Revised: 20 May 2013
Committees
Minutes of the 127th Medicines Adverse Reactions Committee Meeting - 14 September 2006
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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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
1.1 Welcome and Apologies
1.2 Minutes of the 126th MARC Meeting
1.2.1 Report to the Minister's Delegate
1.3 Dates of Future MARC Meetings
1.4 Potential Conflicts of Interest
1.5.1 Schedule of Planned Prescriber Update
Articles
1.5.2 Draft Prescriber Update Articles for MARC
comment
2.1 Report on Actions Arising from the 126th MARC Meeting, 15 June 2006
2.1.1 Schedule of Planned Prescriber UpdateArticles
2 .1.2 MARC Membership – Vacant Positions
2.1.3 Future Arrangements for Pharmacovigilance in New
Zealand
2.1.4 Dextropropoxyphene/Paracetamol Combination Products
and the Risk of Overdose
2.1.5 Topical Pimecrolimus and the Risk of Malignancy
2.1.6 Bisphosphonates and Osteonecrosis of the Jaw
2.1.7 Tramadol and Hepatic Reactions: Watching Brief Review
2.1.8 Baclofen and cardio-respiratory arrest, abdominal
pain, hypertension, vomiting and coughing [death] (CARM case 70111)
2.1.9 Alteplase and oedema [death] (CARM cases 70710, 70711
and 70712
2.1.10 Quinine and purpura and thrombocytopenia (CARM
case 70373)
2.1.11 Leflunomide / hydroxychloroquine and deep venous
thrombosis, aggravated hepatitis, arthritis, myalgia and leg cramps (CARM
case 70028)
2.1.12 Oral Terbinafine Serious Adverse Reactions
2.2 REPORT ON ACTIONS ARISING FROM PREVIOUS MEETINGS OF THE MARC
2.2.1 Selective Serotonin Reuptake Inhibitors (SSRIs)
and Haemorrhage: Watching Brief Rview
2.2.2 Selective Serotonin Reuptake
Inhibitors (SSRIs) and Withdrawal Reactions: Watching Brief Rview
2.2.3 Anti-Tumour Necrosis Factor (Anti-TNF) Agents and
the Risk of Hepatitis B Reactivation
2.2.4 All Serious or Unexpected Adverse Reactions to Rosiglitazone:
Standing Agenda Item
2.2.5 GRINZ party pill and convulsions (CARM case 67675)
2.2.6 Citalopram / fentanyl and neonatal respiratory depression
(CARM case 69860)
2.2.7 Tramadol - Interactions and Serious Reactions
2.2.8 Clozapine and Haematological Malignancies
2.3 REPORT ON UNRESOLVED ACTIONS ARISING FROM RECOMMENDATIONS OF THE MARC
2.3.1 Low Molecular Weight Heparins (LMWHs) in Renal
Impairment
2.3.2 COX-2 Inhibitors/Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs) and Impaired Fracture Healing: Watching Brief Review
2.3.3 Heparin and thrombocytopenia (CARM case 69852)
3.1 QUININE, NOCTURNAL LEG CRAMPS AND THROMBOCYTOPENIA
3.3 SSRIS AND USE IN PREGNANCY: WATCHING BRIEF REVIEW
3.4 LIPID-LOWERING AGENTS AND PSYCHIATRIC ADVERSE REACTIONS: ACTIVE MONITORING REVIEW
4. MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE
4.1 Centre for Adverse Reactions Monitoring (CARM) Spontaneous Case Reports
4.1.1 Deaths
4.1.2 Antibacterial Medicines
4.1.3 Anti-Inflammatory Medicines
4.1.4 Endocrine Medicines
4.1.5 Immunosuppressive Medicines
4.1.6 Musculoskeletal Medicines
4.1.7 Psychiatric Medicines
4.1.8 Other Reports
4.3 intensive medicines monitoring programme (IMMP)
4.3.1 Atypical Antipsychotics in Children
4.3.2 Clozapine and Myocarditis
5. PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY
6. NEW ZEALAND PHARMACOVIGILANCE-RELATED ACTIVITIES
7. INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES
8. SUMMARY LISTINGS OF CASE REPORTS CONSIDERED BY MARC (1997-2006)
MINUTES OF THE 127TH MEDICINES ADVERSE
REACTIONS COMMITTEE MEETING,
14 SEPTEMBER 2006
The one hundred and twenty-seventh meeting of the Medicines Adverse Reactions Committee (MARC) was held on 14 September 2006 at the De Havilland room, Wellington Airport Conference Centre, Wellington, New Zealand. The meeting commenced at 9:00am and closed at 3:10pm.
marc members present
Associate Professor T Maling (Chair)
Honorary Associate Professor M Rademaker
Dr H Kingston
Professor D Skegg
Dr F McClure
Professor P Ellis
Dr D Reith
Ms L Bryant
Dr M Tatley
Dr S Jessamine
marc secretariat present
Ms S Von Afehlt (Senior Pharmacy Advisor/Editor of Prescriber Update,
Medsafe)
Dr K Maclennan (Senior Pharmacovigilance Advisor, Medsafe)
Dr K Moses (Pharmacovigilance Advisor/MARC Secretary, Medsafe)
invited guests and experts
Dr R Hammett (Principal Medical Advisor, Therapeutic Goods Administration) and Dr C Cameron (Clinical Pharmacology registrar, Capital and Coast District Health Board) observed the meeting.
Dr R Savage and Dr M Harrison-Woolrych participated by teleconference for items related to the Centre for Adverse Reactions Monitoring (CARM) and the Intensive Medicines Monitoring Programme (IMMP) respectively.
1. Matters of Administration
1.1 Welcome and Apologies
The Chair welcomed the attendees to the meeting. He welcomed two new members to the Committee: Dr D Reith (Paediatrician and Clinical Pharmacologist) and Ms L Bryant (Clinical Pharmacist). He also welcomed Dr S Jessamine, who had been appointed as an alternative to Dr S Sime as the Ministry of Health's ex officio representative on the Committee.
Prof Skegg informed the Committee that he intended to let his appointment to the MARC expire in December 2006 and that this would therefore be his last MARC meeting. The Committee thanked Prof Skegg for his valuable input over the preceding 17 years and wished him well for the future.
1.2 Minutes of the 126th MARC Meeting
Members agreed that the minutes of the 126th MARC meeting were a true and accurate record of the meeting. The Chair and Acting Chair of that meeting subsequently ratified the minutes.
1.2.1 Report to the Minister's Delegate
Members noted that all of the recommendations made at the 126th MARC meeting had been accepted by the Minister's Delegate.
1.3 Dates of Future MARC Meetings
The date for the next MARC meeting was confirmed as being Thursday 14 December 2006. The subsequent MARC meetings were scheduled for 15 March 2007, 14 June 2007, 13 September 2007 and 13 December 2007.
1.4 Potential Conflicts of Interest
Committee members submitted their Conflict of Interest Declaration forms to the Secretary. The Chair reminded the MARC members that, in addition to conflicts disclosed in the declaration forms, members should declare conflicts of interest at the commencement of discussion of any relevant agenda item.
Four members declared potential conflicts of interest. The Committee considered that these potential conflicts of interest would not influence the discussions or decisions of the Committee.
1.5 Prescriber Update
1.5.1 Schedule of Planned Prescriber Update Articles
Discussion
The Committee noted the schedule of planned Prescriber Update articles. The Editor informed members that some of the articles, which had been recommended more than three years ago, would be published as short 'watching brief' paragraphs.
1.5.2 Draft Prescriber Update articles for MARC comment.
References
- Dextropropoxyphene/Paracetamol Combination Products and the Risk of Overdose
- Evidence for Tramadol-Warfarin Interaction.
- Watching Briefs
- Terbinafine and serious adverse reactions
- Psychiatric reactions with cholesterol-lowering agents
- Statin reminder – myopathy, rhabdomyolysis and interactions
- Watch for muscle disorders with ezetimibe too
Discussion
The Committee reviewed the draft Prescriber Update articles and provided comments to the Editor.
2. actions arising
2.1 Report on Actions Arising from the 126th MARC Meeting, 15 June 2006
Please refer to the minutes of the 126th MARC meeting, held on 15 June 2006, available on the Medsafe web site at www.medsafe.govt.nz/Profs/adverse/Minutes126.htm for background information surrounding these issues.
2.1.1 Schedule of Planned Prescriber Update Articles
June 2006 minute item 1.5.2
Issue
In June 2006, the Committee recommended that the scheduled Prescriber Update article on the psychiatric adverse effects of statins should include information about ezetimibe.
Outcome
The NZPhvC publication includes reference to ezetimibe and the Prescriber Update article will, therefore, also include ezetimibe.
Discussion
See minute item 3.4 for a review of the issue of lipid-lowering agents and psychiatric adverse reactions. The Committee noted the above and agreed that no further regulatory action was required at that time.
2.1.2 MARC Membership – Vacant Positions
June 2006 minute item 2.1.2; March 2006 minute item 2.2.1; December 2005 minute item 2.2.1; September 2005 minute item 2.1.1; June 2005 minute item 1.1.1
Issue
In March 2006, the Committee recommended that Medsafe should investigate appointing a pharmacoepidemiologist, a paediatrician and a clinical pharmacist to the MARC.
In June 2006, the Committee recommended that Dr Jessamine (Principal Technical Specialist, Medsafe) should be requested to be available to attend every meeting of the MARC.
Outcome
In August 2006, two new members were appointed to the MARC: Dr D Reith, Paediatrician and Clinical Pharmacologist; and Ms L. Bryant, Clinical Pharmacist. They were both in attendance at the September 2006 MARC meeting.
Dr S. Jessamine was appointed as an alternate to Dr S. Sime as the Ministry of Health’s ex officio representative on the MARC. He gave his assurance that he would be available to attend meetings of the MARC in the future.
Discussion
The Committee welcomed the new MARC members, Dr Reith and Ms Bryant.
Prof Skegg informed the Committee that he planned to let his MARC appointment expire in December 2006. Therefore, a new member would need to be appointed to the MARC, rather than an alternate to Prof Skegg as had previously been agreed. Medsafe explained that when appointing new members, nominations for a number of candidates must be sought, then a short list of nominees must be provided to the Minister of Health from which he chooses his preferred candidate. Medsafe had contacted several candidates with expertise in epidemiology and/or biostatistics seeking nominations. Unfortunately, the person who had previously agreed to be appointed as Prof Skegg's alternate did not wish to be nominated as a MARC member due to other commitments.
2.1.3 Future Arrangements for Pharmacovigilance in New Zealand
June 2006 minute item 2.1.18
Issue
In June 2006, the Committee asked that an invitation be extended to the Minister of Health to attend a MARC meeting. The Secretary agreed to do so.
Outcome
Medsafe was in the process of coordinating with the Minister's office regarding an invitation to the Minister to attend a MARC meeting. In addition, the Chair had an appointment to meet with the Minister separately. Medsafe was awaiting the outcome of the meeting between the Chair and the Minister before progressing the invitation to attend a MARC meeting.
Discussion
The Committee noted the above.
2.1.4 Dextropropoxyphene/Paracetamol Combination Products and the Risk of Overdose
June 2006 minute item 2.2.9; March 2006 minute item 2.1.3; December 2005 minute item 2.2.7; September 2005 minute item 2.1.2; June 2005 minute item 3.1
Issue
In June 2006, the Committee recommended that Medsafe should investigate to whom the Capadex Dear Healthcare Professional letter had been sent.
In December 2005, the Committee recommended that Medsafe should explore the option of publishing an article in Prescriber Update recommending that dextropropoxyphene/paracetamol combination products should not be used except in appropriate clinical situations, and to increase awareness of the risk of inadvertent overdose with concomitant alcohol use.
Outcome
Healthcare Logistics informed Medsafe in August 2006 that the Capadex Dear Healthcare Professional letter had been faxed to all general practitioners, retail and hospital pharmacists, psychiatrists and their registrars on 27 April 2006. There were 4,771 faxes sent in total.
Discussion
The Committee noted the above. A Prescriber Update article had been drafted and provided to members for their comment (see minute item 1.5.2). The Committee noted that this issue was scheduled for review by MARC in December 2007.
2.1.5 Topical Pimecrolimus and the Risk of Malignancy
June 2006 minute item 3.1; June 2005 minute item 5.1
Issue
In June 2006, the Committee recommended that Medsafe should request that Novartis update the New Zealand data sheet for Elidel 1% cream in line with the Core Data Sheet, once updated. The following changes would be required at a minimum:
- Harmonisation of the 'Indications' section with the Australian Product Information.
- Inclusion of information on the risk of malignancy in the 'Adverse Effects' and 'Warnings and Precautions' sections of the data sheet.
- Harmonisation of the information on the positive findings of the monkey carcinogenicity study in line with the information contained in the European Summary of Product Characteristics.
In June 2006, the Committee recommended that Novartis should disseminate a Dear Healthcare Professional letter (following update of the data sheet) advising New Zealand prescribers of the available evidence regarding topical pimecrolimus and the risk of malignancy; the relevant changes to the Elidel cream data sheet; and that they should advise patients of the need for appropriate protection against the sun during Elidel cream use.
In June 2006, the Committee recommended that the issue of topical pimecrolimus and the risk of malignancy should be placed on the watching brief list.
In June 2006, the Committee recommended that Medsafe should obtain the Medicines Assessment Advisory Committee (MAAC) meeting minute regarding the approval of topical pimecrolimus for use in paediatric populations between 3 and 23-months of age. This should be provided to the MARC at the next meeting.
In June 2006, the Committee recommended that Medsafe should ask Novartis to provide general safety data for the use of Elidel 1% cream in under 2-year-olds and subsequently bring these data back to the MARC.
Outcome
Novartis submitted an updated Elidel 1% cream data sheet to Medsafe in July 2006, in line with the Core Data Sheet, with updates regarding the risk of malignancy in the 'Dosage and Method of Administration', 'Special Warnings and Special Precautions for Use' and 'Adverse Effects' sections. These updates were reviewed by Medsafe and considered acceptable.
In August 2006, Medsafe wrote to Novartis outlining the recommendations made at the June 2006 MARC meeting, as detailed below. A response had not yet been received.
Updates to the Elidel cream data sheet were requested in the 'Indications' and 'Toxicology Studies after Oral Administration' sections. Upon review, Medsafe considered that some of the wording of the indications in the European Summary of Product Characteristics (SmPC) for Elidel cream (i.e. Intolerance to topical corticosteroids; Lack of effect of topical corticosteroids; Use on the face and neck where prolonged intermittent treatment with topical corticosteroids may be inappropriate) better reflected current guidelines for the treatment of atopic dermatitis than the Australian Elidel cream Product Information. Therefore, Medsafe requested that the indications in the New Zealand Elidel cream data sheet be amended to read as follows:
Patients 3 months of age and older with atopic dermatitis (eczema) for the:
- short-term treatment of signs and symptoms; and
- intermittent long-term treatment of emerging and resolving lesions in atopic dermatitis where topical corticosteroids are ineffective, intolerable or inappropriate.
In addition, Medsafe compared the NZ Elidel cream data sheet with the Australian Product Information and European SmPC and requested a number of changes to the 'Dosage and Administration' section.
Novartis was also requested to disseminate a Dear Healthcare Professional letter to general practitioners, dermatologists and pharmacists once the data sheet changes were completed and an updated Elidel data sheet published on the Medsafe web site.
Furthermore, Novartis was asked to supply Medsafe with data on the safety of Elidel 1% cream in children aged under 2-years. These data, along with the minute of the MAAC from March 2002, would be supplied to the MARC at its December 2006 meeting.
The issue of topical pimecrolimus and the risk of malignancy had been placed on the watching brief list with the first annual review scheduled for June 2007.
Discussion
The Committee noted the above and agreed to review the safety of pimecrolimus in infants in December 2006.
2.1.6 Bisphosphonates and Osteonecrosis of the Jaw
June 2006 minute item 3.2; March 2006 minute item 2.2.6; December 2005 minute item 2.1.4; September 2005 minute item 3.2
Issue
In June 2006, the Committee recommended that Medsafe should write to the New Zealand Guidelines Group asking them to give consideration to revising their guideline on The Prevention of Hip Fracture Amongst People Aged 65-Years and Over to reflect the current evidence on the risks of osteonecrosis of the jaw associated with the use of nitrogen-containing oral bisphosphonates.
In June 2006, the Committee recommended that Medsafe should liaise with the experts (who had participated in the MARC meeting by teleconference) regarding their planned New Zealand Medical Journal article.
In June 2006, the Committee recommended that the issue of bisphosphonates and osteonecrosis of the jaw should remain on the active monitoring list, for review in June 2007. Data provided should include usage data for the nitrogen-containing oral bisphosphonates, such as alendronate.
Outcome
Medsafe wrote to the New Zealand Guidelines Group in August 2006, informing them of the recommendation made at the June 2006 MARC meeting.
Medsafe was liaising with the experts regarding their planned New Zealand Medical Journal article.
The issue of bisphosphonates and osteonecrosis of the jaw remained on the active monitoring list with the next review scheduled for June 2007.
Discussion
The Committee noted the above and agreed that no further regulatory action was required at that time.
2.1.7 Tramadol and Hepatic Reactions: Watching Brief Review
June 2006 minute item 3.3
Issue
In June 2006, the Committee recommended that Medsafe should ask the Zytram sponsor to update the data sheet, in line with the other tramadol brands, with respect to hepatic enzyme elevation.
In June 2006, the Committee recommended that the issue of tramadol and hepatic reactions should be removed from the watching brief list.
Outcome
Medsafe wrote to Pharmaco NZ Ltd in August 2006 requesting an update to the Zytram data sheet with respect to hepatic enzyme elevation.
The issue of tramadol and hepatic reactions had been removed from the watching brief list.
Discussion
Medsafe informed the Committee that Pharmaco had updated the Zytram data sheet as requested in August 2006.
The Committee noted the above and agreed that no further regulatory action was required at that time.
2.1.8 Baclofen and cardio-respiratory arrest, abdominal pain, hypertension, vomiting and coughing [death] (CARM case 70111)
June 2006 minute item 4.1.1.2
Issue
In June 2006, the Committee recommended that NZPhvC should seek further information from the reporter in this case (70111).
In June 2006, the Committee recommended that NZPhvC should add 'withdrawal syndrome' to the adverse reaction terms in this case (70111) if the baclofen pump was found to have been faulty.
Outcome
Further information had been received about the events, but as yet this feedback had not contained information on the potential device failure.
Discussion
The Committee noted the above and asked that NZPhvC report back once feedback on the potential device had been received.
2.1.9 Alteplase and oedema [death] (CARM cases 70710, 70711 and 70712)
June 2006 minute item 4.1.1.4
Issue
In June 2006, the Committee recommended that NZPhvC should report back to the MARC once further information had been received from the sponsor on these three cases (70710, 70711 and 70712) and the report dates had been checked.
Outcome
As at August 2006, no further information had been received from the reporter.
Discussion
The Committee noted the above and asked that NZPhvC report back once further information had been received from the reporter.
2.1.10 Quinine and purpura and thrombocytopenia (CARM case 70373)
June 2006 minute item 4.1.3.1
Issue
In June 2006, the Committee recommended that NZPhvC should review the 12 cases of thrombocytopenia with quinine received in the last five years and discuss this issue with Medsafe, then bring it back to the MARC if warranted.
Outcome
This issue was reviewed by Medsafe and NZPhvC, and brought back to the MARC at this meeting.
Discussion
See minute item 3.1 for a full review of this issue.
2.1.11 Leflunomide / hydroxychloroquine and deep venous thrombosis, aggravated hepatitis, arthritis, myalgia and leg cramps (CARM case 70028)
June 2006 minute item 4.1.7.1
Issue
In June 2006, the Committee recommended that NZPhvC should analyse the cases of hepatitis with leflunomide in the WHO database more fully and bring the results back at the next Adverse Reactions of Current Concern (ARCC) review in March 2007.
Outcome
NZPhvC had noted this recommendation.
Discussion
The Committee noted the above and agreed that no further regulatory action was required at that time.
2.1.12 Oral Terbinafine Serious Adverse Reactions
June 2006 minute item 9.2
Reference
NZPhvC. Reports of Blood Dyscrasias and Other Severe and Serious Reactions Attributed to Terbinafine in the CARM and WHO Databases. Report for MARC September 2006.
Issue
In June 2006, the Committee recommended that Medsafe and NZPhvC should review the issue of serious adverse reactions to oral terbinafine and bring it back to the MARC if warranted.
Outcome
Medsafe and NZPhvC reviewed this issue in July 2006. It was considered that regulatory action could be taken without a MARC review.
At its 293rd meeting in June 2006, the Australian Adverse Drug Reactions Advisory Committee (ADRAC) reviewed the issue of terbinafine and blood dyscrasias. ADRAC recommended that Novartis should be requested to provide case reports in its possession so that the Adverse Drug Reactions Unit (ADRU) could perform an analysis. The Product Information could then be amended based on the findings of the analysis. An article entitled 'Life threatening blood dyscrasias with oral terbinafine' was published in the August 2006 edition of the Australian Adverse Drug Reactions Bulletin.
NZPhvC provided a summary of haematological and other serious and severe reports to CARM for oral terbinafine. From a total of 253 reports for terbinafine there had been seven of neutropenia and one report each of agranulocytosis, thrombocytopenia, leucopenia and lymphocytopenia. Two of these were life-threatening reactions (agranulocytosis and neutropenia with ulcerative stomatitis and elevated hepatic enzymes). Five of the patients improved on de-challenge. There were a number of other serious reports to CARM where the causality was considered at least possible, including hepatic reactions, dermatological reactions, anaphylaxis and taste perversion.
NZPhvC also provided a similar analysis from the WHO database (Vigibase). From a total of 12,587 reports for terbinafine there were 84 of thrombocytopenia, 63 of neutropenia, 48 of agranulocytosis and 115 of leucopenia. Eight of these cases died. The information component (IC) values for thrombocytopenia, leucopenia and agranulocytosis were all negative and the value for neutropenia was not obtainable. There were a number of serious adverse reactions with positive IC values, including a number of hepatic and dermatological reactions.
A paragraph had been prepared for publication in Prescriber Update to bring serious adverse reactions to oral terbinafine to the attention of prescribers and to encourage appropriate use of the medicine (see minute item 1.5.2).
The data sheets for oral terbinafine products available in New Zealand (Lamisil, Novartis; Apo-Terbinafine, Apotex; Arrow-Terbinafine, Arrow Pharmaceuticals; Terbafin, Pacific Pharmaceuticals) were reviewed by Medsafe and compared with the Australian Generic Terbinafine Tablet Product Information. The data sheets were found to be inconsistent with one another and most were found to contain insufficient warnings about haematological, hepatic and dermatological serious adverse effects. Medsafe considered that the best approach would be to ask each sponsor to harmonise the oral terbinafine data sheets with the Australian Generic Terbinafine Tablet Product Information in the first instance. Then, should any amendments be made to the Australian Product Information as a result of the ADRAC review, the New Zealand data sheets should be equivalently updated.
Medsafe wrote to the oral terbinafine sponsors in September 2006 requesting the above data sheet changes.
Discussion
The Committee noted the above and considered that Medsafe's regulatory actions to date had been appropriate.
Medsafe informed the Committee that Apotex (Apo-Terbinafine) had responded agreeing to make the data sheet changes as requested. Members asked that Medsafe report back once responses had been received from the other sponsors.
Members commented that the use of oral terbinafine should generally be limited to treating fungal infections that were serious or that occurred in paediatric patients where alternatives were limited. However, it was reportedly often prescribed for minor dermatophyte conditions, or for misdiagnosed non-dermatophyte conditions. Members commented that alternative oral treatments for dermatophyte disease were limited to the azole-antifungals which also carried risks. They considered that when oral terbinafine was used for appropriate indications, the risk:benefit profile was positive. The data sheet and Consumer Medicine Information (CMI) updates, and the Prescriber Update article would assist in ensuring that the medicine was used appropriately.
Members queried whether there was any pattern of patient characteristics, particularly age, in the reports to CARM, and asked that NZPhvC investigate and report back. They also asked that Medsafe continue to correspond with the Australian Therapeutic Goods Administration regarding their review of this issue. Members considered that this issue should be placed on the active monitoring list.
Recommendations
The Committee recommended that Medsafe should continue to correspond with the Australian Therapeutic Goods Administration regarding outcomes of their review of the safety of oral terbinafine and regulatory actions taken, and report back to the MARC.
The Committee recommended that NZPhvC should provide an analysis of the patient characteristics, particularly age, in the case reports to CARM of serious adverse reactions to oral terbinafine.
The Committee recommended that the issue of oral terbinafine and serious adverse reactions (blood dyscrasias, hepatotoxicity and dermatological reactions) should be placed on the active monitoring list.
2.2 Report on Actions Arising from Previous Meetings of the MARC
2.2.1 Selective Serotonin Reuptake Inhibitors (SSRIs) and Haemorrhage: Watching Brief Review
June 2006 minute item 2.2.10; March 2006 minute item 2.1.6; December 2005 minute item 3.1.2
Issue
In December 2005, the Committee recommended that the SSRI data sheets should be updated to adequately address the risk of abnormal bleeding and to be consistent with one another.
In December 2005, the Committee recommended that Medsafe should write a paragraph for publication in Prescriber Update informing prescribers of the risk of abnormal bleeding with SSRIs, and emphasising the risks of co-prescribing NSAIDs/aspirin.
In December 2005, the Committee recommended that SSRIs and haemorrhage should be removed from the watching brief list, following resolution of the above regulatory actions.
Outcome
All sponsors of the SSRIs had agreed to update the data sheets with warning statements regarding the risk of haemorrhage.
A paragraph was being drafted for publication in the next edition of Prescriber Update.
Medsafe considered that this issue could now be removed from the watching brief list.
Discussion
The Committee noted the above and agreed that this issue could be removed from the watching brief list.
Recommendation
The Committee recommended that the issue of SSRIs and haemorrhage should be removed from the watching brief list.
2.2.2 Selective Serotonin Reuptake Inhibitors (SSRIs) and Withdrawal Reactions: Watching Brief Review
June 2006 minute item 2.2.11; March 2006 minute item 2.1.9; December 2005 minute item 3.1.5
Issue
In December 2005, the Committee recommended that Medsafe should review the evidence regarding the risks of withdrawal reactions with citalopram, and consider asking the product sponsors to update the data sheets.
Outcome
The data sheets for all three brands of citalopram (Cipramil, Pharmacy Retailing; Celapram, Pacific Pharmaceuticals; and Arrow-Citalopram, Arrow Pharmaceuticals) had been updated as requested regarding the risk of withdrawal reactions.
Discussion
The Committee noted the above and agreed that no further regulatory action was required at that time.
2.2.3 Anti-Tumour Necrosis Factor (Anti-TNF) Agents and the Risk of Hepatitis B Reactivation
June 2006 minute item 2.1.4; March 2006 minute item 3.2
Issue
In March 2006, the Committee recommended that Medsafe should require the sponsors of all three anti-tumour necrosis factor (anti-TNF) agents to include a consistent warning statement in the data sheets regarding the risk of hepatitis B virus reactivation, including the need to test hepatitis B serology prior to initiating therapy.
In March 2006, the Committee recommended that Medsafe should disseminate a 'Dear Healthcare Professional' letter to all prescribers, once the data sheet changes for the anti-TNF agents had been finalised.
Outcome
The sponsors of the anti-TNF agents (Enbrel [etanercept], Remicade [infliximab] and Humira [adalimumab]) responded to Medsafe's request for data sheet changes in June and July 2006. All three sponsors disagreed with the MARC's recommendation that all patients should be screened for hepatitis B virus (HBV) prior to initiation of anti-TNF therapy. However, they agreed to include warning statements, including the advice that patients at risk for HBV should be screened prior to initiation of anti-TNF therapy.
Medsafe reviewed the text proposed by the three sponsors and wrote back in August 2006 requesting that the following be included under 'Warnings and Precautions':
Use of TNF blockers has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients at risk for HBV infection should be evaluated for evidence of prior HBV infection before initiating TNF blocker therapy. Prescribers should exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Patients who are carriers of HBV and require treatment with TNF blockers should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. In patients who develop HBV reactivation, [product name] should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.
Medsafe intended to disseminate a Dear Healthcare Professional letter to New Zealand prescribers when the data sheets for all anti-TNF agents were updated.
Discussion
Medsafe informed the Committee that all three sponsors of anti-TNF agents had responded agreeing to update the data sheets as detailed above. A Dear Healthcare Professional letter was still to be drafted and disseminated by Medsafe.
The Committee noted the above and agreed that this issue should be removed from the active monitoring list.
Recommendation
The Committee recommended that the issue of anti-TNF agents and hepatitis B reactivation should be removed from the active monitoring list.
2.2.4 All Serious or Unexpected Adverse Reactions to Rosiglitazone: Standing Agenda Item
June 2006 minute item 2.1.5; March 2006 minute item 3.3
Issue
In March 2006, the Committee recommended that Medsafe should ask GlaxoSmithKline to update the Avandia data sheet with the most recent evidence on the risk of congestive cardiac failure with rosiglitazone.
Outcome
GlaxoSmithKline (GSK) submitted an updated Avandia data sheet to Medsafe in June 2006. The changes related to the risk of congestive cardiac failure were in line with the GSK Global Datasheet for rosiglitazone. Medsafe reviewed the changes and considered them acceptable.
In July 2006, GSK submitted further data and further updates to the Avandia data sheet regarding the risk of cardiac failure with Avandia. These data were being reviewed by Medsafe.
Discussion
Medsafe informed the Committee that collaboration was being undertaken with the Australian Therapeutic Goods Administration to ensure harmonisation of the warning statements in the Australian rosiglitazone Product Information sheets and the New Zealand Avandia data sheet.
The Committee noted the above and agreed that the Avandia data sheet should be harmonised with the Australian Product Information.
2.2.5 GRINZ party pill and convulsions (CARM case 67975)
June 2006 minute item 2.1.7; March 2006 minute item 4.1.3.1
Issue
In March 2006, the Committee recommended that NZPhvC should discuss with the Expert Advisory Committee on Drugs (EACD) the possibility of providing CARM adverse reaction data for party pill products to the EACD.
Outcome
The EACD had indicated that they were interested in receiving reports of events in association with party pill and benzylpiperazine-containing products. The NZPhvC was in the process of providing the EACD with the details they required.
Discussion
The Committee noted the above.
2.2.6 Citalopram / fentanyl and neonatal respiratory depression (CARM case 69860)
June 2006 minutes item 2.1.12; March 2006 minute item 4.1.8.1
Issue
In March 2006, the Committee recommended that Medsafe should ask the citalopram product sponsors to update the data sheets with information on the risks to neonates following maternal use.
Outcome
The data sheets for all three brands of citalopram (Cipramil, Pharmacy Retailing; Celapram, Pacific Pharmaceuticals; and Arrow-Citalopram, Arrow Pharmaceuticals) had now been updated as requested regarding the risk of neonatal respiratory depression.
Discussion
The Committee noted the above and agreed that no further regulatory action was required at that time.
See minute item 3.3 for a review of the use of SSRIs in pregnancy.
2.2.7 Tramadol - Interactions and Serious Reactions
June 2006 minute item 2.1.14; March 2006 minute item 4.2.1
Issue
In March 2006, Medsafe agreed to investigate the inconsistency between the maximum intravenous (IV) dose of tramadol in the Tramal data sheet (600mg) and DrugDex 2005 (400mg).
Outcome
CSL Pharmaceuticals responded in June 2006 to Medsafe's request for evidence to support a maximum daily dose of 600mg for IV Tramal. CSL informed Medsafe that DrugDex 2005 was referenced to the 1991 edition of Martindale – The Complete Drug Reference. Editions of Martindale subsequent to 1996 all contained a maximum recommended daily dose for parenteral administration of tramadol of 600mg. Furthermore, the British National Formulary, the Australian Tramal Product Information and the Tramal Core Data Sheet all stated a maximum IV daily dose of 600mg.
Medsafe considered that the above evidence was satisfactory and that no further regulatory action was required.
Discussion
The Committee noted the above and agreed that no further regulatory action was required at that time.
2.2.8 Clozapine and Haematological Malignancies
June 2006 minute item 2.1.17; March 2006 minute item 4.5.2
Issue
In March 2006, the Committee recommended that Medsafe should ask the clozapine sponsors to provide further data on the potential association between clozapine and haematological malignancies.
Outcome
Douglas (Clopine) supplied Medsafe with data on the potential association between clozapine and haematological malignancies in July 2006. Novartis (Clozaril) were not able to provide Medsafe with data in time for the September 2006 MARC meeting. Therefore, data from both sponsors will be provided to the Committee for review at the December 2006 MARC meeting.
Discussion
The Committee noted the above and agreed to review this issue in December 2006.
2.3 Report on Unresolved Actions Arising from Recommendations of the MARC
The following is a list of recommendations made by the MARC that had yet to be resolved. Prescriber Update articles are not included, as they are listed in the Schedule of Planned Prescriber Update Articles (see minute item 1.5.1). Nor are actions arising from the previous MARC meeting included, as they are listed in the Report on Actions Arising from the 126th Meeting of the MARC (see minute item 2.1).
2.3.1 Low Molecular Weight Heparins (LMWHs) in Renal Impairment
December 2005 minute item 2.2.12; September 2005 minute item 2.2.6; June 2005 minute item 2.2.11; September 2004 minute item 2.1.6; June 2004 minute item 2.1.4; March 2004 minute item 2.1.8; December 2003 minute item 4.1.1.5
Issue
In June 2005, the Committee recommended that Medsafe should contact the DHBNZ Safe Use of Medicines Group to enquire on the progress of the development of a protocol for the safe use of LMWHs in patients with severe renal impairment.
Outcome
The DHBNZ Safe Use of Medicines Group responded to Medsafe in October 2005. Medsafe was informed that an alert was currently being developed to advise prescribers on the required enoxaparin dosage adjustment for patients with renal impairment (creatinine clearance <50mL/min). In view of a lack of data for other LMWHs, this advice would not be extrapolated to the other LMWHs available in New Zealand. After consultation throughout New Zealand, the Safe Use of Medicines Group determined that there was only limited ability to perform anti-Xa monitoring in New Zealand and therefore monitoring could not be routinely recommended.
In December 2005, the Committee noted the above and agreed that Medsafe should bring the DHBNZ Safe Use of Medicines Group protocol to the MARC once it was finalised.
Discussion
Members noted that the DHBNZ Safe Use of Medicines Group protocol on the safe use of LMWHs in patients with severe renal impairment was still in development.
2.3.2 COX-2 Inhibitors/Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Impaired Fracture Healing: Watching Brief Review
March 2006 minute item 2.1.7; December 2005 minute item 3.1.3; March 2003 minute item 2.2.6; December 2002 minute item 2.1.7; September 2002 minute item 4.4
Issue
In December 2005, the Committee recommended that Medsafe should write again to experts in this area, seeking an updated opinion on the clinical risk of impaired fracture healing with COX-2 inhibitors/NSAIDs.
Outcome
In March 2006 the New Zealand Orthopaedic Association (NZOA) informed Medsafe that none of their New Zealand members had the relevant expertise to offer advice on this issue. The NZOA considered that further clinical studies were required before this question could be answered definitively.
In March 2006, the Committee noted the NZOA response and asked that Medsafe continue to attempt to contact experts for advice on this issue.
This issue was on the watching brief list, scheduled for review in December 2006.
Discussion
The Committee noted the above and asked that Medsafe contact national or international experts to seek their opinion on the clinical risk of impaired fracture healing with the COX-2 inhibitors/NSAIDs, and subsequently bring the results back for the review in December 2006.
2.3.3 Heparin and thrombocytopenia (CARM case 69852)
June 2006 minute item 2.1.9; March 2006 minute items 4.1.4.2 and 4.1.4.3
Issue
In March 2006, the Committee agreed that no further regulatory action was required at that time, however asked that NZPhvC report back once experience in other countries was known.
Outcome
In June 2006, NZPhvC reported that Australia and the Netherlands had been approached. Australia had not noticed an association with brand change and, as yet, there had been no response from the Netherlands.
In June 2006, the Committee noted the above and agreed that no further regulatory action was required at that time, however, asked that NZPhvC report back once experience in the Netherlands was known.
As at August 2006, no feedback was available from the Netherlands.
Discussion
The Committee noted the above and agreed that no further regulatory action would be required. This issue could be removed from the list of unresolved actions.
Recommendation
The Committee recommended that the issue of heparin and thrombocytopenia could be removed from the list of unresolved actions arising from MARC recommendations.
3. Pharmacovigilance Issues
3.1 Quinine, Nocturnal Leg Cramps and Thrombocytopenia
References
- Medsafe report for the MARC. August 2006.
- Patient Notes: Nocturnal Leg Cramps. Postgraduate Medicine 2002;111(2):125-126.
- Q200 and Q300 data sheet (funded brand of quinine 200mg and 300mg tablets) – Pacific Pharmaceuticals Ltd
- Graph of Pharmac data showing numbers of quinine prescriptions dispensed between Jan 2001-April 2006.
- Arroll B. Cochrane Corner – Treatment for leg cramps. NZ Family Physician 2003;30(5):353.
Issue
At the June 2006 MARC meeting, the Committee considered a case report of purpura and thrombocytopenia associated with quinine used in the treatment of nocturnal leg cramps. The Committee recommended that NZPhvC should review the 12 cases of thrombocytopenia with quinine it had received in the last five years and discuss the issue with Medsafe, then bring it back to the MARC if warranted (see minute item 2.1.10). For this meeting, Medsafe prepared a report for the MARC, including data from NZPhvC, in order to:
- provide the MARC with the necessary information to determine whether the risk of thrombocytopenia outweighed the benefits of quinine in the treatment of nocturnal muscle cramps.
- seek the expert opinion of MARC on to how best to manage this risk.
Nocturnal leg cramps are sudden, involuntary contractions of the calf muscles that occur during the night or while at rest. It had been estimated that between one-third and half of elderly people suffer from leg cramps. The aetiology of muscle cramps was largely unknown; most cases seemed to be idiopathic with no obvious underlying cause. The lack of explicit diagnostic criteria or a universally accepted definition for muscle cramp reflected the fact that many in the medical profession regarded it as a trivial or benign condition. This view was not shared by those who suffered from its distressing symptoms, which could cause sleep disruption and reduced quality of life for patients.
Quinine and its derivatives, quinine sulphate, hydroquinine and quinidine had been used for the relief of nocturnal muscle cramps ever since a series of studies reported beneficial effects in the 1940s. However, these studies were basic prospective intervention studies that were neither controlled nor randomised.
Quinine sulphate tablets had been available in New Zealand since at least 1980. At the time of this meeting there were three brands marketed: Q200 (200mg tablets) and Q300 (300mg tablets), Pacific Pharmaceuticals; Apo-Quinine (200mg and 300mg tablets), Apotex; Quinoc-F (300mg tablets), Douglas Pharmaceuticals. All three brands were indicated:
- concurrently with tetracycline or clindamycin or pyrimethamine plus sulphadiazine or sulphadoxine in the treatment of chloroquine-resistant malaria caused by Plasmodium falciparum.
- for prophylaxis and treatment of nocturnal recumbency leg muscle cramps, including those associated with arthritis, diabetes, varicose veins, thrombophlebitis, arteriosclerosis and static foot deformities.
- for treatment of myotonia.
The data sheets for all three brands stated under 'Dosage and Administration – Nocturnal leg cramps':
200 to 300mg at bedtime; an additional dose of 200 to 300mg may be taken following the evening meal.
In the treatment of nocturnal recumbency leg cramps quinine should be discontinued if leg cramps do not occur after several consecutive nights of therapy to determine if continued therapy is needed.
PHARMAC informed Medsafe that from January 2001 to April 2006, the number of prescriptions dispensed for quinine tablets (both 200mg and 300mg) ranged from 4268 to 6871 each month.
In March 2006, quinine salts were reclassified to Prescription-only medicines, except in medicines containing 50 mg or less per recommended daily dose which were classified as General Sales medicines. The classification change was implemented to harmonise with Australia where quinine was rescheduled in 2004 because of the risk of thrombocytopenia.
The first meta-analysis (107 patients) of quinine's efficacy in muscle cramp was published in 1995 and combined the results of six randomised, double-blind, controlled trials that measured nocturnal leg cramps. It concluded that treatment with quinine sulphate significantly reduced the number of cramps over a 4-week period by 8.83 (95% confidence interval (CI) 4.2 to 13.5) fewer cramps compared to placebo. However, quinine did not significantly change the duration and intensity of individual cramps. The same authors published a second meta-analysis (659 patients) in 1998 that included data from three unpublished trials which, when incorporated, decreased the magnitude of the initial result. It was found that patients taking quinine had 3.6 (95% CI 2.2 to 5.1) fewer cramps in a 4-week treatment period, compared to placebo. There was a statistically significant reduction in severity but no additional analysis was undertaken for duration.
Quinine carries not only a risk of dose-related (therefore predictable and potentially preventable) cinchonism-type adverse effects but also the risk of hypersensitivity-type reactions, which are not predictable and can be life-threatening. The dose-related toxic effects of quinine were more commonly, but not exclusively, seen with the doses used for malaria (1800mg daily for 3-7 days, compared to the 200-300mg dose used for leg cramps). However, toxicity had occurred at the dose used for leg cramps.
A 1998 review of published reports of drug-induced thrombocytopenia (excluding heparin) reported quinine to be second only to quinidine as the most common medicine implicated in drug-induced thrombocytopenia. This idiosyncratic hypersensitivity reaction occurs via an immune-based mechanism, and has even occurred following ingestion of tonic water. Therefore, patients who have experienced quinine-induced thrombocytopenia should be advised to avoid all quinine-containing products, including tonic water. Other quinine-related hypersensitivity reactions include intravascular coagulation, pancytopenia and haemolytic uraemic syndrome.
A review of 53 spontaneous reports from FDA MedWatch data of quinine-induced thrombocytopenia found a median time-to-onset of seven days; seven of the cases occurred within one day. However, some cases reported ‘prn’ (as needed) dosing, which may have skewed the time-to-onset range.
As at 19 July 2006, CARM had received 125 reports of adverse reactions to quinine; of these 43 were of thrombocytopenia, including two deaths. Interestingly, 12 of the 43 thrombocytopenia reports were lodged in the last five years (i.e. Jan 2000-June 2006); and between 1996 and 2000 there were no cases of thrombocytopenia reported to CARM.
An analysis of the 12 reports to CARM lodged in the past five years of thrombocytopenia with quinine showed the following:
| Males 4; Females 8. Age range: 40 to 93 years (median age 65 years) | ||
|---|---|---|
| Duration of treatment | <24 hours | 6 |
| 24 hours to <7 days | 4 | |
| 7 days to <30 days | 1 | |
| Unknown | 1 | |
| Seriousness* | Life-threatening | 4 |
| Hospital admission | 8 | |
| Severity | Platelet counts as low as 1, 2 and 5 x 109/L | |
| Three patients haemorrhaged (one cerebral); one had severe purpura; and one also had haemolytic uraemic syndrome. | ||
| Outcome | Improvement on dechallenge | 8 |
| Recurred on rechallenge | 1 | |
| Not recovered | 2 | |
| Unknown | 1 | |
*Of the eight patients admitted to hospital, two were also taking aspirin
(one with bleeding) and two were taking co-suspect medicines (imipenem and
ciprofloxacin). Of the four with life-threatening reactions (one reclassified
from 'hospital admission' to 'life-threatening' since the June 2006 MARC
meeting), one was taking a co-suspect medicine (celecoxib); one had hepatic
disease and other significant medical conditions; and another had undocumented
other medicines and conditions.
| In the WHO database (Vigibase) there were: | |
|---|---|
| Total reports for quinine (first in 1970) | 2041 |
| Total reports of thrombocytopenia | 451 |
| Information Component (IC) | 3.9 |
| IC025 (the 95% lower confidence limit) | 3.77 |
| IC025 (old) | 3.76 |
| Number of deaths** | 12 |
** Three deaths were coded as 'medicine may be contributory'. Of the other
nine, there were co-suspect medicines in three reports but quinine was the
only suspect medicine in the six other cases.
In October 2004, the Australian Therapeutic Goods Administration (TGA) determined that, due to the risk of thrombocytopenia with quinine, the indication of nocturnal cramps should be removed. Information supplied by the Adverse Drug Reactions Unit (ADRU) was that the number of Pharmaceutical Benefits Scheme-subsidised prescriptions dispensed per month had dropped from 50,000-60,000 in 2003 to 20,000 by the end of 2005.
In 1994, the United States Food and Drug Administration (FDA) ruled that over-the-counter (OTC) medicines containing quinine for leg cramps were prohibited from being marketed. This decision followed the FDA's consideration of the risks and benefits of OTC quinine for nocturnal leg cramps. The FDA concluded that quinine was no longer safe and effective for this use because: no studies demonstrated that quinine was effective against night leg cramps; night leg cramps were not a threat to life or health; and risks of harm outweighed any potential benefits.
In the United Kingdom, at the time of this meeting, quinine sulphate 200mg and 300mg tablets were classified as Prescription-only medicines and were indicated for the treatment of falciparum malaria and nocturnal leg cramps.
Quinine had been marketed in Canada since at least 1966. It was classified as a Prescription-only medicine and was not officially approved for nocturnal leg cramps. Up to March 2006, Health Canada had received 14 reports of thrombocytopenia associated with quinine use.
Discussion
The Committee noted the report by Medsafe, summarised above.
Members noted that there was strong evidence that thrombocytopenia was a rare but potentially serious adverse reaction to quinine which could occur after a short duration of treatment and was potentially fatal. Furthermore, there were limited data to support the efficacy of quinine in nocturnal leg cramps.
Members commented that there were limited pharmacological and non-pharmacological alternatives available to treat nocturnal leg cramps. They noted the data provided by Pharmac suggesting that prescribing rates of quinine in New Zealand had been relatively stable since 2001.
In Australia, members noted that the indication of nocturnal leg cramps had been removed from quinine products in 2004 due to the risk of thrombocytopenia. An Adverse Drug Reactions Bulletin published at that time informed prescribers of the removal of the indication. The number of prescriptions dispensed in Australia subsequently decreased by approximately two-thirds up until the end of 2005.
Medsafe reminded the Committee that removing the quinine indication of nocturnal leg cramps would harmonise the regulatory status of quinine with that in Australia. However, this would not prevent quinine from being prescribed off-label, as it would continue to be available for the treatment of malaria. Additionally, the removal of the indication could only occur after the product sponsors had been given the opportunity to provide harm and efficacy data. Medsafe also advised the Committee that removing the indication of nocturnal leg cramps from quinine would limit the ability to issue advice on the use of the medicine for leg cramps.
The Committee considered that the risk of thrombocytopenia was unpredictable and potentially fatal; that it may occur even with short exposure; and that the efficacy of quinine for leg cramps was not clearly established. As a result, the Committee recommended that the indication of nocturnal leg cramps should be removed from quinine products in New Zealand in order to manage the risk of thrombocytopenia and to harmonise with Australia. They also agreed that Medsafe should write an article for publication in Prescriber Update informing prescribers of the removal of the indication.
The Committee queried whether there were any other medicines available in New Zealand which contained quinine. Medsafe advised that Nicobrevin (a General Sale medicine used for smoking cessation) contained 15mg of quinine and that some foods such as tonic water also contained small quantities (10-15mg per 200ml glass) of quinine. Medsafe informed the Committee that there had been a small number of international reports of thrombocytopenia occurring following ingestion of tonic water, and that patients who had experienced thrombocytopenia with quinine were advised to subsequently avoid tonic water. The Committee agreed that, as the quantities of quinine in Nicobrevin and tonic water were small, no regulatory action on these products was warranted at that time.
Recommendations
The Committee recommended that Medsafe should pursue removal of the indication "prophylaxis and treatment of nocturnal recumbency leg muscle cramps, including those associated with arthritis, diabetes, varicose veins, thrombophlebitis, arteriosclerosis and static foot deformities" from quinine products.
The Committee recommended that, following resolution of the above, Medsafe should write an article for publication in Prescriber Update informing prescribers of the change to the indications for quinine.
3.2 Inhaled Long-Acting Beta-Adrenoceptor Agonists (LABAs) and the Risk of Fatal and Non-Fatal Asthma Exacerbations
References
- Medsafe report for the MARC. August 2006.
- Pharmac. Units Dispensed of Long-Acting Beta Agonist Inhalers. January 2003 to May 2006.
- NZPhvC. LABAs and fatal / non-fatal asthma exacerbations. WHO, CARM and IMMP data. August 2006.
- FDA Public Health Advisory. Serevent Diskus (salmeterol xinafoate inhalation powder), Advair Diskus (fluticasone proprionate and salmeterol inhalation powder) and Foradil Aerolizer (formoterol fumarate inhalation powder). 18 November 2005, updated 15 May 2006.
- Medicines and Healthcare products Regulatory Agency. Reminder: Salmeterol
(Serevent) and formoterol (Oxis, Foradil) in asthma management. 21 November
2005.
- Medicines and Healthcare products Regulatory Agency. Questions and answers: safety of Long-Acting Beta-Adrenoceptor agonists (formoterol and salmeterol) in the treatment of asthma. 18 November 2005.
- AstraZeneca. Letter dated 17 August and Analysis of Safety Data for Formoterol Regarding Asthma-related Adverse Effects, based on data for Oxis and Symbicort. 21 October 2005.
- Nelson HS et al. The Salmeterol Multicenter Asthma Research Trial – A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol. Chest 2006;129:15-26
- Salpeter SR et al. Meta-analysis: Effect of Long-Acting Beta-Agonists on Severe Asthma Exacerbations and Asthma-Related Deaths. Ann Int Med 2006; 144:904-912
- Glassroth J. The Role of Long-Acting β-Agonists in the Management of Asthma: Analysis, Meta-Analysis and More Analysis. Ann Intern Med 2006;144:936-937
- Crane J. Long-acting beta agonists – prescribe with care. NZMJ 7 July 2006, Vol 119, No 1237.
- Data sheets:
- Novartis NZ Ltd. Foradil data sheet. 21 March 2006.
- GlaxoSmithKline NZ Ltd. Serevent Accuhaler data sheet. 19 October 2005.
- GlaxoSmithKline NZ Ltd. Seretide Accuhaler data sheet. 19 October 2005.
- AstraZeneca Ltd. Oxis Turbuhaler data sheet. 15 August 2002.
- AstraZeneca Ltd. Symbicort 100/6 and 200/6 Turbuhaler data sheet. 30 April 2004.
Late papers:
- AstraZeneca. Letter and accompanying papers re: Oxis Turbuhaler. 27 June 2006.
- Dr P. Black (consultant to Medsafe). Report on Oxis Turbuhaler. August 2006.
- Dr A. Bolotovski (Senior Medical Advisor, Evaluation team, Medsafe). Letter to AstraZeneca re: Oxis Turbuhaler. 29 August 2006.
Background
In March 2003, the MARC reviewed the interim results of the Salmeterol Multicenter Asthma Research Trial (SMART), which showed a higher, although not statistically significant, number of life-threatening experiences in salmeterol-treated patients. The Committee recommended that the LABA product data sheets should be updated to emphasise that the use of these agents as maintenance therapy should be in addition to inhaled corticosteroid therapy. Although the MARC recommended in March 2003 that a Prescriber Update article be written on this issue, this was later rescinded as the final results of the SMART study were not yet available.
In September 2003, the MARC was informed that Novartis had declined to strengthen the warnings in the Foradil data sheet as they considered the data sheet to already adequately convey that Foradil must only be used as maintenance therapy in addition to inhaled corticosteroids. In December 2003, the MARC was informed that GlaxoSmithKline had updated the Serevent data sheet as requested.
The interim IMMP data for salmeterol and eformoterol were presented to the MARC in March 2003. Preliminary analyses had suggested a signal of tachyphylaxis (blunting of the effect of short-acting beta agonist relievers).
Products
The long-acting beta-adrenoceptor agonists (LABAs) are inhaled bronchodilators used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). The mono-ingredient LABA products marketed in New Zealand at the time of this meeting were:
- Serevent Inhaler (salmeterol 25mcg/dose; GlaxoSmithKline)
- Serevent Accuhaler (salmeterol 50mcg/dose; GlaxoSmithKline)
- Foradil (eformoterol 12mcg/dose; Novartis)
- Oxis Turbuhaler (eformoterol 6mcg/dose and 12mcg/dose; AstraZeneca)
The combination products containing a LABA and an inhaled corticosteroid marketed in New Zealand at the time of this meeting were:
- Seretide Inhaler (fluticasone 50, 125 or 250mcg with salmeterol 25mcg; GlaxoSmithKline)
- Seretide Accuhaler (fluticasone 50, 100 or 250mcg with salmeterol 50mcg; GlaxoSmithKline)
- Symbicort 100/6, 200/6 and 400/12 Turbuhalers (budesonide 100, 200 or 400mcg with eformoterol 6mcg; AstraZeneca)
Funding
From 1 August 2006, PHARMAC increased the funding and availability of LABAs. Changes included:
- The Special Authority restriction was removed from Serevent Accuhaler (salmeterol), Oxis Turbuhaler (eformoterol) and Foradil (eformoterol) inhalers, and a Prescription Guide was applied. These products were all fully funded.
- Access to combination inhaled corticosteroid and LABA inhalers (Seretide and Symbicort) was widened. Seretide became funded for the first time. In total there were seven combination inhalers fully funded, under Special Authority: Seretide 50/25 and 125/25; Seretide Accuhaler 100/50 and 250/50; Symbicort 100/6, 200/6 and 400/12.
Usage
Data provided by PHARMAC showed that the number of units of Symbicort, Serevent and Oxis had increased between January 2003 and May 2006. In particular, the number of units of Symbicort dispensed had increased approximately four-fold.
Adverse reactions data
NZPhvC provided the Committee with an analysis of case reports to CARM, IMMP and the WHO of fatal and non-fatal asthma exacerbations. Eformoterol and salmeterol had been monitored under IMMP from March 1992 to November 2000. In the CARM database, from a total of 16 reports for eformoterol, there had been four exacerbation-type reactions with no deaths. From a total of 14 reports for salmeterol, there had been three exacerbation-type reactions with no deaths. In the WHO database, from a total of 1,002 reports for eformoterol there had been 56 exacerbation-type reports (deaths were not investigated). From a total of 5,415 reports for salmeterol, there had been 725 exacerbation-type reports including 26 deaths.
New Zealand regulatory action
In November 2005, following the United States Food and Drug Administration (FDA) Alert that use of LABAs was associated with an increased risk of worsening asthma, Medsafe wrote to the sponsors of eformoterol and salmeterol products requesting updates to the data sheets in the 'Warnings and Precautions', 'Dosage and Administration' and 'Clinical Trials' sections. Medsafe required that the following information be included in all New Zealand LABA data sheets, as well as details of the LABA clinical trials upon which the FDA warnings were based.
- LABAs must only be prescribed in combination with anti-inflammatory therapy such as inhaled corticosteroids. LABAs must never be prescribed as monotherapy in the treatment of asthma.
- LABAs must not be used to treat acute asthma exacerbations. Short-acting beta agonists must always be available to be used as rescue medication.
- LABAs must not be initiated or the dose increased during an episode of significant worsening or acute deterioration in asthma control.
- Patients must be advised to seek medical treatment immediately if their asthma deteriorates significantly.
Novartis updated the Foradil Core Data Sheet in consultation with the FDA and subsequently submitted an updated Foradil data sheet to Medsafe in March 2006.
In March 2006, GlaxoSmithKline (GSK) agreed to update the Serevent data sheet with the majority of warning statements as requested and proposed some changes to the wording of others. GSK asserted, however, that the changes to the Seretide data sheet were not necessary, on the basis that Seretide is a combination product whereby salmeterol is necessarily administered concurrently with fluticasone. GSK considered this position to be consistent with the findings of the SMART study. The Australian TGA had agreed in November 2005 that no changes were required to the Seretide Product Information consequent to the SMART study. Medsafe agreed that, in the interests of trans-Tasman harmonisation, the existing Seretide data sheet was acceptable.
In December 2005, AstraZeneca requested deferral of changes to the Oxis and Symbicort data sheets until the outcome of data submitted to the Medsafe evaluation team was known. The evaluation of these data had recently been completed. The evaluation concluded that the data submitted did not reassure Medsafe that Oxis did not carry the same risk of asthma exacerbation as salmeterol. At the time of this meeting, the data sheets for Oxis and Symbicort had not been updated as requested in November 2005.
International regulatory action
In the United States, a black-box warning reflecting the SMART mortality data was added to salmeterol (Serevent and Advair) labelling in 2003. On 18 November 2005, the FDA alerted healthcare professionals and patients that LABAs had been associated with possible increased risk of worsening wheezing (bronchospasm) in some people, and requested that manufacturers update warnings in their existing product labelling. The FDA highlighted the following recommendations:
- LABAs should not be the first medicine used to treat asthma. LABAs should be added to the asthma treatment plan only if other medicines do not control asthma, including the use of low-or-medium dose corticosteroids.
- Do not stop using your LABA or other asthma medicines that your healthcare professional has prescribed for you unless you have discussed with your healthcare provider whether or not to continue treatment.
- Do not use your LABA to treat wheezing that is getting worse. Call your healthcare professional right away if wheezing worsens while using a LABA.
- LABAs do not relieve sudden wheezing. Always have a short acting bronchodilator medicine with you to treat sudden wheezing.
On 2 March 2006, the FDA approved new safety labelling and Medication Guides for patients for Serevent Diskus (salmeterol xinafoate) and Advair Diskus (fluticasone propionate; salmeterol xinafoate). On 19 June 2006, the FDA approved Advair HFA and approved a patient Medication Guide and new safety labelling for Foradil (formoterol fumarate).
The Australian Therapeutic Goods Administration (TGA) reviewed the issue of asthma exacerbations with the LABAs in 2004. ADRAC published a Bulletin article in June 2004 entitled 'Corticosteroids should be used with long-acting β2 agonists'. At the time of this meeting, the Drug Safety and Evaluation Branch (DSEB) of the TGA was satisfied that the current Australian Product Information sheets were adequate and consistent with the treatment guidelines prepared by the National Asthma Council.
In November 2005, the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) issued a reminder to prescribers on salmeterol and formoterol in asthma management. The advice was reiterated in the MHRA’s safety bulletin, Current Problems in Pharmacovigilance, in May 2006.
Health Canada issued a Public Advisory in September 2003 informing prescribers of the interim results of the SMART study. In September 2005, Novartis and GlaxoSmithKline issued Dear Healthcare Professional letters in Canada advising of changes to the Product Information sheets for Foradil, Serevent and Advair to reflect the results of the SMART study.
SMART study
The interim analyses of the SMART study were reviewed by the MARC in 2003. The final study report was published in January 2006. The purpose of SMART was to compare the safety of salmeterol xinafoate or placebo added to usual asthma care. SMART was a 28-week, randomised, double-blind, placebo-controlled, observational study. The primary focus of the study was to compare respiratory-related deaths and life-threatening experiences between the two groups.
The SMART study was started in 1996 after the FDA received post-marketing reports of several asthma deaths associated with the use of salmeterol and following the publication of studies raising concern about the regular use of short-acting and long-acting beta-agonists. In January 2003, SMART was terminated prematurely by GlaxoSmithKline (GSK) following a planned interim analysis in 26,355 subjects, due to preliminary findings in African Americans and difficulties in enrolment.
The SMART study found no significant difference between treatments for the primary outcome of respiratory-related deaths or life-threatening experiences. However, there were small, but statistically significant increases in respiratory- and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population in the salmeterol group compared with placebo. The imbalance occurred largely in the African American sub-population. The African American sub-group had more severe asthma and lower rates of inhaled corticosteroid use.
Key weaknesses of the SMART study were:
- The subjects were predominantly poorly controlled asthmatics, with an increased background risk of serious asthma exacerbations.
- The study was not designed to detect the influence of inhaled corticosteroid use. The status of inhaled corticosteroid use was measured at baseline but not throughout the study.
- There were low rates of concomitant inhaled corticosteroid use (49% in Caucasians and 38% in African Americans; 47% of total population).
- The study was not designed to detect differences between ethnic sub-groups. The analysis of ethnic sub-groups was post-hoc.
Meta-analysis
The Salpeter et al meta-analysis, published in 2006, aimed to assess the risk for severe, life-threatening, or fatal asthma exacerbations associated with long-acting beta agonists. The study summarised data from 19 randomised, placebo-controlled trials involving 33,826 participants with asthma. The key results were:
- Severe exacerbations requiring hospitalisation: Odds ratio (OR) 2.6, 95% confidence interval (CI) 1.6 - 4.3.
- Life-threatening exacerbations: OR 1.8, 95% CI 1.1 - 2.9.
- Hospitalisations: Absolute increase over 6 months 0.7%, 95% CI 0.1%
- 1.3%
- Salmeterol OR 1.7, 95% CI 1.1 - 2.7
- Formoterol OR 3.2, 95% CI 1.7 - 6.0
- Children OR 3.9, 95% CI 1.7 - 8.8
- Adults OR 2.0, 95% CI 1.1 - 3.9
- Asthma-related deaths: OR 3.5, 95% CI 1.3 - 9.3
- Pooled risk difference 0.07%, 95% CI 0.01% - 0.1%
The meta-analysis had a number of weaknesses:
- The SMART study, which had a number of weaknesses, had by far the largest numbers, giving it the most influence in the pooled analysis of life-threatening asthma exacerbations (79.9%).
- The analysis of deaths was based entirely on the results of the SMART study.
- There were no details provided of the individual studies with regards to the patient populations (such as ethnicity, severity of asthma, asthma treatments or compliance with treatment) or methodology used. Therefore, there was a possibility of unidentified heterogeneity between studies.
- The SMART study (and a number of the other studies) had low rates of concomitant inhaled corticosteroid use, which was not in line with asthma treatment guidelines.
Discussion
The Committee noted the report by Medsafe, summarised above.
Members reviewed the final report of the SMART study. They agreed that the study lacked external validity, as the proportion of subjects taking concomitant inhaled corticosteroids was not consistent with routine clinical practice. Members agreed with Medsafe that the Salpeter et al meta-analysis did not add appreciably to the existing body of evidence on this issue.
Members commented that it was well-recognised amongst prescribers that LABAs should only be prescribed concomitantly with an inhaled corticosteroid. However, some patients perceived the LABA to be the more effective agent and therefore tended to stop using their inhaled corticosteroid. Members agreed that the best way to ensure that LABAs are always used concomitantly with an inhaled corticosteroid is to prescribe a combination product. Members noted that the recent changes by PHARMAC had widened the availability of LABAs, particularly the combination products. Members also noted that not all asthma is severe enough to warrant use of a LABA and many patients could be maintained on an inhaled short-acting beta agonist for acute relief of asthma symptoms and an inhaled corticosteroid.
The Committee noted that Medsafe continued to have safety concerns about the LABAs. Members reviewed the data provided by AstraZeneca opposing update of their eformoterol product data sheets with information on the risk of serious asthma exacerbations. These data had not been evaluated by the FDA in their assessment of the safety profile of eformoterol, but had previously been reviewed by Medsafe's evaluation team. The MARC concluded that the data did not provide reassurance that eformoterol bore less risk of life-threatening asthma exacerbations than salmeterol. The Committee agreed that Medsafe should again request AstraZeneca to update the Oxis and Symbicort data sheets to include warnings on the risk of serious asthma exacerbations, as previously requested.
The Committee noted that the Best Practice Advocacy Centre (bpac) had published Asthma POEMs (Patient Orientated Evidence that Matters) in February 2003. This POEM did not include information on the risk of asthma exacerbations with the LABAs. Members agreed that Medsafe should ask bpac to consider revising its Asthma POEMs with the most recent evidence on the role and limitations of the LABAs in asthma management.
The Committee also noted that the New Zealand Guidelines Group (NZGG) had published a guideline on the Diagnosis and Treatment of Adult Asthma in September 2002. This guideline did not include information on the risk of asthma exacerbations with the LABAs. Members agreed that Medsafe should ask NZGG to consider revising its guideline with the most recent evidence on the role and limitations of the LABAs in asthma management.
It was considered by the Committee that it would be of value for an article to be published in Prescriber Update summarising the changes to the LABA data sheets and reminding prescribers about the importance of patients continuing to use their inhaled corticosteroids. They agreed that this issue should be placed on the watching brief list.
Recommendations
The Committee recommended that Medsafe should again ask AstraZeneca to update the Oxis Turbuhaler and Symbicort data sheets to include warnings on the risk of serious asthma exacerbations.
The Committee recommended that Medsafe should ask Best Practice Advocacy Centre to consider revising its Asthma POEMs with the most recent evidence on the role and limitations of the LABAs in asthma management.
The Committee recommended that Medsafe should ask the New Zealand Guidelines Group to consider revising its Diagnosis and Treatment of Adult Asthma guideline with the most recent evidence on the role and limitations of the LABAs in asthma management.
The Committee recommended that Medsafe should consider publishing an article in Prescriber Update summarising the changes to the LABA data sheets.
The Committee recommended that the issue of inhaled long-acting beta agonists (LABAs) and the risk of fatal and non-fatal asthma exacerbations should be placed on the watching brief list. The first annual review should include PHARMAC usage data for the mono-ingredient and combination inhaled corticosteroid/LABA products.
3.3 SSRIs and Use in Pregnancy: Watching Brief Review
References
- Medsafe. Report for the MARC. August 2006.
- Oberlander, T. et al (2006) Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Archives of General Psychiatry, 63, 898-906
- Kallen, B (2006) Letter to the Editor: Antidepressant drugs during pregnancy and infant congenital heart defect. Reproductive Toxicology, 21, 221-222
- Cohen, L. et al (2006) Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA, 295(5), 499-507
- Chambers, D. et al (2006) Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. NEJM, 354, 579-587
- Wen, S. et al (2006) Selective serotonin reuptake inhibitors and adverse pregnancy outcomes. American Journal of Obstetrics and Gynecology, 194, 961-966
Issue
This issue had been reviewed by the MARC in September 2005 (minute item 3.5), December 2005 (minute item 2.1.7), March 2006 (minute item 2.2.7) and June 2006 (minute item 2.2.8). The MARC recommended that this issue be placed on the watching brief list in September 2005 and this was the first annual review.
In September 2005, on reviewing preliminary results from two studies suggesting that the use of selective serotonin reuptake inhibitors (SSRIs), in particular paroxetine, during pregnancy may be associated with an increased risk of foetal abnormalities, the MARC concluded that the data available were insufficient to determine the strength of the association. The MARC agreed that the information disseminated by GlaxoSmithKline to New Zealand general practitioners, pharmacists, specialists and midwives in September 2005 was satisfactory, and considered the proposed data sheet update for Aropax adequately addressed this issue. The data sheet for the Paroxetine brand was equivalently updated in May 2006 and the Apo-Paroxetine data sheet contained the warning statements when first published in April 2006.
In December 2005, the United Kingdom Medicines and Healthcare products Regulatory Agency, the United States Food and Drug Administration (FDA) and Health Canada each issued public advisories and/or Dear Healthcare Professional letters advising of the results of two studies that showed an increased risk of congenital abnormalities with paroxetine (these papers were reviewed by MARC in December 2005).
In July 2006, the FDA issued a Public Health Advisory entitled "Treatment challenges of depression in pregnancy". This informed prescribers and patients of the results of two studies (provided to the MARC for this meeting). The study by Cohen et al illustrated the potential risk of relapsed depression after stopping antidepressant medication during pregnancy. The study by Chambers et al suggested there might be an additional, though rare, risk of persistent pulmonary hypertension of the newborn (PPHN) when SSRI medications were used during pregnancy.
NZPhvC provided updated CARM and WHO data on the number of cases of foetal malformation and foetal deaths associated with the use of SSRIs in pregnancy. CARM had received six reports of foetal malformations (various) in relation to SSRIs since 30 September 2005: one with fluoxetine and five with paroxetine. Three of these were reviewed at the March 2006 MARC meeting, one at the June 2006 meeting, one was reviewed at this meeting (see minute item 4.1.7.2). The remaining report was to be brought to MARC at its December 2006 meeting.
Medsafe provided a summary of key publications since September 2005.
Discussion
The Committee noted the report by Medsafe, summarised above.
Members commented that, in their experience, the risk of neonatal withdrawal was well-known among lead maternity carers (LMCs) and paediatricians, but that the risks of congenital abnormalities and persistent pulmonary hypertension of the newborn (PPHN) were less well-known.
Members commented that the risk of cardiac abnormalities with SSRIs was greatest following exposure in the first trimester, and could result in significant morbidity. They noted that some pregnancies are not planned, and therefore women might not be aware that they are pregnant for a number of weeks. In this circumstance, the foetus would be exposed to the SSRI during the first weeks of gestation. The risk of PPHN, however, is greatest in infants exposed after the 20th week of gestation.
The Kallen et al and Cohen et al papers also examined tricyclic antidepressants and noted that the risks of teratogenicity with these were not elevated (apart from with clomipramine). Members also noted that the risks of teratogenicity with the tricyclic antidepressants had been studied in the 1970’s; however the methodologies used in these studies may not have been as rigorous as would be employed now. Members agreed that there was a lack of evidence about which alternative antidepressants would be safer than SSRIs in pregnancy.
Members considered that it would be of value for the risks associated with the use of SSRIs in pregnancy to be communicated to prescribers and LMCs by way of Prescriber Update article. The article should advise prescribers to discuss the risks associated with the use of SSRIs with their female patients of child-bearing age. If a female patient treated with an SSRI is planning to become pregnant, her history should be reviewed and the options discussed.
Members noted that there were some inconsistencies in the SSRI data sheets regarding the risks of use in pregnancy. In particular, the Apo-Paroxetine data sheet incorrectly stated that it was Australian Drug Evaluation Committee pregnancy category B3 instead of category C. Furthermore, the Plinzene and Apo-Fluoxetine data sheets did not describe the risk of neonatal withdrawal and only the Aropax data sheet described the risk of PPHN. The Committee agreed that Medsafe should ask the product sponsors to update the data sheets to address these issues.
The Committee agreed that the issue of SSRIs and use in pregnancy should remain on the watching brief list. They also agreed under minute item 4.1.7.2 that developmental delay should be added to the issue of SSRIs and use in pregnancy monitored on the watching brief list.
Recommendations
The Committee recommended that Medsafe should consider publishing an article in Prescriber Update alerting prescribers and lead maternity carers (LMCs) to the risks associated with the use of SSRIs in pregnancy.
The Committee recommended that Medsafe should ask all sponsors of SSRIs to update the data sheets as per the Aropax data sheet to describe the potential risk of persistent pulmonary hypertension in the newborn (PPHN) following foetal exposure.
The Committee recommended that Medsafe should ask the sponsors of Apo-Fluoxetine (Apotex) and Plinzene (Douglas) to update the data sheets to describe the risk of neonatal withdrawal following foetal exposure.
The Committee recommended that Medsafe should ask the sponsor of Apo-Paroxetine (Apotex) to amend the data sheet categorisation of risk during pregnancy from Australian Drug Evaluation Committee category B3 to category C.
3.4 Lipid-Lowering Agents and Psychiatric Adverse Reactions: Active Monitoring Review
References
- NZPhvC. Report for the MARC. August 2006
- Extract from minutes of the 124th MARC meeting, held on 15 December 2005. Lipid-lowering agents and Psychiatric Adverse Reactions.
Issue
The MARC reviewed the issue of lipid-lowering agents and psychiatric adverse reactions at its meeting in December 2005. Members agreed that NZPhvC should investigate publishing an article on this issue internationally and then subsequently in Prescriber Update. The Committee also recommended that this issue should be placed on the active monitoring list for annual review. This was the first such review, brought forward from December 2006. In June 2006, ezetimibe was added to the list of lipid-lowering agents to be included in the review.
The NZPhvC had submitted a paper "Psychiatric Adverse Reactions with Statins, Fibrates and Ezetimibe – implications for lipid lowering agents" for publication in an international journal.
Between September 2005 and June 2006, there had been 35 reports to CARM of psychiatric adverse reactions in association with simvastatin. 23 of these were pharmaceutical company reports received following media publicity concerning rhabdomyolysis and memory impairment associated with the statins. Three pharmaceutical company reports were for memory-related problems, three were for depression and the remainder reported tiredness/lethargy/fatigue-type symptoms. Of the 12 non-company reports, there were four reports with 'memory' reactions and five with tiredness/lethargy/fatigue reactions, as well as other events such as anxiety, impaired concentration, emotional lability, depression, agitation and sleep disorder.
There had been three reports to CARM for bezafibrate between September 2005 and June 2006 for paroniria (nightmares), memory impairment and malaise. There had also been one psychiatric adverse reaction report to CARM for ezetimibe during that period.
In the WHO database, the IC-2std values had increased between March/June 2005 and June 2006 for a number of psychiatric adverse reaction terms for simvastatin, atorvastatin, ezetimibe and gemfibrozil.
In Australia, the Adverse Drug Reaction Advisory Committee (ADRAC) reviewed the issue of ezetimibe and depression at its meeting in February 2006. At the time of this MARC meeting an ADRAC Bulletin article on this issue was being drafted.
NZPhvC provided a summary of two published papers supporting the association between lipid-lowering agents and psychiatric adverse reactions.
Discussion
The Committee noted the report by NZPhvC, summarised above. They considered that the evidence from case reports and the literature had not added substantially to the body of evidence considered by the Committee in December 2005.
The Committee noted that a short paragraph would be included in Prescriber Update, to alert prescribers to these reactions.
The Committee agreed that the issue of lipid-lowering agents and psychiatric adverse reactions should remain on the active monitoring list but that no further regulatory action was required at that time.
3.5 Ergot-Derived Dopamine Receptor Agonists, Other than Pergolide, and Fibrotic Reactions: Active Monitoring Review
References
- Medsafe. Report for the MARC. August 2006
- Information included in New Zealand data sheets for pergolide, lisuride, bromocriptine, cabergoline, and ergotamine.
- UK Committee on the Safety of Medicines:
- (2002) Fibrotic reactions with pergolide and other ergot-derived dopamine receptor agonists. Current Problems in Pharmacovigilance, 28 (Apr), p.3.
- (2003) Pergolide (Celance) and cardiac valvulopathy. Current Problems in Pharmacovigilance, 29 (Sept), p.7.
- ADRAC (2006) Ergot derivatives and fibrotic reactions. Australian Adverse Drug Reactions Bulletin, 25(1), Feb, p.3.
- ADRAC (2004) Cardiac valvulopathy with pergolide. Australian Adverse Drug Reactions Bulletin, 23(4), Feb, p.14.
- Hoffman, C. et al (2006) Abstract – Lisuride, a dopamine receptor agonist with 5HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis. Clinical Neuropharmacology, 29(2):80-6, Mar-Apr.
- National Institute for Health and Clinical Excellence (2006) Parkinson’s disease – diagnosis and management in primary and secondary care. NICE clinical guideline 35, June (accessed August 06 at www.nice.org.uk).
- University of Birmingham Clinical Trials Unit (2003) Protocol summary: A large randomized assessment of the relative cost-effectiveness of different classes of drugs for Parkinson's disease. (accessed August 06 at www.pdmed.bham.ac.uk)
| Tabled at the meeting: PHARMAC prescription data - prescriptions dispensed per month from Dec 2004 – June 2006: | |
|---|---|
|
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Issue
In December 2004, the MARC first discussed the issue of cardiac valvulopathy in association with pergolide use. In January 2005, a 'Dear Healthcare Professional' letter providing advice about fibrotic conditions and cardiac valvulopathy with pergolide was sent to New Zealand neurologists, geriatricians and general practitioners. The letter advised that all patients undergo cardiovascular evaluation (including an echocardiogram) before initiating treatment with pergolide, followed by subsequent clinical diagnostic monitoring. The New Zealand datasheet for pergolide was updated to include information about:
- serious inflammation and fibrosis; and
- the restriction of pergolide to second-line therapy in patients who are intolerant to, or fail treatment with, a non-ergot compound.
At its meeting in December 2005, the MARC recommended that, as fibrotic reactions are likely a class effect for all ergot-derived dopamine receptor agonists, it would be of value to place agents other than pergolide on the active monitoring list. This was the first review of this issue.
In February 2006, a further 'Dear Healthcare Professional' letter was disseminated to remind New Zealand prescribers that pergolide should not be used off-label to treat restless legs syndrome. Also, a scheduled Prescriber Update article about pergolide and cardiac valvulopathy was rescinded, as it was considered that the planned key messages had been covered in the Dear Healthcare Professional letters.
At the time of this meeting, the following ergot-derived dopamine agonists were available in New Zealand. All of these products were fully subsidised by PHARMAC.
| Product | Active Ingredient | Sponsor | Licence Approval |
|---|---|---|---|
| Alpha-Bromocriptine Tablet (2.5 & 10 mg) | Bromocriptine mesilate | Alpha Pharmaceuticals | Oct 1990 |
| Apo-Bromocriptine Tablet (2.5 mg) | Bromocriptine mesilate | Apotex | July 1996 |
| Dopergin Tablet (0.2 mg) | Lisuride maleate | Schering | Dec 1987 |
| Dostinex Tablet (0.5 mg) | Cabergoline | Pfizer | Mar 1994 |
| Permax Tablet (0.05, 0.25 & 1 mg) | Pergolide mesilate | Pharmacy Retailing NZ | Oct 1993 |
| Cafergot Tablet | Ergotamine tartrate 1 mg caffeine 100 mg | Novartis | Dec 1969 |
No regulatory action regarding ergot-derived dopamine agonists and fibrotic
reactions had been carried out in New Zealand, the United Kingdom, Canada,
or the United States since this issue was placed on the active monitoring
list in December 2005.
The New Zealand datasheets for all of the above products contained warnings and precautions about the potential for fibrotic changes, in particular of the pleura and the retroperitoneum. In addition, the data sheets for Dostinex, Cafergot, and Permax contained warnings specifically about fibrotic changes of the cardiac valves. It was noted that the Australian Product Information for bromocriptine-BC had been updated to include precautions about pericardial effusions and constrictive pericarditis.
In 2002, the United Kingdom Committee on the Safety of Medicines (now the Commission on Human Medicines) advised that patients taking ergot derivatives should be regularly monitored for manifestations of progressive fibrotic disorders. Since that time, the 'Dopaminergic drugs used in Parkinsonism' section of the British National Formulary contained box-text as below:
Fibrotic reactions. The CSM has advised that ergot-derived dopamine receptor agonists, bromocriptine, cabergoline, lisuride, and pergolide have been associated with pulmonary, retroperitoneal, and pericardial fibrotic reactions. Before starting treatment with these ergot derivatives it may be appropriate to measure erythrocyte sedimentation rate and serum creatinine and to obtain a chest X-ray. Patients should be monitored for dyspnoea, persistent cough, chest pain, cardiac failure, and abdominal pain or tenderness. If long-term treatment is expected, then lung-function tests may also be helpful.
In Australia, an Australian Adverse Drug Reactions Bulletin article was published in February 2006 reminding Australian prescribers that they should be aware of the possibility of fibrotic changes associated with long-term administration of ergot derivatives such as cabergoline, bromocriptine, and pergolide. This article followed a Bulletin article on cardiac valvulopathy with pergolide published in August 2004. At the time of the 2006 article, ADRAC had received 15 reports describing pleural or pulmonary fibrosis/effusion or pneumonitis associated with cabergoline. It was noted that no reports of fibrotic complications in association with low-dose cabergoline (Dostinex) for lactation suppression or hyperprolactinaemia had been received.
NZPhvC provided data from the CARM and WHO databases on reports of fibrotic reactions with the ergot-derivative dopamine agonists. Since December 2005, there had been no reports of fibrotic reactions to CARM for any of the products.
Medsafe provided members with a summary of publications of interest since December 2005.
Discussion
The Committee noted the report by Medsafe, summarised above. They also noted the tabled PHARMAC data, showing that the number of prescriptions for pergolide was trending slowly down, and that the levodopa products had the highest usage of the funded anti-Parkinson’s Disease medicines.
The Committee noted that there was strong evidence for fibrotic adverse reactions to occur with all ergot-derived dopamine agonists. They noted that most of the product data sheets already contained warnings of the risk of fibrotic reactions, with the exception of bromocriptine which did not contain warnings of pericardial effusion or constrictive pericarditis. Members agreed that the bromocriptine data sheets should be updated in line with the Australian bromocriptine-BC Product Information in this respect.
Members agreed that this issue should be removed from the active monitoring list.
Recommendations
The Committee recommended that Medsafe should ask the bromocriptine product sponsors to update the data sheets in line with the Australian bromocriptine-BC Product Information with respect to the risk of pericardial effusion and constrictive pericarditis.
The Committee recommended that the issue of all ergot-derived dopamine receptor agonists (other than pergolide) and fibrotic reactions should be removed from the active monitoring list.
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) Spontaneous Case Reports
4.1.1 Deaths
4.1.1.1 Alteplase and intracranial haemorrhage [death] (72217)
Discussion
The Committee noted that there was insufficient information available to assess if this patient was given alteplase within the guidelines in the product information. However, the report stated that the patient was given an appropriate dose of alteplase at an appropriate time interval from the stroke.
NZPhvC informed the Committee that the indications for Actilyse (alteplase) included:
ACTILYSE is indicated for thrombolytic treatment of acute ischaemic stroke. Treatment should only be initiated within 3 hours after the onset of stroke symptoms and after exclusion of intracranial haemorrhage by appropriate imaging techniques such as cranial computerised tomography (CT).
Members noted that haemorrhage with alteplase was a well-described adverse reaction and was well-documented in the Actilyse data sheet.
The causal association with alteplase was deemed to be 'possible' for intracranial haemorrhage. The Committee agreed that no further regulatory action was required at that time.
4.1.1.2 Capecitabine / oxaliplatin and diarrhoea, disease progression [death] (71329)
Discussion
NZPhvC informed the Committee that diarrhoea was a well-recognised adverse reaction with capecitabine and oxaliplatin. The Committee noted that the post-mortem had concluded the cause of death to be metastatic malignancy.
The causal association with capecitabine and oxaliplatin was deemed to be 'unclassifiable' for diarrhoea and disease progression due to inconsistency of the dates. The Committee agreed that no further regulatory action was required at that time.
4.1.1.3 Capecitabine and diarrhoea, disease progression [death] (71330)
Discussion
NZPhvC informed the Committee that diarrhoea was a well-recognised adverse reaction with capecitabine. The Committee noted that the post-mortem had concluded the cause of death to be malignancy.
The causal association with capecitabine was deemed to be 'unclassifiable' for diarrhoea and disease progression due to an absence of dates. The Committee agreed that no further regulatory action was required at that time.
4.1.1.4 Clozapine and myocarditis, heart failure, arrhythmia [death] (66578)
Discussion
NZPhvC informed the Committee that the post-mortem concluded the patient died of myocarditis. A copy of the post-mortem report for this case had been requested by NZPhvC but not yet received. Members agreed that NZPhvC should review the causality assessment once the post-mortem report was available and bring the outcome back to Committee.
Members discussed other possible aetiologies in this case, including viral myocarditis. They commented that it was also possible that an interaction between olanzapine and clozapine had occurred, although olanzapine was being down-titrated.
See minute item 4.3.2 for an Intensive Medicines Monitoring Programme (IMMP) review of this issue.
The causal association with clozapine was deemed to be 'possible' for myocarditis, heart failure and arrhythmia.
Recommendation
The Committee recommended that NZPhvC should await a copy of the post-mortem report in this case (66578), then review the causality assessment and bring the results back to the MARC.
4.1.1.5 Infliximab / methotrexate / prednisone and secondary sepsis, dural abscess, tooth abscess, headache, coma [death] (72110)
Reference
Tabled report: Further analysis and literature report from NZPhvC for MARC 14 September 2006; report 72110.
Discussion
NZPhvC informed the Committee that from a total of 8 reports for infliximab in the CARM database there were none of oral infections/caries. From a total of 118 reports for methotrexate, there was one of sepsis with neutropenia, one of abscess (with piroxicam co-suspect) and one of septicaemia (with leflunomide co-suspect). There were no reports of tooth caries, brain abscess or oral cavity abscess with methotrexate. From a total of 120 reports for prednisone, there were three of sepsis (two with leucopenia and one with a perforated duodenal ulcer). There was one report of encephalomyelitis with prednisone alone, but no reports of tooth caries, brain abscess or oral cavity abscess.
In the WHO database (Vigibase) from a total of 13,528 reports for infliximab there were two of tooth caries, 11 of oral cavity abscess and four of brain abscess. For adalimumab, there were a total of 8,189 reports of which two were for tooth caries and 41 for oral cavity abscess. For etanercept, there were a total of 24,722 reports of which 19 were for tooth caries, 100 for oral cavity abscess and three for brain abscess. From a total of 10,850 reports for methotrexate, there were two of tooth caries and one of oral cavity abscess. From a total of 7,569 reports for prednisone, there were eight of tooth caries, two of oral cavity abscess (one of which had bisphosphonate-induced osteonecrosis of the jaw and in the other case methotrexate and etanercept were co-suspect).
Members considered that it would be of value for NZPhvC to more closely analyse the cases of oral cavity abscess with the anti-tumour necrosis factor (anti-TNF) agents in the WHO database and bring the results back to the Committee.
NZPhvC informed the Committee that there was conflicting evidence in the literature regarding the risk of serious infection with the anti-TNF agents, but that skin and soft tissue infections, as well as intracellular bacterial infections, were of greatest concern.
NZPhvC informed the Committee that Remicade (infliximab) was contraindicated in patients with "severe infections, such as tuberculosis, sepsis, clinically manifested infections and/or abscesses and opportunistic infections". Abscess was listed as an uncommon adverse effect of infliximab therapy. There was no mention in the data sheet, however, of oral or dental infections.
Members commented that patients with rheumatoid arthritis have a two-fold increase in risk of infection compared to healthy persons, irrespective of any treatment. They noted that protocols for treatment with anti-TNF agents did not currently carry advice on assessing the oral health of the patient.
NZPhvC informed the Committee that this case report had recently been presented at the New Zealand Rheumatology Association meeting and that, therefore, rheumatologists had been made aware of this issue. Members considered, however, that general practitioners who would see patients with oral symptoms might not be aware of the association between anti-TNF agents and oral infections. They considered that, if the review of the cases in the WHO database warranted, Medsafe could consider publishing a short paragraph in Prescriber Update to inform prescribers of this association, with a copy sent to the New Zealand Dental Association.
The causal association with infliximab, methotrexate and prednisone was deemed to be 'possible' for secondary sepsis, dural abscess, tooth abscess, headache and coma.
Recommendation
The Committee recommended that NZPhvC should analyse the cases of oral cavity abscess with the anti-TNF inhibitors in the WHO database, and subsequently bring the results back to the MARC.
4.1.1.6 Influenza vaccine and sudden death (71269)
Discussion
NZPhvC informed the Committee that the post-mortem report had been requested. Until confirmatory evidence of a cause of death was received, the causal relationship with influenza vaccine was recorded as 'unclassified'.
The causal association with influenza vaccine was deemed to be 'unclassified' for sudden death.
Recommendation
The Committee recommended that NZPhvC should bring this case (71269) back to the MARC once the post-mortem results were available.
4.1.1.7 Phentermine and pulmonary hypertension [death] (71961)
Discussion
NZPhvC informed the Committee that follow-up information was now available. A post-mortem had confirmed that the cause of death had been pulmonary hypertension. Furthermore, the patient's brother was known to have died of primary pulmonary hypertension.
The Committee noted the follow-up information and considered that the case report should be classified as 'severe' and the causality should be 'possible'.
NZPhvC informed the Committee that the data sheet for Duromine (phentermine)
stated under 'Warnings and Precautions':
Cases of severe, sometimes fatal, primary pulmonary hypertension have been
reported in patients who have received anorectics. PPH has also been reported
in patients receiving phentermine combined with fenfluramine/dexfenfluramine.
The possibility of an association between PPH and the use of phentermine
alone cannot be ruled out. There have been very rare cases of PPH in patients
who reportedly have taken phentermine alone. The initial symptom of PPH
is usually dyspnoea. Other early symptoms include angina pectoris, syncope,
lower extremity oedema or the unexplained onset or aggravation of diminished
exercise tolerance. Under these circumstances, treatment should be immediately
discontinued and the patient referred to a specialist unit for investigation.
Furthermore, Duromine was contraindicated in patients with pulmonary artery hypertension.
However, NZPhvC informed the Committee that the Umine (phentermine) data sheet did not contain a contraindication in patients with pulmonary artery hypertension and the warnings were much briefer than those in the Duromine data sheet. Furthermore, the datasheet contained an error in the 'Contraindications' section, listing "moderate to severe hypotension" rather than hypertension. Members agreed that the Umine data sheet should be updated to adequately address the risk of PPH and to correctly list 'moderate to severe hypertension' as a contraindication.
The causal association with phentermine was deemed to be 'possible' for pulmonary hypertension.
Recommendations
The Committee recommended that NZPhvC should change the severity of this case report (71961) from 'not severe' to 'severe' and the causality from 'unclassified' to 'possible'.
The Committee recommended that Medsafe should ask the sponsor of Umine (phentermine) to update the data sheet to adequately address the risk of pulmonary hypertension, including contraindications in patients with pulmonary artery hypertension and with moderate to severe hypertension.
4.1.1.8 Sildenafil and myocardial ischaemia, cardiac arrest [death] (72152)
Discussion
Members noted that the association between phosphodiesterase inhibitors and mycardial ischaemia was well-recognised. They noted that this case report made no mention of the concomitant use of nitrates, which were known to potentiate the hypotensive effects of sildenafil. This interaction was well documented in the literature and an article was published in Prescriber Update in 2001.
Members commented a significant proportion of myocardial infarctions occur during sexual intercourse, irrespective of other risk factors.
The causal association with sildenafil was deemed to be 'probable' for myocardial ischaemia and cardiac arrest. The Committee agreed that no further regulatory action was required at that time.
4.1.2 Antibacterial Medicines
4.1.2.1 Norfloxacin and limb abnormality, induced abortion (71293)
Discussion
NZPhvC informed the Committee that norfloxacin was Australian Drug Evaluation Committee (ADEC) pregnancy category B3 and the Norfloxacin tablets data sheet stated, "The safe use of NORFLOXACIN in pregnant women has not been established and, consequently, the benefits of treatment with NORFLOXACIN should be weighed against potential risks. NORFLOXACIN has been detected in cord blood and amniotic fluid."
Members noted that there was no information available on the duration of treatment with norfloxacin. It is unlikely that the patient would have known she was pregnant at the time of commencement of norfloxacin treatment.
NZPhvC informed the Committee that there were no other reports of foetal abnormalities associated with norfloxacin in the CARM database. In the WHO database, from a total of 5,593 reports for norfloxacin, there were 43 reports of foetal abnormalities including one of limb malformation, one of spine malformation and one of skeletal malformation.
A literature review found no evidence of a causal relationship between norfloxacin and skeletal malformations. There had been no controlled studies on the teratogenic effects of norfloxacin use in human pregnancy.
The causal association with norfloxacin was deemed to be 'possible' for limb abnormality and induced abortion. The Committee agreed that no further regulatory action was required at that time.
4.1.3 Anti-Inflammatory Medicines
4.1.3.1 Diclofenac / ibuprofen / prednisone and gastric ulcer, duodenal ulcer, intestinal ulceration, haematemesis, hypoproteinaemia (71906)
Discussion
The Committee noted that it was likely that the combination ibuprofen/codeine product was purchased over-the-counter. The patient was taking two non-steroidal anti-inflammatory drugs (NSAIDs) simultaneously, which provided more than the maximum recommended daily dose of NSAIDs.
NZPhvC informed the Committee that the adverse reactions experienced in this case were well-documented in the literature, particularly NSAID-induced gastric/duodenal ulcers, ulcer complications and the increased risk when corticosteroids are taken concomitantly. A Prescriber Update article was published in 2001 summarising the adverse effects of NSAIDs on the small and large intestine, including enteropathy with blood and protein loss and intestinal diaphragmatic strictures.
NZPhvC informed the Committee that the data sheets for Brufen (ibuprofen) and Flameril (diclofenac) gave extensive warnings about the risks of gastrointestinal adverse effects, including bleeding and ulceration. The Brufen data sheet did not, however, warn of the risk of lower gastrointestinal adverse effects such as strictures and colitis. Members considered that the NSAID data sheets should be reviewed in this regard and updated as warranted.
The causal association with diclofenac, ibuprofen and prednisone was deemed to be 'probable' for gastric ulcer, duodenal ulcer, intestinal ulceration, haematemesis and hypoproteinaemia.
Recommendation
The Committee recommended that Medsafe should review the NSAID product data sheets with respect to the risk of lower gastrointestinal adverse effects and then request the product sponsors to update the data sheets as warranted.
4.1.4 Endocrine Medicines
4.1.4.1 Rosiglitazone and urticaria (71406)
Discussion
The Committee noted that all adverse reactions to rosiglitazone and pioglitazone were Adverse Reactions of Current Concern, with the next review scheduled for March 2007.
NZPhvC informed the Committee that from a total of 21 reports for rosiglitazone in the CARM database there were no reports of urticaria. In the WHO database there were a total of 7,417 reports for rosiglitazone, of which eight were for urticaria (IC value in June 2005:-3.25).
NZPhvC informed the Committee that in the Avandia (rosiglitazone) data sheet, urticaria was listed as a very rare adverse effect.
The causal association with rosiglitazone was deemed to be 'unlikely' for urticaria. The Committee agreed that no further regulatory action was required at that time.
4.1.4.2 Pioglitazone and neutropenia, thrombocytopenia, myeloid dysplasia (71590)
Discussion
The Committee noted that all adverse reactions to rosiglitazone and pioglitazone were Adverse Reactions of Current Concern (ARCC), with the next review scheduled for March 2007.
NZPhvC informed the Committee that there was a small amount of evidence from the literature and WHO reports that rosiglitazone and pioglitazone might cause thrombocytopenia and neutropenia. The mechanism was unclear, although the finding of antibodies in a published report was of interest. There was only one report of myeloid dysplasia with pioglitazone in the WHO database from a total of 3,672 reports and it was not noted in published case reports. Anaemia occurred commonly in patients taking glitazones and was attributed to haemodilution.
NZPhvC informed the Committee that the Actos (pioglitazone) data sheet discussed the risk of anaemia but there was no mention of other haematological disorders.
Members noted this case report did not report the results of a blood film or bone marrow biopsy, and queried what the criteria for diagnosis of myelodysplasia might have been.
The Committee agreed that haematological disorders, including neutropenia and thrombocytopenia, should be included in the ARCC review in March 2007. Results of haematological investigations in this case should also be sought for the review.
The causal association with pioglitazone was deemed to be 'possible' for neutropenia, thrombocytopenia and myeloid dysplasia. The Committee agreed that no further regulatory action was required at that time.
4.1.4.3 Pioglitazone and generalised oedema (72087)
Discussion
The Committee noted that all adverse reactions to rosiglitazone and pioglitazone were Adverse Reactions of Current Concern (ARCC), with the next review scheduled for March 2007.
NZPhvC informed the Committee that this was a well-documented adverse effect of the glitazones, but that this and the next report (minute item 4.1.4.4) suggested that oedema could be severe enough to warrant hospitalisation.
The Committee agreed that the severity of the reports of oedema with the glitazones should be analysed for the ARCC review in March 2007.
The causal association with pioglitazone was deemed to be 'possible' for generalised oedema. The Committee agreed that no further regulatory action was required at that time.
4.1.4.4 Pioglitazone and generalised oedema (72088)
Discussion
The Committee noted that all adverse reactions to rosiglitazone and pioglitazone were Adverse Reactions of Current Concern, with the next review scheduled for March 2007.
See minute item 4.1.4.3 for discussion on this issue.
The causal association with pioglitazone was deemed to be 'probable' for generalised oedema. The Committee agreed that no further regulatory action was required at that time.
4.1.5 Immunosuppressive Medicines
4.1.5.1 Thalidomide and hyperglycaemia (71621)
Discussion
Medsafe informed the Committee thalidomide was a Class A Drug and that only members of the Royal Australasian College of Physicians could prescribe it. Because of the potential for severe teratogenicity, Pharmion Pty Ltd would only supply thalidomide if the prescriber, patient and dispensing pharmacist agreed to participate in the Pharmion Risk Management Programme, designed to ensure that pregnant women are not exposed to thalidomide.
NZPhvC informed the Committee that from a total of 24 reports for thalidomide in the CARM database there were no reports of metabolic disorders. In the WHO database, from a total of 9,348 reports for thalidomide there were 142 reports of hyperglycaemia (IC-2std = +1.14).
There were no references to hyperglycaemia with thalidomide found in the literature or the product data sheet.
Members noted that, based on the list of medications the patient was taking, he was likely to have had chronic renal failure.
The Committee agreed that the causal relationship in this case should be changed from 'probable' to 'possible'.
The causal association with thalidomide was deemed to be 'possible' for hyperglycaemia. The Committee agreed that no further regulatory action was required at that time.
Recommendation
The Committee recommended that NZPhvC should change the causality in this case report (71621) from 'probable' to 'possible'.
4.1.6 Musculoskeletal Medicines
4.1.6.1 Pamidronate and hypocalcaemia, tetany, laryngismus, respiratory arrest (71566)
Discussion
Members noted that this was a life-threatening reaction. The dose of pamidronate was lower than the maximum recommended, but the infusion rate was not reported.
NZPhvC informed the Committee that from a total of 54 reports for pamidronate in the CARM database there were three of hypocalcaemia, including two with convulsions. In the WHO database, from a total of 1,692 reports for pamidronate, there were 116 of hypocalcaemia, 17 of tetany, one of laryngismus/stridor (considered to be anaphylactoid) and two of stridor.
NZPhvC informed the Committee that the Pamisol data sheet stated in the 'Precautions' section "Serum electrolytes, calcium and phosphate should be monitored following initiation of therapy with Pamisol". The 'Adverse Effects' section of the data sheet stated "The most common adverse reactions are asymptomatic hypocalcaemia and fever […] Symptomatic hypocalcaemia is rare."
Members commented that this adverse reaction was very rare, and that anecdotal evidence was that prescribers did routinely measure serum calcium before prescribing pamidronate.
Members noted that it was unclear from the case report whether there was a positive re-challenge with pamidronate. For this reason, and due to the multiple co-morbidities and poly-pharmacy in this case, the Committee agreed that the causal relationship should be changed from 'certain' to 'probable'.
The causal association with pamidronate was considered to be 'probable' for hypocalcaemia, tetany, laryngismus and respiratory arrest.
Recommendation
The Committee recommended that NZPhvC should change the causality in this case report (71566) from 'certain' to 'probable'.
4.1.7 Psychiatric Medicines
4.1.7.1 Melatonin and fatigue, impaired concentration, abnormal thinking, aggressive reaction, somnolence (71499)
Discussion
Medsafe informed the Committee that melatonin was a Prescription-only medicine supplied in New Zealand under Section 29 of the Medicines Act 1981.
NZPhvC informed the Committee that published reports suggested one of the most common side effects of melatonin therapy was daytime drowsiness, occurring in up to 20% of users. Whilst there had been reports of transient depressive symptoms, anxiety, irritability and confusion, NZPhvC had not found other reports of abnormal thinking or aggressive reactions. There were, however, two case reports of elderly patients who, in the one instance, became lethargic and disoriented after eight tablets of melatonin and another who was hospitalised for an acute psychotic episode after taking ten 3mg tablets of melatonin.
Members commented that both melatonin and dexamphetamine decrease the seizure threshold and that the symptoms in this case could have represented a status partial complex seizure. However, members agreed that, as reported, a causal association of 'probable' was appropriate.
The causal association with melatonin was considered to be 'probable' for fatigue, impaired concentration, abnormal thinking, aggressive reaction and somnolence. The Committee agreed that no further regulatory action was required at that time.
4.1.7.2 Paroxetine and developmental delay, congenital brain damage (71816)
Discussion
The Committee noted that the issue of selective serotonin reuptake inhibitors (SSRIs) and use in pregnancy was on the watching brief list. See minute item 3.3 for a review of this issue.
NZPhvC informed the Committee that from a total of 320 reports for paroxetine in the CARM database there were no reports of congenital brain damage or developmental delay. In the WHO database, from a total of 34,079 reports for paroxetine, there were six of brain damage, seven of developmental delay and one of psychomotor delay. Other medicines were recorded as co-suspect in some of these reports and in many the trimester of exposure was not recorded.
Members noted that the case report did not state on what basis the diagnosis of brain damage had been made. They agreed, however, that it would be of value to monitor the issue of developmental delay with the SSRIs as part of the watching brief.
The causal association with paroxetine was considered to be 'possible' for developmental delay and 'unclassified' for congenital brain damage.
Recommendation
The Committee recommended that developmental delay should be added to the issue of 'SSRIs and use in pregnancy' monitored on the watching brief list.
4.1.8 Other Reports
4.1.8.1 Nature Bee Potentiated Bee Pollen (71365)
4.1.8.2 Red Raspberry (71498)
4.1.8.3 Ginkgo, acetylsalicylic acid (71616)
4.1.8.4 Glucosamine (72100)
4.1.8.5 Glucosamine and chondroitin (72277)
4.1.8.6 Leflunomide (72144)
4.1.8.7 Leflunomide (72145)
4.1.8.8 Leflunomide (72146)
4.1.8.9 Leflunomide (71182)
4.1.8.10 Vancomycin (72172)
4.1.8.11 Adalimumab (71404)
4.2 Quarterly Reports from CARM as at 30 June 2006
Discussion
The Committee noted the quarterly reports from CARM as at 30 June 2006.
4.3 Intensive Medicines Monitoring Programme (IMMP)
4.3.1 Atypical Antipsychotics in Children
Reference
- Safety and Usage of the Atypical Antipsychotic Medicines in New Zealand Children: A Targeted Post-Marketing Surveillance Study. Final Study Report for the Medicines Adverse Reactions Committee. August 2006.
Issue
This IMMP study was undertaken because of evidence of increasing use of atypical antipsychotic medicines in children and concerns regarding the limited amount of safety data available in this population. In this study, IMMP employed both the routine IMMP prescription event monitoring (PEM) and also record-linkage between the IMMP patient cohorts and national morbidity and mortality databases to identify adverse events in children taking atypical anti-psychotic medicines. The cohort for this study consisted of 420 patients. Total exposure was 7,694 patient-months, of which 94% was for risperidone.
The Committee was provided with a copy of the final study report.
Discussion
IMMP explained the methodology of the study to the MARC. This nationwide cohort study had been undertaken due to increasing usage of the atypical antipsychotics in New Zealand. The study used dual methodology: follow-up questionnaires with assessable information had a response rate of 65% and record linkage was performed for 100% of subjects.
The Committee discussed the data on indications for use: Of the patients prescribed an atypical antipsychotic, 42.6% were treated for disruptive disorders including conduct disorders and attention deficiency hyperactivity disorders (ADHD); 33.6% for pervasive developmental disorders; 16.6% for cognitive impairment; 6.5% for anxiety disorders; and 4.9% for mood/affective disorders. The MARC noted that the target symptoms were aggression-type for 47% of patients and behavioural difficulties in 26% of patients. The Committee was concerned about the 3% of patients being treated for sleep disturbances, as this alone would not usually be an indication for use.
Weight increase was the most commonly reported adverse reaction, reported in 10.7% of the questionnaires returned. These results were consistent with those found in other studies and this adverse reaction was well-recognised.
Four children with a returned questionnaire (1.5%) were reported to have developed symptoms of depression whilst taking risperidone. Risperidone had not previously been associated with symptoms of depression in children. Members commented that one of these cases might have been experiencing extrapyramidal adverse effects rather than depression.
Of the children with returned questionnaires, one developed new-onset diabetes and one experienced worsening of pre-existing diabetes. This potential adverse reaction had been previously recognised from case reports and case series. IMMP calculated an estimated incidence of 4 per 1000 patient-years of exposure, which appeared to be higher than the background rate of diabetes in children. The MARC commented that there are difficulties estimating incidence when the numerator is only two patients and that it would be useful to calculate the confidence intervals surrounding this estimate. Given the small number of cases and expected low incidence of this adverse effect, a larger study might be needed to investigate this potential adverse effect.
IMMP reported that the incidence of dental caries and extractions was higher than the background rate. However, members commented that dental hygiene is often poor in these patients and dental treatment is often difficult to undertake. Therefore it would be preferable to compare the incidence in the IMMP cohort with a similar population of children not taking atypical antipsychotic medicines.
Medsafe queried whether information on co-morbidities and co-prescriptions had been collected. IMMP advised that data on concurrent medications had been collected but not included in this report.
Members commented that it might be useful for IMMP to investigate the potential long-term adverse effects of the atypical antipsychotics in paediatric populations. It would also be interesting to analyse the adverse reaction data by duration of treatment (short-, medium- or long-term).
4.3.2 Clozapine and Myocarditis
References
- IMMP Report for MARC. September 2006.
- Medsafe Editorial Team. Clozapine and Cardiac Safety: Updated Advice for Prescribers. Prescriber Update 2003; 24(1): 13
- Extract from: Novartis NZ Ltd. Clozaril tablets data sheet. 15 February 2006. www.medsafe.govt.nz/profs/Datasheet/c/Clozariltab.htm
- Health Canada. Duplicate of Dear Healthcare Professional letter issued by Novartis. Association of Clozaril (clozapine) with cardiovascular toxicity. 14 January 2002.
- Novartis Pharmaceuticals Australia Ltd. Clozaril and Myocarditis: Clinical Guidelines. 16 December 1999.
- Merrill DB et al. Adverse Effects Associated with Clozapine. J Clin Psychopharmacol 2005; 25: 32-41
- K. Ronaldson, J. McNeil. Protocol for Proposed Case-Control Study. 2006.
Issue
See minute item 4.1.1.4 for a case report of a death due to myocarditis in a patient taking clozapine.
The association between clozapine and myocarditis had previously been documented in case reports and an analysis of the WHO database in 2001. Two Prescriber Update articles had been published on this issue: October 2000 entitled "Potentially fatal complications of clozapine therapy: myocarditis, venous thromboembolism and constipation" and May 2003 entitled "Clozapine and Cardiac Safety: Updated Advice for Prescribers". The clozapine data sheets contain warnings of the risk of myocarditis and cardiomyopathy.
In Australia, Novartis developed clinical guidelines, independently of the Therapeutic Goods Administration (TGA), for monitoring clozapine patients for myocarditis and published these immediately after an Australian case series was published in the Lancet in 1999. However, the guidelines had not been incorporated into the Australian Product Information and were not mandatory. The effectiveness of this monitoring had not been investigated and there had been no similar advice disseminated in New Zealand.
IMMP provided an analysis of its data for the MARC. There were 24 reports of myocarditis with clozapine received by IMMP since 2000. Eighty-seven percent of these cases were in males with a mean age of 35-years-old. Ethnicity data were available for 23 of the 24 cases: 16 patients (67%) were New Zealand European, 5 (21%) were New Zealand Maori, one (4%) was a Pacific Islander and one was of other ethnicity. The dose ranged from 12.5mg daily for an elderly patient (the first report of myocarditis associated with clozapine therapy under 50mg daily) to 500mg daily.
Twenty of the 24 cases (83%) experienced myocarditis within one month of starting clozapine. This duration to onset was in line with that reported in the literature. Three of the IMMP cases presented more than a year after starting clozapine, with one case presenting more than nine years after starting treatment.
Two patients (8%) died due to the adverse reaction, which was a lower proportion than in other case series but was consistent with the experience in Australia. Sixteen of the 20 patients who discontinued clozapine recovered (positive dechallenge).
An Australasian case-control study was to be undertaken to identify risk factors which may predispose patients to the development of clozapine-induced myocarditis. The proposed protocol for this study was provided for the MARC.
Discussion
The Committee noted the IMMP report, as summarised above.
Members noted that the 87% preponderance of male patients in the case series was reflective of the usage of clozapine.
Members discussed Novartis' clinical guideline for Clozaril and myocarditis published in Australia. The guideline advised baseline monitoring of family history; Clozaril Patient Monitoring Service haematology including eosinophil count; electrocardiogram; troponin I or troponin T; and serum creatinine or creatinine kinase-myocardial bound. At days 7 and 14 following initiation of clozapine therapy, an electrocardiogram; troponin I or troponin T; and serum creatinine or creatinine kinase-myocardial bound should be monitored. At approximately six months, an echocardiogram should be obtained. The Committee queried the predictive value of these tests for detecting myocarditis and agreed that Medsafe should request expert opinion from a cardiologist.
The Committee agreed that once expert opinion had been obtained, it would be of value for a reminder paragraph to be published in Prescriber Update. Medsafe could then consider approaching the Royal Australian and New Zealand College of Psychiatrists to reprint the article.
Members noted that all clozapine patients are required to be seen at a psychiatric clinic weekly for the first 18 weeks of therapy for assessment of efficacy, adverse effects, physical examination and blood tests. However, patients with symptoms of myocarditis are likely to present to general practitioners and therefore members agreed that any communication on this issue should be disseminated to general practitioners as well as psychiatrists.
Recommendations
The Committee recommended that Medsafe should request expert opinion from a cardiologist on the predictive value of electrocardiograms, echocardiograms and serum cardiac markers for detecting myocarditis in patients treated with clozapine.
The Committee recommended that Medsafe should consider publishing a paragraph in Prescriber Update reminding prescribers of the risk of myocarditis with clozapine.
5. pharmacovigilance issues for information only
The following information was included in the meeting dossier. However, the Committee did not discuss this material. It included updates on issues already known to the Committee, commentaries, review articles and preliminary information on emerging issues. Members were asked to read this material, with the option of requesting that it be discussed.
- Bisphosphonates:
- Gibbs RD et al. Bisphosphonates and Osteonecrosis of the Jaws; Our Current Practice for Removal of Teeth in Patients who are Taking Oral Alendronate (Fosamax). New Zealand Dental Association News 2006; 130: 36-37
- Odvina CV et al. Severely Suppressed Bone Turnover: Potential Complication of Alendronate Therapy. J Clin Endocrinol Metab March 2005; 90(3) 1294-1301
- Black cohosh:
- Medicines and Healthcare Products Regulatory Agency. Press Release: MHRA action on safety concerns over black cohosh and liver injury. 18 July 2006
- European Medicines Agency. EMEA Public Statement on Herbal Medicinal Products Containing Cimicifugae Racemosae Rhizoma (Black Cohosh, Root) – Serious Hepatic Reactions. 18 July 2006.
- Health Canada Advisory. Health Canada is advising consumers about a possible link between black cohosh and liver damage. 18 August 2006.
- National Institutes of Health. Workshop on the Safety of Black Cohosh in Clinical Studies. 22 November 2004. ('Contents' and 'Summary and Next Steps' only).
Discussion
Medsafe informed the Committee that, in Australia, ADRAC had asked the Office of Complementary Medicines to consider establishing a working group to evaluate the risks of hepatotoxicity with black cohosh. The Committee asked that Medsafe keep it informed of any New Zealand and international regulatory actions on this issue, and bring data to the Committee if warranted.
- Others:
- Schering Plough letter dated 22 May 2006 and paper: Bongartz et al. Anti-TNF Antibody Therapy in Rheumatoid Arthritis and the Risk of Serious Infections and Malignancies – Systematic Review and Meta-analysis of Rare Harmful Effects in Randomized Controlled Trials. JAMA 2006; 295: 2275-2285
- Verhamme KM et al. Spironolactone and risk of upper gastrointestinal events: population based case-control study. BMJ July 2006. Accessed online August 2006. doi:10.1136/bmj.38883.479549.2F
- Cooper WO et al. Major Congenital Malformations after First-Trimester Exposure to ACE Inhibitors. N Engl J Med. 2006; 354: 2443-51
- Friedman JM. ACE Inhibitors and Congenital Anomalies. N Engl J Med. 2006; 354: 2498-99
- Meador KJ et al. In utero antiepileptic drug exposure – Fetal death and malformations. Neurology 2006; 67: 407-412
- Lamberti JS et al. Prevalence of the Metabolic Syndrome Among Patients Receiving Clozapine. Am J Psychiatry 2006; 163: 1273-76
- 9. Palmer JR et al. Prenatal Diethylstilbestrol Exposure and Risk of Breast Cancer. Cancer Epidemiol Biomarkers Prev 2006; 15(8): 1509-14
- Merry A and Seddon M. Quality improvement in healthcare in New Zealand. Part 2: are our patients safe – and what are we doing about it? NZMJ 2006 Vol 119 No 1238
6. new zealand pharmacovigilance-related activities
- Meningococcal B vaccine:
- Letter from Health Research Council. 22 May 2006.
- Ministry of Health, Meningococcal Vaccine Strategy Data Management Group. Meningococcal B Vaccine (MeNZB) Effectiveness Assessment. May 2006.
- Ministry of Health, Meningococcal Vaccine Strategy Data Management Group. Meningococcal B Vaccine (MeNZB) Safety Monitoring Programme – Final Report to the Independent Safety Monitoring Board. 23 May 2006.
- Centre for Adverse Reactions Monitoring (CARM). MeNZB Adverse
Event Assessments. Summary of spontaneous reports following MeNZB
vaccination received by CARM for the period 19 July 2004 to 30 June
2006.
Discussion
NZPhvC outlined for the new Committee members the methodologies used in monitoring the safety of the MeNZB vaccine, and the main results of the monitoring (detailed in previous MARC minutes).
- Others:
- Record of the Pharmacology and Therapeutics Advisory Committee Meeting held on 24 and 25 May 2006.
- New Zealand Pharmacovigilance Centre. Risperidone and peripheral oedema. New Zealand Doctor. 31 May 2006, page 25.
7. international pharmacovigilance-related Activities
7.1 Australia
- Minutes of the 292nd meeting of the Adverse Drug Reactions Advisory Committee held on 5 May 2006.
- Minutes of the 293rd meeting of the Adverse Drug Reactions Advisory Committee held on 23 June 2006.
- Adverse Drug Reactions Bulletin. Vol. 25; No. 3. June 2006.
- Adverse Drug Reactions Bulletin. Vol. 25; No. 4. August 2006.
- Australian Prescriber. Vol. 29; No. 3. June 2006. (Cover page only)
- Australian Prescriber. Vol. 29; No. 4. August 2006. (Cover page only)
7.2 Canada
- Canadian Adverse Reaction Newsletter. Vol. 16; Issue 3. July 2006.
7.3 Singapore
- Adverse Drug Reaction News. Vol. 8; No. 2. July 2006.
7.4 WHO
- The Uppsala Monitoring Centre. Signal – Analyses of Adverse Reaction Reports in the WHO Database. June 2006. (Cover page)
8. Summary LISTINGS of case reports considered by MARC (1997-2006)
- CARM case reports considered by the MARC since 1997, by medicine class.
- Vaccine adverse reaction reports considered by the MARC since 1997.
- Complementary and alternative medicine (CAM) case reports considered by the MARC
There being no further business, the Acting Chair thanked members, guests and the secretariat for their attendance and closed the meeting at 3:10pm.
