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Committees

Updated 20 May 2013

Minutes of the 123rd Medicines Adverse Reactions Committee Meeting - 15 September 2005

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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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

1. MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies
1.2 Minutes of the 122nd 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 Prescriber Update Vol. 26; No. 1. June 2005.
1.5.2 Schedule of planned Prescriber Update articles.

1.5.3 Article for peer-review - Methadone and QT Interval Prolongation

2. ACTIONS ARISING

2.1 Report on Actions Arising from the 122nd MARC Meeting, 9 June 2005

2.1.1 MARC Membership
2.1.2 Dextropropoxyphene/Paracetamol Combination Products and the Risk of Overdose
2.1.3 The Legacy of Diethylstilboestrol (DES)
2.1.4 Valdecoxib and Serious Cutaneous Adverse Reactions (SCARs)
2.1.5 Atypical Antipsychotics and Increased Mortality in Elderly Patients with Dementia
2.1.6 Cabergoline and antepartum haemorrhage, multiple malformations, respiratory disorder neonate (CARM case 63154)
2.1.7 Streptokinase, anticoagulants, acetylsalicylic acid, clopidogrel and haematoma, anaemia, cardiac arrest, myocardial infarction (CARM case 62444)
2.1.8 Sodium valproate and pancreatitis (CARM case 63175)
2.1.9 Mometasone and rosacea (CARM case 62554)
2.1.10 Phenytoin, fluorouracil and ataxia, dizziness, drug level increased (CARM case 62606)
2.1.11 Flucloxacillin and renal failure acute, rash maculopapular, pruritus (CARM case 63623)
2.1.12 Miconazole, warfarin interaction and haematuria, prothrombin increased (CARM case 63753)
2.1.13 Methotrexate, leflunomide (CARM cases 63532 and 64391)
2.1.14 Colchicine Dosage
2.1.15 Salamol Inhaler - Device Failure Issues
2.1.16 Analysis of IMMP Events Reported for Risperidone
2.1.17 Joint Trans-Tasman Therapeutic Products Agency (JTA) 14 2.2 Report on Actions Arising from Previous Meetings of the MARC

2.2 REPORT ON ACTIONS ARISING FROM PREVIOUS MEETINGS OF THE MARC

2.2.1 COX-2 Inhibitors and Cardiovascular Safety
2.2.2 General Recommendations Regarding the Cardiovascular Safety of the COX-2 Inhibitors - IMMP studies.

2.2.3 Atypical Antipsychotics and Lipid Abnormalities.

2.2.4 Pergolide and Cardiac Valvulopathy.

2.2.5 Domperidone and the Risk of QT Prolongation.
2.2.6 Low Molecular Weight Heparins (LMWHs) in Renal Impairment.
2.2.7 Alendronate and synovitis, carpal tunnel syndrome, ankle oedema and arthralgia (CARM case 62186)

3. PHARMACOVIGILANCE ISSUES

3.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk

3.2 Bisphosphonates and Osteonecrosis of the Jaw

3.3 Review of Adverse Reactions of Current Concern

3.4 Review of Watching Briefs

3.5 Paroxetine and Use in Pregnancy

4. MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 Centre for Adverse Reactions Monitoring (CARM) Case Reports

4.1.1 Deaths
4.1.2 Alternative Medicines

4.1.3 Analgesics

4.1.4 Antifungals
4.1.5 Cardiovascular Medicines
4.1.6 Immunosuppressives
4.1.7 Musculoskeletal Medicines
4.1.8 Vaccines
4.1.9 Other Reports

4.2 Intensive Medicines Monitoring Programme (IMMP)

4.2.1 Analysis of IMMP Events Reported for Sibutramine
4.2.2 Sibutramine and Bruising

4.2.3 Paper for Information - Sibutramine and QT Interval Prolongation

4.3 Intensive Vaccines Monitoring Programme (IVMP) - Meningococcal B Vaccine

4.3.1 MeNZB Adverse Event Assessments
4.3.2 Urticaria Following MeNZB Immunisation

4.4 Quarterly Report from CARM as at 30 June 2005 37

5. PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

5.1 Analgesics and use in children

5.2 Combined oestrogen-progestagen contraceptives and carcinogenicity

5.3 Others

6. NEW ZEALAND PHARMACOVIGILANCE-RELATED ACTIVITIES

7. INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

7.1 Australia

7.2 Canada

7.3 Singapore

7.4 WHO

8. SUMMARY OF CASE REPORTS CONSIDERED BY MARC (1997-2005)

9. OTHER BUSINESS


Minutes:

The one hundred and twenty-third meeting of the Medicines Adverse Reactions Committee (MARC) was held on 15 September 2005 at the Eagle room, Miramar Links Conference Centre, Wellington, New Zealand. The meeting commenced at 0900 and closed at 1630.

marc members present

Associate Professor T.J.B Maling (Chair)
Professor D. Skegg
Dr H. Kingston
Dr M. Tatley
Dr M. Rademaker
Dr S. Sime

marc secretariat present

Dr S. Jessamine (Principal Technical Specialist, Medicines Regulation and Pharmacovigilance, Medsafe)
Dr K. Moses (Pharmacovigilance Advisor/MARC Secretary, Medsafe)

invited guests

Dr P. Jansen (Treatment Injury and Patient Safety Medical Advisor) and Ms R. Taylor (Clinical Analyst, Patient Safety) of the Accident Compensation Corporation joined the afternoon session in order to observe the MARC's processes in assessing spontaneous adverse reaction reports.

Dr D. Graham (National Manager, Therapeutic Goods Administration) and Dr S. Martindale (Team Leader, Business Development & Support, Medsafe) observed the afternoon session for a short time.

1. Matters of Administration

1.1 Welcome and Apologies

Apologies had been received from Professor P. Ellis and Dr F. McClure. They provided written comments on some issues, which were distributed to the other members prior to the meeting.

1.2 Minutes of the 122nd MARC Meeting

The members agreed that the minutes of the 122nd 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

The Committee reiterated the importance of item 1.2, that the Joint Trans-Tasman Therapeutic Products Agency (JTA) legislation should include provision that product sponsors be required to conduct post-marketing studies. Medsafe explained that, although this provision would not be included in the JTA Bill, it would be possible through the Ministerial Council Rules to impose conditions on product licence holders. There would be no provision for requiring any post-marketing studies to be conducted specifically in NZ. (Also see minute item 2.2.2).

The Committee noted that two recommendations made at the 122nd MARC meeting had not been accepted by the Minister's Delegate, on the advice of Medsafe (see minute items 2.1.15 and 2.1.16 in these minutes for details). The Committee supported the revised recommendations.

1.3 Dates of Future MARC Meetings

The date for the next MARC meeting was confirmed as being Thursday 15 December 2005. The date for the subsequent MARC meeting would be Thursday 16 March 2006.

1.4 Potential Conflicts of Interest

Committee members submitted the Conflict of Interest Declaration forms to the Secretary. Prof Ellis and Dr McClure had submitted declaration forms by email and fax respectively. The Chair reminded 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.

Dr Rademaker declared that his previous involvement in clinical trials had not started (treatment for male pattern baldness, Glaxo, declared at 25/11/1999 meeting; topical treatment for atopic eczema, Novartis, declared at 22/3/2000 meeting; 5-alpha reductase inhibitor, declared at 11/9/2002 meeting).

Prof Ellis declared continued involvement supervising a PhD study in comparing the cognitive effects of risperidone and olanzapine in schizophrenia - sponsored by Eli Lilly and investigator initiated. He continued to hold shares in several pharmaceutical companies.

The potential conflicts of interest were discussed and were not considered to influence the discussions or decisions of the Committee.

1.5 Prescriber Update

1.5.1 Prescriber Update. Vol. 26; No. 1. June 2005.

Discussion

The Committee noted the June 2005 edition of Prescriber Update.

1.5.2 Schedule of planned Prescriber Update articles.

Schedule

The Committee briefly discussed the schedule of planned articles. It was noted that some articles had been recommended a long time previously and that further regulatory action had occurred in the interim. Members considered that some articles could be removed from the schedule; however, in the absence of Sarita Von Afehlt (Editor of Prescriber Update) it was decided to defer decision making to the 124th MARC meeting.

Pergolide and cardiac valvulopathy

The planned article on pergolide and cardiac valvulopathy was discussed (also see minute item 2.2.4). Medsafe had proposed that the recommendation for this article be rescinded, as there was no further information for prescribers other than that already provided by the 'Dear Health Professional' letter and revised data sheet. The Committee reiterated that a Prescriber Update article would be of value in advising against the off-label use of pergolide in restless legs syndrome.

Members noted that the issue of pergolide and cardiac valvulopathy was becoming increasingly topical with regards to the difficulties in monitoring patients. It was noted the sponsor had advised in the data sheet and Dear Healthcare Professional letter that before initiating treatment all patients should undergo a cardiovascular evaluation, including an echocardiogram, in order to detect the potential presence of occult valvular disease. The core international data sheet contained the same advice. The Committee commented that pre-treatment echocardiograms for all patients would require extensive resources. There was some discussion around the necessity for pre-treatment echocardiograms in those patients not showing clinical signs of valvular disease. Medsafe explained that they could not write a Prescriber Update article giving advice different from that in the data sheet unless there was good evidence for doing so, and that resources should not influence the advice given on safety issues. Medsafe referred the Committee to the minutes of the December 2004 MARC meeting, in which it was agreed that the monitoring requirements recommended by the sponsor were appropriate. The Committee considered that it would be valuable to solicit the advice of cardiologists before a Prescriber Update article was written on this issue.

Cutaneous reactions

Regarding the planned article on 'Cutaneous reactions: top 10 causally associated medicines', the Committee considered that it was more important for the article to be written on the medicines that caused serious cutaneous adverse reactions (SCARs).

Recommendations

The Committee recommended that the Chair should seek the advice of cardiologists regarding the issue of cardiac monitoring for patients prescribed pergolide.

The Committee recommended that the planned Prescriber Update article on 'Cutaneous reactions: top 10 causally associated medicines' should be replaced with an article on the medicines that caused serious cutaneous adverse reactions (SCARs).

1.5.3 Article for peer-review - Methadone and QT Interval Prolongation

Discussion

The Committee noted that CARM had brought two methadone case reports to the MARC at this meeting (see minute items 4.1.1.5 and 4.1.3.1).

The Committee noted that the article had already been peer-reviewed by a General Physician/Clinical Pharmacologist and a representative of the Capital and Coast Alcohol and Drug Service.

The Committee made several suggestions for improvement of the article, as detailed below.

Recommendation

The Committee recommended that Medsafe should consider making the following changes to the Prescriber Update article on methadone and QT prolongation:

2. actions arising

2.1 Report on Actions Arising from the 122nd MARC Meeting, 9 June 2005

Please refer to the minutes of the 122nd MARC meeting, held on 9 June 2005, available on the Medsafe website at www.medsafe.govt.nz/Profs/adverse/Minutes122.htm for background information surrounding these issues.

2.1.1 MARC Membership

June 2005 minute item 1.1.1

Issue

The Committee recommended that Medsafe should liaise with Prof. Skegg regarding the need for the appointment of a second epidemiologist to the MARC.

The Committee recommended that Medsafe should investigate possible candidates for MARC membership, with expertise in pharmacoepidemiology.

Outcome

Following discussion with Prof. Skegg, Medsafe identified a number of experts with expertise in biostatistics or epidemiology. Medsafe sought the opinion of the Committee with respect to inviting each potential candidate to attend a MARC meeting. This would allow them to become acquainted with the functions of the Committee before seeking a recommendation to appoint a second epidemiologist. Appointment of any new member should be considered within the proposals to establish a single adverse reactions expert advisory committee to advise the Joint Trans-Tasman Therapeutic Products Agency (JTA).

Discussion

Medsafe detailed to the Committee the possible candidates for MARC membership. It was explained that any new member should be interested in participating in the joint Australia/NZ advisory committee, which was anticipated to meet six times a year from 1 July 2006 (see minute item 2.1.17). The Committee considered that a pharmacoepidemiologist would be preferable to a bio-statistician. The Committee identified a preferred candidate. Prof. Skegg agreed to speak with the candidate and invite that person to the next MARC meeting.

Recommendation

The Committee recommended that Prof. Skegg should liaise with the preferred candidate for MARC membership.

2.1.2 Dextropropoxyphene/Paracetamol Combination Products and the Risk of Overdose

June 2005 minute item 3.1

Reference
Issue

The Committee recommended that the data sheets for Paradex, Capadex and Apo-Paradex should be updated to remove inconsistencies between them and to state the dosages of active ingredients.

The Committee recommended that Medsafe should obtain usage data for dextropropoxyphene/ paracetamol combination products.

The Committee recommended that Medsafe should investigate options for restricting the period for which dextropropoxyphene/paracetamol combination products could be dispensed to thirty days.

The Committee recommended that Medsafe should undertake a period of consultation with stakeholders and then report back to the MARC.

Outcome
Data sheet changes

In August 2005 Medsafe contacted the sponsors of Paradex (Healthcare Manufacturing Group (HMG)), Capadex (Pharmacy Retailing NZ Ltd, trading as Healthcare Logistics) and Apo-Paradex (Apotex NZ Ltd) requesting data sheet changes for their products. Apo-Paradex was not marketed in NZ at that time.

The requested data sheet changes were related to the following issues.

The sponsors had not yet responded to the above requests.

Usage data

PHARMAC provided monthly dispensing data for Paradex and Capadex from June 2004 to May 2005. The number of scripts written for Paradex was approximately 15,500-19,000 per month, and for Capadex was approximately 600-800 per month. The number of scripts written for both medicines remained reasonably stable over that year.

In the letters of August 2005 the sponsors of dextropropoxyphene/paracetamol combination products were asked to provide monthly usage data for their products for the previous 12 months, and continue to provide this data until notified otherwise.

Options for restricting dispensing period

The PHARMAC provision called 'Close Control' restricted or reduced the quantities of particular medicines that could be dispensed. However, the Pharmaceutical Schedule specified the following criteria that needed to be met before a medicine could be dispensed as 'Close Control' (note: dextropropoxyphene was a Class C Controlled Drug):

'Close Control' meant "the dispensing of a Community Pharmaceutical, in accordance with a Prescription, in quantities less than one 90 day lot or, in the case of oral contraceptives, less than one 180 day lot for a Community Pharmaceutical referred to in Section F Part I, or in quantities less than a Monthly Lot for any other Community Pharmaceutical, as applicable, where all of the following conditions are met:

  1. The Community Pharmaceutical is a tri-cyclic antidepressant, antipsychotic, benzodiazepine, a Class B Controlled Drug, or any other Community Pharmaceutical that has been prescribed for a patient who:
    1. is not a resident in a Penal institution, Rest Home or Residential disability Care institution; and
    2. in the opinion of the prescribing Doctor, Midwife or Nurse Prescriber is:
      1. frail; or
      2. infirm; or
      3. unable to manage their medication without additional support; or
      4. intellectually impaired; and
    3. requires that Community Pharmaceutical to be dispensed in a smaller quantity than that for which it is currently funded; and
  2. The prescribing Doctor, Midwife or Nurse Prescriber has
    1. endorsed each Community Pharmaceutical on the Prescription clearly with the words "close control" or "CC"; and
    2. initialled the endorsement in the prescriber's own handwriting; and
    3. specified the maximum quantity or period of supply to be dispensed at any one time."

Therefore, dextropropoxyphene/paracetamol combination products could only be dispensed under 'Close Control' on an individual patient basis; and only if the above criteria were met (including the prescriber having assessed the patient as being frail, infirm, unable to manage their medicine, or intellectually impaired).

Consequently, Medsafe advised the MARC that there was no mechanism at that time by which the quantities of dextropropoxyphene/paracetamol combination products dispensed could be restricted to 30 days supply for all patients prescribed these medicines.

Submissions sought from stakeholders

In August 2005 Medsafe contacted stakeholders (The Royal NZ College of General Practitioners, The NZ Rheumatology Association, The NZ Pain Society, The Australian and NZ College of Anaesthetists, Arthritis NZ and Hospice NZ) seeking submissions on the use of dextropropoxyphene/paracetamol combination products. Stakeholders were asked to respond by 14 October 2005, in order for a further assessment of the safety of these products to be undertaken at the December 2005 MARC meeting.

Discussion

The Committee noted the above outcomes. They expressed disappointment that there was no mechanism available to restrict the period of supply of dextropropoxyphene/paracetamol combination products to 30 days.

The Committee agreed to make a further assessment of the safety of dextropropoxyphene/ paracetamol combination products at the 124th MARC meeting, including a review of stakeholder and sponsor submissions.

2.1.3 The Legacy of Diethylstilboestrol (DES)

June 2005 minute item 3.2

Issue

The Committee recommended that a Prescriber Update article should be written updating prescribers about the current evidence and to remind them about monitoring recommendations.

Outcome

A Prescriber Update article was being drafted.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.4 Valdecoxib and Serious Cutaneous Adverse Reactions (SCARs)

June 2005 minute item 3.3

References
  1. EMEA press release: European Medicines Agency concludes action on COX-2 inhibitors. 27 June 2005.
  2. EMEA: Questions and Answers on COX-2 Inhibitors. 27 June 2005.
  3. Health Canada News Release: Health Canada responds to Expert Advisory Panel on COX-2 drugs. 7 July 2005.
Issue

The Committee recommended that the data sheet for valdecoxib should be updated to address its cardiovascular risks, as per the recommendations made at the 121st MARC meeting in March 2005.

The Committee recommended that Medsafe should accept Pfizer's proposed data sheet changes for valdecoxib, in order to manage the risk of serious cutaneous adverse reactions, including:

Outcome

On 27 June 2005 the European Medicines Agency (EMEA) announced that the marketing authorisation for valdecoxib would be suspended for one year in view of the identified risks of SCARs. This suspension was to be reviewed within one year.

In response to this announcement, Medsafe notified the members of the MARC of the EMEA decision and offered the opportunity of a Committee teleconference in order to re-evaluate the recommendations made at the 122nd MARC meeting. This offer was declined and the members reiterated that the recommendations made were an appropriate risk-management strategy for New Zealand. Medsafe supported this decision.

On 7 July 2005, Health Canada's expert advisory committee recommended that valdecoxib not be allowed back on the Canadian market. Valdecoxib was not marketed in Australia at that time.

Medsafe contacted Pfizer on 2 September 2005 advising them of the MARC's recommendations regarding valdecoxib made at the 121st and 122nd MARC meetings, and requesting specific changes to the data sheet. A response had not yet been received.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.5 Atypical Antipsychotics and Increased Mortality in Elderly Patients with Dementia

June 2005 minute item 3.4

Issue

The Committee recommended that the product sponsor for quetiapine should be required to update the New Zealand data sheet to include information on the increased risk of mortality associated with use of their product in elderly patients with dementia.

The Committee recommended that the NZPhvC should maintain a watching brief on risperidone and mortality in elderly patients (particularly those with dementia).

Outcome

Medsafe contacted AstraZeneca in July 2005 to request that the following information be included in the Warnings and Precautions section of the quetiapine data sheet:

"Safety Experience in Elderly Patients with Dementia-Related Psychosis In elderly patients with dementia-related psychosis, the efficacy of quetiapine has not been established. In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in quetiapine-treated patients was significantly greater than placebo-treated patients ( % vs. % respectively [sponsor to insert product-specific percentages]). Risk factors that may predispose this patient population to increased mortality when treated with quetiapine include age >80 years, sedation, concomitant use of benzodiazepines, or presence of pulmonary conditions (e.g. pneumonia, with or without aspiration)."
Discussion

Medsafe informed the Committee that an updated quetiapine data sheet had been submitted. The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.6 Cabergoline and antepartum haemorrhage, multiple malformations, respiratory disorder neonate (CARM case 63154)

June 2005 minute item 4.1.1.1

Issue

The Committee recommended that the NZPhvC should investigate patterns of foetal abnormalities with other ergot derivatives such as bromocriptine, ergotamine, lisuride, pergolide, and ropinirole, and report back to the MARC.

The Committee recommended that the NZPhvC should investigate whether the pattern of abnormalities that occurred in this neonate represented a known syndrome and report back to the MARC.

Outcome

A literature review by the NZPhvC found papers suggesting a lack of association between bromocriptine and foetal abnormalities. Ergotamine may have had a potential role in the occurrence of isolated cases of neural tube defects, but the evidence was equivocal. No literature reports were found of foetal abnormalities with lisuride, pergolide or ropinirole.

The NZPhvC had been unsuccessful in identifying a syndrome linking the foetal malformations in this report.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.7 Streptokinase, anticoagulants, acetylsalicylic acid, clopidogrel and haematoma, anaemia, cardiac arrest, myocardial infarction (CARM case 62444)

June 2005 minute item 4.1.1.2

Issue

The Committee recommended that Medsafe should report back to the MARC on how adverse reaction reports were managed in the context of clinical trials.

Outcome

Medsafe reported to the Committee that clinical trials had internal safety monitoring in place, and in NZ were required to report serious adverse reactions, which resulted in the study code being unblinded, in an expedited manner to the Standing Committee on Therapeutic Trials (SCOTT). Adverse reactions occurring in clinical trials were not required to be reported to CARM, as they were managed by the trial Data Safety Monitoring Committee and then separately published, after the study code was broken at the end of the trial, in the study report.

In this case, the study's protocol was considered and approved not only by the SCOTT but also by a number of other expert committees around the world. In drawing up the study protocol clinicians were involved to ensure protection of the safety of the study participants, and appropriate study design. In general, the intent of clinical trials was to explore the safety and effectiveness of a product in new circumstances.

Discussion

The Committee noted the above.

2.1.8 Sodium valproate and pancreatitis (CARM case 63175)

June 2005 minute item 4.1.4.1

Issue

The Committee recommended that a brief Prescriber Update article should be written by Dr Tatley to highlight medicines that commonly cause pancreatitis.

Outcome

A Prescriber Update article was to be written.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.9 Mometasone and rosacea (CARM case 62554)

June 2005 minute item 4.1.7.1

Issue

The Committee recommended that the NZPhvC should write a brief Prescriber Update article to remind prescribers about the risks associated with the use of corticosteroids on the face.

Outcome

A Prescriber Update article was to be written.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.10 Phenytoin, fluorouracil and ataxia, dizziness, drug level increased (CARM case 62606)

June 2005 minute item 4.1.10.1

Issue

The Committee recommended that the data sheet for 5-fluorouracil should be updated to address the interaction with phenytoin.

Outcome

Medsafe was in the process of contacting sponsors regarding this issue.

Discussion

The Committee noted the above and agreed that Medsafe should report back to the MARC once a response had been received from the sponsors.

2.1.11 Flucloxacillin and renal failure acute, rash maculopapular, pruritus (CARM case 63623)

June 2005 minute item 4.2.1.1

Issue

The Committee recommended that CARM should review the post-mortem report for this case and report back to MARC.

Outcome

The post mortem report for this case was not yet available for discussion. CARM agreed to continue to follow up this issue.

Discussion

The Committee noted the above and agreed that CARM should report back to MARC once the post mortem report was available.

2.1.12 Miconazole, warfarin interaction and haematuria, prothrombin increased (CARM case 63753)

June 2005 minute item 4.2.3.2

Issue

The Committee recommended that there should be a short article published in Prescriber Update reminding prescribers of the interaction between miconazole and warfarin.

The Committee recommended that Medsafe should write to the DHBNZ Safe Use of Medicines Group, the New Zealand Dental Association and the Pharmaceutical Society of New Zealand asking them to remind members of the interaction between miconazole and warfarin.

Outcome

The Medsafe editorial team was drafting a reminder paragraph for Prescriber Update on this issue.

In August 2005 Medsafe contacted the DHBNZ Safety and Quality Use of Medicines Group, the New Zealand Dental Association, the Pharmaceutical Society of New Zealand and the Royal NZ College of General Practitioners asking them to disseminate a reminder of the interaction between miconazole oral gel and warfarin to their members. The groups were also referred to the 2003 Prescriber Update article, as well as the 'Warfarin Alert' and the 'Primary Care Guidelines for Anticoagulation using Warfarin', both of which could be found on the Quality Safe Use of Medicines website at: www.safeuseofmedicines.co.nz.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.13 Methotrexate, leflunomide (CARM cases 63532 and 64391)

June 2005 minute items 4.2.11.2 and 4.2.11.3

Issue

The Committee recommended that a brief Prescriber Update article should be written to update prescribers on the respiratory adverse effects of leflunomide.

The Committee recommended that CARM should investigate how best to initiate dialogue between respiratory physicians and rheumatologists on this issue.

Outcome

A Prescriber Update article was to be written.

At the NZRA meeting in early September it would be discussed how best to initiate dialogue between respiratory physicians and rheumatologists.

Discussion

The Committee was informed that at the NZRA meeting on 2-3 September 2005, the NZPhvC presented a case series on leflunomide pneumonitis, which had been recently accepted for publication. Feedback on this presentation indicated that most rheumatologists were aware of the potential for leflunomide to cause pneumonitis.

However, discussion with NZRA members and a respiratory physician suggested that it was possible that not all respiratory physicians were aware of this issue. It was considered that it would be valuable to communicate with respiratory physicians through the Thoracic Society.

Recommendation

The Committee recommended that the NZPhvC should write to the Thoracic Society asking them to remind members of the respiratory adverse effects of leflunomide.

2.1.14 Colchicine Dosage

June 2005 minute item 4.3.2

Issue

The Committee recommended that Medsafe should ask the sponsor for colchicine to review the dosage advice in the current data sheet.

The Committee recommended that the NZPhvC should liaise with the NZRA and communicate the Committee's position regarding colchicine dosage in the elderly.

Outcome

Medsafe's investigations revealed that the tender to supply colchicine to the NZ market had been awarded to Colgout (Anspec; 0.5mg colchicine). Colgout was currently under evaluation by Medsafe. Medsafe was informed that Abbott, the sponsor of Colchicine 0.6mg, intended to cease marketing this product once current supply was exhausted, which was expected to occur in December 2005 or January 2006.

The NZPhvC communicated the above information and the Committee's position regarding colchicine dosage to the NZRA in July 2005. The NZRA responded that:

Medsafe contacted Anspec and requested changes to the proposed data sheet for Colgout as follows:

Discussion

Medsafe informed the Committee that shortly before the MARC meeting Anspec had responded that the proposed data sheet for Colgout would be updated as requested. Medsafe was pursuing comparable data sheet changes for Colchicine (0.6mg colchicine; Abbott), despite the intention for this product to be discontinued, as it would be possible for the product to return to the NZ market within five years without the need for re-evaluation.

The Committee agreed that the restrictions on dosage in the elderly were satisfactory. They noted that the NZRA Consensus Statement dosage advice for colchicine appeared in the May 2005 issue of MIMS New Ethicals.

The Committee considered that a Prescriber Update article on colchicine that referenced the NZRA Consensus Statement (altered to reflect the change to a 0.5mg tablet) would be of value. However, it was agreed that this should not be published until the 0.5mg product was available on the NZ market.

Recommendation

The Committee recommended that Medsafe should explore the option of publishing a Prescriber Update article on colchicine, referencing the NZRA Consensus Statement (altered to reflect the change to a 0.5mg tablet), once the 0.5mg product was marketed in NZ.

2.1.15 Salamol Inhaler - Device Failure Issues

June 2005 minute item 4.3.3

References
  1. Tatley, MV. Reports to the NZPhvC of Problems Arising in Patients Transferring from Ventolin to Salamol Inhalers. 17 August 2005.
  2. PHARMAC media release. Two salbutamol brands to remain funded. 8 June 2005.
  3. Extract from Record of the Pharmacology and Therapeutics Advisory Committee (PTAC) meeting held on 19 May 2005. (See section 6 of dossier for full record.)
  4. Gillies J. et al. PHARMAC and Ventolin in New Zealand. NZ Med Journ. 12 August 2005. Vol 119; No. 1220. http://www.nzma.org.nz/journal/118-1220/1616/
  5. Metcalfe S et al. PHARMAC responds on salbutamol. NZ Med Journ. 26 August 2005. Vol. 118; No. 1221. http://www.nzma.org.nz/journal/118-1221/1644/
  6. Patient information
    • New Zealand Salamol box. November 2002.
    • New Zealand Salamol package insert. November 2002.
    • Air Flow Products Ltd. Salamol "Dear Pharmacist" letter. 22 April 2005.
    • Air Flow Products Ltd. Salamol "Dear Doctor" letter. 5 May 2005.
    • Air Flow Products Ltd. Salamol "Dear Asthma Educator" letter. 13 May 2005.
    • Air Flow Products Ltd. Salamol patient cleaning information leaflet. Distributed May 2005.
    • Isler, N. (Air Flow Products Ltd). Letter to D Fitzgerald re: revision of consumer information leaflet for Salamol.
    • Air Flow Products Ltd. Consumer information leaflet for Salamol.
  7. Air Flow Products Ltd. Paper for PTAC re: Salamol CFC-free inhaler. 19 May 2005.
Late papers
  1. Air Flow Products Ltd. Comments on Minute of the 122nd Medicines Adverse Reactions Committee (MARC) Meeting, 9 June 2005, Item 4.3.3 Salamol Inhaler Testing. Emailed to MARC members on 13 September 2005.
  2. IVAX Pharmaceuticals (UK) Ltd. Response to the Minutes of the 122nd Medicines Adverse Reactions Committee (MARC) Meeting, 9 June 2005. Tabled at the MARC meeting 15 September 2005.
Issue

The Committee recommended that Medsafe should identify the issues that occurred with the Salamol inhaler in the UK and how these issues were resolved, and report back to the MARC at the next meeting.

The Committee recommended that Medsafe should assess the results of the further tests of Salamol inhalers and report back to the MARC at the next meeting.

The Committee recommended that Medsafe should ask the product sponsor to update the information in the package insert of Salamol inhalers, in order to provide clear instructions about cleaning the inhaler device once weekly.

The Committee recommended that Medsafe should convey updated information to prescribers and pharmacists through a 'red Dear Health Professional' letter.

Outcome

Medsafe requested that the Minister's Delegate reject the fourth MARC recommendation that "Medsafe should convey updated information to prescribers and pharmacists through a 'red Dear Health Professional' letter" for the following reasons:

In the interim, Medsafe included the following brief note in the June 2005 issue of Prescriber Update:

"Salamol inhalers - clean once weekly There have been reports of Salamol (salbutamol) inhalers blocking. As a result, Medsafe is testing the devices. In the interim, please remind patients of the importance of cleaning the inhaler devices once every week. Instructions are enclosed with each inhaler."
UK issues

Medsafe reviewed the Air Flow Products paper for PTAC (19 May 2005) in which the issues that arose in the UK were addressed.

The Salamol CFC-free product was first approved for marketing in the UK in April 2000. There were 204 consumer complaints (131 complaints per million units distributed) in the first year of Salamol product launch in the UK. A review of these complaints revealed that the majority of cases were due to dose delivery failure caused by excessive drug deposition around the actuator stem block. Cleaning of the returned inhalers following normal instructions gave a properly functioning product in the majority of cases. Further study concluded that the instructions to clean the inhaler on a weekly basis were adequate if followed properly by the patient.

A number of steps were implemented by the sponsor to reduce the level of customer complaints received and increase the patient awareness required to ensure the product functioned correctly at all times:

In addition, the issue was addressed in the UK by a patient education campaign, in association with the National Asthma Campaign. As the product launch of CFC-free Salamol in the UK coincided with the introduction of other CFC-free formulations of aerosol inhalers, there was a general campaign of health professional and patient education at that time. The changes in the physical characteristics of the CFC-free inhalers (including the taste and feel when inhaling) and the need for weekly cleaning were emphasised.

Included for members' information were papers discussing the washing of Ventolin inhalers once weekly, and comparison testing of Ventolin and Salamol.

Further testing of Salamol inhalers

The results of the further testing of the Salamol inhalers, being undertaken by the TGA, were not available at the time of this meeting. They would be brought to the attention of the MARC in due course.

Patient information

In April and May 2005 Air Flow Products distributed Dear Health Professional letters to doctors, pharmacists and asthma educators via the asthma societies. These letters addressed the efficacy, cleaning, ethanol content and taste of Salamol inhalers. Additionally, a patient cleaning information leaflet was distributed to all of the above in May 2005. The consumer information leaflet was revised and distributed to all pharmacists in August 2005.

Discussion

The Committee noted that one recommendation made at the June 2005 MARC meeting had been rejected by the Minister's Delegate on the advice of Medsafe, and they supported that decision.

The Committee noted the references detailed above, including the late papers provided by email and tabled at the meeting. Medsafe had been informed that the market share for Salamol had continued to increase.

The Committee noted that in the UK there had been a prescriber and patient education campaign initiated in response to the change of all inhalers to CFC-free formulations in the year 2000. Shortly thereafter there was a peak of adverse reaction reports, which decreased over 3-6 months. The Committee noted a post-marketing study, conducted in the UK in 2000/2001, of 1009 general practice patients randomised to Salamol CFC-free or Salamol CFC9, which showed no significant difference in the rate of serious adverse events.

The Committee noted that Salamol inhaler testing undertaken by the sponsor showed that cleaning the inhaler as per the instructions in the patient information ensured the correct functioning of the inhaler in the majority of cases. Additionally, whether the Salamol inhaler was cleaned or not, the dose delivery did not significantly decrease over time. Furthermore, testing had shown that, even if the inhaler was not cleaned as instructed, it was likely to continue to function correctly. Members commented, however, that in real-world situations Salamol inhalers were known to clog.

Members reiterated their previous opinion that this issue was predominantly one of insufficient patient education. They considered that it was vital to provide adequate information to patients prior to a change of Sole Subsidised Supply by PHARMAC, and subsequently at the point of dispensing. They considered that, in the case of Salamol, the flow of information from the sponsor to prescribers and pharmacists and on to patients had not been timely, and may have contributed to heightened patient concern. The Committee considered that Medsafe should explore options for improving these processes in the future.

Members commented that the instructions around drying the device after washing were unclear. Additionally, they expressed concern that the patient instructions advocated test-firing the inhaler prior to use if there was doubt about it's function, which was contrary to the general advice disseminated by Bpac and would increase wastage.

The Committee noted that, contrary to the minutes of the 122nd MARC meeting, the data sheet for Ventolin CFC-free inhaler contained instructions on cleaning the inhaler once weekly.

The Committee concluded that the prescriber and patient information disseminated by the Salamol sponsor was satisfactory, and no further distribution of information was required at that time.

Recommendation

The Committee recommended that Medsafe should explore options with relevant stakeholders in order to improve the management of future brand-switch issues arising from brand changes to Sole Subsidised Supply medicines.

2.1.16 Analysis of IMMP Events Reported for Risperidone

June 2005 minute item 4.4.2

Issue

The Committee recommended that the data sheet for risperidone should be updated to include reference to the adverse reactions of seizures, epistaxis, nocturnal enuresis and dysphagia.

Outcome

As there was an IMMP study underway to investigate the potential for risperidone to cause nocturnal enuresis, Medsafe considered that it would be prudent to wait for these results before asking the sponsor to update the data sheet on this issue. Therefore, Medsafe requested that the Minister's Delegate reject the MARC recommendation above, and instead accept the following recommendation:

'That the data sheet for risperidone should be updated to include reference to the adverse reactions of seizures, epistaxis, and dysphagia.'

Medsafe had contacted Janssen-Cilag in July 2005 requesting that the data sheet be updated as detailed above. Janssen-Cilag had not yet responded to the request.

Discussion

The Committee noted the above, supported the revised recommendation and agreed that Medsafe should report back to the MARC once a response had been received from the sponsor.

2.1.17 Joint Trans-Tasman Therapeutic Products Agency (JTA)

June 2005 minute item 9.1

Issue

The Committee recommended that Medsafe should disseminate the dates of future Australian Adverse Drug Reactions Advisory Committee (ADRAC) meetings to MARC members.

The Committee recommended that Medsafe should invite members of the Australian Adverse Drug Reactions Advisory Committee (ADRAC) to attend future meetings of the MARC.

Outcome

The dates for future ADRAC meetings were provided to MARC members. Members of ADRAC and the ADRAC secretariat were invited to attend future MARC meetings.

Medsafe invited members of the MARC to express their interest in participating in the joint Australia/NZ medicines adverse reactions advisory committee.

Discussion

Medsafe explained to the Committee that the joint Australia/NZ medicines adverse reactions advisory committee would replace MARC and ADRAC, and be charged with risk:benefit assessments and analysis of adverse reaction reports. It would be likely to have 12 Ministerially appointed members with expertise in a variety of fields. Members of the joint committee would not be representing any organisation but would be selected for their expertise. A limited number of positions would be linked to NZ- or Australian-specific expertise. Joint committee members would be remunerated in accordance with a scale to be developed and agreed by the Ministerial Council.

Medsafe explained that it was anticipated that the joint committee would meet six times a year, twice in NZ and four times in Australia on a rotating basis. It was likely that the joint committee would meet prior to the establishment of the JTA to discuss procedural matters.

Each member of the MARC expressed to Medsafe his or her interest in participating in the joint Australia/NZ medicines adverse reactions advisory committee.

2.2 Report on Actions Arising from Previous Meetings of the MARC

2.2.1 COX-2 Inhibitors and Cardiovascular Safety

June 2005 minute item 2.1.1; March 2005 minute items 3.1.8.1,2,4,5 and 6

Issue

In March 2005 the Committee recommended that the data sheets and consumer medicine information (CMIs) for celecoxib, etoricoxib, lumiracoxib, parecoxib and meloxicam should be updated (see the minutes of the 121st MARC meeting for details).

Outcome

Following negotiation with the COX-2 inhibitor product sponsors, the required data sheet changes were in the process of being finalised at the time of this meeting. The majority of the required warning statements, or words of the same intent, had been accepted by the sponsors. However, as a result of the negotiations, Medsafe accepted variations to some of the required warning statements, as detailed below:

Statement 1

Medsafe's original request was to add the following to the Indications section of the data sheet: "[Product name] should not be used unless alternative therapies have been used and found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient."

Following negotiation an alternative statement was considered by Medsafe to be acceptable: "The decision to prescribe a selective COX-2 inhibitor should only be made:

Statement 2

Medsafe's original request was to add the following to the Indications section of the data sheet: "[Product name] should be used primarily for the short-term treatment of acute conditions (up to one week). In patients for whom longer-term use may be required, treatment efficacy should be reviewed after two weeks and [product name] withdrawn if there is a lack of therapeutic benefit. Patients on long-term treatment should be reviewed every three months with regards to risk factors and the ongoing need for treatment."

Following negotiation an alternative statement was considered by Medsafe to be acceptable: "As the cardiovascular risks of the selective COX-2 inhibitors may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. Patients on long-term treatment should be reviewed regularly, such as every three months, with regards to efficacy, risk factors and ongoing need for treatment."

Statement 6

Medsafe's original request was to add the following to the Contraindications section of the data sheet:
"Use in patients at high risk of cardiovascular disease who are undergoing major surgery"

Following negotiation an addition to the Warnings and Precautions section was accepted: "Two large, controlled clinical trials of a different COX-2 selective inhibitor for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. In the absence of comparable data with [product name], it may be assumed that patients at high risk of cardiovascular disease (including patients with diabetes, ischaemic heart disease, cardiac failure, hyperlipidaemia, hypertension, or smokers) who are undergoing any major surgery may face an increased risk of developing a cardiovascular event. Patients with significant risk factors for cardiovascular events should only be treated with [product name] after careful consideration of the patient's overall risk and the potential risks and benefits of alternative analgesic therapies."

Discussion

The Committee reviewed the variations on the data sheet statements negotiated between Medsafe and the sponsors of the COX-2 inhibitors, as detailed above. Members were informed that prior to finalising the negotiations, Medsafe had discussed the alternative statements with the Chair. The Chair commented to the other members that, having heard the explanations behind the changes, he believed them to be practical and appropriate.

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.2 General Recommendations Regarding the Cardiovascular Safety of the COX-2 Inhibitors - IMMP studies.

June 2005 minute item 2.1.5; March 2005 minute item 3.1.8.8, dot point three.

Issue

In June 2005 the Committee recommended that the Joint Trans-Tasman Therapeutic Products Agency (JTA) legislation should include provision that product sponsors be required to conduct post-marketing studies.

Outcome

Medsafe had notified the project team working on developing the structure of pharmacovigilance services in the JTA of the Committee's recommendation. Although this provision would not be included in the JTA Bill, it would be possible through the Ministerial Council Rules to impose conditions on product licence holders.

Discussion

See minute 1.2.1 for discussion on this issue. The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.3 Atypical Antipsychotics and Lipid Abnormalities.

June 2005 minute item 2.2.2; December 2004 minute item 2.1.4; September 2004 minute item 2.2.2; December 2003 minute item 3.1

Reference
  1. Newcomer JW. Second-Generation (Atypical) Antipsychotics and Metabolic Effects - A Comprehensive Literature Review. CNS Drugs 2005; 19 Suppl. 1: 1-93. (Extract - pages 54-65).
Issue

In June 2005 the Committee recommended that Medsafe should complete their review of lipid abnormalities associated with risperidone, including review of the CNS Drugs supplement, and report back to the Committee at the September 2005 meeting.

Outcome

After reviewing the data supplied by Janssen-Cilag, as well as other available literature including the CNS Drugs supplement mentioned at the June 2005 MARC meeting, Medsafe concluded that the current evidence did not conclusively support an association between risperidone use and the development of hyperlipidaemia. Therefore, Medsafe elected not to request that Janssen-Cilag include lipid abnormalities in the Adverse Effects section of the risperidone data sheet at that time.

However, Medsafe informed the Committee that it would continue to monitor the literature on this issue and report back if further information became available.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.4 Pergolide and Cardiac Valvulopathy.

June 2005 minute item 2.2.6; December 2004 minute item 3.3

Reference
  1. Extract from Record of the Pharmacology and Therapeutics Advisory Committee (PTAC) meeting held on 19 May 2005. (See section 6 of dossier for full record.) Safety of antiparkinson agents (pergolide, tolcapone).
Issue

In December 2004 the Committee recommended that a Prescriber Update article should be written on pergolide and cardiac valvulopathy. The article should indicate that pergolide should not be used for the treatment of restless leg syndrome.

In June 2005 the Committee recommended that Medsafe should write to PHARMAC again with a brief reminder of the previous request, and asking to be kept informed of any review of funding for a non-ergot derivative dopamine agonist.

Outcome

Since MARC had made the recommendation for a Prescriber Update article to be written, the sponsor (Eli Lilly) had distributed a further and more extensive 'Dear Doctor' letter in January 2005 about Permax (pergolide) and cardiac valvulopathy, as well as pulmonary fibrosis. In February 2005, the Permax data sheet was updated to indicate that pergolide should only be used for second-line treatment in patients who were intolerant or non-responsive to non-ergot compounds. Therefore, Medsafe proposed that the MARC recommendation for a Prescriber Update article about pergolide and cardiac valvulopathy be rescinded, as Medsafe had no further information for prescribers other than that already provided by the 'Dear Doctor' letter and revised data sheet.

Medsafe had received a response from PHARMAC in early August 2005. Medsafe was informed that PHARMAC was actively considering listing a non-ergot dopamine agonist for the treatment of Parkinson's disease and would keep Medsafe and the MARC informed as progress was made in this regard.

Discussion

See minute item 1.5.2 for discussion and recommendations regarding the proposed Prescriber Update article.

2.2.5 Domperidone and the Risk of QT Prolongation.

June 2005 minute item 2.2.7; December 2004 minute item 3.4

Issue

In June 2005 the Committee recommended that Medsafe should write to Janssen-Cilag again, to request that the New Zealand data sheet for domperidone be updated to adequately inform prescribers of the risk of QT prolongation and/or sudden cardiac death with oral domperidone.

In June 2005 the Committee recommended that Medsafe should inform the Medicines Classification Committee (MCC) that the MARC did not support the reclassification of oral domperidone to over-the-counter (OTC) status.

In December 2004 the Committee recommended that the product sponsor be asked to supply Medsafe with evidence of the cardiovascular safety of domperidone when it is administered with other CYP3A4 inhibitors such as erythromycin. Alternatively the product sponsor should be asked to include the following statement included in the domperidone data sheet:
"Domperidone should not be prescribed in combination with CYP3A4 inhibitors such as erythromycin"

Outcome

In July 2005, Medsafe informed Janssen-Cilag that the MARC did not accept the company's assertion that there was no evidence that oral domperidone use was associated with an increased risk of QTc prolongation and/or sudden death. Janssen-Cilag were asked to include the following information in the Warnings and Precautions section of the domperidone data sheet:

"Cases of QTc prolongation, arrhythmia and sudden death have occurred with domperidone use. Although most reported cases have occurred in patients receiving the intravenous form of domperidone, an association with oral domperidone cannot be ruled out. Therefore, domperidone should be used with caution in patients with other risk factors for QTc prolongation including hypokalaemia, severe hypomagnesaemia, structural heart disease, the concomitant administration of other QTc prolonging medicines or an underlying genetic predisposition."

Janssen-Cilag was also informed that the MARC was prepared to await the results of the proposed healthy volunteer study evaluating a potential interaction between erythromycin and domperidone before requiring further changes to the data sheet regarding interactions with CYP3A4 inhibitors other than ketoconazole and itraconazole.

Medsafe was awaiting a response from Janssen-Cilag on this issue.

In addition, Medsafe informed the MCC that the MARC did not support the reclassification of domperidone to OTC status until this important safety issue had been resolved.

Discussion

The Committee noted the above and agreed that Medsafe should report back to the MARC once a response had been received from the sponsor.

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

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

Medsafe had contacted the Safe Use of Medicines Group in July 2005, indicating that the MARC had elected to await the development of the group's LMWH protocol before requiring changes to the New Zealand LMWH data sheets with respect to anti-Xa monitoring in patients with severe renal impairment. The sponsors of all LMWHs in New Zealand were also informed of this.

Medsafe asked to be kept informed of any progress that was made on developing this protocol.

Discussion

The Committee noted the above and agreed that this issue should be reviewed again once a response had been received from the Safe Use of Medicines Group.

2.2.7 Alendronate and synovitis, carpal tunnel syndrome, ankle oedema and arthralgia (CARM case 62186)

December 2004 minute item 4.1.7.2

Issue

In December 2004 the Committee recommended that Medsafe review the literature to see if there were sufficient data to support publishing a Prescriber Update article on the pro-inflammatory adverse effects associated with alendronate use.

Outcome

Medsafe considered there was insufficient literature available to support publishing an article at that time. Medsafe recommended that the NZPhvC continue to review adverse reaction reports received regarding alendronate, and reconsider publishing an article at a later date.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

3. pharmacovigilance issues

3.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk

References
  1. FDA Public Health Advisory: FDA Announces Important Changes and Additional Warnings for COX-2 Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). http://www.fda.gov/cder/drug/advisory/COX2.htm
  2. Health Canada. Report of the Expert Advisory Panel on the Safety of Cox-2 Selective Non-steroidal Anti-Inflammatory Drugs (NSAIDs). 6 July 2005. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/sci-consult/cox2/sap_report_gcs_rapport_cox2_e.html
  3. MHRA. Cardiovascular safety of the NSAIDs- review of the evidence. 2 August 2005. http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con1004303.pdf
  4. EMEA press release. August 2005 http://www.emea.eu.int/pdfs/human/press/pr/24732305en.pdf
  5. Hippisley-Cox J and Coupland C. Risk of myocardial infarction in patients taking cyclooxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005 Jun 11; 330(7504): 1366.
  6. Fischer LM et al. Current use of non-steroidal anti-inflammatory drugs and the risk of acute myocardial infarction. Pharmacotherapy 2005 April; 25 (4): 503-510.
  7. Johnsen SP et al. Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib and other NSAIDs: a population-based case-control study. Arch Intern Med 2005 May 9; 165 (9): 978-984.
Issue

In April 2005, at the completion of the FDA's review of COX-2 inhibitor cardiovascular safety, they announced that, despite the absence of long-term clinical trial data for most of the non-selective NSAIDs, there was sufficient evidence to suggest that use of non-selective NSAIDs might also increase cardiovascular risk. The FDA announced that it would require the product information for all NSAIDs to include the following information:

International regulatory activity

In response to the FDA's announcement, a number of international regulators declared their intention to review the cardiovascular safety of the non-specific NSAIDs.

Health Canada

On 7 April 2005, Health Canada announced that its expert advisory committee had concluded that all NSAIDs (other than naproxen) were associated with an increased risk of clinically important cardiovascular events compared to placebo, but the absolute risk likely increased with longer-term use and in the presence of risk factors for, or a history of, cardiovascular disease. The expert advisory committee recommended that the product labels for all NSAIDs be updated to include information on the cardiovascular risks associated with the use of their products.

UK MHRA

On 2 August 2005, the MHRA announced that its Committee on Safety of Medicines (CSM) had made the following conclusions:

European EMEA

On 2 August 2005 the EMEA announced that after reviewing the available evidence regarding the thrombotic risk associated with the non-selective NSAIDs it did not consider that any changes were required to the product information or consumer information for these medicines.

Australian TGA

In April 2005, the TGA requested that the sponsors of all non-specific NSAIDs available in Australia (36 sponsors) provide the following data to the TGA:

It was likely that this review would not be completed until 2006.

Recently published literature
  1. Hippisley-Cox J and Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005 Jun 11; 330(7504): 1366.

    A nested case-control study was conducted using the UK QRESEARCH database. 9,218 cases (patients who had presented with their first myocardial infarction (MI) between 2000 and 2004) and 86,349 controls matched for age, sex, calendar time and GP practice were selected. All prescriptions for NSAIDs were identified in the 3 years prior to the development of MI and were classified as not prescribed within previous 3 years, prescribed more than 90 days ago or prescribed within the previous 90 days.

    Odds ratios were calculated and logistic regression was used to adjust for potential confounding factors. Cases were noted to have more baseline risk factors for cardiovascular disease than controls.

    Results:

    After adjustment for potential confounders there was a statistically significant increase in the odds ratio for developing an MI in current users of rofecoxib (1.32, 95% CI 1.09-1.61), ibuprofen (1.24, 95% CI 1.11-1.39), diclofenac (1.55, 95% CI 1.39-1.72) and naproxen (1.27, 95% CI 1.01-1.60) compared to non-users but not for celecoxib. There was a statistically significant increase in the odds ratio for developing an MI in patients whose last script for diclofenac was more than 3 months previously (1.13, 95% CI 1.05-1.21) compared to non-users.

    Discussion:

    In view of the observational nature of this study, it was likely to be subject to significant bias and confounding. Misclassification of NSAID use and/or the misdiagnosis of a first MI were possible. As no information was collected on indication for use, confounding by indication was possible. Patients might have been prescribed NSAIDs for the treatment of musculoskeletal pain that was actually of cardiovascular origin. In addition, although the study adjusted for a diagnosis of rheumatoid arthritis, other inflammatory conditions that might have increased the risk of MI were not identified or adjusted for. Patients receiving NSAIDs might also have had lower levels of physical activity that might have increased their risk of developing an MI.

    As cases were more likely to have had risk factors for cardiovascular disease than controls, residual confounding due to an inability to fully control for confounding variables in the analyses was possible. This was particularly likely for smoking, as smoking could not be adjusted for as a continuous variable which would be much more accurate.

    Conclusion:

    Although this was a well-designed nested case-control study, the presence of significant bias and confounding meant that a causal relationship between NSAID use and MI risk could not be inferred from this study.

  2. Fischer LM et al. Current use of nonsteroidal anti-inflammatory drugs and the risk of acute myocardial infarction. Pharmacotherapy 2005 April; 25 (4): 503-510.

    A nested case-control study was conducted using the UK GPRD database. 8,688 cases (first-time acute myocardial infarction between January 1995 and April 2001) and four controls were selected for each case (total of 33,923) and matched for age, sex, general practice attended, number of years of history in the database and calendar time.

    Data were collected on exposure to any NSAID (but not COX-2 inhibitors) and patients were classified as "non-users" (no previous history of NSAID use), or "current users" (most recent NSAID prescription not due to run until after the index date).

    Odds ratios were calculated for the development of a first MI in current users of NSAIDs compared to non-users. Logistic regression was used to adjust for potential confounding factors. Cases were more likely than controls to have had other risk factors for cardiovascular disease.

    Results:

    After adjustment for the potential confounding factors, there was a non-statistically significant increase in the odds ratio for developing a first MI in current users of NSAIDs compared to non-users of NSAIDs (OR 1.07, 95% CI 0.96-1.19). There was a non-statistically significant increase in the risk of MI in current users of diclofenac (OR 1.23, 95% CI 1.00-1.51), and in current users of ibuprofen (OR 1.16, 95% CI 0.92, 1.46).

    There was a non-statistically significant reduction in the risk of MI in users of naproxen (OR 0.96, 95% CI 0.66-1.38). There was a statistically significant increase in the risk of MI in patients who had discontinued NSAIDs 1-29 days previously (OR 1.52, 95% CI 1.33-1.74) and 30-59 days previously (OR 1.44, 95% CI 1.21-1.70).

    Discussion:

    This study did not find a statistically significant increase in the risk of MI in current users of NSAIDs. The authors asserted that, as discontinuation of NSAID therapy was associated with an increased risk of MI, this might indicate that NSAID use might counteract the increased risk of MI caused by chronic inflammation.

    This study was subject to many of the biases and confounding factors associated with the study above. The authors did attempt to control for some confounding by indication by adjusting for a diagnosis of systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) in their analyses. The inability to account for over-the-counter (OTC) NSAID use might have biased this study towards the null hypothesis and hence have hidden a true difference in risk. A weakness of this study was the inability to control for smoking history as a continuous variable.

    Conclusion:

    Although this study did not show an increased risk of MI in current users of NSAIDs, the presence of significant bias and confounding limited the ability to draw firm conclusions from these results.

  3. Johnsen SP et al. Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study. Arch Intern Med 2005 May 9;165 (9): 978-984.

    A case-control study was conducted using hospital discharge registries in three Danish counties. 10,280 cases (first MI between 1 January 2000 and 31 December 2003) and 102,797 sex and age matched community controls were selected. Data on prescription of all non-aspirin NSAIDs were collected from prescription databases. Individuals were classified as new users (patients who had filled their first prescription within the previous 0-30 days), current users (patients who had filled a prescription within the last 30 days), recent users (patients who had filled a prescription within 31-90 days), former users (prescription >90 days prior to MI) or non-users (no previous prescriptions). Information on confounding factors was obtained from discharge and prescription registries.

    Odds ratios were calculated for the risk of hospitalisation for a first MI in new users, current users, recent users and former users of rofecoxib, celecoxib, naproxen, other COX-2 selective inhibitors and other non-aspirin NSAIDs compared to non-users of NSAIDs. Conditional logistic regression was used to adjust for potential confounding factors.

    Results:

    After adjustment for confounding factors there was a statistically significant increase in the odds ratio for developing a first MI in new users of rofecoxib (OR 2.52, 95% CI 1.74-3.64), celecoxib (2.13, 95% CI 1.45-3.13), other COX-2 selective inhibitors (3.37, 95% CI 2.05-5.53), and users of other non-aspirin NSAIDs (2.65, 95% CI 2.00-3.50) but not naproxen (1.65, 95% CI 0.57-4.83).

    There was also a statistically significant increase in the odds ratio for developing a first MI in current users of rofecoxib (1.80, 95% CI 1.47-2.21), other COX-2 inhibitors (1.45, 95% CI 1.09-1.93) but not celecoxib (1.25, 95% CI 0.97-1.62), and also in users of non-aspirin NSAIDs other than ibuprofen, naproxen and diclofenac (1.68, 95% CI 1.52-1.85).

    Discussion:

    This study found that there was an increased risk of MI in new and current users of all NSAIDs except for naproxen. However, this study was subject to similar biases and confounding as the other studies discussed above. In particular, confounding by indication could explain the results if patients had been prescribed NSAIDs for the treatment of musculoskeletal pain that was actually of cardiovascular origin. In addition, there was likely to be significant unidentified confounding in this study due to the absence of data on known risk factors for MI such as smoking and obesity.

    Conclusion:

    As this study was unable to account for many important confounding variables, it had limited internal and external validity. Thus, it was not possible to infer a causal association between NSAID use and the development of MI from the results of this study.

WHO reports (prepared by NZPhvC)

Proportional Reporting of Myocardial Infarction with selected standard NSAIDs in the WHO International Drug Monitoring Database (Vigibase).

NSAID/COX-2 inhibitor Years monitored Total reports Myocardial infarction
No. reports
Myocardial infarction
% total reports
Diclofenac 1976-2004 25412 51 0.20
Ibuprofen 1969-2004 24742 41 0.17
Naproxen 1974-2004 20931 39 0.19
Piroxicam 1981-2004 15877 29 0.18
Celecoxib 1999-2004 20307 190 0.94
Rofecoxib 1999-2004 15877 560 2.40


There was a small increase in reporting of MI for diclofenac, ibuprofen and naproxen in late 2004 and 2005. This increase was more marked for celecoxib and much more so for rofecoxib so that the disparity in proportions between celecoxib and rofecoxib was increasing.

Summary and recommendations

At the time of this report there was a paucity of long-term controlled studies evaluating the cardiovascular safety of the non-selective NSAIDs. Recent published observational studies had been subject to considerable bias and confounding thus limiting the applicability of their results. In addition, the results from different observational studies had been inconsistent. International regulators had differed in their interpretation of the available data and proposed risk-management strategies. The US FDA and Health Canada had required that the same cardiovascular warning statements be added to all NSAID data sheets. However, the European EMEA and UK MHRA had determined that the available data did not support making changes to NSAID prescribing information.

Medsafe considered that, as the available evidence was insufficient to allow an accurate assessment of the relative cardiovascular safety of the non-specific NSAIDs compared to the COX-2 inhibitors, no regulatory action should be undertaken at that time. Medsafe would continue to monitor the literature and liaise with international regulators on this issue and would report back to the MARC as new information became available.

Discussion

The Committee reviewed the studies discussed above and noted that database studies required a very high level of skill and experience to conduct.

The Committee noted that the results of the Hippisley-Cox et al study5 were likely to have been affected by both residual and unidentified confounding. In every case the odds ratios for use of NSAIDs within the previous three years moved closer to one after adjustment for confounding, which indicated that residual confounding was likely. The Committee had concerns about the quality and interpretation of the data in this paper.

Members noted that highly experienced and well-respected researchers conducted the Fischer et al study6, and thus its results could be interpreted with relative confidence. It was noted that, although it showed no association between NSAID use and increased cardiovascular risk, this study was still subject to considerable potential confounding and bias that may have affected the results.

The Committee considered that the Johnsen et al study7 was weaker than the other studies due to the lack of information on significant potential confounders such as smoking. It was noted that, as with the Hippisley-Cox et al study, the odds ratios moved closer to one after adjustment for confounding.

The Committee discussed the difficulties associated with observational and particularly retrospective studies in obtaining accurate and complete patient histories.

The Committee noted that the evidence suggested that naproxen might be associated with a different cardiovascular risk to the other NSAIDs.

The Committee discussed the evidence that chronic inflammatory conditions such as rheumatoid arthritis or systemic lupus erythematosus (SLE) could increase a patient's risk of cardiovascular adverse events. It was considered that the Fischer et al study provided some evidence that NSAID use may in fact mitigate some of the increased cardiovascular risk associated with chronic inflammatory conditions.

The Committee concluded that the available evidence did not justify further regulatory action at that time. However, they agreed that recent studies had raised a "red flag", and that Medsafe and the MARC should continue to monitor and review all new information on this issue as it became available.

Recommendations

The Committee recommended that Medsafe should continue to monitor the literature and liaise with international regulators regarding the potential for non-specific NSAIDs to increase the risk of cardiovascular adverse events. Medsafe should report back to the MARC on this issue, should new information become available.

The Committee recommended that Medsafe and the MARC should review the Australian evaluation of the non-specific NSAIDs when it became available.

3.2 Bisphosphonates and Osteonecrosis of the Jaw

References
  1. Marx R. Pamidronate (Aredia) and zolendronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 2003; 61:1115-1118
  2. Ruggiero S et al. Osteonecrosis of the Jaws Associated With the Use of Bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 2004; 62:527-534
  3. Bagan J et al. Avascular jaw osteonecrosis in association with cancer chemotherapy: series of 10 cases. J Oral Pathol Med 2005; 34:120-123
  4. Expert Panel Recommendations for the Prevention, Diagnosis and Treatment of Osteonecrosis of the Jaws: June 2004
  5. Purcell P and Boyd I. Bisphosphonates and osteonecrosis of the jaw. MJA 2005; 182(8): 417-418. http://www.mja.com.au/public/issues/182_08_180405/pur10144_fm.pdf
  6. Novartis Patient Information leaflet. Dental Health. Taking Care of Yourself while Living With Cancer. May 2005
  7. Novartis Dear Doctor letter. June 8th 2005
  8. Carter G et al. Bisphosphonates and avascular necrosis of the jaw: a possible association. MJA 2005; 182 (8): 413-414.
  9. Hellstein J et al. Bisphosphonate Osteochemonecrosis (Bis-Phossy Jaw): Is This Phossy Jaw of the 21st Century? J Oral Maxillofac Surg 2005;63: 682-9.
Issue

Osteonecrosis of the jaw (ONJ) is a rare condition characterised by necrosis and sequestration of bone in the maxilla and/or mandible.

In most reported cases, ONJ is known to occur following tooth extraction and presents as a non-healing tooth extraction site. Other signs and symptoms include tooth and/or jaw pain, soft tissue swelling and infection, purulent discharge, loose teeth, visible areas of exposed bone (commonly at the site of previous tooth extractions), numbness or heaviness in the jaw.

Although the cause of ONJ is unknown, a number of risk factors have been identified including dental extractions, infections and/or trauma, blood dyscrasias, an underlying malignancy and cancer treatment regimens including chemotherapy, corticosteroids and radiotherapy. A possible association with intravenous bisphosphonate therapy was first suggested in 2003. At the time of this report there had been more than 100 case reports published worldwide of ONJ occurring in patients receiving bisphosphonate therapy, including the occasional report with oral bisphosphonate therapy.

Although the mechanism by which bisphosphonates may increase the risk of ONJ is unknown, it has been suggested that bisphosphonate mediated osteoclast inhibition may prevent the normal remodelling of bone required after an insult such as tooth extraction or tooth abscess, thus causing necrosis of the bone. It has also been suggested that the jaws are vulnerable to insults that cause an increase in bone turnover because they are directly exposed to the external environment via the teeth, and also because the mucosa of the jaw is very thin thus increasing the risk of exposure of the bone to the external environment1.

It is possible that not all bisphosphonates are associated with the same risk of ONJ. Pamidronate and zoledronic acid, potent nitrogen containing bisphosphonates, are not metabolised by the body. The likelihood of ongoing effects is increased, as they can remain in the bone for more than 10 years1. Although alendronate is also a nitrogen containing bisphosphonate, it is a less potent oral formulation and hence may be associated with a lower risk of developing ONJ. Bisphosphonates such as etidronate and risedronate are rapidly metabolised and therefore, as they are not retained in the body, may also be associated with a lower risk.

New Zealand Regulatory Action

In February 2005, the product sponsors for all bisphosphonates available in New Zealand were asked to update their data sheets to include information on the risk of ONJ. In March 2005, Mayne Pharma (as the sponsors for Pamisol, the only funded intravenous bisphosphonate in New Zealand) distributed a "Dear Doctor" letter to inform New Zealand prescribers, including dentists, of the risk of ONJ with bisphosphonate use.

In June 2005, Novartis distributed a "Dear Doctor" letter to New Zealand prescribers who had been using their non-funded intravenous bisphosphonates. A patient information leaflet and a report from an expert advisory committee convened by Novartis earlier in 2005 accompanied Novartis' letter. Novartis highlighted the following advice of its expert advisory committee regarding how best to manage the risk of ONJ associated with bisphosphonate treatment4:

In August 2005, Medsafe was informed that oral medicine specialists in Christchurch had seen four recent cases of ONJ in patients receiving bisphosphonate therapy and were in the process of writing an article on ONJ for publication in the New Zealand Dental Association publication.

New Zealand bisphosphonate data sheets:

The data sheets for the intravenous bisphosphonates Pamisol (pamidronate), Aredia (pamidronate) and Zometa (zoledronic acid) had been updated to include detailed information on the risk of ONJ with bisphosphonate therapy. The data sheets for the oral bisphosphonates Etidrate (etidronate) and Fosamax (alendronate) had been updated to include ONJ as a rare adverse reaction of bisphosphonate therapy.

New Zealand reports of osteonecrosis of the jaw

The NZPhvC had received three reports of ONJ associated with bisphosphonate use (see minute items 4.1.7.1, 2 and 3).

International regulatory action

US FDA

Novartis issued a "Dear Health Professional" letter to US prescribers on 24 September 2004 to inform them of spontaneous reports of osteonecrosis of the jaw that occurred mainly in cancer patients, who received bisphosphonates as a component of their therapy.

Health Canada

A "Dear Healthcare Professional" letter was distributed in Canada on 5 November 2004 in line with that distributed in the US.

Australia

The TGA disseminated information on ONJ to prescribers via a Bulletin article in February 2005, informing Australian prescribers that ADRU had received 9 reports of osteonecrosis of the jaw with bisphosphonate therapy. Prescribers were advised to have a dental review conducted in patients prior to starting intravenous bisphosphonate therapy. In April 2005, an article was published in the Medical Journal of Australia detailing 13 cases of ONJ with bisphosphonates that had been reported to ADRU.

Summary

There was evidence from case reports and case series that the use of bisphosphonates might increase the risk developing ONJ. The available evidence suggested that this risk was greatest in patients with an underlying malignancy receiving intravenous bisphosphonates as part of their treatment regimen, although there had also been reports in patients receiving oral bisphosphonates for the treatment of osteoporosis.

Although the mechanism by which bisphosphonates caused ONJ is unclear, it appears that the nitrogen containing bisphosphonates pamidronate and zoledronic acid might be associated with the greatest risk due to their persistence in bone for up to 10 years. It appears that the jaw is most vulnerable to osteonecrosis due to its constant exposure to the external environment and the need for continuous bone remodelling. ONJ can be very difficult to treat and tooth extraction or debridement may exacerbate the problem. Prevention of ONJ and the use of non-invasive treatments if the condition develops are very important.

Medsafe supported the advice issued by the expert advisory committee convened by Novartis on how to prevent and/or manage cases of ONJ that occur in patients receiving bisphosphonate therapy.

Discussion

The Committee noted the available evidence for the association between bisphosphonates and ONJ, as detailed above.

The Committee commented that the potential association between bisphosphonates and ONJ had only recently been well described and many prescribers would not be aware of the association. Members agreed that although ONJ had been reported more commonly with the intravenous bisphosphonates there had also been reports with the oral bisphosphonates.

Members noted that the use of oral bisphosphonates appeared to be increasing in New Zealand due to relaxation of PHARMAC prescribing restrictions. Bisphosphonates were increasingly becoming the treatment of choice for osteoporosis, and they were increasingly being prescribed for bone prophylaxis during long-term steroid use.

The Committee considered that Medsafe's regulatory action on this issue had been appropriate. However, the Committee agreed that due to the serious nature of this adverse reaction it was important that all prescribers, including GPs, were made aware of the potential for ONJ to occur with bisphosphonate therapy.

Recommendations

The Committee recommended that a Prescriber Update article be written to inform prescribers of the potential for ONJ to occur with bisphosphonate therapy and to reiterate management advice.

The Committee recommended that the Pamisol data sheet should be updated in line with the Aredia and Zometa data sheets. Novartis and Mayne Pharma should highlight osteonecrosis of the jaw as a heading in the Warnings and Precautions sections of their data sheets.

The Committee recommended that Medsafe should continue to monitor the literature on this issue particularly with respect to the occurrence of ONJ with the oral bisphosphonates.

The Committee recommended that the NZPhvC should monitor reports of ONJ with bisphosphonates and report back to Medsafe and the MARC in six months, or earlier if required.

3.3 Review of Adverse Reactions of Current Concern

References
  1. Extract from the CARM Quarterly Report as at 30 June 2005, pages 13-15. Adverse Reactions of Current Concern - Summary to 30 June 2005.
Issue

The MARC first initiated the list of Adverse Reactions of Current Concern (ARCC) in December 1994, as a means of bringing particular medicine adverse reactions to the attention of prescribers and to evoke reports so more information could be gathered, and further action taken if necessary.

Each Prescriber Update edition contains a listing of the ARCC along with information on what and how to report. The Medsafe website also contains this information, as well as historical information about additions to, and removals from the listing.

The MARC undertook the most recent review of ARCC in March 2004. At that time it was recommended that six ARCCs should be removed from the list, due to a good level of prescriber awareness having been achieved. It was decided that complementary medicines and SSRIs should remain on the list, and all adverse reactions to leflunomide were added at the same meeting.

Current ARCCs
Medicine Adverse reactions Date of addition to list
Complementary and alternative medicines* (previously listed as Herbal medicines) all adverse reactions October 1996
Leflunomide (Arava®) all adverse reactions April 2004
Selective Serotonin Reuptake Inhibitors (SSRIs) severe agitation, severe restlessness/akathisia, and/or increased suicidality October 2002

* Includes herbal medicines, bee products, homoeopathic products, dietary supplements, minerals and any other medicines containing animal or plant extracts.

Australian situation

The Australian equivalent of ARCC was 'Drugs of Current Interest' (DOCI). At the time of this report there were nine medicines on the DOCI list. Prescribers were encouraged to report all adverse reactions to the medicines on the DOCI list.

Not all new medicines were put on the DOCI list. The Adverse Drug Reactions Advisory Committee (ADRAC) made recommendations for particular medicines to be added to the list, and occasionally the Australian Drug Evaluation Committee (ADEC) also made a suggestion. The requirements for inclusion were similar to those for the IMMP, for example:

Medicines usually stayed on the list for 2 years, but if usage was low and/or there were outstanding safety concerns they might stay on the list longer. For example, sibutramine was on the list for at least 3 years. Additionally, pioglitazone and rosiglitazone were on the list for about 4 years each, as they were given PBS listing (subsidy) about 2 years after they first became available.

There was a record kept indicating when each medicine had been reviewed by ADEC, by ADRAC, when it became a DOCI and when it was reviewed again by ADRAC. Each medicine on the DOCI list was reviewed by ADRAC every year, roughly on its anniversary. A report was produced which detailed the background, reports in the ADRAC database, review of the product safety update report (PSUR), information from international agencies, a literature review and information in the product data sheet.

UK situation

The Committee on Safety of Medicines (CSM)/MHRA encouraged the reporting of all suspected reactions to newer medicines and vaccines, known as 'Black Triangle Drugs'. These products were indicated by an inverted black triangle symbol (down triangle) against product entries in the British National Formulary (BNF), MIMS, the ABPI Compendium of Datasheets and Summaries of Product Characteristics and advertising material. This indicated that the CSM/MHRA were intensively monitoring that product. A black triangle was assigned to a product if the drug contained a new active substance. However, a product containing previously licensed active substances might also be monitored if it met one or more of the following criteria:

There was no standard time for a product to retain black triangle status. However, an assessment was usually made following two years of post-marketing experience and the black triangle (down triangle) symbol was not removed until the safety of the drug was well established.

Discussion

The Committee noted that there was a low level of awareness of the ARCC system among prescribers in NZ. The Committee commented that it was difficult to assess whether the current ARCC system was achieving its purpose of encouraging prescribers to report the adverse reactions of interest to CARM. Anecdotal evidence suggested that reporting of adverse reactions did not increase in response to being listed on ARCC. However, following the removal of oral contraceptives from the list the numbers of spontaneous reports for these products decreased. This could be due in part to increased prescriber awareness of the adverse reaction, so that it was not seen as necessary to report.

A visual symbol such as the black triangle used in the UK was considered to be an effective method of bringing ARCC to the attention of prescribers. The Committee discussed a variety of mechanisms for introducing such a symbol into NZ. It was suggested that the symbol could appear next to entries in MIMS New Ethicals, pop-up in prescribing software, and be included in product advertising. Medsafe explained that it might be possible to explore options for introducing such a symbol for use in the JTA.

Another suggested method to increase awareness of ARCCs, and other adverse reactions of interest, was having information presented at Grand Rounds in hospitals. Medsafe explained that this would not be straightforward to organise, as around 80 separate hospitals in NZ would need to be contacted. Members noted that the Chief Medical Officer (CMO) at each District Health Board (DHB) would be responsible for organising Grand Rounds, and should be the point of contact. It was suggested that it would be more efficient to have changeable information available on a website, which the CMOs could download each week.

The Committee recommended that the current list of Adverse Reactions of Current Concern should remain unchanged.

Recommendations

The Committee recommended that Medsafe should investigate options for an Adverse Reactions of Current Concern/Drugs of Current Interest scheme for use in the JTA, including the use of a visual symbol.

The Committee recommended that the NZPhvC should investigate options for having adverse reactions of interest displayed during Grand Rounds.

3.4 Review of Watching Briefs

Reference
  1. Watching briefs recommended by the MARC since March 2001.
Issue

'Watching Brief' is one of the tools available to MARC for managing pharmacovigilance issues. Since March 2001, the MARC recommended that a Watching Brief be held for an adverse reaction to a medicine on 35 occasions. A Watching Brief generally meant that the adverse reaction data and international literature should be actively monitored for that particular pharmacovigilance issue. At the time of this report there were no formal procedures in place for the assessment or review of Watching Briefs.

Australian situation

In Australia there was a 'Watching Brief' category, which was very similar to that in NZ. There were no specific rules or processes around that status, including when it should be reviewed. It was considered to have value primarily in responding to the media or members of the public, by providing assurance that the regulator and/or committee were aware of the pharmacovigilance issue and were monitoring it.

Discussion

The Committee considered that it would be valuable to have formal processes in place for the review of medicines under Watching Brief. Following discussion, a process was decided upon, as detailed under Recommendations.

The Committee discussed how best to assess the existing list of Watching Briefs. They concluded that Medsafe and CARM should, following investigation of each issue, remove any items from the list for which regulatory action had been concluded. The results of this process should be reported back to the MARC. Subsequently, starting from those Watching Briefs recommended in 2001, Medsafe should review each item (including a literature search, CARM data and an update on regulatory action taken) and present ten items per meeting to the MARC. Additionally, CARM should reassess the criteria for recommending a Watching Brief to the Committee.

Recommendations

The Committee recommended that the following process should be followed for the assessment of Watching Briefs:

  1. The issue should be clearly identified at the time of the recommendation.
  2. Medsafe and CARM should actively monitor emerging data and bring the issue back to the MARC as necessary.
  3. Medsafe should undertake an annual review of the issue on the anniversary of the recommendation, including a literature search, presentation of CARM data and assessment of national and international regulatory actions.
  4. A decision of whether to maintain the Watching Brief should be made following the annual review.

The Committee recommended that Medsafe and CARM should analyse the existing list of Watching Briefs and bring the results back to the MARC.

The Committee recommended that CARM should reassess the criteria for recommending a Watching Brief to the Committee.

3.5 Paroxetine and Use in Pregnancy

References

Note: The following references were provided as late papers to the Committee, by email on 8 September 2005.

  1. Medsafe media statement re: the use of paroxetine in pregnancy. 8 September 2005.
  2. GlaxoSmithKline NZ Dear Health Professional fax. 8 September 2005.
  3. GlaxoSmithKline NZ Dear Health Professional letter. 9 September 2005.
  4. GlaxoSmithKline proposed NZ data sheet for Aropax. 6 September 2005.
  5. Therapeutic Goods Administration media release. Caution Over Antidepressant Paroxetine During Pregnancy. 7 September 2005.
  6. GlaxoSmithKline Australian Dear Health Professional letter. 5 September 2005.
  7. GlaxoSmithKline revised Australian product information for Aropax. 6 September 2005.
  8. Therapeutic Goods Administration: Information for Health Professionals Concerning Use of SSRI Antidepressants in Pregnant Women. September 2005.
  9. Therapeutic Goods Administration: Advice for women taking paroxetine intending to become pregnant or in early pregnancy. September 2005.
  10. Therapeutic Goods Administration: General information concerning use of SSRI antidepressants in pregnant women. September 2005.
  11. Cole JA et al for GlaxoSmithKline. Bupropion in Pregnancy and the Occurrence of Cardiovascular and Major Congenital Malformation. Preliminary Report. 2 February 2005.
  12. Extract of paroxetine data from the bupropion study (reference 5). 2 February 2005.
  13. Alwan S et al. Maternal Use of Selective Serotonin Re-uptake Inhibitors and Risk for Birth Defects. Clinical and Molecular Teratology 73:291, 2005. Abstract only.
  14. Wogelius P et al. Maternal Use of Selective Serotonin Re-uptake Inhibitors and Risk of Adverse Pregnancy Outcomes. Pharmacoepidemiology and Drug Safety (2005) 14: S1-S218. Abstract only.
  15. Hallberg P et al. The Use of Selective Serotonin Re-uptake Inhibitors During Pregnancy and Breast-feeding: A Review and Clinical Aspects. Jour Clin Psychopharm 25;1 Feb 2005.
  16. Ericson A et al. Delivery Outcome After the Use of Antidepressants in Early Pregnancy. Eu J Clin Pharmacol (1999) 55: 503-508.
Issue

The issue emerged in the week prior to the MARC meeting, following the release of the preliminary results of two studies12,14 suggesting that use of selective serotonin reuptake inhibitors (SSRIs) might be associated with a small increase in risk of foetal abnormality, specifically cardiac abnormalities such as ventricular septal defects. The risk appeared highest amongst women taking paroxetine. At the time of this meeting the paroxetine brands available in NZ were Aropax (GlaxoSmithKline) and Paroxetine (AFT Pharmaceuticals). Medsafe took the position that, as these results were preliminary and were contradicted by findings from other research, and as the NZ data sheets already contained warnings for use in pregnancy, it was most appropriate for this issue to be discussed by the MARC on 15 September 2005 before providing definitive advice to prescribers, or updating the data sheets.

On 8 September 2005 the references above were emailed to MARC members for their consideration at this meeting. On 8 September 2005, GlaxoSmithKline (GSK) disseminated a 'Dear Health Professional' fax to New Zealand GPs, specialists, pharmacists and midwives and followed this with a letter on 9 September 2005 containing more detailed information. Medsafe prepared a media statement, which was to be released if there was media interest in this issue.

In Australia, the TGA updated the product information for paroxetine on 6 September 2005 to contraindicate use in pregnancy. They issued a press release on 7 September 2005, and GSK disseminated letters to prescribers. At the time of the MARC meeting the UK MHRA and the US FDA had not completed their assessments of the evidence.

Discussion

The Committee discussed the available evidence provided as late papers, by email on 8 September 2005.

The Committee noted that the data provided by GSK were preliminary.11,12 The data, when women taking other teratogenic drugs were excluded, showed an adjusted odds ratio of 2.20 (95% confidence interval (CI) 1.34-3.63) for congenital malformation with paroxetine and an adjusted odds ratio of 2.08 (95% CI 1.03-4.23) for cardiovascular malformation with paroxetine.

The Committee noted the abstract of the Wogelius et al study14, which showed the adjusted odds ratio among women who redeemed SSRI prescriptions during pregnancy was 1.4 (95% CI 1.1-1.9) for congenital malformations overall and 1.6 (95% CI 1.0-2.6) for congenital cardiac malformations.

The Committee noted that the large Swedish database study (Ericson et al16) showed no increase in risk of congenital abnormalities with paroxetine.

Members suggested that there was evidence from animal models for a potentially plausible mechanism for an association between SSRIs and congenital malformations, particularly cardiovascular and craniofacial malformations. The potential mechanism was through activation of the 5-hydroxytryptamine (5-HT2B) receptor. However, the Committee commented that the doses used in the animal studies were high and the abnormalities observed were non-specific.

It was noted that a higher subsidy for paroxetine was available by endorsement ('certified condition' written on the prescription) for patients who:

The Committee commented that, due in part to the subsidy restrictions detailed above, usage would be restricted to those patients with a genuine clinical need for paroxetine.

The Committee considered that communication with prescribers, including midwives, and patients was imperative in this situation. They considered that the 'Dear Health Professional' letter and fax disseminated to GPs, specialists, pharmacists and midwives by GSK were satisfactory.2,3

The Committee concluded that the currently available data were insufficient to determine whether there was a causal association between paroxetine use in pregnancy and the development of congenital abnormalities, and if so, what the strength of this association might be. They recommended that a Watching Brief should be held on this issue, and that it should be reconsidered by the MARC should further data become available. The Committee considered that the proposed data sheet for Aropax4 adequately addressed this issue, and recommended that the changes should be made to all paroxetine product data sheets.

Recommendations

The Committee recommended that a Watching Brief should be held for all SSRIs in pregnancy.

The Committee recommended that the data sheets for all paroxetine products should be updated as per the proposed data sheet for Aropax.

4. matters arising from the new zealand pharmacovigilance centre

Spontaneous reporting programme

All spontaneous reports presented at the MARC meeting have been assessed by the Centre for Adverse Reactions Monitoring (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 case report to the MARC, etc.

Note: In the comment associated with each report, the case has been given a causality designation using terms and definitions developed by the WHO. The precise definitions are available on the website of the WHO Collaborating Centre http://www.who-umc.org/. These designations (certain, probable, possible, unlikely, unclassified and unclassifiable) refer to the degree of certainty about the relationship between the medicine and the adverse event. The terms should not be understood literally. For example, "certain" means that the appropriate elements are present to match the international definition. It does not mean there is absolute certainty that the medicine caused the adverse event.

Explanations of the terms used by CARM and MARC can be accessed by hyperlink at each causality designation.

4.1 Centre for Adverse Reactions Monitoring (CARM) Case Reports

4.1.1 Deaths

Please note that an additional case of a death in a neonate is discussed alongside that of the mother, as minute item 4.1.6.2.

4.1.1.1 Carvedilol and sudden death (66536)

Discussion

The Committee noted that there was scant information provided by the reporter in this case.

Members noted that there had been a total of 10 reports to CARM for carvedilol, including one death, which was considered non-causal (cardiomyopathy and congestive heart failure).

The NZ data sheet for Dilatrend contraindicated use in unstable or decompensated heart failure, however there was no mention of unexplained or sudden death as an adverse reaction. The pharmaceutical company that made this report stated that unexplained death was listed in the core data sheet for carvedilol.

The Committee concluded that there were insufficient data to make a clear assessment of causality in this case. Therefore, they recommended that the causal association with carvedilol should be changed to 'unclassified' for sudden death.

Recommendation

The Committee recommended that the causal association with carvedilol should be changed to 'unclassified' for sudden death in this case.

4.1.1.2 Chlorpromazine and neuroleptic malignant syndrome (64723)

Discussion

The Committee noted that this case was of a death due to neuroleptic malignant syndrome (NMS). The Committee noted that NMS and serotonin syndrome overlap considerably, and that chlorpromazine was an uncommon treatment option. They noted that there have been two reports in the literature of cases in which chlorpromazine was found to be useful in treating serotonin syndrome, however chlorpromazine was not indicated for that purpose in NZ. The Committee considered that it would be of value to seek the opinion of intensive care specialists with regards to the off-label use of chlorpromazine in serotonin syndrome.

NMS was a well-documented adverse reaction to chlorpromazine, and was included in the product data sheets.

The causal association with chlorpromazine was deemed to be 'probable' for neuroleptic malignant syndrome.

Recommendation

The Committee recommended that NZPhvC should seek the opinion of intensive care specialists with regards to the off-label use of chlorpromazine in serotonin syndrome and subsequently bring this issue back to the MARC.

4.1.1.3 Imatinib and pulmonary oedema, fever, anaemia, tinnitus, periorbital oedema, rash, eosinophilia (65165)

Discussion

The Committee noted that all of the reactions that occurred in this case are recognised adverse reactions to imatinib. They noted that the pre-terminal events occurred whilst taking a reducing dose of imatinib, and six days after discontinuation the patient died. The half-life of imatinib was noted to be 13 hours.

The causal association with imatinib was deemed to be 'unlikely' for pulmonary oedema and fever, and 'possible' for anaemia, tinnitus, periorbital oedema, rash and eosinophilia. The Committee agreed that no further regulatory action was required at that time.

4.1.1.4 Lamotrigine and sudden death, convulsion, cardiac disorder (65637)

Discussion

The Committee noted that lamotrigine was the only treatment at the time of this patient's death, and that although the exact dose was unknown it was at least 600mg/day.

The Committee noted that sudden unexpected death in epilepsy (SUDEP) accounts for approximately 2% of deaths in population-based cohorts of epilepsy, and up to 25% of deaths in cohorts of more severe epilepsy.

The causal association with lamotrigine was deemed to be 'unclassified' for sudden death (in epilepsy), convulsion and cardiac disorder. The Committee agreed that no further regulatory action was required at that time.

4.1.1.5 Methadone and arrhythmia, drug overdose (64756)

Discussion

See minute item 1.5.3 for peer-review of a Prescriber Update article on methadone and QTc interval prolongation. See minute item 4.1.3.1 for a further methadone case report.

The Committee noted that the Coroner had found the cause of death to be probable cardiac arrhythmia, however the unexplained high level of methadone in the blood was a contributing factor. The post-mortem ESR analysis stated that the level of methadone in the deceased's blood was higher than that expected from therapeutic doses, and was in the range associated with methadone-related fatalities. The Committee noted that there was international protocol in place for toxicological sampling of post-mortem blood.

The Committee noted that, in addition to use in opioid dependence, methadone was increasingly being used for the treatment of chronic pain.

The causal association with methadone was deemed to be 'possible' for arrhythmia and 'unclassified' for drug overdose. The Committee agreed that no further regulatory action was required at that time.

4.1.2 Alternative Medicines

4.1.2.1 Cosmic Jet, venlafaxine and headache, vomiting, dysphasia, cerebral haemorrhage, concentration impaired (65636)

Discussion

The Committee noted that Cosmic Jet was temporally associated with the adverse events in this case, over and above venlafaxine and the oral contraceptive. However, members commented that cerebral haemorrhage was occasionally seen as an adverse reaction to oral contraceptives, and recommended that oral contraceptive should be added to the suspect medicines in this case.

The Committee noted that there were 80 cases of thrombocytopenia with venlafaxine in the WHO database, and only one case of ecchymosis with venlafaxine in the CARM database.

There had been no reports to CARM of haemorrhage or bleeding with other "party pills"; however there had been one report of haematemesis and melaena with Euphoria/Voyager. Members discussed anecdotal evidence that hospitals were seeing adverse reactions to "party pills", which were mostly related to fluid imbalance and concomitant alcohol consumption.

The causal association with Cosmic Jet, venlafaxine and oral contraceptive was deemed to be 'possible' for headache, vomiting, dysphasia, cerebral haemorrhage and concentration impaired.

Recommendation

The Committee recommended that the oral contraceptive should be added to the suspect medicines in this case.

4.1.2.2 Tea Tree Oil and application site reaction, bullous eruption, rash vesicular, expired medicine (64773)

Discussion

The Committee noted the literature evidence that Tea Tree Oil oxidises easily to form irritant by-products. Members commented that contact dermatitis secondary to Tea Tree Oil application was not uncommon.

The causal association with Tea Tree Oil was deemed to be 'certain' for application site reaction, bullous eruption, rash vesicular and expired medicine. The Committee agreed that no further regulatory action was required at that time.

4.1.2.3 Thyroform and palpitations, T4 increased, TSH decreased, T3 increased (66334)

Discussion

The Committee noted that the patient was recommended a non-compliant dietary supplement by a chiropractor. Thyroform contained a prescription medicine, porcine thyroid extract, and was sold in breach of the Medicines Act 1981.

The Committee commented that the content of the patient information sheet for Thyroform, supplied by the manufacturer, was alarmist. The suggested treatments for adverse effects were inappropriate and unsafe.

The causal association with Thyroform was deemed to be 'probable' for palpitations, T4 increased, TSH decreased and T3 increased. The Committee noted that Medsafe's Compliance Team had been informed and was responsible for further regulatory action.

4.1.3 Analgesics

4.1.3.1 Methadone and torsades de pointes, QT prolonged, convulsions (64757)

Discussion

See minute item 1.5.3 for discussion on a Prescriber Update article being written on methadone and QTc prolongation. See minute item 4.1.1.5 for a further methadone case report.

The causal association with methadone was deemed to be 'probable' for torsades de pointes, QT prolonged and convulsions. The Committee agreed that no further regulatory action was required at that time.

4.1.4 Antifungals

4.1.4.1 Terbinafine and hepatic enzymes elevated, iritis (67246)

Discussion

The Committee commented that the usage of terbinafine was increasing due to direct-to-consumer advertising and over-the-counter availability of the topical preparations. The oral formulation, however, was only fully subsidised when recommended by a specialist.

The Committee noted that there were four reports in the WHO database of uveitis with terbinafine, with one published case report of uveitis in the literature.

The causal association with terbinafine was deemed to be 'probable' for hepatic enzymes elevated and 'possible' for iritis. The Committee agreed that no further regulatory action was required at that time.

4.1.5 Cardiovascular Medicines

4.1.5.1 Atorvastatin and aggressive reaction (67166)

Discussion

The Committee noted that out of a total of 122 reports in the CARM database for atorvastatin, 30 were for psychiatric reaction, with no previous reports of aggressive reactions. For simvastatin, of a total of 590 reports there were 161 reports of psychiatric reactions, and three of aggressive reaction all of which recovered on dechallenge.

In the WHO database there were 43 reports of aggressive reaction for atorvastatin (total reports 14,747) and 56 for simvastatin (total reports 19,787). However, the IC was negative for both medicines.

The literature was noted to contain references to memory impairment and depression with statins. The Committee commented that the literature showed that if psychiatric reactions to statins occurred there was generally a dramatic reaction shortly after initiating treatment, which stabilised over time.

The Committee concluded that this case added further credence to an emerging signal for psychiatric adverse effects of statins, and considered that a Prescriber Update article written on this matter might be of value.

The causal association with atorvastatin was deemed to be 'probable' for aggressive reaction.

Recommendation

The Committee recommended that CARM should explore the option of writing a Prescriber Update article on the psychiatric adverse effects of the statins.

4.1.6 Immunosuppressives

4.1.6.1 Infliximab, mesalazine, metronidazole, azathioprine and labour premature, birth premature (66534)

Discussion

See minute item 4.1.6.2 for the neonate's case report.

It was noted that the patient conceived when the inflammatory bowel disease was active, and also while on several medications that could have impacted on her pregnancy outcome. It was noted that there was evidence for all of the suspect medicines to be implicated in premature labour.

The causal association with infliximab, mesalazine, metronidazole and azathioprine was deemed to be 'possible' for labour premature and birth premature. The Committee agreed that no further regulatory action was required at that time.

4.1.6.2 Infliximab, mesalazine, metronidazole, azathioprine and birth premature, cerebral haemorrhage neonatal, pulmonary haemorrhage (66535)

Discussion

See minute item 4.1.6.1 for the mother's case report.

The Committee noted that extreme prematurity is a risk factor for neonatal haemorrhage.

The data sheet for Pentasa (mesalazine) states "Blood disorders (leucopenia, thrombocytopenia, anaemia) have been reported in newborns of mothers being treated with Pentasa." The data sheet for Thioprine (azathioprine) states "Leucopenia and/or thrombocytopenia have been reported in a proportion of neonates whose mothers took azathioprine throughout their pregnancies. Extra care in haematological monitoring is advised during pregnancy."

The causal association with infliximab, mesalazine, metronidazole and azathioprine was deemed to be 'possible' for birth premature, cerebral haemorrhage neonatal and pulmonary haemorrhage. The Committee agreed that no further regulatory action was required at that time.

4.1.7 Musculoskeletal Medicines

4.1.7.1 Zolendronate and gingivitis, osteonecrosis (65711)

Discussion

See minute item 3.2 for discussion and recommendations on this issue.

The causal association with zolendronate was deemed to be 'possible' for gingivitis and osteonecrosis.

4.1.7.2 Zolendronate and osteonecrosis, healing impaired (66668)

Discussion

See minute item 3.2 for discussion and recommendations on this issue.

The causal association with zolendronate was deemed to be 'possible' osteonecrosis and healing impaired.

4.1.7.3 Pamidronate and osteonecrosis, healing impaired (66671)

Discussion

See minute item 3.2 for discussion and recommendations on this issue.

The causal association with pamidronate was deemed to be 'possible' for osteonecrosis and healing impaired.

4.1.8 Vaccines

4.1.8.1 Influenza vaccine and nausea, faintness, fever, cardiac arrest (66615)

Discussion

The Committee noted that several features of this case (timing, fever and dilated pupils) were more consistent with a syncopal event than an anaphylactic reaction. They considered it would be valuable for CARM to seek further information on this case.

The causal association with influenza virus vaccine was deemed to be 'possible' for nausea, faintness, fever and cardiac arrest.

Recommendation

The Committee recommended that CARM should seek further information on case report 66615, influenza vaccine and nausea, faintness, febrile, cardiac arrest, and report back to the MARC.

4.1.9 Other Reports

4.1.9.1 Arthrix FX (64727)
4.1.9.2 Immune Defence Formula (65427)
4.1.9.3 Aloe Vera Juice (65540)
4.1.9.4 Tiotropium (66263)
4.1.9.5 Leflunomide (66304)
4.1.9.6 Mebo Ulcer Repair (66526)
4.1.9.7 Remifemin (66890)
4.1.9.8 Buccaline (67026)
4.1.9.9 Tranexamic acid (67081)
4.1.9.10 Omeprazole (67185)

Recommendation

The Committee recommended that CARM should bring the full details of case report 67081, tranexamic acid and transient ischaemic attack (TIA), to the MARC at the next meeting.

4.2 Intensive Medicines Monitoring Programme (IMMP)

4.2.1 Analysis of IMMP Events Reported for Sibutramine

Discussion

The Committee noted that the cohort for sibutramine was closed on 31 March 2004 at which time there were 17,420 patients in the total cohort. The IMMP was conducting a follow-up study in a cohort of 9,532 patients, the analysis of which was due to be completed by late 2005.

The Committee noted the top-ten reactions for sibutramine, and the frequency of those reactions. The potential safety issues that were to be followed-up in future cohort analyses were cardiovascular reactions, psychiatric events, male genito-urinary events and Bell's Palsy.

The Committee noted the table of adverse events that were listed in the US product information for sibutramine but not in the NZ data sheet. They considered that it was difficult to assess the significance of this information without knowing where in the US product information the statements appeared. Therefore, it would be of value for Medsafe to obtain the US product information for further analysis.

Recommendation

The Committee recommended that Medsafe should obtain and review the US product information for sibutramine.

4.2.2 Sibutramine and Bruising

Discussion

The Committee noted the six cases of bruising with sibutramine in the IMMP cohort, one with a positive rechallenge. In the WHO database there were 31 cases of causally associated bruising with sibutramine. 11 of these cases had a positive dechallenge and there was one case of recurrence of ecchymosis on rechallenge.

It was noted that there were no published reports in the literature of this reaction. The NZ data sheet for Reductil stated, "There have been reports of bleeding in patients taking sibutramine. While a causal relationship is unclear, caution is advised in patients predisposed to bleeding events and those taking concomitant medications known to affect haemostasis or platelet function." The Committee noted that the US product information also contained information on ecchymosis/bleeding under 'Clinical studies'. They asked that Medsafe also review the US product information with regards to bruising.

The Committee considered that a potential mechanism was inhibition of serotonin re-uptake, as haemorrhage had also been associated with SSRIs. They commented that the time from onset of sibutramine treatment to onset of bruising was long in some cases, and that it would be valuable to review further details of the cases.

The Committee supported the publication of this case series.

Recommendation

The Committee recommended that IMMP should bring the full details of the cases of bruising with sibutramine to the MARC.

4.2.3 Paper for Information - Sibutramine and QT Interval Prolongation

4.3 Intensive Vaccines Monitoring Programme (IVMP) - Meningococcal B Vaccine

4.3.1 MeNZB Adverse Event Assessments

Discussion

The Committee noted that there had been almost 2 million doses of MeNZB vaccine administered between 19 July 2004 and 12 August 2005, and that the pattern of adverse reactions was unchanged. They noted that the Independent Safety Monitoring Board had reviewed the CARM data, and had expressed no concerns regarding the safety of the MeNZB vaccine.

4.3.2 Urticaria Following MeNZB Immunisation

Discussion

The Committee noted that, of a total of 925 reports of adverse events with the MeNZB vaccine (19 July 2004 to 17 June 2005) there were 116 spontaneous reports of serious hypersensitivity reactions. Urticaria was the most commonly reported hypersensitivity adverse event, accounting for 73 reports. The majority of events occurred within 24 hours of immunisation with nearly half of the cases recovered from the event at the time of reporting. The Committee noted that, of the 73 reports of urticaria, 57 events occurred following the first dose of MeNZB, 11 occurred following the second dose and three occurred following the third dose.

Members commented that some children had experienced a negative rechallenge, which provided some reassurance. Members commented that the majority of urticarial reactions to medicines are not allergic in nature, and therefore should not recur with subsequent exposures. However, care should be taken when rechallenging patients.

4.4 Quarterly Report from CARM as at 30 June 2005

Discussion

The Committee noted the quarterly report from CARM as at 30 June 2005.

5. pharmacovigilance issues for information only

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

5.1 Analgesics and use in children

5.2 Combined oestrogen-progestagen contraceptives and carcinogenicity

5.3 Others

6. new zealand pharmacovigilance-related activities

7. international pharmacovigilance-related Activities

7.1 Australia

7.2 Canada

7.3 Singapore

7.4 WHO

8. Summary of case reports considered by MARC (1997-2005)

9. Other business

There being no further business, the Chair thanked members for their attendance and closed the meeting at 16:30.

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

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