Committees

Updated 20 May 2013

Minutes of the 136th Medicines Adverse Reactions Committee Meeting - 11 December 2008

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

INVITED GUESTS AND EXPERTS

1 MATTERS OF ADMINISTRATION

2 STANDING AGENDA ITEMS

2.1 REPORT ON STANDING AGENDA ITEMS FROM PREVIOUS MEETINGS OF THE MARC

2.1.1 SSRI antidepressants and increased suicidality in children and adolescents
2.1.2 Black cohosh and hepatotoxicity
2.1.3 Conventional antipsychotics and mortality risk
2.1.4 Eltroxin formulation change adverse reactions
2.1.5 Inhaled LABAs and the risk of fatal and non-fatal asthma exacerbations
2.1.6 Fleet oral preparation and renal failure, hyperphosphataemia [death] (79049)
2.1.7 Flucloxacillin and anaphylactic reaction [death] (78269)
2.1.8 Enoxaparin and haemorrhage stroke [death] (78673)
2.1.9 Adalimumab, leflunomide, methotrexate, anticoagulant unspecified and pneumonia- gram negative bacterial, sepsis, multiple organ failure, haemorrhage cerebral, hypertension [death] (78436)
2.1.10 Aprotinin and increased mortality risk
2.1.11 Symbicort and exacerbation of asthma [death] (75986)
2.1.12 Atorvastatin and rhabdomyolysis [death] (77591), Simvastatin and abdominal pain, rhabdomyolysis, acute renal failure, respiratory failure [death] (76185) Simvastatin and rhabdomyolysis [death] (77669) Simvastatin and rhabdomyolysis, creatine kinase increased, hepatic function abnormal, hyperkalaemia, cardiac arrest [death] (78076)
2.1.13 Alendronate and osteonecrosis, jaw pain (77351)
2.1.14 Clozapine and neutropenia, lymphopenia, anaemia [death] (76419)
2.1.15 Issues monitored by the MARC, Medsafe and NZPhvC as at June 2007
2.1.16 Anti-epileptics and the risk of suicidality
2.1.17 Lamotrigine and mania (77337,77338)
2.1.18 Methylene Blue, tramadol, fentanyl, paroxetine and serotonin syndrome (77178)
2.1.19 Etanercept and uveitis (76978, 76980)
2.1.20 The safety and efficacy of cough and cold medicines for use in children
2.1.21 Lamotrigine and convulsion [death] (74826)
2.1.22 Clozapine and haematological malignancies

3 PHARMACOVIGILANCE ISSUES

3.1 STATINS, NEUROMUSCULAR DEGENERATIVE DISEASE AND AMYOTROPHIC LATERAL SCLEROSIS-LIKE SYNDROME- SCHEDULED REVIEW
3.2 ORAL TERBINAFINE AND SERIOUS ADVERSE REACTIONS (BLOOD DYSCRASIAS, HEPTATOTOXICITY AND DERMATOLOGICAL REACTIONS) – INCLUDING PRESCRIBING DATA - SCHEDULED REVIEW
3.3 ORAL BISPHOSPHONATES AND THE RISK OF ATRIAL FIBRILLATION
3.4 PARACETAMOL ASSOCIATED WITH CHILDHOOD ASTHMA

4 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

5 PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

6 NEW ZEALAND PHARMACOVIGILANCE-RELATED ACTIVITIES

7 INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

7.1 AUSTRALIA
7.2 UNITED KINGDOM
7.3 UNITED STATES

8 SUMMARY LISTINGS OF CASE REPORTS CONSIDERED BY THE MARC (1997- 2007)

9 ANY OTHER BUSINESS

9.1 9.1 Monitoring of adverse events following immunisation for the Human Papillomavirus (HPV) Immunisation programme
9.2  SSRI antidepressants
9.3  Update on Safe Medicines Management Programme
9.4 Removal of specialist prescribing restriction from retinoinds
9.5 Reporting of patient allergies to the Centre for Adverse Reactions Monitoring CARM

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 OF THE 136th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING,
11 December 2008.

The one hundred and thirty sixth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 11 December 2008 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9am and closed at 3 pm.

MARC Members Present

Professor T Maling (Chair)
Dr L Bryant
Professor P Ellis
Associate Professor C Frampton
Dr H Kingston
Associate Professor M Rademaker
Associate Professor D Reith
Dr R Savage
Dr M Tatley

marc secretariat present

A Cutfield (Advisor, Pharmacovigilance)
J Hart (Senior Advisor, Complementary Medicines, Medsafe)
S Kenyon (Senior Advisor, Pharmacovigilance)
C James (Pharmacy Advisor/Editor Prescriber Update, Medsafe)
J McNee (MARC Secretary)
K Sheehey (Senior Advisor, Medical, Medsafe)

invited guest and experts

Ian Smith (Wellington Coroner) attended the meeting during the discussion of minute item 9.

Professor Richard Beasley attended the meeting during the discussion of minute item 3.4.

Greg Simmons (Chief Advisor, Population Health, Ministry of Health) made a presentation to the Committee on the monitoring of adverse events following immunisation for the Human Papillomavirus (HPV) immunisation programme.

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. He welcomed Susan Kenyon, who was attending the meeting for the first time. She gave a brief synopsis of her background. Apologies were received from Dr F McClure, who provided written comments for some agenda items, and Dr S Jessamine.

1.2 Minutes of the 135th MARC Meetings

The minutes of the 135th meeting of the Committee were accepted as a true and accurate record of the meeting.

1.3 Dates of Future MARC Meetings

The date for the next MARC meeting was confirmed as being 12 March 2009. The subsequent MARC meetings for 2009 were scheduled for 11 June, 10 September and 10 December.

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.

There were no potential conflicts of interest considered to 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. They suggested an article on the oral retinoids, following PHARMAC's removal of the specialist prescribing restriction. They noted that a report on the IMMP interim analysis of varenicline (Champix) would be included in the March dossier and suggested that an article be published following this.

NZPhvC advised that no further serious reports regarding injectable gold had been received since the report reviewed by the MARC in December 2003 and usage was now very low, with patients most likely having been on long term therapy. The Committee recommended that this topic be removed from the schedule of planned Prescriber Update articles, and reconsidered if another report is received.

The Committee noted that the topic of 'ADRs with herbal medicines' was very broad and non-specific. They considered it would be more useful to focus on the more widely used herbal medicines and the more serious adverse effects that had been reported. They recommended that a short paragraph on one specific herbal product be included in each issue of Prescriber Update, in order to remind prescribers that herbal medicines may be a possible cause of adverse reactions.

The Editor advised that the next issue of Prescriber Update is scheduled for January 2009.

Recommendations

The Committee recommended that the topic 'Nitritoid reactions with injectable gold' be removed from the schedule of planned Prescriber Update articles, and reconsidered if another report is received.

The Committee recommended that a short paragraph on one specific herbal product be included in each issue of Prescriber Update, in order to remind prescribers that herbal medicines may be a possible cause of adverse reactions.

2. STANDING AGENDA ITEMS

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

2.1 Report on Standing Agenda Items from previous meetings of the MARC Meeting

Background information on these issues is available on the Medsafe web site at www.medsafe.govt.nz/profs/MARC/Minutes.asp.

2.1.1 SSRI antidepressants and increased suicidality in children and adolescents
September 2008 minute item 3.1, May 2008 minute item 2.1.5, March 2008 minute item 3.1

MARC Recommendation

In September 2008, the Committee recommended that the amended Dear Healthcare Professional Letter entitled "Advice about the use of SSRI antidepressants in children and adolescents" be published in Prescriber Update.

In May 2008, the Committee recommended that Assoc Prof Frampton prepare information to be submitted for publication in the New Zealand Medical Journal.

Outcome

The draft letter has been sent to the Mental Health Policy Group for comment and in order to ensure alignment with the child and adolescent mental health strategy. It will be published in the next edition of Prescriber Update.

Information is being prepared to be submitted to the New Zealand Medical Journal for publication.

Discussion

The Committee noted the above.

2.1.2 Black cohosh and hepatotoxicity
September 2008 minute item 3.2

MARC Recommendation

In September 2008, the Committee recommended that Medsafe publish a paragraph in Prescriber Update, reminding prescribers to:

In September 2008, the Committee recommended that Medsafe investigate the mechanisms to disseminate the above information as widely as possible.

In September 2008, the Committee recommended that the issue of black cohosh and hepatic reactions be placed on the Scheduled review list for 12-monthly review.

Outcome

Medsafe is currently investigating options regarding suitable mechanisms to disseminate information about black cohosh and other safety issues arising with complementary medicines, including the use of complementary medicine practitioner associations.

The issue of black cohosh and hepatic reactions has been placed on the Scheduled review list for 12-monthly review.

Discussion

The Committee noted the above.

2.1.3 Conventional antipsychotics and mortality risk
September 2008 minute item 3.3

MARC Recommendation

In September 2008, the Committee recommended that product sponsors for all antipsychotic medicines be required to update their New Zealand datasheets to include information about the increased risk of mortality in elderly dementia patients.

In September 2008, the Committee recommended that Medsafe approach psychogeriatricians to seek their opinion and advice in defining the risks associated with the use of antipsychotics in elderly patients with dementia, and advising on the group of patients most likely to benefit. Along with a review of other available guidelines, this advice could be used as the basis for an article in Prescriber Update.

In September 2008, the Committee recommended that the issue of antipsychotics and increased risk of mortality in elderly patients with dementia be placed on the Scheduled Review list for 12-monthy review. This review should include an overview of usage patterns in elderly dementia patients and consultation with relevant specialists.

Outcome

In October 2008, BPAC released a Best Practice Guide entitled 'Antipsychotics in Dementia'. This guide is based upon and supported by the joint PHARMAC and Royal Australian and New Zealand College of Psychiatrists 'Clinical Recommendations on the Use of Antipsychotics in Residential Aged Care', which was also released in early October. These two documents will be circulated to psychogeriatricians to obtain their opinion as to their appropriateness in light of the risk of mortality associated with the use of antipsychotics. This information will be conveyed to healthcare practitioners in an article for Prescriber Update.

Medsafe has initiated the process to request sponsors update their datasheets.

The issue of antipsychotics and increased risk of mortality in elderly patients with dementia has been placed on the Scheduled Review list for 12-monthy review.

Discussion

The Committee noted the above.

2.1.4 Eltroxin formulation change adverse reactions
September 2008 minute item 3.4

MARC Recommendation

In September 2008, the Committee recommended that Medsafe continue to work with PHARMAC to encourage an alternative brand to be approved and supplied in New Zealand.

In September 2008, the Committee recommended that Medsafe, in conjunction with the NZPhvC, continue to monitor adverse reaction reports and inform the MARC of any further developments.

Outcome

The Goldshield brand of levothyroxine was listed, fully subsidised, in the Pharmaceutical Schedule from 1 November 2008. Another brand, Synthroid, has been approved by Medsafe, but is not currently subsidised by PHARMAC.

Medsafe, in conjunction with the NZPhvC, will continue to monitor adverse reaction reports and inform the MARC of any further developments.

Discussion

The Committee noted the above.

2.1.5 Inhaled LABAs and the risk of fatal and non-fatal asthma exacerbations
September 2008 minute item 3.5

MARC Recommendation

In September 2008, the Committee recommended that the issue of inhaled long-acting beta-agonists and risk of fatal and non-fatal asthma exacerbations be removed from the Scheduled Review list.

Outcome

The issue of inhaled long-acting beta-agonists and risk of fatal and non-fatal asthma exacerbations has been removed from the Scheduled Review list.

Discussion

The Committee noted the above.

2.1.6 Fleet oral preparation and renal failure, hyperphosphataemia [death] (79049)
September 2008 minute item 4.1.1.1

MARC Recommendation

In September 2008, the Committee recommended that the possibility of an article based on the New Zealand experience to be published in Prescriber Update, be investigated, in order to raise awareness of the dehydration and electrolyte disturbances that can occur during bowel preparation in predisposed individuals.

Outcome

An article will be prepared for publication in Prescriber Update.

Discussion

The Committee noted the above.

2.1.7 Flucloxacillin and anaphylactic reaction [death] (78269)
September 2008 minute item 4.1.1.3

MARC Recommendation

In September 2008, the Committee recommended that further information be brought back to the MARC once the post-mortem has been received.

Outcome

The NZPhvC will bring back any further information to the MARC when received.

Discussion

The Committee noted the above.

2.1.8 Enoxaparin and haemorrhage stroke [death] (78673)
September 2008 minute item 4.1.1.8

MARC Recommendation

In September 2008, the Committee recommended that NZPhvC change the causality from 'probable' to 'possible'.

Outcome

The NZPhvC has amended the causality as recommended.

Discussion

The Committee noted the above.

2.1.9 Adalimumab, leflunomide, methotrexate, anticoagulant unspecified and pneumonia- gram negative bacterial, sepsis, multiple organ failure, haemorrhage cerebral, hypertension [death] (78436)
September 2008 minute item 4.1.1.12

MARC Recommendation

In September 2008, the Committee recommended that NZPhvC add prednisone and naproxen to the suspect medicines in this report.

Outcome

The NZPhvC has added the additional medicines to the suspect medicines listed in the report.

Discussion

The Committee noted the above.

2.1.10 Aprotinin and increased mortality risk
September 2008 minute item 2.1.3, May 2008 minute item 2.1.18, March 2008 minute item 2.1.4, December 2007 minute item 3.4

MARC Recommendation

In September 2008, the Committee recommended that Medsafe determine whether NZ clinicians will be able to access worldwide stocks of aprotinin, and this information then be communicated to the relevant clinicians.

The Committee recommended that a response be sent to each clinician, expressing their gratitude at their input into this issue.

The Committee recommended that the issue of aprotinin and increased mortality risk be removed from the 'Scheduled Review' list.

Outcome

Medsafe is awaiting a response from Bayer regarding access to worldwide stocks of aprotinin. Once a response has been received, Medsafe will write to the relevant clinicians, expressing the Committee's gratitude at their input into the issue and providing them with information regarding access to worldwide stocks of aprotinin.

The issue of aprotinin and increased mortality risk has been removed from the 'Scheduled Review' list.

Discussion

The Committee noted the above.

2.1.11 Symbicort and exacerbation of asthma [death] (75986)
September 2008 minute item 2.1.4, May 2008 minute item 2.1.19, March 2008 minute item 2.1.10, December 2007 minute item 4.1.1.12

MARC Recommendation

In December 2007, the Committee recommended that the issue of the sharing of relevant information between the data collected by national mortality review process and CARM be further investigated.

In May 2008, the Committee recommended that Medsafe further investigate possible ways of sharing relevant information.

Outcome

Medsafe will further investigate possible ways of sharing relevant information.

Discussion

The Committee noted the above.

2.1.12 Atorvastatin and rhabdomyolysis [death] (77591), Simvastatin and abdominal pain, rhabdomyolysis, acute renal failure, respiratory failure [death] (76185) Simvastatin and rhabdomyolysis [death] (77669) Simvastatin and rhabdomyolysis, creatine kinase increased, hepatic function abnormal, hyperkalaemia, cardiac arrest [death] (78076)
September 2008 minute item 2.1.8, May 2008 minute items 4.1.1.3, 4.1.1.4, 4.1.1.5, 4.1.1.6

MARC Recommendation

The Committee recommended that a sub group of two Committee members review the dose response data and report back to the MARC at the next meeting.

Outcome

This issue is continuing to be investigated.

Discussion

The Committee noted the above.

2.1.13 Alendronate and osteonecrosis, jaw pain (77351)
September 2008 minute item 2.1.10, May 2008 minute item 4.1.4.2

MARC Recommendation

The Committee recommended that the issue of the risk of atrial fibrillation in association with oral bisphosphonates be placed on the agenda to be discussed at a subsequent MARC meeting.

Outcome

This issue has been placed on the agenda for the December 2008 MARC meeting.

Discussion

The Committee noted the above.

2.1.14 Clozapine and neutropenia, lymphopenia, anaemia [death] (76419)
September 2008 minute item 2.1.11, May 2008 minute item 2.1.2, March 2008 minute item 2.1.9, December 2007 minute item 4.1.1.7

MARC Recommendation

In March 2008, the Committee recommended that the College of Psychiatrists be approached to undertake a formal audit of the elderly patients in New Zealand who are receiving treatment with clozapine.

Outcome

The College of Psychiatrists will be approached to undertake a formal audit of the elderly patients in New Zealand who are receiving treatment with clozapine.

Discussion

The Committee noted the above.

2.1.15 Issues monitored by the MARC, Medsafe and NZPhvC as at June 2007
September 2008 minute item 2.1.12, May 2008 minute item 2.1.4, March 2008 minute item 2.1.15, December 2007 minute item 2.1.7, September 2007 minute item 3.9, June 2007 minute item 1.6

MARC Recommendation

In March 2008, the Committee recommended that the Chair write to BPAC on behalf of the MARC, highlighting the higher dose of hydrochlorothiazide contained in Amizide, and suggesting that they review the place of Amizide in the treatment of hypertension.

Outcome

The Chair has written to BPAC on behalf of the MARC, highlighting the higher dose of hydrochlorothiazide contained in Amizide, and suggesting that they review the place of Amizide in the treatment of hypertension.

Discussion

The Committee noted the above.

2.1.16 Anti-epileptics and the risk of suicidality
September 2008 minute item 2.1.14, May 2008 minute item 2.1.10, March 2008 minute item 3.4

MARC Recommendation

In September 2008, the Committee recommended that the outcome of negotiations between the sponsors of innovator antiepileptic drugs and other international regulators be awaited before a final decision is made on the wording of warning statements to be included in New Zealand anti-epileptic drugs datasheets.

Outcome

The outcome of negotiations between the sponsors of innovator antiepileptic drugs and other international regulators is still awaited.

Discussion

The Committee noted the above.

2.1.17 Lamotrigine and mania (77337,77338)
September 2008 minute item 2.1.17, May 2008 minute item 2.1.14, March 2008 minute items 4.1.3.2, 4.1.3.3

MARC Recommendation

The Committee recommended that the NZ datasheets for lamotrigine be amended to include references to mania in the post-marketing reports of the Adverse Reactions section.

Outcome

All of the NZ sponsors of lamotrigine, with the exception of the innovator (Lamictal), have amended their datasheets to include references to mania in the post-marketing reports of the Adverse Reactions section. The sponsor of Lamictal challenged the Medsafe request and provided justification as to why they decline to list mania in their datasheet at this time.

Discussion

The Committee noted the above.

2.1.18 Methylene Blue, tramadol, fentanyl, paroxetine and serotonin syndrome (77178)
September 2008 minute item 2.1.18, May 2008 minute item 2.1.15, March 2008 minute item 4.1.4.1

Issue

In March 2008, the Committee recommended that NZPhvC change the causality in this case report from 'probable' to 'unlikely'.

In May 2008, the Committee noted the above change in causality in the CARM case report. At the September 2008 meeting, a member commented that he had received a communication from a psychiatrist with a special interest in psychopharmacology querying the reclassification from 'probable' to 'unlikely'.

In September 2008, the Committee recommended that the Committee member forward this communication to the NZPhvC, for further review.

Outcome

This communication will be forwarded to the NZPhvC for further review.

Discussion

The Committee noted the above.

2.1.19 Etanercept and uveitis (76978, 76980)
September 2008 minute item 2.1.19, May 2008 minute item 2.1.16, March 2008 minute item 4.1.5.2

MARC Recommendation

In May 2008, the Committee recommended that Medsafe obtain international information regarding uveitis in association with etanercept.

In May 2008, the Committee recommended that NZPhvC analyse the reports of uveitis in association with etanercept in the WHO database, and bring this information back to the MARC.

In September 2008, the Committee recommended that a paragraph be published in Prescriber Update advising prescribers of the risk of uveitis in association with TNF inhibitors, and this information be disseminated to the Ophthalmologists Society.

Outcome

The Medsafe report on this issue was included in the December dossier. The NZPhvC report, previously presented at the September 2008 meeting, was included in the December dossier.

A paragraph will be prepared for publication in Prescriber Update.

Discussion

The Committee noted that there were very few reports of uveitis in association with infliximab compared with etanercept and that if these uveitis cases were only due to the patient's condition it would be expected that the numbers would be similar. The Committee recommended that the New Zealand data sheet for Enbrel be updated to include a warning that uveitis has been reported in association with etanercept.

Recommendation

The Committee recommended that the New Zealand data sheet for Enbrel be updated to include a warning that uveitis has been reported in association with etanercept.

2.1.20 The safety and efficacy of cough and cold medicines for use in children
September 2008 minute item 2.1.20, May 2008 minute item 2.1.17, March 2008 minute item 2.1.3, December 2007 minute item 3.3

MARC Recommendation

In December 2007, the Committee recommended that all cough and cold medicines be contraindicated in children under two years of age.

In December 2007, the Committee recommended that Medsafe investigate options for disseminating advice to consumers in line with that issued by Health Canada regarding the safe use of cough and cold medicines in children.

In December 2007, the Committee recommended that further information and expert advice be sought from different professional bodies such as the Paediatric Society, the College of General Practitioners and the College of Physicians regarding the safety and efficacy of cough and cold medicines in children over two years.

In December 2007, the Committee recommended that the Medicines Classification Committee consider rescheduling the active ingredients in cough and cold medicines from pharmacy only medicines to pharmacist only medicines.

Outcome

All 19 sponsors of cough and cold products, registered in New Zealand, have responded to requirements imposed pursuant to Section 36 of the Medicines Act 1981 to update the package artwork for their products to include "must not be used in children under 2 years of age" or words to this effect. The sponsors have been advised that all products in distribution and on shelf must be compliant with the revised package artwork by 1 May 2009.

Medsafe is currently in the process of actioning the other recommendations of the December MARC meeting. In addition, Medsafe intends to seek further input from the Committee regarding the use of cough and cold medicines in children aged 2-11 years of age, once the collection of further data on this issue (including the results of the FDAs analyses of ADR data) is completed.

At its June 2008 meeting, the Medicines Classification Committee agreed that in view of the actions already taken as a result of the MARC recommendations, they did not think it was necessary to reclassify these medicines.

Discussion

The Committee noted the above.

2.1.21 Lamotrigine and convulsion [death] (74826)
September 2008 minute item 2.1.21, May 2008 minute item 2.1.14, March 2008 minute item 2.1.18, December 2007 minute item 2.1.17, September 2007 minute item 2.1.9, June 2007 minute item 4.1.1.3

MARC Recommendation

In June 2007, the Committee recommended that NZPhvC should provide a follow up report to the MARC when the Coroner's report or further information that facilitates assessment becomes available.

Outcome

The NZPhvC will bring any further information to a future MARC when received.

Discussion

The Committee noted the above.

2.1.22 Clozapine and haematological malignancies
September 2008 minute item 2.1.22, May 2008 minute item 2.1.28, March 2008 minute item 2.1.20, December 2007 minute item 2.1.20, September 2007 minute item 2.2.1, June 2007 minute item 2.1.1; March 2007 minute item 2.1.2; December 2006 minute item 2.2.3

MARC Recommendation

The Committee recommended that Medsafe, in consultation with Assoc. Prof. Frampton, explore a protocol for obtaining age-standardised data on the frequency of haematological events with clozapine.

Outcome

Medsafe and Assoc. Prof. Frampton are developing a protocol for obtaining these data.

Discussion

The Committee noted the above.

3. pharmacovigilance issues

3.1 STATINS, NEUROMUSCULAR DEGENERATIVE DISEASE AND AMYOTROPHIC LATERAL SCLEROSIS-LIKE SYNDROME- SCHEDULED REVIEW

References

  1. Edwards et al. (2007). Statins, neuromuscular degenerative disease and an amyotrophic lateral sclerosis-like syndrome - An analysis of individual case safety reports from Vigibase. Drug Safety. 30(6): 515-525.
    With accompaning transcript of a 'People's Pharmacy' interview with the author (Dr Ralph Edwards) explaining the significance of his research.
  2. Rowland L.P. and Shneider N.A. (2001). Amyotrophic lateral sclerosis. New England Journal of Medicine. 344(22): 1688-1700.
  3. FDA alert: FDA analysis shows cholesterol lowering medications do not increase the risk of 'Lou Gehrig's Disease'. 29 September 2008. Available from URL: www.fda.gov/bbs/topics/NEWS/2008/NEW01892.html
  4. Colman et al. (2008). An evaluation of a data mining signal for amyotrophic lateral sclerosis and statins detected in FDA's spontaneous adverse event reporting system. Pharmacoepidemiology and Drug Safety. 17(11): 1068-1076.
  5. Dupuis et al (2008). Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology. 70(13: 1004-1009.
  6. Zinman et al (2008). Are statin medications safe in patients with ALS? Amyotrophic Lateral Sclerosis. 9(4): 223-228.
Issue

Medsafe provided a report for the MARC's Scheduled Review on the issue of statins, neuromuscular degenerative disease and amyotrophic lateral sclerosis-like syndrome.

At its September 2007 meeting, the Committee were advised of a recently published paper from the WHO Uppsala Monitoring Centre which identified a potential signal of neuromuscular degenerative disease and an amyotrophic lateral sclerosis (ALS)-like syndrome in association with statin use. The Committee agreed that this association was an early signal and recommended that the issue of statins, neuromuscular degenerative disease and ALS-like syndrome be placed on the 'Scheduled Review' list for a 12-monthly review.

The purpose of the December 2008 report was to inform the Committee of recent data and regulatory action regarding this potential signal. The Committee was asked to evaluate the information provided and to determine whether the risk-benefit profile of statins had changed as a result of this new information. If the risk-benefit profile was deemed to have changed, the Committee was asked to recommend appropriate risk management.

Discussion

The Committee noted the 2008 Medsafe report.

The Committee noted that in September 2008, the FDA advised they had completed an analysis of the association between statin use and the development of ALS. Data obtained from placebo-controlled clinical trials provided new evidence that the use of statins does not increase the incidence of ALS. The FDA concluded that based on currently available information, no change in prescribing and use of statins was recommended. The FDA stated that although the lack of an increase in the incidence of ALS in patients treated with statins in clinical trials was reassuring, given the extensive use of this class of drugs and the serious nature of ALS, continued study of this issue was warranted.

The Committee noted that there is a case-control or epidemiological study of ALS and statin use currently being carried out in the United States and the findings are anticipated within the next 12 months.

The Committee agreed that there is insufficient evidence to warrant a change to the prescribing and use of statins with regard to the risk of ALS-like syndrome at this time. The Committee agreed that the results of the case-control or epidemiological study of ALS and statin use that is currently being conducted in the U.S. be awaited and recommended that the issue of statins, neuromuscular degenerative disease and ALS-like syndrome remain on the 'Scheduled Review' list for a 12-monthly review.

Recommendation

The Committee recommended that the issue of statins, neuromuscular degenerative disease and amyotrophic lateral sclerosis-like syndrome remain on the 'Scheduled Review' list for a 12-monthly review.

3.2 ORAL TERBINAFINE AND SERIOUS ADVERSE REACTIONS (BLOOD DYSCRASIAS, HEPTATOTOXICITY AND DERMATOLOGICAL REACTIONS) - INCLUDING PRESCRIBING DATA - SCHEDULED REVIEW

  1. Pillans P, Boyd W. Toenails and agranulocytosis. Internal Medical Journal 2007; 37:572-575
  2. Lorentz K, et al. Subacute cutaneous lupus erythematosus induced by terbinafine: case report and review of literature. Journal der Deutschen Dermatologischen Gesellschaft 2008; 6(10): 823-827
  3. Hivnor CM, et al. Terbinafine-induced subacute cutaneous lupus erythematosus. Cutis 2008; 81(2): 156-7
  4. Magro C, et al. Terbinafine-induced dermatomyositis: a case report and literature review of drug-induced dermatomyositis. Journal of Cutaneous Pathology 2008; 35 (1): 74-81
  5. Rubegni P, et al. Terbinafine-induced acute generalized exanthematous pustulosis. G Ital Dermatol Venereol 2008;143:151-155
Issue

Medsafe provided a report for the MARC on the issue of oral terbinafine & serious adverse reactions (blood dyscrasias, hepatotoxicity and dermatological reactions).

The issue of serious adverse reactions attributed to terbinafine was brought to the MARC following a review by the Australian Adverse Drug Reactions Advisory Committee (ADRAC) of terbinafine and blood dyscrasias in February 2006. ADRAC requested information on serious adverse reactions from the sponsor of the innovator product (Novartis), in order to review the adequacy of the PI and CMI. The initial response from Novartis was considered inadequate and the Committee requested the actual case reports, so that the Adverse Drugs Reactions Unit (ADRU) could analyse these. Terbinafine was also of interest in New Zealand as there has been direct to consumer advertising and this raised the concern that it may be used when a topical application may be more appropriate. These considerations led to a search of the CARM and WHO databases for reports of blood dyscrasias and other severe and serious reactions to terbinafine. The results were presented to the MARC in September 2006.

Summary of MARC report, September 2006

The list of positive Information Component (IC) combinations in the WHO database (Vigibase) supported the evidence from the CARM database that hepatic and skin disorders were prominent and potentially serious adverse reactions to terbinafine. There was also evidence of a causal role for terbinafine in serious blood dyscrasias, including life-threatening reactions despite lack of statistical disproportionality (negative IC values) in the WHO database, and these were reported as often as hepatic reactions in the CARM database.

In September 2006, the warnings about the haematological, hepatic and dermatological serious adverse effects in the New Zealand data sheets for oral terbinafine products were updated in line with the Australian Generic Terbinafine Tablet Product Information. In September 2006, the MARC considered that if amendments to the Australian Product Information were made as a result of the ADRAC review, the New Zealand data sheets should then be equivalently updated.

The Committee recommended that the issue be reviewed again in 12 months time.

Summary of MARC report, September 2007

The Committee noted that since the last analysis there had been no change in the reporting rate to CARM of adverse reactions attributed to terbinafine. Four reports of serious reactions had been received, three affecting the skin and one hepatic. No fatal reactions attributed to terbinafine in the skin, hepatic and the white cell and platelet categories had ever been reported to CARM. However, the WHO reports indicate that on rare occasions terbinafine may have contributed to death and one report of a fatal hepatic reaction was received in the previous year. The conclusion from the September 2006 analysis was unchanged. The list of statistically prominent combinations in the WHO database supported the evidence from the CARM database that hepatic and skin disorders were prominent and sometimes serious. There was also evidence of a causal role for terbinafine in serious blood dyscrasias, despite negative IC values.

The Committee noted that an article entitled "Terbinafine: serious hepatic and haematological reactions" was published in the November 2006 edition of Prescriber Update. They felt it was important to disseminate this information as widely as possible and recommended that the Best Practice Advocacy Centre (BPAC) be approached and asked to include a paragraph in their publication about the appropriate prescribing of oral terbinafine.

The Committee recommended that the issue of oral terbinafine and serious adverse reactions (blood dyscrasias, hepatotoxicity and dermatological reactions) be placed on the 'Scheduled Review' list for 12-monthly review. This review was to include prescribing data, to assess if communications to prescribers had been effective.

The purpose of the December 2008 report was to inform the Committee of recent data and regulatory action over the last 15 months. The Committee was asked to evaluate the information provided and to determine whether the risk-benefit profile of oral terbinafine had changed as a result of this information. If the risk-benefit profile was deemed to have changed, the Committee was asked to recommend appropriate risk management.

Discussion

The MARC noted the November 2008 Medsafe report.

The Committee noted that following the September 2007 recommendation, a paragraph regarding the appropriate prescribing of oral terbinafine was included in the BPAC December 2007 publication.

NZPhvC advised that the level of reporting for oral terbinafine has decreased markedly over the past year. There were no reports of blood dyscrasias or disorders, or hepatic disorders in association with oral terbinafine received in the last year. Two serious reports of skin reactions suspected to be in association with oral terbinafine had been received in the previous 12 months. The level of prescribing has shown an overall decline since May 2006.

The Committee considered that the inappropriate use was of concern, with a large proportion of patients having a condition which would not respond to terbinafine treatment. They noted that a cure was only achieved in a minority of patients at one year, and the relapse rate was high.

The Committee considered that while oral terbinafine was a useful medication for other indications, its widespread use for the treatment of non-responsive infections of the toe nail was not appropriate. They expressed their concern that this product was advertised directly to consumers and considered that it was important that patients be warned of the adverse effects of this medicine, along with the warning signs to be aware of.

The Committee agreed that this issue continued to be of concern and recommended that the issue of oral terbinafine and serious adverse reactions (blood dyscrasias, hepatotoxicity and dermatological reactions) remain on the 'Scheduled Review' list for 12-monthly review.

Recommendation

The Committee recommended that the issue of oral terbinafine and serious adverse reactions (blood dyscrasias, hepatotoxicity and dermatological reactions) remain on the 'Scheduled Review' list for 12-monthly review.

3.3 ORAL BISPHOSPHONATES AND THE RISK OF ATRIAL FIBRILLATION

References
  1. FDA Early Communication of an Ongoing Safety Review dated 1 October 2007.
  2. FDA Safety Information Alert dated 1 October 2007.
  3. MHRA Drug Safety Update. Bisphosphonates: Atrial Fibrillation dated July 2008.
  4. Black DM, Delmas PD, Easell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Sellmeyer D, Eriksen EF & Cummings SR (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis N Engl J Med 356(18): 1809-1822.
  5. Cummings SR, Swartz AV & Black DM (2007) Alendronate and atrial fibrillation N Engl J Med 356(18): 1895-6.
  6. Sorensen HT, Christensen S, Mehnert F, Pederson L, Chapurlat RD, Cummings SR & Baron JA (2008) Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study BMJ 336: 813-16.
  7. Heckbert SR, Li G, Cummings SR, Smith NL & Psaty BM (2008) Use of alendronate and risk of incident atrial fibrillation in women Arch Intern Med 16(8): 826-31.
  8. Kerr M (2008) Bisphosphonates Linked to Higher Incidence of Serious Atrial Fibrillation. Reuters Health Information.
  9. Karam R, Camm & McClung M (2007) Letter to the Editor N Engl J Med 357(7): 712.
  10. Majumdar SR (2008) Oral bisphosphonates and atrial fibrillation BMJ 336: 784-5.
  11. Cauley JA & Ensrud KE (2008) Considering competing risks … not all black and white Arch Intern Med 168(8): 793-5.
  12. Compston J (2007) Treatments for osteoporosis - looking beyond the HORIZON. N Engl J Med 356(18): 1878-80.
  13. FDA Update of Safety Review Follow-up to the October 1, 2007 Early Communication dated 12 November 2007.
Issue

Medsafe provided a report for the MARC on the issue of oral bisphosphonates and atrial fibrillation (AF). In May 2007, the New England Journal of Medicine published the findings of a double blind, placebo controlled clinical trial in which older women with osteoporosis were randomly assigned to receive a single 15 minute infusion of zoledronic acid or placebo at yearly intervals for 3 years. This study reported a secondary safety endpoint of 'serious' atrial fibrillation, which was significantly more frequent in the zoledronic acid group.

In a review of the results of the Fracture Intervention Trial (FIT), published in the same edition an increase in serious AF events was reported, which neared a statistical level of significance.

In October 2007, the FDA released an Early Communication informing prescribers and patients of an ongoing safety review of bisphosphonates in which these findings were discussed. The FDA reported that it had reviewed spontaneous adverse reaction reports of AF in association with oral and IV bisphosphonates but could not define users at-risk of AF. At that time, the FDA concluded that it did not believe prescribing practices or the use of bisphosphonates needed to be changed.

Since late 2007 two further case-control studies in older women with osteoporosis have explored the relationship between AF and bisphosphonates, drawing different conclusions.

In July 2008, the UK MHRA informed prescribers that the risk of AF in association with bisphosphonates was low. It was also stated that the product information for zoledronic acid had been updated to include AF as a possible side effect and AF was being added to the product information for pamidronic acid. The MHRA indicated the risk of AF in association with alendronic acid would be subject to ongoing review.

On 12 November 2008, the FDA released an update of safety review follow-up to the October 2007 early communication to healthcare professionals with the results of its review of the safety data. FDA found no clear association between overall bisphosphonate exposure and the rate of serious or non-serious AF and recommended healthcare professionals not alter their prescribing patterns for bisphosphonates. This advice was issued for alendronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate and zoledronic acid.

The Committee was asked to consider if the evidence is sufficient to warrant taking regulatory action at this time.

Discussion

The Committee noted the November 2008 Medsafe report.

The Committee noted that the purpose of the report was to consider only the issue of AF in association with the oral bisphosphonates rather than zoledronic acid, which is administered by infusion. The risk of AF associated with the use of zoledronic acid infusions was an unexpected finding arising from the 'HORIZON PFT' clinical trial, a trial sufficiently powered to detect such rare adverse events. This study provided an adequate level of evidence that there was a risk of serious AF in association with the use of zoledronic acid infusions in postmenopausal osteoporosis patients, although it was clearly an uncommon adverse effect (1-2%). The low level of risk of AF in patients with postmenopausal osteoporosis receiving zoledronic acid infusions was outweighed by the considerable benefits in preventing fracture in this population. The product sponsors for zoledronic acid have already included information in their New Zealand data sheets on the increased risks associated with zoledronic acid reported in the HORIZON PFT, therefore no regulatory action is required for these products.

In considering the issue of AF in association with oral bisphosphonates, the Committee noted that currently, conflicting data exists regarding this risk. They noted that in the Sorensen et al. study, a large and well-designed observational study which was sufficiently powered to detect rare adverse effects, no significant increase in AF and atrial flutter was found in women taking oral bisphosphonates. They noted that other studies retrieved that have examined the risk of AF in association with oral bisphosphonates were less reliable in that they have been underpowered and other possible confounders were not adequately accounted for in the analyses. The Committee however recommended that [..] be asked to provide an opinion on the risk of AF in association with oral bisphosphonates.

The Committee agreed that the risk:benefit ratio for all bisphosphonates remains favourable. The well-established benefits of oral bisphosphonates in osteoporosis patients in reducing the incidence of fractures is likely to outweigh a low risk of AF if and when it can be conclusively established this risk exists.

The Committee considered that the evidence for an association between oral bisphosphonate use in postmenopausal women for osteoporosis and atrial fibrillation was insufficient to warrant regulatory action being taken at present. They recommended that the issue of oral bisphosphonates and atrial fibrillation be placed on the list for a 12-monthly Scheduled Review, to include responses to a Medsafe request for Periodic Safety Update Report (PSUR) data accumulated by product sponsors of oral bisphosphonates in respect of AF.

Recommendations

The Committee recommended that [..] be asked to provide an opinion on the risk of AF in association with oral bisphosphonates.

The Committee recommended that the issue of oral bisphosphonates and atrial fibrillation be placed on the list for a 12-monthly Scheduled Review, to include responses to a Medsafe request for Periodic Safety Update Report (PSUR) data accumulated by product sponsors of oral bisphosphonates in respect of AF.

3.4 PARACETAMOL ASSOCIATED WITH CHILDHOOD ASTHMA

References
  1. Beasley R, Clayton T, Crane J, Von Mutius E, Lai CKW, Montefort S, Stewart A, 2008, Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6 - 7 years: analysis from Phase Three of the ISAAC programme, The Lancet 372; 1039 - 1048.
  2. Medsafe, September 2008, Paracetamol associated with asthma symptoms, Dear Healthcare Professional letter, Wellington: Medsafe.
  3. Ministry of Health, September 2008, Keep using paracetamol for pain and fever in infants and children. Wellington: Ministry of Health.
  4. MHRA, November 2008, Paracetamol use in infancy: no strong evidence for asthma link Drug Safety Update 2(4), London, Medicines and Healthcare products Regulatory Agency.
  5. Shaheen SO, Newson RB, Henderson AJ, Headley JE, Stratton FD, Jones RW, Strachan DP and ALSPAC Study Team, 2005, Prenatal paracetamol exposure and risk of asthma and elevated immunoglobulin E in childhood, Clinical and Experimental Allergy 35; 18 - 25.
  6. McKeever TM, Lewis SA, Smit HA, Burney P, Britton JR, Cassano PA, 2005, The Association of Acetaminophen, aspirin and ibuprofen with respiratory disease and lung function, American Journal of Respiratory and Critical Care Medicine 171; 966 - 971.
  7. Barr RG, Wentowski CC, Curham GC, Somers SC, Stampfer MJ, Schwartz J, Speizer FE, Camargo CA, 2004, Prospective study of acetaminophen use and newly diagnosed asthma among women, American Journal of Respiratory and Critical Care Medicine 169; 836 - 841.
  8. Lesko SM, Louik C, Vezina RM, Mitchell A, 2002, Asthma morbidity after the short term use of ibuprofen in children, Pediatrics 109; e20.
  9. Shaheen SO, Sterne JA, Songhurst CE, Burney PGJ, 2000, Frequent paracetamol use and asthma in adults, Thorax 55; 266 - 270.
  10. Newson RB, Shaheen SO, Chinn S, Burney PGJ, 2000, Paracetamol sales and atopic disease in children and adults: an ecological analysis, European Respiratory Journal 16; 817 - 823.
Issue

Medsafe provided a report to inform the MARC of the current evidence for an association between paracetamol use and asthma. This followed the publication of a paper by Professor Richard Beasley and colleagues in The Lancet in 2008. This paper presented an analysis of data looking at paracetamol use and asthma, rhinoconjunctivitis and eczema from Phase III of The International Study of Asthma and Allergies in Childhood (ISAAC). The Beasley et al paper found an association between children who were given paracetamol for fever in the first year of life and an increased risk of having asthma, rhinoconjunctivitis or eczema when aged 6 - 7 years. Another paper by Asher et al reporting on Phase III of the ISAAC study found the twelve month prevalence rates of asthma, rhinoconjunctivitis and eczema in New Zealand to have declined for 13 - 14 year olds. For 6 - 7 year olds the asthma rates have declined but the rhinoconjunctivitis and eczema rates have increased.

The Beasley et al paper adds to previously published studies finding an association between asthma and paracetamol use in adults, children, infants and during pregnancy. Currently the evidence does not support the association being due to a causal effect.

Due to potential public interest in the association between paracetamol and asthma at the time of publishing of the Beasley et al paper, three MARC members were asked for preliminary comment, prior to a letter being faxed to prescribers and pharmacists. In September 2008, Medsafe distributed a fax to prescribers and pharmacists stating that there is insufficient evidence to change current prescribing practices regarding paracetamol.

The Ministry of Health issued information in the form of a press release and on the MOH website to advise that the current evidence did not alter the recommendations for using paracetamol in children and recommending that carers give paracetamol only as recommended by the Paediatric Society New Zealand.

The Committee was asked if the current data supported a strong enough signal of risk of paracetamol use being associated with developing asthma to require further communication to prescribers or the public. The Committee was also asked whether the Shaheen et al study, regarding paracetamol use in pregnancy, constituted strong enough evidence to change the information on the paracetamol data sheet about the use of paracetamol in pregnancy.

Discussion

The MARC noted the August 2008 Medsafe and NZPhvC reports. Members welcomed Professor Richard Beasley, who provided the Committee with an overview of the recent Lancet paper, in which he was one of the primary authors. Professor Beasley presented the following information:

[..]

The Beasley et al study concluded that the study provided further evidence that the use of paracetamol in childhood could increase the risk of developing asthma and related allergic disorders. However, the authors acknowledged that while the study provided evidence of an association, the design of the study did not allow causality to be established. They concluded that multiple confounders were present, and that further research was needed into the long-term effects of paracetamol to enable evidence-based guidelines for the recommended use of paracetamol in childhood to be made.

The MARC accepted that there may be an association and potential risk with the use of paracetamol and asthma. They agreed that further evidence from the international research currently being undertaken was required before any firm recommendations could be made. The Committee noted that alternatives are limited, both during pregnancy and for children. In the interim, they agreed that paracetamol remained the agent of choice. As the association was stronger with increased frequency of paracetamol use, however, paracetamol should be used sparingly for the treatment of fever and significant pain in all age groups. The Committee recommended that an article be published in Prescriber Update, advising of a possible risk of asthma in association with paracetamol, and warning of the other risks of frequent use of paracetamol. The main messages to be communicated in the article were:

The Committee recommended that a warning about the association between paracetamol use in pregnancy and the infant developing asthma should be included in the New Zealand data sheets for paracetamol.

The Committee noted that Medsafe will continue to monitor the literature on this issue, and report back to the Committee as necessary.

Recommendation

The Committee recommended that an article be published in Prescriber Update, advising of a possible risk of asthma in association with paracetamol, and warning of the other risks of frequent use of paracetamol. The article should include the advice that there is currently not enough evidence to change current prescribing. The Committee recommended that Medsafe write to sponsors of paracetamol and require them to include a warning in product datasheets about the possible risk of paracetamol use in pregnancy leading to asthma in the infant.

4. Matters arising from the New Zealand Pharmacovigilance Centre

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

Spontaneous reporting programme

All spontaneous reports presented at the MARC meeting have been assessed by the Centre for Adverse Reactions Monitoring (CARM) and responses 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 entering 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 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.

4.1.1 Deaths

4.1.1.1 Ropivacaine and convulsion grand mal, cardiac arrest, drug overdose [death] (80093)

Discussion

NZPhvC advised that the WHO database includes reports of convulsions and cardiac events in association with ropivicaine, and these are included in the product datasheet.

The Committee noted that the patient was reported to have other co-morbidities which were not specified, and it was unclear if the death could be attributed to the medicine. They noted that this case has been referred to the Coroner and recommended that NZPhvC provide a follow-up report when this information has been received.

The causal association with ropivacaine was considered to be 'possible' for convulsion grand mal, cardiac arrest, drug overdose.

Recommendation

The Committee recommended that NZPhvC provide a follow-up report to the MARC when the Coroner's report has been received.

4.1.1.2 Hydroxychloroquine and convulsion, hepatic enzymes raised, drug interaction [death] (80045)

Discussion

NZPhvC advised that the CARM and WHO databases include reports of convulsions and hepatic abnormalities in association with hydroxychloroquine.

NZPhvC advised that there were insufficient details provided in the report to consider a causal association.

The Committee noted that a post-mortem report was awaited and further information would be brought back to the MARC as appropriate.

The causal association with hydroxychloroquine was considered to be 'unclassifiable' for convulsion, hepatic enzymes raised, drug interaction.

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

4.1.1.3 Erlotinib and dyspnoea, sudden death [death] (80222)

Discussion

NZPhvC advised that there are a small number of reports in the CARM database for erlotinib, with none for dyspnoea. They advised that dyspnoea has occurred in clinical trials of erlotinib.

The Committee noted that the patient/s death may have been due to disease progression or to an underlying disorder.

The causal association with erlotinib was considered to be 'unclassifiable' for dyspnoea, sudden death.

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

4.1.1.4 Rituximab, cyclophosphamide, doxorubicin and vincristine and neutropenia, cerebral haemorrhage [death] (80223)

Discussion

NZPhvC advised that the CARM database includes reports of neutropenia in association with rituximab, cyclophosphamide, doxorubicin and vincristine, however, there are no reports of cerebral haemorrhage with any of these medicines.

The Committee considered the causal association with rituximab, cyclophosphamide, doxorubicin and vincristine, to be 'possible' for neutropenia, cerebral haemorrhage.

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

4.1.1.5 Raltegravir and cerebral infarction [death] (80788)

Discussion

NZPhvC advised that there are no reports in either the CARM or WHO databases of cerebral infarction or related events. The literature indicates that antiretroviral agents increase the risk of myocardial infarction, however, this is rare.

The Committee considered the causal association with raltegravir was 'unclassified' for cerebral infarction.

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

4.1.1.6 Dianeal and sudden death [death] (80214, 80215)

Discussion

NZPhvC advised that the CARM database does not include any reports for any peritoneal dialysis solution.

The Committee noted that the details provided in both cases were inadequate to determine causality and considered the causal association with Dianeal to be 'unclassifiable' for sudden death.

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

4.1.1.7 Dianeal, Icodextrin and sudden death [death] (80216)

Discussion

See minute item 4.1.1.6.

The causal association with Dianeal was considered to be 'unclassifiable' for sudden death.

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

4.1.1.8 Simvastatin, citalopram, omeprazole, cilazapril, metoprolol, furosemide, metformin, gliclazide, warfarin, aspirin and muscle weakness, sudden death [death] (79981)

Discussion

NZPhvC advised that there were insufficient details provided in the report to consider a causal association and that further details had been requested.

The causal association with simvastatin, citalopram, omeprazole, cilazapril, metoprolol, furosemide, metformin, gliclazide, warfarin, aspirin was considered to be 'unclassifiable' for sudden death.

The causal association with simvastatin, citalopram, omeprazole, cilazapril, metoprolol, furosemide, metformin, gliclazide, warfarin, aspirin was considered to be 'unclassifiable' rather than 'possible' for muscle weakness.

Recommendation

The Committee recommended that NZPhvC change the causality for muscle weakness from 'possible' to 'unclassifiable'.

Secretary's note:
A typographical error was noted by the Committee and the severity of sudden death amended to 'severe'.

4.1.1.9 Thyroxine and hyponatraemia, demyelination, hepatic function abnormal, vomiting, diarrhoea, product formulation change [death] (80112)

Discussion

The NZPhvC advised that the CARM database includes one other report of hyponatraemia in association with Eltroxin.

The Committee noted that this patient had significant underlying pathology, which from the hospital record appears to be the key factor accounting for the death of this patient.

The causal association with thyroxine was considered to be 'unclassified' for hyponatraemia, demyelination, hepatic function abnormal, vomiting, diarrhoea, product formulation change.

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

4.1.1.10 Presumed unspecified SSRI and suicide [death] (81023)

Discussion

NZPhvC advised that further information to enable a causality assessment has been requested.

The Committee noted that the issue of SSRI use and suicidality has been considered on an ongoing basis by the MARC since 2004. During this time, both individual cases and full reviews have been evaluated. These have resulted in a number of actions, including strengthening product datasheet information and prescribing advice.

The causal association with presumed unspecified SSRI was considered to be 'unclassified' for suicide.

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

Please also refer to minute item 9.2.

4.1.1.11 Clozapine and agranulocytosis, pneumonia, hypertension [death] (80225)

Discussion

NZPhvC advised that agranulocytosis and neutropenia are known adverse events occurring in association with clozapine. Testing of blood levels throughout the treatment period is mandatory, and these requirements are included in boxed warnings in the product datasheets.

The Committee noted that this was an unexpected event, which occurred in a patient who appeared to haven been properly monitored and had been otherwise well prior to the onset of events.

The causal association with clozapine was considered to be 'possible' for pneumonia- gram negative bacterial, sepsis, multiple organ failure, haemorrhage cerebral, hypertension.

The causal association with clozapine was considered to be 'probable' rather than 'possible' for agranulocytosis.

Recommendation

The Committee recommended that NZPhvC change the causality from 'possible' to 'probable'.

4.1.1.12 Ascorbic acid and renal failure, drug overdose, medication error [death] (80229)

Discussion

NZPhvC advised that while the CARM database does not include reports of any renal adverse reactions in association with ascorbic acid, the WHO database includes some reports of renal failure and impairment in association with ascorbic acid. They advised that this case was recently reported in the literature in Anaesthesia and Intensive Care.

The Committee noted that ascorbic acid is available as an over-the-counter medicine, and the product statements refer to renal effects of high dosages.

The causal association with ascorbic acid was considered to be 'possible' for renal failure, drug overdose, medication error.

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

4.1.2 Musculoskeletal

4.1.2.1 Diclofenac and ibuprofen and renal failure acute, nephritis interstitial, medication error (80184)

Discussion

NZPhvC advised that there were reports of interstitial nephritis and renal failure in association with nonsteroidal anti-inflammatory drugs (NSAIDS) in the CARM database, and these are listed as adverse reactions in the product information for both ibuprofen and diclofenac.

NZPhvC advised that acute interstitial nephritis is a recognised adverse reaction to NSAIDs which is not likely to be dose related. In this case however, the patient was taking the maximum recommended dose of diclofenac, as well as a dose of over-the-counter (OTC) ibuprofen greater that that recommended when purchased OTC. This high NSAID dose may have exacerbated the acute renal failure that developed as a consequence of acute interstitial nephritis.

NZPhvC advised that they have four recent reports of serious renal or gastrointestinal reactions in patients taking excessive doses or combined NSAID products. The Committee noted that a paragraph on this topic had recently been published in NZ Doctor and considered it was important to disseminate this information more widely to prescribers, and also to patients. They recommended that a paragraph be prepared in conjunction with [..], for publication in the BPAC publication and Prescriber Update.

The causal association with diclofenac, ibuprofen was considered to be 'probable' for renal failure acute, nephritis interstitial, medication error.

Recommendation

The Committee recommended that a paragraph be prepared in conjunction with [..], for publication in the BPAC publication and Prescriber Update.

4.1.3 Psychiatric

4.1.3.1 Citalopram and akathisia, anxiety reaction, agitation, thoughts of self harm (79307)

Discussion

NZPhvC advised that the CARM database includes reports of these symptoms in association with citalopram. The product datasheets for the SSRI antidepressants refer to clinical worsening and suicide risk.

The causal association with citalopram was considered to be 'probable' for akathisia, anxiety reaction, agitation, thoughts of self harm.

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

4.1.4 Other Reports

The Committee noted the following case reports:

Leflunomide, bendrofluazide (79366)
Leflunomide (79450)
Leflunomide, methotrexate, metformin, naprosyn, Inhibace(80986)
Adlimumab, leflunomide, celecoxib (80221)
Cefaclor (80966)

4.2 Quarterly Reports from CARM as at September 2008

Discussion

NZPhvC presented the report. They noted that a continuing issue was the number of reports received for the Dr Reddy brand of both omeprazole and pantoprazole, which largely describe reduced effect. Reports have also been received for the other two currently subsidised brands of omeprazole.

Reports have been received following the quetiapine brand change, describing reduced therapeutic effect, hallucinations, GI symptoms, anxiety, sleep disturbances and hyperglycaemia.

NZPhvC advised that the frequency of reports for Eltroxin has decreased since the Goldshield brand was listed on the Pharmaceutical Schedule on 1 November 2008. There have been a small number of brand switch reports received for the Synthroid brand of thyroxine, and one report in a patient changing from the Synthroid brand to the new formulation of Eltroxin.

NZPhvC noted that reports had been received of tendon rupture in association with norfloxacin. Recent overseas regulatory action has been undertaken. Medsafe advised that it has requested further information on this from the manufacturer in order to determine if any action is required in NZ. The Committee recommended that NZPhvC present the cases they have received of tendon rupture in association with norfloxacin at the next MARC meeting.

The Committee discussed the broader issue of brand switch reports. They noted that there were many confounders involved, and there was a lack of published literature on the topic. They discussed the evaluation process with respect to bioequivalence and the checks and balances in place to ensure the quality of generic medicines. The Committee recommended that Medsafe provide a paper describing the evaluation of bioequivalence and detailing signal detection procedures in general, but including a focus on brand switches. The Committee recommended that the paper proposes mechanisms by which the MARC could assist in evaluating safety signals and suggesting appropriate regulatory actions. The paper should be presented at the June MARC meeting.

The Committee noted the quarterly reports from CARM as at September 2008.

Recommendation

The Committee recommended that NZPhvC present the cases they have received of tendon rupture in association with norfloxacin at the next MARC meeting.

5. pharmacovigilance issues for information only

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

Taylor DR et al. (2008) "As required" combination therapy with inhaled corticosteroids and long-acting beta-2 agonists for asthma: current evidence and recommendations. NZMJ. 121 (1285) 106-118

Record of the Pharmacology and Therapeutics Advisory Committee Meeting held on 23 and 24 July 2008.

PHARMAC media release - New guidance to help with antipsychotic use in elderly.

6. New Zealand Pharmacovigilance-related Activities

7. international pharmacovigilance-related Activities

7.1 Australia

7.2 United Kingdom

7.3 United States

8. Summary listings of case reports considered by the MARC (1997- 2008)

9. OTHER BUSINESS

9.1 Monitoring of adverse events following immunisation for the Human Papillomavirus (HPV) Immunisation programme

Members welcomed Greg Simmons, who provided the Committee with an overview of the monitoring that is in place for adverse events following immunisation for the HPV programme.

Delivery of the government funded HPV immunisation programme through primary care commenced on 1 September 2008. The next stage in the programme takes place with the commencement of the new school year in 2009, largely via a school-based system. A monitoring plan is in place, between the Centre for Adverse Reactions Monitoring (CARM) and the Ministry of Health. This will include regular reports of all adverse reactions, with any significantly serious, or rare and important report being notified to the Ministry immediately. These reports will be included in the quarterly report presented to the Committee by CARM.

The MARC acknowledged that this was an important issue and agreed to receive quarterly reports of the adverse events following HPV immunisation.

9.2 SSRI antidepressants

Ian Smith, Wellington Coroner, addressed the meeting to advise the Committee of his concerns regarding the use of SSRI antidepressants. In his experience, patients are not adequately informed of the risks of the use of the SSRIs and other antidepressants. In particular, the risk of clinical worsening of depression and suicide risk, as described in product datasheets, should be highlighted to patients, and also to their immediate families. He expressed concern that the follow-up system for GP appointments was not robust enough, and patients diagnosed with depression who do not attend a scheduled appointment are not adequately followed up. He considered that counselling should be accessible, and always used in conjunction with medication.

The Committee expressed their agreement with the Coroner's comments and advised that the issue of the SSRI antidepressants and the risk of suicidality was being addressed by the MARC.

The Committee advised that the treatment guidelines for depression in primary care published by the NZ Guidelines Group have recently been revised and published and a concise summary of those will be available early in 2009. A support tool for primary care is also currently being developed.

The Committee expressed their agreement with the Coroner's comments, and recommended that a formal request be made to the Coroner's Office to forward the decisions relating to medication related cases directly to the NZPhvC.

Recommendation

The Committee recommended that a formal request be made to the Coroner's Office to forward the decisions relating to medication related cases directly to the NZPhvC.

9.3 Update on Safe Medicines Management Programme

The Committee was advised of the Safe Management of Medicines Programme, which is part of a quality improvement initiative being undertaken by the Ministry of Health. This project is divided into four sections - one of which is the development of the necessary information systems. This offers an opportunity to improve reporting systems, including the ability to include adverse drug reactions and allergies. The Committee considered that an improvement in the recording and reporting of adverse drug reactions and allergies was an opportunity to improve patient safety and it would be valuable for NZPhvC to be included in the development of these reporting systems.

9.4 Removal of specialist prescribing restriction from retinoinds

The Committee noted that PHARMAC has advised that from 1 March 2009, general practitioners and nurse practitioners working in a relevant scope of practice and meeting certain criteria, will be able to prescribe and have funded oral retinoid products (acitretin and isotretinoin). Previously the oral retinoids in New Zealand were only funded if the prescription was written by a dermatologist.

In response to the MARC's concerns expressed at the September 2008 meeting, Medsafe made a submission to PHARMAC as part of the consultation process around widening access. This requested an in-depth review of the safety literature of the oral retinoids.

The MARC expressed its concern regarding the decision to remove the specialist prescribing restriction from the oral retinoids, specifically about the teratogenicity of these products. They recommended that the Chair write to PHARMAC, asking for details of the risk management strategy to ensure the safe use of these medicines.

Recommendation

The Committee recommended that the Chair write to PHARMAC, asking for details of the risk management strategy to ensure the safe use of the oral retinoids.

9.5 Reporting of patient allergies to the Centre for Adverse Reactions Monitoring CARM

The Committee noted the letter from the Chair published in the 28 November edition of the New Zealand Medical Journal. This reported on two recent cases of fatal allergic reactions to antibiotics which were reported in the media. These cases have highlighted the importance of the reporting of allergic reactions to the Centre for Adverse Reactions Monitoring (CARM).

Recommendation

The Committee recommended that the Chair write to the Chief Medical Officers on behalf of the MARC, highlighting the importance of the reporting of adverse reactions and allergic reactions to the Centre for Adverse Reactions Monitoring (CARM).

The Chair thanked members and the secretariat for their attendance and closed the meeting at 3pm.

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