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 138^th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING,

11 June 2009

The one hundred and thirty eighth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 11 June 2009 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9.05am and closed at 3.50pm.

marc members present

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

MARC Secretariat Present

J McNee (MARC Secretary)

MEDSAFE STAFF present

A Cutfield (Advisor, Pharmacovigilance)
J Hart (Acting Manager, Clinical Risk Management, Medsafe)
C James (Advisor, Pharmacy)
S Kenyon (Senior Advisor, Pharmacovigilance)

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting.

Apologies were received from Dr S Jessamine and Dr R Savage.

1.2 Minutes of the 137th MARC Meeting

The Committee noted that Susan Kenyon had been incorrectly listed among the attendees at the 137^th MARC meeting held in March 2009. The Secretary agreed to make this change.

The minutes of the 137^th meeting of the Committee were otherwise 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 10 September 2009. The subsequent MARC meeting for 2009 was scheduled for 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.

Dr Kingston declared that she had received fees for a pandemic planning exercise and DVD production from the Nelson Marlborough District Health Board in April 2009.

Dr Tatley declared that the New Zealand Pharmacovigilance Centre received industry funding for the Paradex Drug Utilisation Study.

Assoc Prof Frampton declared that he had received fees for speaking at a Roche sponsored meeting in May 2009. He also received fees for statistical summaries of Ambrisentan data for GSK in May/June 2009.

The conflicts of interest were discussed but were not considered to influence the discussions or decisions.

1.5 Prescriber Update

1.5.1 Schedule of Planned Prescriber Update Articles

Discussion

The Committee noted that the schedule of planned Prescriber Update articles was brief and congratulated the Editor on the new format, which allows for articles to be published in a more timely manner. The Committee made suggestions for topics which could be included in future editions.

1.5.2 Prescriber Update. Volume 30, Number 2. May 2009

Discussion

The Committee noted the latest edition of Prescriber Update.

1.6 Medsafe Communication - review and future development

Background

Medsafe provided a report for the MARC in response to their request for information regarding how Medsafe communicates medicines-related safety issues to both healthcare professionals and the public. The paper also provided a basis for discussion on possible future options for communication.

Medsafe's communication aims are to:

Alert healthcare professionals and the public to medicines related safety issues.

Communicate information necessary for healthcare professionals and the public to understand medicines related safety issues.

Communicate information on medicines related safety issues to healthcare professionals and the public in a timely manner.

Notify healthcare professionals and the public of any regulatory action relating to medicines.

Prescriber Update is a Medsafe publication designed to provide healthcare professionals with useful and timely information on medicines related safety issues, along with any regulatory action taken in relation to medicines. In February 2009 Prescriber Update adopted a new format, comprising of short articles, with references to further information should the reader require more detail. The shortened format is expected to enable more timely medicine related safety advice to be provided to healthcare professionals. Prescriber Update is distributed largely in paper form, however, readers may subscribe to an electronic version.

Medsafe also communicates advice to healthcare professionals and the public via avenues such as Ministry of Health media releases, "Dear Dr/Healthcare professional" letters, Medsafe and the Ministry of Health's website, professional bodies such as the Royal College of General Practitioners, the Pharmaceutical Society of New Zealand, and by publishing articles in professional journals such as the Best Practice Journal.

Almost all international regulatory agencies use methods similar to Medsafe to communicate advice to healthcare professionals and the public.

Discussion

The Editor advised that two editions of Prescriber Update in the new format have been published this year and feedback has so far been positive. Information from the May edition had been published in other publications, such as Adverse Reactions Weekly, Scrip, and also by the media.

The Committee noted that Medsafe is aiming to distribute Prescriber Update to as many health professionals as possible, particularly by increasing use of the electronic version. The Committee suggested various methods of increasing readership. They considered hospital doctors to be a key audience, and suggested that it may be possible to distribute Prescriber Update to this audience via the hospital libraries.

The Editor advised that future developments could include:

A website review to improve readability and access to medicines related safety information
Regular email, SMS alerts, and RSS feeds updates to subscribed recipients.
Use of multimedia formats, for example pod-casts and video. Medsafe was currently taking part in a nationwide series of seminars discussing generic medicines in association with PHARMAC, and a presentation from events such as this could be published on the website.

The Committee were shown some examples of PowerPoint summaries which could be shown in Grand Rounds and presentations. These consisted of brief summary points of information, examples of which could include Prescriber Update articles, media releases, and general background about adverse reactions.

The Committee considered a primary aim of communication by Medsafe was to improve awareness of adverse drug reactions and safety issues. They considered the reporting of suspected adverse reactions to CARM to be a vital part of medicine safety and discussed ways in which this could be encouraged.

The Committee agreed that the new format of Prescriber Update was a positive change and noted that future developments would be complementary to the existing communication systems.

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

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

2.1.1 Paracetamol associated with childhood asthma
March 2009 minute item 2.1.6, December 2008 minute item 3.4

MARC Recommendation

In March 2009 the Committee recommended that the issue of paracetamol associated with childhood asthma be placed on the 'Scheduled Review' list for 12-monthly review.

In December 2008 the Committee recommended that Medsafe write to sponsors of paracetamol and require them to include a warning about the possible risk of paracetamol use in pregnancy leading to asthma in the infant.

Outcome

The issue of paracetamol associated with childhood asthma has been placed on the 'Scheduled Review' list for 12-monthly review.

Medsafe has written to sponsors of paracetamol-containing products and asked them to consider including a warning in their datasheet about the possible risk of paracetamol use in pregnancy leading to asthma in the infant.

Discussion

The Committee noted the above.

2.1.2 Clozapine and neutropenia, lymphopenia,anaemia [death] (76419)
March 2009 minute item 2.1.23, December 2008 minute item 2.1.14, 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 2009 the Committee recommended that Medsafe approach the NZ sponsors of clozapine and request a breakdown of the number of patients receiving clozapine in NZ over the age of 60 years, divided into five year age bands, with a diagnosis if available.

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

Medsafe has been advised that the product sponsors do not hold the requested information. Medsafe is investigating alternate options for obtaining this information.

Medsafe was attempting to obtain a copy of a recently published paper on patterns of clozapine prescribing in New Zealand.

Discussion

Medsafe provided a breakdown of the number of patients receiving clozapine in New Zealand over the age of 60 years. These figures, provided by the Ministry of Health, were divided into five year age bands, with diagnosis where available.

Medsafe advised that in patients aged 60 to 69 years, the majority of patients received clozapine for the treatment of schizophrenia. As the age of the patient increased, the proportion of cases where the diagnosis was unknown increased. The Committee noted that over the age of 70 years a significant number of the patients receiving clozapine did not have a recorded diagnosis of schizophrenia. They noted however, that there were limitations of the data, and it was possible that a diagnosis of schizophrenia had been made outside of the recording period.

A member reminded the Committee that the Faculty of Psychiatry of Old Age of the College of Psychiatrists have previously provided information regarding clozapine prescribing in the elderly. The College expressed the view that there was a place for the use of clozapine in the elderly, particularly in the treatment of dementia related psychosis in patients with Parkinson's disease. They provided an estimate of the number of patients aged 65 years or older currently receiving clozapine and noted that approximately half of these patients are being prescribed clozapine by members and associates of the Faculty of Psychiatry of Old Age (NZ). They considered that members were very aware of the adverse drug reactions that the elderly may be particularly vulnerable to. The College commented that a Prescriber Update article regarding the use of clozapine in the elderly, targeting those prescribers who are not prescribing under the Specialist Old Age service, would be of benefit, and this was published in the June 2008 edition. The College offered to conduct a more formal audit of the elderly patients in New Zealand who are receiving treatment with clozapine. The MARC agreed this would be of value and recommended that Medsafe approach the College.

Recommendation

The Committee recommended that Medsafe approach the College of Psychiatrists to undertake an audit of clozapine prescribing in elderly patients in New Zealand.

2.1.3 All adverse reactions to rosiglitazone and pioglitazone (ARCC), particularly fracture/bone density - Scheduled Review
March 2009 minute item 3.1

MARC Recommendation

In March 2009 the Committee recommended that the issue of all adverse reactions to rosiglitazone and pioglitazone remain on the 'Scheduled Review' list for 12-monthly review, to include periodic safety update reports (PSURs).

Outcome

The issue of all adverse reactions to rosiglitazone and pioglitazone has been placed on the 'Scheduled Review' list for 12-monthly review, to include periodic safety update reports (PSURs).

Discussion

The Committee noted the above.

2.1.4 Anti-epileptics and the risk of suicidality
March 2009 minute item 3.2, 2.1.24, December 2008 minute item 2.1.16, September 2008 minute item 2.1.14, May 2008 minute item 2.1.10, March 2008 minute item 3.4

MARC Recommendation

In March 2009 the Committee recommended that the issue of anti-epileptics and suicidality be removed from the 'Scheduled Review' list.

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 issue of anti-epileptics and suicidality has been removed from the 'Scheduled Review' list.

Following release of the outcome of negotiations between the sponsors of innovator antiepileptic drugs and other international regulators, Medsafe contacted the sponsors of anti-epileptic medicines in New Zealand, requiring them to update their data sheets as requested in February 2008.

All data sheets for antiepileptic medicines have been, or are in the process of, being updated with the required warning regarding the risk of suicidality.

Discussion

The Committee noted the above.

2.1.5 Methylphenidate SR (Rubifen SR) brand switch-aggressive and defiant behavioural reactions- Scheduled Review
March 2009 minute item 3.4

MARC Recommendation

In March 2009 the Committee recommended that the issue of aggressive and defiant behaviour in association with brand-switching from Ritalin SR to Rubifen SR be removed from the 'Scheduled Review' list.

In March 2009 the Committee recommended that Medsafe review the CHMP risk-benefit review for methylphenidate-containing medicines and reports back to the MARC.

Outcome

The issue of aggressive and defiant behaviour in association with brand-switching from Ritalin SR to Rubifen SR has been removed from the 'Scheduled Review' list.

Medsafe has requested a copy of the CHMP risk-benefit review from the MHRA and from the innovator.

Discussion

The Committee noted the above.

2.1.6 Lipid-lowering agents and psychiatric adverse reactions - Scheduled Review
March 2009 minute item 3.5

MARC Recommendation

In March 2009 the Committee recommended that the issue of lipid-lowering agents and psychiatric adverse reactions be removed from the 'Scheduled Review' list.

Outcome

The issue of lipid-lowering agents and psychiatric adverse reactions has been removed from the 'Scheduled Review' list.

Discussion

The Committee noted the above.

2.1.7 Diclofenac and intestinal perforation, sepsis, multiple organ failure [death] (82166)
March 2009 minute item 4.1.1.2

MARC Recommendation

In March 2009 the Committee recommended that NZPhvC seek further details about this case.

Outcome

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

Discussion

The Committee noted the above.

2.1.8 Clozapine and cardiomyopathy [death] (82098)
March 2009 minute item 4.1.1.7

MARC Recommendation

In March 2009 the Committee recommended that NZPhvC change the causality from 'possible' to 'probable' for cardiomyopathy.

Outcome

NZPhvC has amended the causality as above.

Discussion

The Committee noted the above.

2.1.9 Infanrix-hexa, Prevenar and sudden death [death] (82290)
March 2009 minute item 4.1.1.9

MARC Recommendation

In March 2009 the Committee recommended that NZPhvC bring further information to the MARC when the Coroner's report has been received.

In March 2009 the Committee recommended that NZPhvC change the causality from 'unclassified' to 'unclassifiable' for sudden death.

Outcome

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

NZPhvC has amended the causality as above.

Discussion

The Committee noted the above.

2.1.10 Trastuzumab, tamoxifen and renal disorder not-otherwise-specified (NOS), respiratory infection, oligohydramnios (mother), pregnancy exposure (mother) [death] (81237)
March 2009 minute item 4.1.1.10

MARC Recommendation

In March 2009 the Committee recommended that NZPhvC seek further information, including ultrasound information if available.

Outcome

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

Discussion

The Committee noted the above.

2.1.11 Sodium valproate, topiramate, levetiracetam and hyponatraemia, cerebral infarction, peripheral oedema (81286)
March 2009 minute item 4.1.3.1

MARC Recommendation

In March 2009 the Committee recommended that an article be published in Prescriber Update alerting prescribers to the problem of drug-induced hyponatraemia.

Outcome

An article will be published in Prescriber Update alerting prescribers to the problem of drug-induced hyponatraemia.

Discussion

The Committee noted the above.

2.1.12 Vitamin D and renal failure, hypervitaminosis D, medication error (81804)
March 2009 minute item 4.1.4.1

MARC Recommendation

In March 2009 the Committee recommended that this event be followed up through Medsafe.

In March 2009 the Committee recommended that NZPhvC change the causality from 'probable' to 'certain' for medication error.

In March 2009 the Committee recommended that renal failure and hypervitaminosis D be removed from the list of suspect reactions.

Outcome

Medsafe has begun the follow up process.

NZPhvC has amended the causality from 'probable' to 'certain' for medication error.

The NZPhvC requested that the ADR terms renal failure and hypervitaminosis D be retained in the list of suspect reactions. The NZPhvC acknowledges that medication error was the prime adverse event and the outcomes were secondary to this. However, the CARM database needs to be searchable for specific adverse reactions related to particular medicines or to particular circumstances e.g. medication error and this will not be possible if specific terms are not included.

Discussion

The Committee noted the above and agreed that the ADR terms renal failure and hypervitaminosis D be retained in the list of suspect reactions.

Recommendation

The Committee recommended that the ADR terms renal failure and hypervitaminosis D be retained in the list of suspect reactions in case report 81804.

2.1.13 Norfloxacin and tendon rupture
March 2009 minute item 4.5

MARC Recommendation

In March 2009 the Committee recommended that Medsafe request that BPAC include information in their publication regarding the risk of tendonopathy associated with fluoroquinolone use.

Outcome

An article entitled "Fluoroquinolone-associated tendon disorders" was scheduled for publication by BPAC in May 2009.

Discussion

The Committee noted the above.

2.1.14 Intensive Monitoring of varenicline tartrate (Champix)
March 2009 minute item 4.5

MARC Recommendation

In March 2009 the Committee recommended that the next Intensive Medicines Monitoring Programme (IMMP) report for varenicline be presented to the MARC at the December 2009 meeting.

In March 2009 the Committee recommended that an article be published in Prescriber Update describing the psychiatric adverse events, including withdrawal symptoms that have been reported in association with varenicline use, and reminding prescribers to continue reporting adverse drug reactions.

Outcome

The next IMMP report for varenicline will be presented to the MARC at the December 2009 meeting.

An article describing the interim results from IMMP monitoring has been published in the May 2009 edition of Prescriber Update.

Discussion

The Committee noted the above.

2.1.15 Etanercept and uveitis (76978, 76980)
December 2008 minute item 2.1.19, 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 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 disseminated to the Ophthalmologists Society.

In December 2008 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.

Outcome

A paragraph has been prepared for publication in the August 2009 edition of Prescriber Update.

The New Zealand data sheet for Enbrel has been updated to list uveitis as an uncommon adverse effect associated with etanercept.

Discussion

The Committee agreed that this information be distributed to the optometrists via their professional body.

Recommendation

The Committee recommended that this information also be distributed to the optometrists via their professional body.

2.1.16 Oral bisphosphonates and the risk of atrial fibrillation
December 2008 minute item 3.3

MARC Recommendation

In December 2008 the Committee recommended that [..] be asked to provide an opinion on the risk of atrial fibrillation in association with oral bisphosphonates.

Outcome

[..] has agreed to provide an opinion on the risk of atrial fibrillation in association with oral bisphosphonates.

Discussion

The Committee noted the above.

2.1.17 Ropivacaine and convulsion grand mal, cardiac arrest, drug overdose [death] (80093)
December 2008 minute item 4.1.1.1

MARC Recommendation

In December 2008 the Committee recommended that NZPhvC provide a follow-up report to the MARC when the Coroner's report has been received.

Outcome

NZPhvC will provide a follow-up report to the MARC when the Coroner's report has been received.

Discussion

The Committee noted the above.

2.1.18 Diclofenac and ibuprofen and renal failure acute, nephritis interstitial, medication error (80184)
December 2008 minute item 4.1.2.1

MARC Recommendation

In December 2008 the Committee recommended that a paragraph be prepared in conjunction with [..], for publication in the BPAC publication and Prescriber Update.

Outcome

A paragraph reminding prescribers to advise patients about their use of OTC non steroidal anti-inflammatories when prescribing NSAIDS has been published in the May 2009 edition of Prescriber Update.

The issue of interstitial nephritis in association with NSAIDs is being investigated further, and a paragraph will be published in a future edition of Prescriber Update.

Discussion

The Committee noted the above.

2.1.19 SSRI antidepressants
March 2009 minute item 2.1.12, December 2008 minute item 9.2

MARC Recommendation

In December 2008 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.

Outcome

The Waikato Coroner has agreed to forward his decisions related to medication related cases to the MARC and NZPhvC.

A similar request will be made to the other Coroner's Offices throughout the country.

Discussion

The Committee noted the above.

2.1.20 Removal of specialist prescribing restriction from retinoinds
March 2009 minute item 9.1, 2.1.13, December 2008 minute item 9.4

MARC Recommendation

In December 2008 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.

In March 2009, following a meeting between PHARMAC and Medsafe, it was decided that Medsafe would further investigate options for risk management.

In March 2009, the Committee noted that PHARMAC has communicated its final decision to broaden access to oral retinoid treatments. In the light of this, a letter from the MARC is not able to influence the PHARMAC decision. Medsafe is currently in the process of requiring the sponsors of oral retinoids to develop a Risk Management Plan. Details of the Risk Management Plans will be communicated to the MARC at a later stage.

Outcome

Medsafe will provide details of the Risk Management Plans to the MARC when available.

Discussion

The Committee noted that an article entitled "Reminding prescribers of the risks of the oral retinoids" was published in the May 2009 edition of Prescriber Update.

2.1.21 Reporting of patient allergies to the Centre for Adverse Reactions Monitoring (CARM)
March 2009 minute item 2.1.14, December 2008 minute item 9.5

MARC Recommendation

In December 2008 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).

In March 2009 the Chair advised that this is a complex issue, which is being discussed with District Health Boards New Zealand (DHBNZ).

Discussion

A member informed the Committee that they had become aware that redevelopments to the NHI system presently underway would result in the Medical Warning Module which is an integral part of the existing NHI, cease operating by June 2010. A working group of which they were a member had been established to develop a business case to secure funding and commitment to developing a replacement system to be operational by the time the current version of the NHI ceased to operate. In formulating the business case the group was not only considering the importance of the continued existence of a Medical Warning System, but was also considering its current limitations and how any replacement would integrate improvements that add value to its use.

The Committee expressed support for initiatives and actions to ensure continuity through a replacement that improved the value of the medical warning system to users.

Recommendation

The Committee recommended that a letter be drafted expressing its support for initiatives and actions to ensure continuity through a replacement that improved the value of the medical warning system to users.

2.1.22 SSRI antidepressants and increased suicidality in children and adolescents

March 2009 minute item 2.1.15, December 2008 minute item 2.1.1, September 2008 minute item 3.1, May 2008 minute item 2.1.5, March 2008 minute item 3.1

MARC Recommendation

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

Outcome

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

A paper entitled 'Do SSRIs or antidepressants in general increase suicidality?' has recently been published by the World Psychiatric Association Section on Pharmacopsychiatry. This paper was included in the June 2009 dossier.

Discussion

The Committee noted that the paper was an attempt to bring together current data, and no firm conclusions were made. The Committee considered that it was no longer necessary to publish information in the NZMJ.

2.1.23 Black cohosh and hepatotoxicity
March 2009 minute item 2.1.16, December 2008 minute item 2.1.2, September 2008 minute item 3.2

MARC Recommendation

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

Outcome

Medsafe has investigated appropriate mechanisms to disseminate this information. Under the current legislation, products containing black cohosh are generally regarded as dietary supplements and regulated as foods. Medsafe will pass the MARC's recommendations and any advice Medsafe issues to prescribers on to the New Zealand Food Safety Authority for their dissemination using their existing networks. Medsafe will review this if and when the regulation of these products changes.

Discussion

The Committee noted the above.

2.1.24 Conventional antipsychotics and mortality risk
March 2009 minute item 2.1.17, December 2008 minute item 2.1.3, 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.

Outcome

The data sheets for conventional antipsychotics have been updated to include information about the increased risk of mortality in elderly dementia patients.

Discussion

The Committee noted the above.

2.1.25 Fleet oral preparation and renal failure, hyperphosphataemia [death] (79049)
March 2009 minute item 2.1.18, December 2008 minute item 2.1.6, 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 entitled "Phosphate containing laxatives - hyperphosphataemia and kidney damage" was published in the May 2009 edition of Prescriber Update.

Discussion

The Committee noted the above.

2.1.26 Flucloxacillin and anaphylactic reaction [death] (78269)
March 2009 minute item 2.1.19, December 2008 minute item 2.1.7, 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 report has been received.

Outcome

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

Information not received by June 2009 and item removed from Standing Agenda list.

Discussion

The Committee noted the above.

2.1.27 Aprotinin and increased mortality risk

March 2009 minute item 2.1.20, December 2008 minute item 2.1.10, 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.

Outcome

Medsafe has been in recent contact with Bayer regarding access to worldwide stocks of aprotinin and provided a verbal update at the June 2009 MARC meeting.

Once a response has been received, Medsafe, together with the Chair, 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.

Discussion

Bayer has informed Medsafe that it was not in a position to supply aprotinin at this time.

2.1.28 Symbicort and exacerbation of asthma [death] (75986)

March 2009 minute item 2.1.21, December 2008 minute item 2.1.11, 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

The legislation covering the mortality review process does not allow for the sharing of identifying information outside of the mortality review process, and non-identifying information would be of limited value to CARM and MARC.

Discussion

The Committee noted the above.

2.1.29 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)

March 2009 minute item 2.1.22, December 2008 minute item 2.1.12, 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

A report is being prepared by [..].

Discussion

The Committee noted the above.

2.1.30 The safety and efficacy of cough and cold medicines for use in children

December 2008 minute item 2.1.10, 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.

Outcome

Medsafe has formed a Review Group to advise on the safety and efficacy of cough and cold medicines in children over two years of age. The Review Group will include representatives from community, industry, pharmacy, paediatrics, general practice and other healthcare professions

The Review Group will also investigate options for disseminating advice to healthcare professionals and the public regarding the use of cough and cold products in children.

A summary report was provided in the June 2009 dossier.

Discussion

Please refer to minute item 3.3 for discussion on this issue.

2.1.31 Lamotrigine and convulsion [death] (74826)
December 2008 minute item 2.1.21, 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.

2.1.32 Clozapine and haematological malignancies
December 2008 minute item 2.1.22, 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 ALL ADVERSE REACTIONS TO COMPLEMENTARY AND ALTERNATIVE MEDICINES

Issue

NZPhvC provided a report for the MARC's 'Scheduled Review' on the issue of all adverse reactions to complementary and alternative medicines (CAMs). This issue was placed on the Adverse Reaction of Current Concern (ARCC) list in March 2006 when CARM received increasing numbers of reports of adverse reactions to CAMs. In March 2007, the Committee recommended that an annual report be provided. The May 2009 report was the annual updated review and listing of abbreviated details of reports received in the period January 2008 to March 2009. Due to the large number of products available, often containing multiple active ingredients, NZPhvC advised that it was difficult to undertake an exhaustive literature review on the issue. Inconsistencies in international trade names for CAM products make it difficult to search the WHO database for many of the products.

Discussion

The Committee noted the 2009 NZPhvC report. NZPhvC advised that there had been 20 reports received since the last review, describing a wide range of reactions.

NZPhvC advised that the CARM database now includes 85 serious cases of adverse effects associated with CAMs. Of these, there were four deaths, 27 life-threatening reactions, and 42 hospitalisations. NZPhvC advised that the majority of reports received by the Centre were sent by retail pharmacies. The Committee considered that it was likely that there was significant under-reporting of adverse reactions and that it was important that adverse reactions to CAMs continue to be monitored on an annual basis by the MARC. The Committee noted that there appeared to be a universal expectation that complementary medicines were harmless and not associated with risk. However, for many products there was no evidence of efficacy, but there was evidence of harm.

The Committee noted that Prescriber Update now includes a section entitled 'Complementary Corner', consisting of a short paragraph on the adverse drug reactions associated with one specific herbal product to raise awareness that these products often contain pharmacologically active ingredients, and therefore are not without risk.

The Committee agreed to monitor CAMs as an ARCC, and recommended that NZPhvC continue to report serious and/or unusual events to each MARC meeting, and provide an annual ARCC submission of a summary/listing of all reports.

Recommendation

The Committee recommended that NZPhvC continue to report serious and/or unusual events to CAMs at each MARC meeting, and provide an annual ARCC submission of a summary/listing of all reports.

3.2 DEXTROPROPOXYPHENE/ PARACETAMOL COMBINATION PRODUCTS AND THE RISK OF OVERDOSE.

References

Ashton J, Savage R. Paradex. Drug Utilisation Study. Phase II Report. November 2008. A study conducted through the Intensive Medicines Monitoring Programme of the NZPhvC
Medsafe, 2005, Extract of Minutes of the 122nd MARC Meeting. Wellington, www.medsafe.govt.nz/profs/adverse/Minutes122.htm
Medsafe, 2005, Extract of Minutes of the 123rd MARC Meeting. Wellington, www.medsafe.govt.nz/profs/adverse/Minutes123.htm
Medsafe, 2005, Extract of Minutes of the 124th MARC Meeting. Wellington, www.medsafe.govt.nz/profs/adverse/Minutes124.htm
Medsafe (2006) Dextropropoxyphene-paracetamol combination products and risk of overdose, Prescriber Update, 27 (2)
Savage R, 2009 Observations on the place of Paradex in analgesic prescribing in New Zealand, based on the NZPhvC Drug Utilisation Study, Dunedin
Simkin S, Hawton K, Sutton L, Gunnell D, Bennewith O and Kapur N. (2005) Co-proxamol and suicide: preventing the continuing toll of overdose deaths, QJ Med Oxford Journals 98:159 - 170

Issue

Medsafe and NZPhvC provided reports for the MARC on the issue of dextropropoxyphene/paracetamol combination products and the risk of overdose.

The MARC conducted a review of the risk-benefit profile of dextropropoxyphene/paracetamol combination products in June 2005. This followed the UK Medicines and Healthcare Products Regulatory Authority's (MHRA) announcement in January 2005 that it would be withdrawing all dextropropoxyphene/paracetamol combination products over the subsequent 6-12 month period.

This decision was based on an assessment that the risk-benefit profile of these medicines was unfavourable due to inadequate evidence of efficacy and a significant risk of mortality from both intentional and accidental overdose. At that time, there were three dextropropoxyphene/paracetamol combination products available in New Zealand - Apo-paradex (50mg dextropropoxyphene napsylate + 325mg paracetamol), Capadex (32.5mg dextropropoxyphene hydrochloride + 325mg paracetamol), and Paradex (50mg dextropropoxyphene napsylate + 325mg paracetamol). These products are indicated for use in New Zealand for the treatment of mild to moderate pain.

In 2005, the New Zealand Poisons Centre performed an analysis of all opioid-related poisonings reported in New Zealand between 2001 and 2002. Dextropropoxyphene was assessed to be the primary cause of 8 overdose deaths and was implicated in another 8 overdose deaths. During that time period, dextropropoxyphene/paracetamol combination products accounted for almost 50% of all opioid prescriptions in New Zealand. In June 2005, the Committee noted that the UK MHRA's decision to withdraw all dextropropoxyphene-containing products from the market was made only after alternative risk-management strategies had proven ineffective in reducing mortality from dextropropoxyphene-related overdoses.

The MARC was concerned to note that the Paradex, Apo-Paradex and Capadex data sheets at that time contained some inconsistencies and that a maximum daily dose was not clearly stated. The data sheet for Paradex did not state the doses of active ingredients. The Committee recommended that the data sheets for these products be updated to remove inconsistencies between them and to state the dosages of active ingredients. The requested data sheet changes were related to the following issues:

Stating clearly the dosages of active ingredients;
Reducing the maximum daily dose so that a safe dose of paracetamol is administered;
Contraindicating the concurrent use of alcohol and other paracetamol-containing products;
Removing inconsistencies in the 'Warnings and Precautions' and 'Overdosage; Treatment of paracetamol overdosage' sections of the data sheets.

The sponsors of Paradex and Capadex updated their datasheets as requested. The sponsor of Apo-Paradex advised that it was no longer marketed in NZ and requested the datasheet be removed from Medsafe's website. In June 2005, the Committee considered that the presently available evidence suggested dextropropoxyphene/paracetamol combination products had an unfavourable risk-benefit profile.

However, the MARC considered it important that consultation with stakeholders such as healthcare professionals and patient support organisations occurred before any risk-management decisions were made.

At its December 2005 meeting, the MARC noted the submissions from stakeholders. They considered that the submissions presented a strong case that there were patient populations for which the benefits of these products might outweigh the risks. Members noted that there were limited alternative analgesic products funded at that time in NZ. The Committee noted that the stakeholder submissions appeared to support removing the acute indications and noted that the available restrictions were to change the indications for the product, and then review adherence.

The MARC reiterated their previous opinion that the presently available evidence suggested that dextropropoxyphene/paracetamol combination products had an unfavourable risk-benefit profile for routine use as an analgesic in acute pain. They noted that there was still no published evidence of increased efficacy compared to full-strength paracetamol alone. However, as stakeholders had provided opinions that there might be a clinical need for these products for some patients, the Committee considered that they should be allowed to remain on the NZ market, with restrictions. These restrictions included limiting the indications to the treatment of chronic pain of moderate severity for patients in whom treatment with therapeutic doses from alternative therapeutic groups, including combination products, had been used and found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient.

These changes were the subject of a Prescriber Update article published in November 2006.

Following the MARC review, product sponsors were requested to undertake a Drug Utilisation study to assess whether dextropropoxyphene was being prescribed according to the updated indications and in a safe manner. The sponsors of Paradex agreed and the study was conducted by the NZPhvC.

The Committee was asked to evaluate the drug utilisation study report, review the risk-benefit profile of dextropropoxyphene/paracetamol combination products, and recommend risk management strategies if necessary.

Discussion

The MARC noted the November 2008 NZPhvC Paradex Drug Utilisation and May 2009 Medsafe reports.

The Committee noted that the NZPhvC study was based on a retrospective questionnaire was sent to a random sample of prescribers. An analysis of responses showed that prescribers consisted of 92.6% general practitioners, 7.3% specialists, and 0.1% dentists.

They noted that the study indicated that in 53.3% of cases, prescribers had not followed the MARC recommendations. The high level of inappropriate prescribing of dextropropoxyphene is despite Medsafe and the MARC having already taken steps to mitigate the risks posed by the toxicity of dextropropoxyphene when taken in overdose. The appropriateness of dextropropoxyphene prescribing was assessed according to whether the prescriptions were:

Only for chronic pain

Only for pain of moderate intensity

Only prescribed after patients responded inadequately to, or could not tolerate therapeutic doses of alternative analgesics

For appropriate doses.

Severity of pain was the criterion most often met (94.8%), and a prior trial of other analgesics the least (64.3%). The appropriate dose was prescribed by 84.2% and the chronic pain criterion was met by 76.5%. The most frequent indication for Paradex was non-inflammatory arthritis (37.4%), and the mean duration of use was 37.5 months. The Committee was concerned to note that there were 24.5% of patients reported as using at least one concomitant CNS medicine (excluding low-dose tricylic antidepressants).

The Committee noted that the safety data from the literature has shown that death from dextropropoxyphene poisoning is rapid, and has been reported from as little as ten tablets taken. In addition, the interaction with alcohol causes increased blood levels of dextropropoxyphene, which may pose a risk of accidental risk of overdose when the two substances are used together. Also of concern was the pharmacokinetic profile of dextropropoxyphene; it is metabolised to norpropoxyphene, which is cardiotoxic, with a long half-life, and is not reversed by opioid antagonists.

The Committee noted that a Cochrane review in 1999 found that the number needed to treat (NNT) with 65mg dextropropoxyphene (Paradex contains 50mg) and 650mg paracetamol (Paradex contains 325mg) to achieve a 50% pain reduction in acute post-operative pain was 4.4. The Oxford League tables for paracetamol (600/650mg) show an NNT of 4.6. The Committee noted that these figures do not support improved pain relief of combination treatment over full strength paracetamol alone. The Committee agreed that the poor efficacy data did not appear to justify the substantial risk of toxicity in overdose, whether accidental or intentional.

The Committee noted that there were alternative pain relief products available. The best alternative for any one individual was dependent on the type of pain and the underlying aetiology. The Committee considered that it was important to co-ordinate with agencies such as BPAC, to disseminate information about alternative pain relief for each individual.

The Committee considered that while the risk-benefit balance for dextropropoxyphene/paracetamol products may be favourable for some patients, overall the risk-benefit profile of these products was negative. They noted that the previous restrictions had been ineffective and that there were alternative products available. The Committee noted that there was provision under Section 36 of the Medicines Act 1981 to request a company to supply Medsafe with further information regarding a medicine if there are reasons to believe that it may be unsafe or ineffective for the therapeutic purpose for which it has consent for marketing. The Committee recommended that Medsafe write to the sponsors of Paradex and Capadex under Section 36 of the Medicines Act 1981 requesting that they provide further data in support of the safety and efficacy of their respective products to allow a full risk-benefit review to be conducted.

Recommendation

The Committee recommended that Medsafe write to the sponsors of Paradex and Capadex under Section 36 of the Medicines Act 1981 requesting that they provide further data in support of the safety and efficacy of their respective products to allow a full risk-benefit review to be conducted.

3.3 THE SAFETY AND EFFICACY OF COUGH AND COLD MEDICINES FOR USE IN CHILDREN.

Issue

Medsafe provided an update for the MARC on the issue of the safety and efficacy of cough and cold medicines for use in children.

In December 2007 the Medicines Adverse Reactions Committee (MARC) considered the evidence relating to use of cough and cold medicines in children (mainly in those under 2 years). The MARC recommended that all cough and cold medicines be contraindicated in children under 2 years of age.

Sponsors of cough and cold medicines committed to ensuring that all products would carry the warning not to use in children under 2 years by 1 May 2009.

In December 2008, Health Canada contraindicated the use of cough and cold products in children under 6 years. Similarly in February 2009, the UK Medicines and Healthcare products Regulatory Agency (MHRA) recommended that cough and cold medicines should not be used in children under 6 years and restricted the sale of products for 6 to 12 year olds to pharmacy only. The decision to restrict the use of cough and cold medicines to children 6 years and over was based on the following points:

Recommendations from health professionals and experts after review of the available evidence.
The weight of some 6 year olds being similar to some 2 year olds, and the associated risk of overdose.
The high incidence of colds in children 6 years and under and therefore the increased exposure to cough and cold medicines.
The increased communication skills in children 6 years and over.
The age distribution of reported suspected adverse drug reactions.

Serious adverse reactions have been reported in the UK and the US in children given therapeutic doses of cough and cold medications. There are also many cases of overdoses given to children by their parents, both intentionally and accidentally. These overdoses have been associated with fatalities. In addition there have been numerous serious cases of accidental ingestion by children. These events are not confined to the under two year age group.

Serious adverse reactions have also been reported in New Zealand when cough and cold medicines have been given according to the labelled dose. Mainly these reactions are either allergic in nature or involve adverse central nervous system effects. Some of the adverse reactions reported in New Zealand have resulted in hospital admission. Accidental ingestion of these products also appears to be a problem in children under six years.

Data from the National Poisons Centre indicates that the two to six year age group are at the highest risk of overdose in New Zealand. These include both child exploratory and unintentional overdose.

Medsafe has undertaken a preliminary review of the data and decided that further advice is needed on this issue. Since not all the key-stakeholders are represented on the MARC, Medsafe is arranging a Review Group to advise on the use of cough and cold medicines in children.

The MARC was asked to evaluate the information provided and to determine if the risk-benefit profile of cough and cold products in children between two to six years had changed as a result of this information.

Discussion

The Committee noted the May 2009 Medsafe report.

The Committee noted the various risk management options for the use of cough and cold medicines in children, including introducing an age restriction and reclassification to pharmacy or pharmacist-only medicines.

Members noted that spontaneous reporting to CARM of suspected adverse reactions indicated that New Zealand children do experience adverse events after exposure to cough and cold medicines, and this is not restricted to children under 2 years old. The pattern of reporting of suspected adverse reactions is similar in New Zealand to that found in other countries.

The Committee noted that one of the major difficulties with spontaneous reporting systems is under reporting and it is expected that the proportion of adverse drug reactions that are reported for over-the-counter medicines is even lower. They considered that young children may not always be able to communicate to carers that they are experiencing a possible adverse drug reaction. Parents and carers may also not be aware that they can report suspect reactions with their child's medicine.

The Committee noted that many of the cough and cold products are scheduled as 'General Sale' medicines, allowing them to be sold both in pharmacies and other retail outlets such as supermarkets. They considered that restricting the sale of cough and cold products to pharmacies, involving rescheduling to either pharmacy-only or pharmacist-only, would allow parents and caregivers to receive appropriate advice about the use of these medicines. The Committee also considered that it was more likely that adverse reactions were reported to the pharmacy where the medicine was purchased, rather than to an alternative retailer such as a supermarket.

The Committee noted that there was insufficient evidence to allow differentiation either by age or weight on the basis of the current data. The pharmacokinetic profile of these medicines varied with age, and it was not possible to extrapolate on the basis of weight. They noted that dosing regimes are historical, and not evidence based but based on proportions of an adult dose. Members noted that the use of cough and cold medicines in children is based on extrapolation from data in adults. They considered that the data on efficacy of cough and cold medicines in adults are sparse and often of poor quality. The Committee agreed that in the two to six year age group there was only weak evidence of efficacy, but there was evidence of harm, making the risk-benefit negative for this age group. It was also noted that there was often little difference in weight between a large two year old and a small five year old.

A member advised that the International Committee for Harmonisation's classification of age ranges for children includes those under two years, and those under 12 years. An intermediary range of under six years is often used. The Committee agreed with that the evidence supported the decision made by other international regulatory agencies. They recommended that the Cough and Cold Review Group be advised that, after consideration of the evidence provided for the MARC meeting, the MARC considered that cough and cold medicines be contraindicated in children under six years and the sale of products restricted to pharmacist-only.

The Committee recommended that communication to both healthcare professionals and the public regarding the use of cough and cold products in children be included as part of the risk management strategy.

Recommendation

The Committee recommended that the Cough and Cold Review Group be advised that, after consideration of the evidence provided for the MARC meeting, the MARC considered that cough and cold medicines be contraindicated in children under six years and the sale of restricted to pharmacist-only.

3.4 SIGNAL DETECTION AND EVALUATION IN NEW ZEALAND.

References

Kunac et al. 2008. Pharmacovigilance in New Zealand. NZ Med J 121: 76-89
Waller & Evans. 2003. A model for the future conduct of Pharmacovigilance. Pharmacoepidemiology and Drug Safety 12: 17-29
Waller et al. 2005. Impact Analysis of signals detected from spontaneous adverse drug reaction reporting data. Drug Safety 28 (10): 843-850
Clark & Harrison-Woolrych. 2006. The role of the New Zealand Intensive Medicines Monitoring Programme in identification of previously unrecognized signals of adverse drug reactions. Current Drug Safety 1: 162-178

Issue

Medsafe and NZPhvC provided reports for the MARC on the issue of signal detection and evaluation in New Zealand. The purpose of the report was to inform the Committee of the procedures in place for detecting and investigating possible safety signals associated with medicines registered for use in New Zealand. The role of MARC in advising Medsafe on these signals was highlighted.

Discussion

The Committee noted the May 2009 Medsafe and NZPhvC reports.

NZPhvC advised that it is working with Medsafe in order to develop tools which extend past the identification of signals and further into evaluation of these signals, in an attempt to formalise the decision making process and methods of evaluating signals further. A project is underway looking at the feasibility of a Bayesian approach to data-mining in the CARM database to detect signals not found using current methods. This is part of a spectrum of tools being developed to extend the current level of pharmacovigilance/ pharmacoepidemiology. The Committee noted that the detection of safety signals, evaluation and decision making process is still largely based on judgment, experience and expert opinion. Some advances such as risk management plans have attempted to introduce a more proactive approach to pharmacovigilance, but need supporting legislation.

The Committee supported the steps in place to evaluate safety signals and noted that the monitoring of signals for adverse drug reactions is an evolving process. Medsafe will continue to evaluate the processes in place and incorporate published processes as appropriate for New Zealand systems.

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 discussion notes for each report, the case has been given a causality designation using terms and definitions developed by the World Health Organisation. The precise definitions are available on the website of the The Uppsala Monitoring Centre, which is the WHO Collaborating Centre for International Drug Monitoring - 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 these terms can be found on the Medsafe website via the hyperlink at each causality designation.

4.1.1 Deaths

4.1.1.1 Medroxyprogesterone, tranexamic acid and cerebral infarction, thrombosis carotid [death] (83423)

Discussion

NZPhvC advised that the WHO database includes evidence for arterial thrombosis in association with tranexamic acid, with a positive IC value. There is no convincing evidence that medroxyprogesterone increases the risk of arterial thrombosis, although high doses may increase the risk of venous thromboembolism.

The causal association with medroxyprogesterone, tranexamic acid was considered to be 'possible' for cerebral infarction, thrombosis carotid.

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

4.1.1.2 Adalimumab, methotrexate, sulphasalazine, prednisone and cardiac failure, pulmonary infiltration, respiratory failure, pneumonia, myocardial infarction, cellulitis [death] (82435)

Discussion

NZPhvC advised that the CARM database includes evidence that adalimumab, methotrexate, and sulphasalazine could have contributed to components of the events that occurred. The Committee noted that the underlying condition could also have contributed.

The causal association with adalimumab, methotrexate, sulphasalazine, prednisone was considered to be 'possible' for cardiac failure, pulmonary infiltration, respiratory failure, pneumonia and 'unclassified' for myocardial infarction, cellulitis.

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

4.1.1.3 Thalidomide, cyclophosphamide and interstitial lung disease, embolism pulmonary, pulmonary carcinoma, diarrhoea [death] (83005)

Discussion

NZPhvC advised that the CARM database includes reports of pulmonary embolism and deep vein thrombosis in association with thalidomide, and pneumonitis and pulmonary fibrosis in association with cyclophosphamide. Both thalidomide and cyclophosphamide have positive IC values in the WHO database for pulmonary infiltration, pulmonary embolism, and pulmonary carcinoma. However the reports for pulmonary carcinoma often included information that suggested that a causal relationship with the medicine was unlikely.

The thalidomide datasheet includes warnings of thrombogenicity, but no mention of pulmonary infiltration or carcinoma. The cyclophosphamide datasheet notes that some patients receiving cyclophosphamide have developed secondary malignancies.

NZPhvC advised that follow up information indicated that thalidomide use was short term and recent, while the initial report intimated that use had been for the past two years. It was therefore possible that thalidomide had been used for a short period earlier, and then again more recently.

The causal association with thalidomide, cyclophosphamide was considered to be 'possible' for interstitial lung disease, embolism pulmonary, diarrhoea and 'unlikely' for pulmonary carcinoma.

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

4.1.1.4 Thalidomide, dexamethasone, cyclophosphamide and pancytopenia, sepsis, disease progression [death] (83006)

Discussion

NZPhvC advised that the thalidomide datasheet includes neutropenia, anaemia and thrombocytopenia as adverse effects.

The Committee noted that while some of the medications may have contributed to the events described, it would appear that disease progression also contributed.

The Committee considered the causal association with thalidomide, dexamethasone, cyclophosphamide to be 'unclassifiable' for pancytopenia, 'possible' for sepsis, and 'unlikely' for disease progression.

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

4.1.1.5 Leflunomide, adalimumab, prednisone and pulmonary infiltration, respiratory failure, dyspnoea, cardiac arrest [death] (83251)

Discussion

NZPhvC advised that the CARM database includes reports of fatal suspected respiratory reactions in New Zealand with adalimumab and leflunomide in combination with prednisone. All but one patient had pneumonia. The NZPhvC plans to investigate whether these findings have been observed elsewhere and have been identified as a concern by rheumatologists. These results would be presented to the MARC if warranted.

The Committee considered the causal association with leflunomide, adalimumab, prednisone was 'possible' for pulmonary infiltration, respiratory failure, dyspnoea, cardiac arrest.

4.1.1.6 Venlafaxine and pulmonary infiltration [death] (83195)

Discussion

NZPhvC advised that the CARM database includes no reports of interstitial lung disease or related conditions in association with either venlafaxine or citalopram. The WHO database includes reports of lung disorders in association with both venlafaxine and citalopram, with a negative IC value.

NZPhvC advised that there are five published literature reports of pneumonitis attributed to venlafaxine.

The Committee noted that there is tentative evidence that lung infiltration in the form of pneumonitis is an adverse reaction of venlafaxine and considered the causal association with venlafaxine to be 'possible' for pulmonary infiltration.

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

4.1.1.7 Citalopram and palpitations, ventricular tachycardia,cardiac arrest, QT prolonged [death] (83042)

Discussion

The Committee noted that details were limited, and the time period between the change in antidepressant therapy was unknown. It was noted that she experienced palpitations following the change to citalopram, but was unknown how often she had previously experienced palpitations.

The Committee considered the causal association with citalopram was 'possible' for palpitations, ventricular tachycardia,cardiac arrest, QT prolonged.

4.1.2 Anti-infectives

4.1.2.1 Ornidazole and vertigo, somnolence, vision disorder (83131)

Discussion

NZPhvC advised that the CARM database includes reports of vertigo, dizziness, and vision disorders in association with ornidazole. The product datasheet includes these symptoms as adverse effects.

The Committee noted that the adverse reactions experienced are well-documented in the literature. However, they considered it would be useful for prescribers to be reminded of these adverse reactions, particularly drowsiness, and the need to inform patients of this as a possible adverse effect. They recommended that an article be published in Prescriber Update.

The Committee considered that there were other possible explanations for the reactions experienced by this patient and from the information given considered the causal association with ornidazole to be 'possible' rather than 'probable' for vertigo, somnolence, vision disorder.

Recommendations

The Committee recommended that NZPhvC change the causality from 'probable' to 'possible' for vertigo, somnolence, vision disorder.

The Committee recommended that an article be published in Prescriber Update reminding prescribers of the adverse effects of ornidazole, and the need to inform patients of this as a possible adverse effect.

4.1.3 Anti-obesity

4.1.3.1 Sibutramine and myocardial infarction (83491)

Discussion

NZPhvC advised that sibutramine had been monitored on the IMMP, and the database contained reports of myocardial infarction in association with sibutramine. The WHO database also includes reports of myocardial infarction in association with sibutramine, some in younger age groups. A similar case report, involving a young woman, with no apparent risk factors, had been published in the literature.

The product datasheet indicates that Reductil is contraindicated in patients with a history of coronary artery disease but makes no mention of myocardial infarction or angina.

The Committee noted that it was difficult to attribute causality due to the patient's other risk factors.

Members noted the temporal relationship to sibutramine and considered the causal association with sibutramine to be 'possible' for myocardial infarction. They noted that NZPhvC will continue to monitor cardiovascular reports for sibutramine and present any such serious reports to the Committee.

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

4.1.4 Immunosuppressives

4.1.4.1 Entanercept and meningoencephalitis (82750)

Discussion

NZPhvC advised that there are no cases of a similar nature in the CARM database. A literature search and a search of the WHO database revealed three reports of meningoecephalitis in association with etanercept, and only one case appeared to be aseptic.

The Committee noted that this child may have had a recent viral infection which caused the diarrhoea and vomiting, and queried if this could have been a varicella infection. The Committee considered it would be useful to obtain viral test results if available and recommended that NZPhvC seek further information about this case.

The causal association with etanercept was considered to be 'possible' for meningoencephalitis.

Recommendation

The Committee recommended that NZPhvC obtain further details about this case (82750).

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

4.1.5 Musculoskeletal

4.1.5.1 Aledronate and osteonecrosis (82825)

Discussion

NZPhvC advised that there is one other report of osteonecrosis of the jaw in association with an oral bisphosphonate in the CARM database. The WHO database includes reports of avascular necrosis bone in association with alendronate, with a positive IC value.

The Committee noted that the issue of osteonecrosis of the jaw, as well as atypical fractures with oral bisphosphonates used for osteoporosis have been reviewed by the MARC previously, and will continue to be monitored. An article co-authored by Professor Ian Reid was published in Prescriber Update in 2007. The Committee noted Professor Reid's recent review of the epidemiology and proposed mechanisms for the development of osteonecrosis of the jaw associated with bisphosphonates use. In this review he concluded that it was not clear if the incidence of osteonecrosis of the jaw in patients using oral bisphosphonates for osteoporosis was different from that in the general population.

The causal association with alendronate was considered to be 'possible' for osteonecrosis.

4.1.6 Psychiatric

4.1.6.1 Sodium valproate and foetal valproate syndrome, drug exposure during pregnancy (82615)

Discussion

A member advised that an article had recently been published in the New England Journal of Medicine entitled 'Cognitive Function at 3 years of Age after Fetal Exposure to Antiepileptic Drugs'. The study concluded that in utero exposure to valproate was associated with an increased risk of impaired cognitive function at three years of age, when compared with other commonly used antiepileptic drugs.

The Committee considered that the number of women of child bearing age being treated with valproate was increasing. The Committee noted that the warnings section in the product datasheet focused primarily on the use of valproate for the treatment of epilepsy. They recommended that the datasheet for sodium valproate be reviewed at the next MARC meeting to determine if the warning information should be strengthened.

The Committee noted that the diagnosis of foetal valproate syndrome would have been made on exposure and clinical presentation and considered the causal association with sodium valproate to be 'certain' rather than 'possible' for foetal valproate syndrome.

The Committee noted that both babies had been diagnosed with foetal valproate syndrome, and recommended that NZPhvC create a second report to reflect this.

Recommendations

The Committee recommended that NZPhvC change the causality from 'possible' to 'certain' for foetal valproate syndrome.

The Committee recommended that the datasheet for sodium valproate be reviewed to determine if the warning information should be strengthened.

The Committee noted that both babies had been diagnosed with foetal valproate syndrome, and recommended that NZPhvC create a second report to reflect this.

Secretary's note:
A typographical error was noted by the Committee and the severity of the foetal valproate syndrome reaction amended to 'severe'.

4.1.6.2 Citalopram, zopiclone and ventricular septal defect, atrial septal defect, drug exposure in pregnancy (83472)

Discussion

NZPhvC advised that there are no reports of foetal disorders in association with zopiclone in the CARM database. A study published in the literature did not show any increase in risk of malformations with zopiclone, when compared with controls.

The Committee had previously considered evidence which showed that maternal exposure to the SSRI paroxetine may be causally related to foetal cardiac malformations.

The causal association with citalopram, zopiclone was considered to be 'unclassified' for ventricular septal defect, atrial septal defect, and 'certain' for drug exposure in pregnancy.

4.1.7 Vaccines

4.1.7.1 Infanrix-hexa (DTaP-IPV & HepB-Hib) (83019)

Discussion

NZPhvC advised that fever, lethargy, irritability, and abnormal crying are typical reactions reported following childhood vaccinations, and usually resolve quickly. This is the first report to CARM of cerebral oedema.

NZPhvC advised that cerebral events reported previously have largely related to whole cell pertussis component of the vaccine. The current pertussis component of the vaccine is acellular, and reports of crying and irritability are reported less often.

The causal association with Infanrix-hexa was considered to be 'possible' for fever, lethargy, irritability, crying abnormal.

The Committee noted that some of the events in this case suggest an encephalopathy and there was insufficient information available to determine causality. They considered the causal association with Infanrix-hexa to be 'unclassifiable' rather than 'possible' for cerebral oedema.

Recommendation

The Committee recommended that NZPhvC change the causality from 'possible' to 'unclassifiable' for cerebral oedema.

4.1.7.2 Influenza virus vaccine and cardiac arrest, bradycardia, diarrhoea, abdominal pain, gastrointestinal disorder NOS (83406)

Discussion

NZPhvC advised that the immediate onset events of abdominal pain and diarrhoea are some of the typical reactions reported to CARM following influenza vaccination. The small bowel oedema, combined with the abdominal pain and diarrhoea may suggest an acute hypersensitivity reaction.

The Committee noted that the patient had a significant cardiac history and this may have contributed to the bradycardia and cardiac arrest.

The Committee noted that the product datasheets contained very little information regarding gastrointestinal adverse events following immunisation despite these events being widely reported to CARM. The Committee recommended that the influenza virus vaccine datasheets be reviewed and strengthened regarding the potential gastrointestinal adverse effects.

The causal association with influenza virus vaccine was considered to be 'unclassified' for cardiac arrest, bradycardia, and 'probable' for diarrhoea, abdominal pain, gastrointestinal disorder NOS.

Recommendation

The Committee recommended that the influenza virus vaccine datasheets be reviewed and strengthened regarding the potential gastrointestinal adverse effects.

4.1.7.3 MMR, HiB, cotrimoxazole and deafness nerve, fever, rash (83538)

Discussion

NZPhvC advised that the CARM database does not include any supportive evidence, and the WHO database does not suggest a strong signal.

NZPhvC advised that the vaccine adverse event reporting system database (1990-2003) includes eleven cases of hearing loss and 44 cases of idiopathic sensorineural hearing loss following immunisation with measles and mumps containing vaccines. Onset in the majority of cases were consistent with the incubation period of wild measles and mumps vaccine. It was estimated that the reporting rate of hearing loss following immunisation with measles and mumps containing vaccines was 1: 6-8 million doses. The Committee noted that it was a theoretical possibility that the measles component could have mutated to wild measles virus and therefore could have been responsible for the adverse effect of deafness. There was no literature evidence in support of either HiB or cotrimoxazole induced deafness.

A member noted that sensorineural deafness can be a progressive disease and queried if there was any relevant family history. The Committee noted that follow-up information stated that the child had a long history of viral infections and there were other possible explanations for the deafness.

The causal association with MMR, HiB, cotrimoxazole was considered to be 'unclassifiable' for deafness nerve, fever, rash.

4.1.8 Company death reports

These reports originate from the Pharmaceutical Companies. They are typically due to disease progression, or contain insufficient data for an assessment to be made.

The Committee noted the following case reports:

4.1.8.1 Thalidomide, allopurinol, frusemide, losartan, felodipine, aspirin, prednisone, omeprazole, warfarin, bendrofluazide, celipolol, bezafibrate, paracetamol, coloxyl and senna,morphine (82881)
4.1.8.2 Thalidomide (82882
4.1.8.3 Thalidomide, paracetamol, omeprazole, tranexamic acid, metformin, salbutamol, ipratropium (82883)
4.1.8.4 Thalidomide,acyclovir,metoprolol,allopurinol,cyanocobalamin,dexamethasone (82885)
4.1.8.5 Peg interferon alfa 2A (82449)
4.1.8.6 Epoetin beta (82452)
4.1.8.7 Filgrastim,dexamethasone,haloperidol,oxycodone (82454)
4.1.8.8 Rofecoxib,cilazapril,beclomethasone,furosemide,etidronate,calcium carbonate (83419)
4.1.8.9 Muromonab (83497)
4.1.8.10 Olanzapine,lithium,diazepam,ethanol (83498)

4.1.9 Dianeal death reports

These reports originate from the Marketing Authorisation Holder (MAH) and identify the death of the patient when the reporting nurse informed the MAH that no further solution was required because the patient had since died in the context of end-stage renal failure. The reason for reporting to the MAH was not due to concern that the death may be related to exposure to the solution, but for supply management purposes. Discussion with the MAH established that these cases were recorded and passed on as under ICH regulations, it is a requirement for the MAH to report all cases of death identified whether or not the death is related to the medicine.

Reports of a similar nature were considered at the December 2008 meeting. These reports, which were received subsequently, are of the same nature, and are reported here following the recommendation of the MARC.

4.1.9.1 Dianeal (82460)
4.1.9.2 Dianeal (82461)
4.1.9.3 Dianeal (82462)
4.1.9.4 Dianeal (82501)
4.1.9.5 Dianeal (82502)
4.1.9.6 Dianeal (82503)
4.1.9.7 Dianeal (82504)
4.1.9.8 Dianeal (82505)
4.1.9.9 Dianeal (82506)
4.1.9.10 Dianeal (82506)
4.1.9.11 Dianeal (82508)

4.1.10 Other Reports

The Committee noted the following case reports relating to medicines included on the Scheduled Review list:

4.1.10.1 Leflunomide,bendromethazide,metoprolol,omeprazole,prednisone,calcium carbonate,potassium chloride slow-release (Slow K),multivitamins (82614)

4.1.10.2 Methotrexate,leflunomide (82905)

4.10.1.3 Methotrexate,leflunomide,prednisone,folic acid,omeprazole, aledronate/cholecalciferol (Fosamax Plus) (81739)

4.1.10.4 Terbinafine (83225)

4.2 Quarterly Reports from CARM as at 31 March 2009

Discussion

The Committee noted the quarterly reports from CARM as at 31 March 2009.

4.3 Human Papillomavirus Vaccine (HPV) reports

Discussion

The Committee noted the CARM report of reactions to the HPV vaccine for the period 1 May 2007 to 30 April 2009. The report for the period until 31 May 2009 was distributed at the meeting.

NZPhvC advised that further information had been received regarding report 84015, submitted by the Pharmaceutical Company, based on a media report. NZPhvC considered that there were insufficient clinical details provided to assess the original report, and the report was assessed as "unclassifiable'. Further information had been received, and the reaction of "paralysed left arm" revised to "sore arm".

NZPhvC advised that the main pattern of reactions observed were those of local reactions (injection site/limb pain, injection site inflammation); somatic immune responses (fever, headache, gastrointestinal and musculoskeletal symptoms), hypersensitivity (skin reactions - mostly rash) and vasovagal or fainting episodes. The Committee noted that these findings were in keeping with the pattern of reports received in the past and were those expected events following any immunisation. NZPhvC advised that similar findings have been reported by other national reporting centers.

NZPhvC advised that overall the patterns of events observed were typical of post immunisation symptoms, although the vasovagal episodes were more marked for the HPV than other vaccines in the CARM database. Nevertheless, despite this disproportionality, these vasovagal events were not unexpected in the context of an immunisation programme such as the HPV campaign focusing on adolescent girls. The Committee agreed that these patterns do not raise any concerns, and noted that reports following HPV immunisation will continue to be regularly reviewed by NZPhvC and Medsafe, and reported to the MARC.

4.4 Proton pump inhibitors report

Discussion

The Committee noted the proton pump inhibitors reports from NZPhvC for the period 1 June 1990 to 30 April 2009.

NZPhvC advised that reports continued to be received by CARM following brand changes of proton pump inhibitors. They advised that the majority of the reports involve the gastrointestinal system, nervous system (headaches, malaise, insomnia) and skin (rash).The pattern of reactions is largely that of reduced therapeutic effect.

Medsafe advised that the product sponsor for the Dr Reddy's brands for both omeprazole and pantoprazole has provided periodic safety update reports (PSURs) and these have been reviewed by the Medsafe Clinical Risk team. No issues of concern warranting regulatory action or additional review at the present time were identified by Medsafe.

The MARC noted that NZPhvC and Medsafe will continue to monitor this issue and report back to the Committee as necessary.

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.

Summary of Medsafe Signal Detection and Evaluation, May 2009.

Hviid A, Melbye M. 2008. Measles-Mumps-Rubella Vaccination and Asthma-like Disease in Early Childhood. Am J Epidemiology 168 (11): 1277-1283

6. New Zealand pharmacovigilance-related activities

DHBNZ Safe and Quality Use of Medicines Group. 2009. Newsletter. Volume 5, Number 2.

7. international pharmacovigilance-related Activities

7.1 Australia

[..]

7.2 Canada

Canadian Adverse Reaction Newsletter. 2009. Volume 19, Issue 2

7.3 Singapore

Health Sciences Authority (HSA). 2009.Adverse Drug Reaction. Volume 11, Number 1

7.4 United Kingdom

Medicines and Healthcare products Regulatory Agency (MHRA). 2008. Drug Safety Update. Volume 2, Issue 8
Medicines and Healthcare products Regulatory Agency (MHRA). 2009. Drug Safety Update. Volume 2, Issue 9
Medicines and Healthcare products Regulatory Agency (MHRA). 2009. Drug Safety Update. Volume 2, Issue 10

7.5 United States

Food and Drug Administration (FDA). 2009. Drug Safety Newsletter. Volume 2, Issue 1

7.6 World Health Organization (WHO)

The Uppsala Monitoring Centre. Signal - Analyses of adverse Reaction Reports in the WHO database. February 2009

8. Summary listings of case reports considered by the MARC (1997- 2009)

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

9. OTHER BUSINESS

The Committee thanked Assoc Prof Maling for his valuable input, both as a Committee member, and later as Chair, over the preceding 28 years and wished him well for the future.

The Chair thanked members and the secretariat for their attendance and closed the meeting at 3.50pm.

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

Committees