZ sponsors of non-selective NSAIDs asking that NZ datasheets, amended to include the latest Australian PI information, be provided for Medsafe review. Medsafe is awaiting responses. Once this process has been completed, a Prescriber Update article and 'Dear Health Professional' letter will be disseminated.

Discussion

The Committee noted the above.

2.2.4 Omeprazole and headache (72715)

March 2007 minute item 1.2, 2.1.8; December 2006 minute item 4.1.2.1

Issue

In December 2006, the Committee recommended that an article be written for publication in Prescriber Update informing prescribers of headaches as a possible adverse effect of omeprazole.

Outcome

Medsafe will liaise with NZPhvC to draft a Prescriber Update article informing prescribers of headaches as an adverse effect of omeprazole in children.

Discussion

The Committee noted the above.

2.2.5 Roxithromycin, warfarin, and decreased prothrombin (73165)

March 2007 minute item 2.1.9; December 2006 minute item 4.1.4.2

Issue

In December 2006, the Committee recommended that an article be written for publication in Prescriber Update informing prescribers of the interaction between roxithromycin and warfarin, and to include erythromycin.

Outcome

A Prescriber Update article will be authored by Medsafe.

Discussion

The Committee noted the above.

2.2.6 Sodium valproate and foetal valproate syndrome (73289)

March 2007 minute item 2.1.10; December 2006 minute item 4.1.5.1

Issue

In December 2006, the Committee recommended that an article is written for publication in Prescriber Update on anticonvulsants and risk of congenital malformations, and the importance of pre-pregnancy counselling for all women of child-bearing age taking anti-convulsants.

Outcome

A Prescriber Update article will be authored, probably by Medsafe.

Discussion

The Committee noted the above.

2.2.7 Candesartan and palpitations (73162)

March 2007 minute item 2.1.11; December 2006 minute item 4.1.8.1

Issue

In December 2006, the Committee recommended that Medsafe review the Australian and International data sheets for candesartan and palpitations, and update the New Zealand data sheet if warranted.

Outcome

A letter requesting the inclusion of palpitations in the NZ datasheet for Atacand (candesartan) was sent to AstraZeneca in May 2007. Medsafe is awaiting a response.

Discussion

The Committee noted the above.

2.2.8 Quinine, Nocturnal Leg Cramps, and Thrombocytopenia

March 2007 minute item 2.2.2; December 2006 minute item 2.1.3; September 2006 minute item 3.1; June 2006 minute item 4.1.3.1

Issue

In September 2006, the Committee recommended that Medsafe should pursue removal of the indication "prophylaxis and treatment of nocturnal recumbency leg muscle cramps, including those associated with arthritis, diabetes, varicose veins, thrombophlebitis, arteriosclerosis and static foot deformities" from quinine products. In September 2006, the Committee recommended that, following resolution of the above, Medsafe should write an article for publication in Prescriber Update informing prescribers of the change to the indications for quinine.

Outcome

The data sheets of the quinine products (Apotex and Pacific brands) currently available in New Zealand have been updated and have been published on the Medsafe website.

The Prescriber Update article is in the process of being drafted by Medsafe.

Discussion

The Committee noted the above.

2.2.9 Inhaled Long-Acting Beta-Adrenoceptor Agonists (LABAs) and the Risk of Fatal and Non-Fatal Asthma Exacerbations

March 2007 minute 2.2.3; December 2006 minute item 2.1.4; September 2006 minute item 3.2

Issue

In September 2006, the Committee recommended that Medsafe should again ask AstraZeneca to update the Oxis Turbuhaler and Symbicort data sheets to include warnings on the risk of serious asthma exacerbations.

In September 2006, the Committee recommended that Medsafe should consider publishing an article in Prescriber Update summarising the changes to the LABA data sheets.

Outcome

The data sheets for Oxis Turbuhaler and Symbicort have been updated as requested.

A first draft of the Prescriber Update article was included in Section C of the MARC dossier.

Discussion

Please refer to minute item 1.5.1 for discussion on the Prescriber Update article.

2.2.10 SSRIs and Use in Pregnancy: Watching Brief Review

December 2006 minute item 2.1.5; September 2006 minute item 3.3; June 2006 minute item 2.2.8; March 2006 minute item 2.2.7; December 2005 minute item 2.1.7; September 2005 minute item 3.5

Issue

In September 2006, the Committee recommended that Medsafe should consider publishing an article in Prescriber Update alerting prescribers and lead maternity carers (LMCs) to the risks associated with the use of SSRIs in pregnancy.

In September 2006, the Committee recommended that Medsafe should ask all sponsors of SSRIs to update the data sheets as per the Aropax data sheet to describe the potential risk of persistent pulmonary hypertension in the newborn (PPHN) following foetal exposure.

In September 2006, the Committee recommended that Medsafe should ask the sponsors of Apo-Fluoxetine (Apotex) and Plinzene (Douglas) to update the data sheets to describe the risk of neonatal withdrawal following foetal exposure.

In September 2006, the Committee recommended that Medsafe should ask the sponsor of Apo-Paroxetine (Apotex) to amend the data sheet categorisation of risk during pregnancy from Australian Drug Evaluation Committee category B3 to category C.

Outcome

A Prescriber Update article is being written by Medsafe.

With the following exceptions, all datasheets have been updated as requested:

Lundbeck and Eli Lilly did not consider the inclusion of PPHN justified at this time. At the March 2007 meeting, the MARC accepted the reasoning provided by these companies.

Pfizer is yet to provide a response but has committed to reply to Medsafe as soon as possible.

Discussion

The Committee noted the above.

2.2.11 Clozapine and myocarditis, heart failure, arrhythmia [death] (CARM case 66578)

March 2007 minute item 2.2.6; December 2006 minute item 2.1.7; September 2006 minute item 4.1.1.4

Issue

In September 2006, the Committee recommended that NZPhvC should await a copy of the post-mortem report in this case (66578), then review the causality assessment and bring the results back to the MARC.

Outcome

The NZPhvC has requested the post-mortem report and follow-up re-assessment and will bring the results back to the MARC in due course.

Discussion

The Committee noted the above.

2.2.12 Clozapine and Myocarditis

March 2007 minute item 2.2.7; December 2006 minute item 2.1.8; September 2006 minute item 4.3.2

Issue

In September 2006, the Committee recommended that Medsafe should request expert opinion from a cardiologist on the predictive value of electrocardiograms, echocardiograms and serum cardiac markers for detecting myocarditis in patients treated with clozapine.

In September 2006, the Committee recommended that Medsafe should consider publishing a paragraph in Prescriber Update reminding prescribers of the risk of myocarditis with clozapine.

Outcome

Medsafe has followed up with the cardiologist and had hoped to receive his opinion before the June MARC meeting.

Discussion

Medsafe advised that receipt of the opinion from the cardiologist was still pending. Medsafe will report back at the September 2007 MARC meeting.

2.2.13 Influenza vaccine and sudden death (CARM case 71269)

March 2007 minute item 2.2.8; December 2006 minute item 2.1.10; September 2006 minute item 4.1.1.6

Issue

In September 2006, the Committee recommended that NZPhvC should bring this case (71269) back to the MARC once the post-mortem results were available.

Outcome

The NZPhvC is still awaiting the post-mortem report and will bring the report back to MARC once this has been received.

Discussion

The Committee noted the above.

2.2.14 Diclofenac/ibuprofen/prednisone and gastric ulcer, duodenal ulcer, intestinal ulceration, haematemesis, hypoproteinaemia (CARM case 71906)

March 2007 minute item 2.2.9; December 2006 minute item 2.1.12; September 2006 minute item 4.1.3.1

Issue

In September 2006, the Committee recommended that Medsafe should review the NSAID product data sheets with respect to the risk of lower gastrointestinal adverse effects and then request the product sponsors to update the data sheets as warranted.

Outcome

This recommendation will be actioned as part of the outcomes arising from the MARC review of the safety of the non-selective NSAIDs at the December 2006 MARC meeting.

Discussion

The Committee noted the above.

2.2.15 Tramadol-Drug Interactions and Serious Reactions

March 2007 minute item 2.2.11; December 2006 minute item 2.2.4; June 2006 minute item 2.1.14; March 2006 minute item 4.2.1

Issue

In March 2006, the Committee recommended that [..] should write two Prescriber Update articles on tramadol. The first should be on increased International Normalised Ratio (INR) when tramadol is administered with warfarin and/or other medicines known to increase INR. The second article should be on serious adverse effects of tramadol, specifically serotonin syndrome and convulsions.

Outcome

An article entitled 'Evidence for tramadol-warfarin interaction' was published in the November 2006 edition of Prescriber Update. A first draft of the tramadol - serious reactions and interactions Prescriber Update article was included in Section C of the MARC dossier.

Discussion

Please refer to minute item 1.5.1 for the discussion of the Prescriber Update article.

2.3 Report on Unresolved Actions Arising from Recommendations of the MARC

The following list is of recommendations made by the MARC that have yet to be resolved. Prescriber Update articles are not included, as they are listed in the Schedule of Planned Prescriber Update Articles (see minute item 1.5.1). Nor are actions arising from the last MARC meeting included, as they are listed in the Report on Actions Arising from the 129^th Meeting of the MARC (see minute item 2.1).

2.3.1 Low Molecular Weight Heparins (LMWHs) in Renal Impairment.

December 2005 minute item 2.2.12; September 2005 minute item 2.2.6; June 2005 minute item 2.2.11; September 2004 minute item 2.1.6; June 2004 minute item 2.1.4; March 2004 minute item 2.1.8; December 2003 minute item 4.1.1.5

Issue

In June 2005, the Committee recommended that Medsafe should contact the DHBNZ Safe Use of Medicines Group to enquire on the progress of the development of a protocol for the safe use of LMWHs in patients with severe renal impairment.

Outcome

The DHBNZ Safe Use of Medicines Group responded to Medsafe in October 2005. Medsafe was informed that an alert was currently being developed to advise prescribers on the required enoxaparin dosage adjustment for patients with renal impairment (creatinine clearance <50mL/min). In view of a lack of data for other LMWHs this advice would not be extrapolated to the other LMWHs available in New Zealand. After consultation throughout New Zealand the Safe Use of Medicines Group determined that there was only limited ability to perform anti-Xa monitoring in New Zealand and therefore monitoring could not be recommended routinely.

In December 2005, the Committee noted the above and agreed that Medsafe should bring the DHBNZ Safe Use of Medicines Group protocol to the MARC once it was finalised.

In December 2006, the Committee noted that the DHBNZ Safe Use of Medicines Group protocol on the safe use of LMWHs in patients with severe renal impairment was still in development.

Discussion

Members noted that the DHBNZ Safe Use of Medicines Group protocol on the safe use of LMWHs in patients with severe renal impairment was still in development.

3 Pharmacovigilance Issues

3.1 ADVERSE REACTIONS TO LEFLUNOMIDE: ACTIVE MONITORING REVIEW

References

• NZ datasheet for Arava
• NZ datasheet for AFT-Leflunomide
• Leflunomide and Pneumonitis, Prescriber Update (June 2006)
• Savage et al (2006) Pneumonitis associated with leflunomide: a profile of New Zealand and Australian reports. Internal Medicine Journal. 36: 162-169.
• Leflunomide and Peripheral Neuropathy, ADRAC Bulletin (Oct 2006)
• Leflunomide and Interstitial Lung Disease, ADRAC Bulletin (Dec 2006)
• McEwen et al (2007) The incidence of pancytopenia in patients taking leflunomide alone or with methotrexate. Pharmacoepidemiology and Drug Safety. 16: 65-73
• Mueli KA et al. Leflunomide-associated infections in rheumatoid arthritis, Draft paper, Christchurch Hospital Rheumatology Department.

Issue

This report was generated as part of the MARC's annual active monitoring review of the safety of leflunomide. The purpose of the report is to inform the Committee of recent regulatory action regarding leflunomide. The Committee was asked to evaluate the information provided in conjunction with a report authored by the NZPhvC, and to determine whether the risk-benefit profile of leflunomide has changed as a result of this new information. If the risk-benefit profile was deemed to have changed, the Committee was asked to comment on appropriate risk management.

Discussion

The Committee noted the NZPhvC and Medsafe reports. Medsafe advised that based on Pharmhouse data, the number of prescriptions for leflunomide had remained fairly constant over the last 25 months. The Pharmhouse data indicated that 43% of patients were taking leflunomide and methotrexate in combination from June to December 2006. This figure is similar to that of the CARM database, in which 38% of reports are in patients taking this combination.

The Committee noted that these agents are a hazardous group of drugs which are used in patients with few other options.

The Committee noted a draft report provided by NZPhvC regarding an audit of leflunomide associated infections in the Rheumatology Department of Christchurch Hospital. NZPhvC noted that out of 171 patients, 12 developed severe infections. Some of these patients had been taking leflunomide for some time, making the assessment of causality difficult. NZPhvC noted that it was the severity of infection, rather than the incidence, which was of concern. Most of these patients were treated with multiple therapy. This is consistent with the information in the CARM database, where most patients who developed severe infections were taking leflunomide in combination with one or more of corticosteroids, other disease-modifying antirheumatic drugs (DMARDS) or a TNF inhibitor.

The Committee noted that published case reports of serious infections have increased, which may be related to impaired healing. There are also several reports of vasculitis, which has is related to infection. The Committee noted that cutaneous necrotising vasculitis is listed as a very rarely reported adverse reaction in the data sheet in other countries, however this is not listed in the New Zealand data sheet.

A bulletin published by ADRAC in 2006 contains 30 case reports of peripheral neuropathy which are listed in the ADRU database. Leflunomide was the sole suspect medicine in 24 reports. The bulletin noted that the clinical features of peripheral neuropathy were similar to the vasculitic component of rheumatoid disease and that this presentation could be a potentially reversible reaction to leflunomide.

Recent Australian data has indicated that the incidence of pancytopenia with leflunomide is increased when taken in combination with methotrexate. It was estimated that the incidence of pancytopenia was approximately 1 in 4000 for leflunomide monotherapy, but increased to 1 in 700 for patients taking leflunomide in combination with methotrexate. The CARM database indicates the same pattern. It was noted that the use of methotrexate is also very high in patients taking leflunomide who were reported to have developed pneumonitis.

The Committee agreed that the warnings in the New Zealand data sheets for leflunomide should be strengthened in line with the Australian data sheet as follows.

1. 'Adverse Reactions' - Post-Marketing Data

Delete as follows:

[Skin and Appendages]

[Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme]

Replace with:

[Allergic reactions, Skin and Appendages]

Common: Mild allergic reactions (including maculopapular and other rashes), pruritis, eczema, dry skin, increased hair loss

Uncommon: Urticaria

Very rare: Severe anaphylactoid reactions. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme. In case reports received so far, a causal relationship with leflunomide treatment could not be established but cannot be excluded.

Vasculitis, including cutaneous necrotising vasculitis. Due to underlying disease, a causal relationship could not be established.

Delete as follows:

Haemic and Lymphatic System

Rare: eosinophilia, leukopenia (leukocytes <2 G/l), pancytopenia, [thrombocytopenia with platelet count <100 x 109/L (<100G/L)]

Very rare: agranulocytosis

Replace with

Haemic and Lymphatic System

Uncommon: thrombocytopenia with platelet count <100 x 109/L (<100G/L)

Rare: eosinophilia, leukopenia (leukocytes <2 G/l), pancytopenia,

Very rare: agranulocytosis

Delete as follows:

Infection

[Very] Rare: Severe infections, including opportunistic infections, and sepsis, which may be fatal. (Most of the case reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness, in addition to rheumatoid disease, which may predispose patients to infection).

2. 'Pharmacokinetics'

Add 'Paediatric Pharmacokinetics' section from Australian PI, and

Delete:

[Age and Gender: Neither age nor gender has been shown to cause a consistent change in the in vivo pharmacokinetics of leflunomide and A771726. Pharmacokinetics in subjects under the age of 18 years has not been studied and data in patients > 65 years are limited.]

Replace with:

Gender: Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of leflunomide and A771726.

Age: has been shown to cause a change in the in vivo pharmacokinetics of leflunomide and A771726 (see 'Paediatric Pharmacokinetics' above). Data in patients > 65 years are limited.

3. 'Clinical Trials'

Add 'Paediatrics' section from Australian PI.

4. 'Precautions'

Delete:

[Patients with Renal Impairment

At present there is not enough experience available to make dosage recommendations for patients with a serum creatinine concentration of >133 micromoles/L (1.5 mg/dL).]

Replace with:

Patients with Renal Impairment

Leflunomide was administered as a single oral 100 mg dose to 3 haemodialysis patients and 3 patients on continuous peritoneal dialysis (CAPD). The pharmacokinetics of A77 1726 in CAPD subjects appeared to be similar to healthy volunteers. A more rapid elimination of A77 1726 was observed in haemodialysis subjects which was not due to extraction of drug in the dialysate but instead to displacement of protein binding. Caution should be used when leflunomide is administered to patients with renal impairment (see 'Special Populations').

5. 'Use in Pregnancy (Category X) - Wash-out procedure'

Add: Both cholestyramine and activated charcoal may influence the absorption of estrogens and progestrogens such that reliable contraception with oral contraceptives may not be guaranteed during the washout procedure with cholestyramine and activated charcoal. Use of alternative contraceptive methods is recommended.

Recommendations

The Committee recommended that an article concerning pancytopenia, hepatic reactions, and pneumonitis in combination with methotrexate should be written for publication in Prescriber Update. The article should also include a reminder about peripheral neuropathy and infection such as tuberculosis.

The Committee recommended that Medsafe contact the sponsors of leflunomide to request the above mentioned data sheet revisions.

The Committee recommended that the issue of adverse reactions to leflunomide should remain on the active monitoring review list.

3.2 BISPHOSPHONATES AND OSTEONECROSIS OF THE JAW: ACTIVE MONITORING REVIEW

References

• Medsafe report for the MARC, May 2007.
• Bolland M, Hay D, Grey A, Reid I, Cundy T. Osteonecrosis of the jaw and bisphosphonates - putting the risk in perspective. NZ Med J 2006 Dec;119(1246).

Issue

Medsafe provided a report for the MARC's annual active monitoring review on the issue of bisphosphonates and osteonecrosis of the jaw. This issue was placed on the active monitoring review list in December 2005, and further discussed at the June 2006 MARC meeting.

The purpose of the May 2007 report from Medsafe was to inform the Committee of recent data and regulatory actions. The Committee was asked to evaluate the information provided and determine whether the risk-benefit profile of bisphosphonates had changed as a result of the recent information; and if so, recommend appropriate regulatory action.

Discussion

The Committee noted the Medsafe report and the two CARM case reports. They agreed that there had been little new information arising in the last year. Current evidence supports the initial conclusions that the injectable bisphosphonates are associated with a higher risk of osteonecrosis than the oral agents. At this time, the risk differences appear to be determined by the clinical indications and relative potencies of the individual bisphosphonates. The Committee agreed that there is no new information that changes the current understanding, and recommended that the issue of bisphosphonates and osteonecrosis of the jaw should be removed from the active monitoring list.

Recommendation

The Committee recommended that the issue of bisphosphonates and osteonecrosis of the jaw should be removed from the active monitoring review list.

3.3 SSRI ANTIDEPRESSANTS AND SEVERE AGITATION, SEVERE RESTLESSNESS/AKATHISIA, AND/OR INCREASED SUICIDALITY; WATCHING BRIEF REVIEW

References

• FDA Clinical review: relationship between antidepressant drugs and suicidality in adults (Stone & Jones, November 2006).
• FDA Statistical evaluation of suicidality in adults treated with antidepressants (Levenson & Holland, November 2006).
• Gibbons et al (2005) The relationship between antidepressant medication use and rate of suicide. Arch Gen Psychiatry. 62: 165-172.
• Gibbons et al (2006) The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry. 163: 1898-1904. (also see related Editorial)
• Olfson et al (2006) Antidepressant drug therapy and suicide in severely depressed children and adults. Arch Gen Psychiatry. 63: 865-872.
• Bridge et al (2007) Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment. JAMA. 297(15): 1683-1696.
• Rubino et al (2007) Risk of suicide during treatment with venlafaxine, citalopram, fluoxetine, and dothiepin: retrospective cohort study. BMJ. 334(7587): 242-247.

Issue

Medsafe provided a report for the MARC's annual watching brief review on the issue of SSRI antidepressants and severe agitation, severe restlessness/akathisia and increased suicidality. This issue was placed on the watching brief review list in March 2006, and was to be removed pending the FDA Psychopharmacologic Drugs Advisory Committee review of antidepressants and suicidality.

The purpose of the May 2007 report from Medsafe was to inform the Committee of recent data and regulatory actions regarding SSRIs and suicidality. The Committee was asked to evaluate the information provided and determine whether the risk-benefit profile of SSRIs has changed as a result of this new information; and if so, comment on appropriate risk management.

Discussion

The Committee discussed the FDA statistical evaluation of suicidality in adults treated with antidepressants. They noted that the data analysis indicated that there was an increased risk in the 18 to 24 year old age group, no increased risk between the ages of 24 and 64, and a decreased risk in the over 65 age group.

The Committee discussed the FDA's request to manufacturers of all antidepressant medications to update the existing "black box" on their product labelling to include warnings about increased risks of suicidal thinking and behaviour (suicidality) in young adults aged 18 to 24 during initial treatment.

The FDA also requested that the labelling state that scientific data do not show an increased risk in adults older than 24 and that adults aged 65 and older taking antidepressants actually have a decreased risk of suicidality. In addition, they requested that warning statements emphasise that depression and certain other serious psychiatric disorders are themselves the most important causes of suicide.

The Committee discussed the difficulties of carrying out trials in this area and translating results into meaningful risk-benefit information. They agreed that while there may be some attributable risk of suicide in the young age group, the literature supported that the risk was small. They noted that the Bridge et al meta-analysis provided some new information but still concluded that the benefits of antidepressant treatment in paediatrics outweighed the risks.

The Committee did not believe the new information provided altered the risk-benefit profile of SSRI antidepressant medicines. They agreed that the current New Zealand SSRI datasheets adequately warn prescribers of the potential risks associated with the use of these medicines, and the need to carefully monitor patients for the emergence or worsening of suicidal thoughts or behaviours, particularly during the initial stages of treatment. They did not consider it is necessary to revise the existing warnings to express the FDA findings that there is no evidence for an increased risk of suicidality in adults over 24 years, or that for those aged 65 years and older, suicidality risk is decreased.

The Committee agreed that the MARC advice issued to prescribers in October 2004 remains valid -

"Monitor all patients with depression

The MARC considers that for all age groups worsening depression remains the most common reason for increased suicidality during treatment with any antidepressant. All patients with MDD should be monitored for the emergence or worsening of suicidal thoughts or behaviours regardless of whether they are taking an antidepressant medicine or not. Evidence suggests that the risk of suicidality may be especially increased during the first few weeks of treatment.

Finally, the MARC considers that the possible increased risk of suicidality in patients applies to all classes of antidepressant medicines, as available data are not adequate to exclude an increased risk of suicidality for any antidepressant (including SSRIs, TCAs and Monoamine Oxidase Inhibitors)."

Recommendation

The Committee recommended that the issue of SSRIs antidepressants and severe agitation, severe restlessness/akathisia and increased suicidality should be removed from the 'watching brief' list.

3.4 TOPICAL PIMECROLIMUS AND THE RISK OF MALIGNANCY: WATCHING BRIEF REVIEW

Reference

• Medsafe report for the MARC, May 2007.

Issue

Medsafe provided a report for the MARC's annual watching brief review on the issue of topical pimecrolimus and the risk of malignancy. This issue was placed on the watching brief review list in June 2006 following an FDA safety review arising from concerns over the possible association between malignancies and topical use of pimecrolimus.

The purpose of the May 2007 Medsafe report was to inform the Committee of recent data and regulatory actions. The Committee was asked to evaluate the information provided and determine whether the risk-benefit profile of pimecrolimus has changed as a result of the recent information; and if so, recommend appropriate regulatory action.

Discussion

The Committee noted the Medsafe report. Medsafe advised that Novartis is conducting three long-term clinical trials looking at the safety and efficacy of pimecrolimus in children aged between three months and seventeen years. The results of these trials are expected to be available sometime between the latter part of 2008 and 2018, and will be provided to regulatory agencies. Medsafe additionally advised that in 2006, the EMEA asked Novartis to establish a data safety monitoring board to review all Elidel data as part of an enhanced pharmacovigilance plan.

The Committee noted that no new or additional evidence has emerged in the last 12 months and that in this time the Elidel data sheet had undergone extensive changes regarding the safe and appropriate use of the product. They agreed that the issue of topical pimecrolimus and the risk of malignancy should be removed from the 'watching brief' list.

Recommendation

The Committee recommended that the issue of topical pimecrolimus and the risk of malignancy should be removed from the 'watching brief' list.

4 Matters arising from the New Zealand Pharmacovigilance Centre

4.1 Centre for Adverse Reactions Monitoring (CARM) Spontaneous Case Reports

4.1.1 Deaths

4.1.1.1 Capecitabine and diarrhoea,vomiting [death] (74872)

Discussion

The Committee considered that diarrhoea, which could be severe, was a well known adverse effect of capecitabine, and this was documented in the data sheet. They queried whether the patient's underlying state could have contributed as she was being treated for metastatic breast cancer and was receiving morphine.

The causal association with capecitabine was considered to be 'probable' for diarrhoea and vomiting.

The Committee considered that no further regulatory action was required at this time.

4.1.1.2 Indomethacin and duodenal ulcer haemorrhagic [death] (74319)

Discussion

The Committee considered that gastrointestinal effects were a well known adverse effect of indomethacin and this was documented in the data sheet.

The causal association with indomethacin was considered to be 'probable' for massive blood loss and duodenal ulcer.

The Committee considered that no further regulatory action was required at this time.

4.1.1.3 Lamotrigine and convulsion [death] (74826)

Discussion

The Committee noted that the Coroner's report was still awaited and the information provided was not adequate to allow a further assessment at this time.

The causal association with lamotrigine was considered to be 'unclassified' for convulsion.

Recommendation

The Committee recommended that NZPhvC should provide a follow up report to the MARC when the Coroner's report or further information that facilitates assessment becomes available.

4.1.1.4 Quetiapine, paroxetine, and neuroleptic malignant syndrome, pneumonia inhalation[death] (74373)

Discussion

NZPhvC noted that there are three reports for neuroleptic malignant syndrome in the IMMP database, with one case very similar to the above case. The WHO database also contains reports, and the data sheet recognises the possibility that neuroleptic malignant syndrome can occur.

The Committee discussed the mechanism of the possible interaction at enzyme level as both quetiapine and paroxetine are involved in the same enzymes at a metabolic level. They agreed that the likelihood of an interaction at this level was weak and at this stage there was not enough evidence to support providing changed advice to prescribers. The Committee noted that the patient was afebrile and so neuroleptic malignant syndrome was unlikely given the information provided. They discussed the possibility that this was a case of an interaction effect causing severe extrapyramidal side effects, leading on to aspiration pneumonia and difficulty swallowing.

The Committee considered the causal association with quetiapine, paroxetine was 'possible' for extrapyramidal effects and inhalation pneumonia.

Recommendation

The Committee recommended that NZPhvC should seek further information about this case and bring the information back to the MARC.

4.1.1.5 Sunitinib and stomatitis, renal failure [death] (74719)

Discussion

NZPhvC noted that this is the first report in the CARM database for sunitinib. The product datasheet states that in metastatic renal cell carcinoma patients, mucositis/stomatitis had occurred in trial patients and in patients with gastrointestinal stromal tumours, 12% showed elevated serum creatinine. The literature confirmed a high level of creatinine abnormalities, with serious creatinine abnormalities occurring in less than 1% of patients.

The Committee considered the causal association with sunitinib was 'possible' for stomatitis and renal failure.

The Committee agreed that no further regulatory action was required at this time.

4.1.1.6 Tiotropium and cardiac failure [death] (74591)

Discussion

NZPhvC advised that there are reports in both the CARM and WHO databases of cardiac failure reported with tiotropium, however, these are not statistically prominent. There is no mention in the product data sheet of cardiac failure.

The Committee noted that there was inadequate information contained in the report to assess the relationship with tiotropium.

The causal association with tiotropium was considered to be 'unclassified' for cardiac failure.

Recommendation

Please refer to minute item 4.1.1.7,

4.1.1.7 Tiotropium and headache [death] (74756)

Discussion

NZPhvC noted a BPAC summary of an update of a Cochrane review, which systematically reviewed trials of more than 12 weeks duration and compared tiotropium to placebo, ipratropium or LABA. The review concluded that tiotropium was an effective option in the stepwise treatment of moderate to severe COPD, but that further trials were required to investigate its effectiveness in mild and very severe COPD, as the trials to date had only included patients with moderate to severe disease.

The Committee discussed the use of tiotropium in New Zealand and queried whether usage had increased.

The causal association with tiotropium was considered to be 'unclassified' for headache.

Recommendation

The Committee recommended that NZPhvC should seek further case details from the company about these reports involving tiotropium (74591, 74756, 74759, 74760, 74838) and bring the information back to the MARC.

4.1.1.8 Tiotropium and sudden death [death] (74759)

Discussion

The causal association with tiotropium was considered to be 'unclassified' for sudden death.

Recommendation

Please refer to minute item 4.1.1.7,

4.1.1.9 Tiotropium and sudden death [death] (74760)

Discussion

The causal association with tiotropium was considered to be 'unclassified' for sudden death.

Recommendation

Please refer to minute item 4.1.1.7,

4.1.1.10 Tiotropium and sudden death [death] (74838)

Discussion

The causal association with tiotropium was considered to be 'unclassified' for sudden death.

Recommendation

Please refer to minute item 4.1.1.7,

4.1.2 Antihistamine

4.1.2.1 Cetirizine and fibrillation ventricular, cardiac arrest (74429)

Discussion

NZPhvC noted that there were no reports of VF in the CARM database. Although there were some reports of VF and QT prolongation in the WHO database, these were not statistically prominent.

The NZPhvC noted that other non-sedating antihistamines are recognised causes of QT prolongation in susceptible patients, although as a third generation antihistamine, cetirizine was unlikely to prolong the QT interval enough to cause VF.

NZPhvC advised that further information had been received:

On arrival at the emergency department, the patient was in sinus rhythm and an ECG did not show a prolonged QT interval. The Committee agreed that there was inadequate evidence to indicate that the VF was due to the cetirizine, and that anaphylaxis, possibly due to occupational exposure, was an alternative explanation.

The causal association with cetirizine was considered to be 'possible' for fibrillation ventricular, cardiac arrest.

The Committee agreed that no further regulatory action was required at this time.

4.1.3 Cardiovascular

4.3.1.1 Atorvastatin and toxic epidermal necrolysis (74553)

Discussion

NZPhvC noted that although minor skin reactions have been reported to CARM, this was the first report of a potentially serious skin reaction. The product data sheet refers to the possibility of bullous skin reactions, which had been reported in post-marketing reports. They noted that this was a rare and unusual reaction to a widely used medicine.

The causal association with atorvastatin was considered to be 'possible' for toxic epidermal necrolysis.

The Committee agreed that no further regulatory action was required at this time.

4.1.4 Complementary and Alternative Medicine

Red Rice Yeast Extract, Saw Palmetto, CoQ10, Multivitamins, and myalgia,CK elevated,LFTs abnormal, chest pain (74641)

Discussion

NZPhvC noted that Red Rice Yeast Extract contains compounds which are very similar to statins, particularly lovastatin, and the product literature suggests that statin-like reactions have been observed. This may be a potential reason for the myalgia, CK elevation, and abnormal LFTs. There have also been reports of hepatitis attributed to Saw Palmetto. This case report illustrates the pharmacologically active nature of some complementary medicines.

The causal association with Red Rice Yeast Extract, Saw Palmetto, CoQ10, Multivitamins was considered to be 'possible' for myalgia,CK elevated,LFTs abnormal, chest pain.

Recommendation

The Committee recommended that a paragraph be published in Prescriber Update to illustrate the pharmacologically active nature of some complementary medicines.

4.1.5 Dermatological

4.1.5.1 Imiquimod and pigmentation abnormal (74330)

Discussion

NZPhvC noted that there was one report of depigmentation in the CARM database, which had not improved at the time of reporting. The WHO data shows quite a strong statistical association with depigmentation, and also includes reports of vitiligo. The data sheet states there have been isolated reports of pigmentation changes, some of which have not resolved.

The Committee noted that imiquimod causes an inflammatory reaction in the course of its action and there is some biological plausibility for it to cause vitiligo. They noted that the literature suggested that patients should be warned that depigmentation can occur when the reaction to imiquimod has subsided. This is usually a reflection of the healing skin, which is pinker and paler, and that this generally resolves. They noted that there could be a more chronic effect but this is not known at this time. The Committee noted that these types of reactions may be difficult to predict.

The causal association with imiquimod was considered to be 'probable' for pigmentation abnormal.

Recommendation

The Committee recommended that an article about imiquimod is published in Prescriber Update informing prescribers of the adverse effects of skin depigmentation and influenza-like symptoms.

4.1.5.2 Imiquimod and application site oedema, bullous eruption, headache, myalgia, hypotension, nausea, epistaxis, diarrhoea, arthralgia, hypertension (74656)

Discussion

The NZPhvC noted that many of the influenza like symptoms experienced by the patient were recognised reactions to imiquimod and a paragraph in Prescriber Update should be published to alert prescribers to this.

The causal association with imiquimod was considered to be 'certain' for application site oedema, 'possible' for bullous eruption, headache, myalgia, nausea, epistaxis, diarrhoea, arthralgia and 'unlikely' for hypotension, hypertension.

Recommendation

See minute item 4.1.5.1 for Prescriber Update article.

4.1.6 Endocrine

4.1.6.1 Pioglitazone, sodium valproate, lamotrigine, and myoclonic jerks, convulsions grand mal, hypoglycaemia, drug interaction(74783)

Discussion

NZPhvC noted that there are no reports of seizures with pioglitazone in the CARM database. There are reports in the WHO database, including one of a patient taking valproate who developed seizures when pioglitazone was started. In most of the other reports there were reasons for convulsions, such as hepatic disorders or hypoglycaemia. The WHO database contains a large number of reports of hypoglycaemia with both pioglitazone and rosiglitazone. The product data sheet does not mention seizures or interactions with sodium valproate or lamotrigine.

The Committee discussed possible mechanisms for an interaction at enzyme level and agreed that there was no obvious mechanism.

The causal association with pioglitazone, sodium valproate, lamotrigine was considered to be 'probable' for myoclonic jerks, convulsions grand mal, hypoglycaemia and 'possible' for drug interaction.

The Committee agreed that no further regulatory action was required at this time.

4.1.7 Psychiatric

4.1.7.1 Fluoxetine, azithromycin, and ectromelia one limb (74428)

Discussion

NZPhvC noted that the CARM database contains one case of multiple malformations after transplacental exposure to fluoxetine. The WHO database includes two reports of skeletal malformations with fluoxetine, however, other medicines were taken in both cases. There were no relevant reports for azithromycin. It is known that fluoxetine crosses the placenta and the MARC has previously considered studies of SSRIs and foetal malformations. One study showed an increased risk of foetal abnormalities, particularly cardiovascular, with first trimester paroxetine use, but it had yet to be shown if this was the case for fluoxetine. There is no evidence in the literature that azithromycin or fluoxetine have caused the type of skeletal malformations described in this report.

The causal association with fluoxetine and azithromycin was considered 'unlikely' for 'ectromelia one limb'.

The Committee agreed that no further regulatory action was required at this time.

4.1.8 Other Reports

The Committee noted the following case reports:

4.1.14.1 Adalimumab (74417)

4.1.14.2 Adalimumab (74502)

4.1.14.3 Pioglitazone (74883)

4.2 Quarterly Reports from CARM as at 31 March 2007

Discussion

NZPhvC presented the report, noting the number of brand switch reports continued to be low.

The Committee noted the quarterly reports from CARM as at 31 March 2007.

The Committee requested that the CARM case reports involving the Meningococcal B vaccine and chronic fatigue be reviewed at the next MARC meeting.

5 pharmacovigilance issues for information only

The following information was included in the meeting dossier. However, the Committee did not discuss this material. It included updates on issues already known to the Committee, commentaries, review articles and preliminary information on emerging issues. Members were asked to read this material, with the option of requesting that it be discussed.

• Thain S, Rubython J. Treatment of anaphylaxis in adults: results of a survey of doctors at Dunedin Hospital, New Zealand. New Zealand Medical Journal 2007; 120: No 1252.

6 new zealand pharmacovigilance-related activities

• DHBNZ Safe and Quality Use of Medicines Group Newsletter. Vol. 3; No. 1, April 2007.
• Proposal to develop a new chapter of ISoP for the Western Pacific Region.
• Record of the Pharmacology and Therapeutics Advisory Committee Meeting held on 21 and 22 February 2007.

7 international pharmacovigilance-related Activities

7.1 Australia

• Minutes of the 299^th meeting of the Adverse Drug Reactions Advisory Committee held on 23 March 2007.

7.2 Canada

• Health Canada. Canadian Adverse Reactions Newsletter. Vol. 17; Issue 2. April 2007.

8 Summary listings of case reports considered by the MARC (1997-2006)

• CARM case reports considered by the MARC since 1997, by medicine class.
• Vaccine adverse reaction reports considered by the MARC since 1997.
• Complementary and alternative medicine (CAM) case reports considered by the MARC.

9 OTHER BUSINESS

9.1 Clozapine and severe gastrointestinal effects

Professor Ellis provided the Committee with an update on the issue of clozapine and severe gastrointestinal motility impairment. There are now 25 cases involving clozapine and gastrointestinal adverse effects which have been reported to the Intensive Medicines Monitoring Programme (IMMP). Of these, there have been five deaths and four cases of toxic megacolon. A Prescriber Update article was published on the Medsafe website in March 2007, which may have alerted prescribers and stimulated reporting in New Zealand. Professor Ellis is part of a group intending to submit a paper for publication in July, regarding an audit of these case reports. At this time, the data sheets for Clopine and Clozaril will be reviewed to ensure the warning statements are adequate.

9.2 Appointment to the honorary editorial committee of Drug Safety Bulletin

The Committee congratulated Dr Ruth Savage on her recent appointment to the honorary editorial committee of Drug Safety Bulletin.

9.3 Vaccine Safety Evaluation: Post Marketing Surveillance Conference - Report on conference

Dr Stewart Reid provided the Committee with a summary of a Vaccine Safety Evaluation: Post Marketing Surveillance Conference held in April 2007. The conference was set up by the United States Institute of Health and the National Vaccine Programme to discuss how surveillance of adverse effects following vaccination could be improved.

Dr Reid presented a paper at the conference on the post-marketing surveillance of the meningococcal vaccine in New Zealand. A key point of interest arising from the paper was the independent safety monitoring board which was set up to monitor the adverse effects of the vaccine. There is a move internationally to move the assessment of adverse events away from the promoters of vaccination, which was essentially the model followed here, where the assessors of the safety of the vaccine were not established by the Ministry of Health but by the Health Research Council.

Vaccine safety history shows that the risks of vaccines, and systems for detecting and assessing this risk are of great importance. Clear communication with the public is important if reduction in vaccination uptake due to 'scares' are to be avoided. The assessment of vaccine safety data independent of manufacturers and promoters of immunisation is essential to improve public confidence in vaccine safety.

A system that monitors vaccine safety should ideally:

• Identify events caused by vaccination
• Enable causality assessment for events which may be caused by vaccination
• Increase public confidence in vaccine programmes, helping to avoid reductions in vaccination uptake caused by unsubstantiated fears of vaccine reactions

Many adverse effects following vaccination are very rare and so require large databases to detect.

Ideally there should be separation between the assessment of adverse events and the communication of the outcome of this assessment. There is the need for the public to be aware that there is an independent group that assesses and makes statements on vaccine safety and is not influenced by manufacturers or promoters of immunisation. A separate group could then communicate this message in a manner that receives public and professional prominence.

The Committee agreed that it was appropriate for the MARC to provide this function.

There being no further business, the Chair thanked members, guests and the secretariat for their attendance and closed the meeting at 3:00pm.

Associate Professor T.J.B Maling
Chair
Medicines Adverse Reactions Committee