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 137^th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING,

12 March 2009

The one hundred and thirty seventh meeting of the Medicines Adverse Reactions Committee (MARC) was held on 12 March 2009 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9am and closed at 3.40 pm.

marc members present

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

MARC secretariat present

J McNee (MARC Secretary)

MEDSAFE STAFF PRESENT

A Cutfield (Advisor, Pharmacovigilance)
J Hart (Acting Manager, Clinical Risk Management, Medsafe)
S Kenyon (Senior Advisor, Pharmacovigilance)
M J McCarthy (Advisor, Pharmacovigilance)
K Sheehy (Senior Advisor, Medical, Medsafe)
E Yousuf (Acting Principal Clinical Advisor, Medsafe)

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. He welcomed Mary Jane McCarthy and Enver Yousuf, who were attending the meeting for the first time.

Apologies were received from Dr Michael Tatley.

Prof Maling informed the members that he intended to resign from the Committee in June 2009 and the June meeting would therefore be his last MARC meeting.

1.2 Minutes of the 136th MARC Meeting

NZPhvC asked that an amendment be made to the minutes of the 136^th MARC meeting, in minute item 1.5.1. The statement 'NZPhvC advised that no further 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' should be amended to '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 Secretary agreed to make this change.

The minutes of the 136^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 11 June 2009. The subsequent MARC meetings for 2009 were scheduled for 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.

1.5.2 Prescriber Update. Volume 30, Number 1. February 2009

Discussion

The Committee noted the latest edition of Prescriber Update. This edition was the first to be published in the new format

The Committee noted that the issue of communication and dissemination of information relating to pharmacovigilance would be discussed further at the June 2009 MARC meeting.

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 Schedule of Planned Prescriber Update Articles
December 2008 minute item 1.5.1

MARC Recommendation

In December 2008 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.

In December 2008 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.

Outcome

The topic 'Nitritoid reactions with injectable gold' has been removed from the schedule of planned Prescriber Update articles.

A short paragraph on one specific herbal product will be included in each issue of Prescriber Update. A paragraph entitled 'Black Cohosh and hepatotoxicity - ask about use and look for signs' was published in the February edition of Prescriber Update.

Discussion

The Committee noted the above.

2.1.2 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 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 that this information be disseminated to the Ophthalmologists Society. The Medsafe and NZPhvC reports on this issue were included in the December 2008 dossier.

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 will be prepared for publication in Prescriber Update.

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

Discussion

The Committee noted the above.

2.1.3 Statins, neuromuscular degenerative disease and amyotrophic lateral sclerosis-like syndrome - Scheduled Review
December 2008 minute item 3.1

MARC Recommendation

In December 2008 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.

Outcome

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

Discussion

The Committee noted the above.

2.1.4 Oral terbinafine and serious adverse reactions (blood dyscrasias, heptatotoxicity and dermatological reactions) - including prescribing data - Scheduled Review
December 2008 minute item 3.2

MARC Recommendation

In December 2008 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.

Outcome

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

Discussion

The Committee noted the above.

2.1.5 Oral bisphosphonates and the risk of atrial fibrillation (AF)
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 (AF) in association with oral bisphosphonates.

In December 2008 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.

Outcome

[..] will be asked to provide an opinion on the risk of atrial fibrillation in association with oral bisphosphonates.

The issue of oral bisphosphonates and atrial fibrillation has been 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.

Discussion

The Committee noted the above.

2.1.6 Paracetamol associated with childhood asthma
December 2008 minute item 3.4

MARC Recommendation

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

Outcome

A paragraph entitled 'An association between paracetamol and asthma' was published in the February edition of Prescriber Update. Medsafe will write to sponsors of paracetamol-containing products and ask them to consider including a warning in the product datasheets about the possible risk of paracetamol use in pregnancy leading to asthma in the infant.

Discussion

The Committee noted the above. They considered this was an important issue which needed to be closely monitored, and recommended that the issue of paracetamol associated with childhood asthma be placed on the 'Scheduled Review' list for 12-monthly review.

Recommendation

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

2.1.7 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.

2.1.8 Simvastatin, citalopram, omeprazole, cilazapril, metoprolol, furosemide, metformin, gliclazide, warfarin, aspirin and muscle weakness, sudden death [death] (79981)
December 2008 minute item 4.1.1.8

MARC Recommendation

In December 2008 the Committee recommended that NZPhvC change the causality from 'possible' to 'unclassifiable'.

Outcome

NZPhvC has amended the causality as above.

Discussion

The Committee noted the above.

2.1.9 Clozapine and agranulocytosis, pneumonia, hypertension [death] (80225)
December 2008 minute item 4.1.1.11

MARC Recommendation

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

Outcome

NZPhvC has amended the causality as above.

Discussion

The Committee noted the above.

2.1.10 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 will be prepared in conjunction with [..], for publication in the BPAC publication and Prescriber Update.

Discussion

The Committee noted the above.

2.1.11 Quarterly Reports from CARM as at September 2008
December 2008 minute item 4.2

MARC Recommendation

In December 2008 the Committee recommended that NZPhvC present the cases they have received of tendon rupture in association with norfloxacin at the next MARC meeting.

Outcome

A report was included in the March 2009 dossier.

Discussion

See minute item 4.5 for the discussion on this topic.

2.1.12 SSRI antidepressants
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

A request will be made to the Coroner's Office to forward the decisions relating to medication related cases directly to the NZPhvC.

Discussion

The Committee noted the above.

2.1.13 Removal of specialist prescribing restriction from retinoids
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.

Outcome

Following a meeting between PHARMAC and Medsafe, it was decided that Medsafe would further investigate options for risk management.

PHARMAC has communicated its final decision to broaden access to oral retinoid treatments. In 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.

Discussion

The Committee noted the above.

2.1.14 Reporting of patient allergies to the Centre for Adverse Reactions Monitoring (CARM)
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).

Outcome

The Chair will 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).

Discussion

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

2.1.15 SSRI antidepressants and increased suicidality in children and adolescents
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 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 Associate Professor Frampton prepare information to be submitted for publication in the New Zealand Medical Journal.

Outcome

A paragraph entitled 'Selective serotonin re-uptake inhibitors (SSRI) in children and adolescents' was published in the February 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.

2.1.16 Black cohosh and hepatotoxicity
December 2008 minute item 2.1.2, 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:

look for signs of liver toxicity in patients taking black cohosh;
seek information from patients about the use of herbal medicines where liver toxicity is suspected; and
report any adverse reactions in patients taking complementary medicines to CARM.

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

Outcome

A paragraph entitled 'Black Cohosh and hepatotoxicity - ask about use and look for signs' was published in the February edition of Prescriber Update.

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.

Discussion

The Committee discussed the possibility of contacting the Pharmaceutical Society and Pharmacy Guild and request that they disseminate information regarding the risk of hepatotoxicity with black cohosh to their members.

2.1.17 Conventional antipsychotics and mortality risk
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 data sheets 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.

Outcome

A paragraph entitled 'Conventional antipsychotics and mortality risk - carefully assess risks and benefits before use in elderly dementia patients' was published in the February edition of Prescriber Update.

Medsafe has initiated the process to request sponsors to update their data sheets.

Discussion

The Committee noted the above.

2.1.18 Fleet oral preparation and renal failure, hyperphosphataemia [death] (79049)
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 will be prepared for publication in Prescriber Update.

Discussion

The Committee noted the above.

2.1.19 Flucloxacillin and anaphylactic reaction [death] (78269)
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 has been received.

Outcome

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

Discussion

The Committee noted the above.

2.1.20 Aprotinin and increased mortality risk
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 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 for their input into the issue and providing them with information regarding access to worldwide stocks of aprotinin.

Discussion

The Committee noted that aprotinin has now been completely withdrawn from the worldwide market. They suggested that Medsafe follow-up with Bayer regarding access in individual cases.

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

Medsafe will further investigate possible ways of sharing relevant information.

Discussion

The Committee noted the above.

2.1.22 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)
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

This issue is continuing to be investigated.

Discussion

The Committee noted that a report is being prepared by [..].

2.1.23 Clozapine and neutropenia, lymphopenia, anaemia [death] (76419)
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 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 that the key information to be obtained was to determine the number of elderly patients who are being prescribed clozapine for conditions other than treatment-resistant schizophrenia. They suggested it may be possible to obtain this information from the product sponsor in the first instance. They 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.

Recommendation

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.

2.1.24 Anti-epileptics and the risk of suicidality
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 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 data sheets.

Outcome

The final wording for inclusion in the prescribing information for all anti-epileptics has been decided and such changes have been required by international regulators including the FDA and TGA. Medsafe is in the process of again contacting the sponsors of anti-epileptic medicines in New Zealand, requiring them to update their data sheets as requested by Medsafe in February 2008.

Refer also to minute item 3.2.

Discussion

The Committee noted the above.

2.1.25 Methylene Blue, tramadol, fentanyl, paroxetine and serotonin syndrome (77178)
December 2008 minute item 2.1.18, 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

Following review of additional data provided by a MARC member, it was noted that published reports supported at least a theoretical causal association between serotonin syndrome and methylene blue. However, whilst there may be evidence for the plausibility of such an association, this particular case report was lacking in clinical data to confirm that the event reported met the Steinbach criteria for serotonin syndrome. Although a causal association for serotonin syndrome in this case was not established, the individual events that reflected part of the full case definition were recorded and considered to be causally associated.

Discussion

The Committee noted the above.

2.1.26 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

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 investigating options for disseminating advice to consumers regarding this issue.

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 FDA's analyses of ADR data) is completed.

Discussion

The Committee noted the above.

2.1.27 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.

2.1.28 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 Associate Professor Frampton, explore a protocol for obtaining age-standardised data on the frequency of haematological events with clozapine.

Outcome

Medsafe and Associate Professor Frampton are developing a protocol for obtaining these data.

Discussion

The Committee noted the above.

3. pharmacovigilance issues

3.1 ALL ADVERSE REACTIONS TO ROSIGLITAZONE AND PIOGLITAZONE (ARCC), PARTICULARLY FRACTURE/BONE DENSITY - SCHEDULED REVIEW

References

Loke YK, Singh S and Furberg CD. 2009. 'Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis' CMAJ . 180: 32-9.
Margolis DJ, Hoffstad O and Strom BL. 2008. 'Association between serious ischemic cardiac outcomes and medications used to treat diabetes' Pharmacoepidemiology and drug safety 17: 753-759.
Selvin E et al. 2008. 'Cardiovascular outcomes in trials of oral diabetes medications' Arch Intern Med 168: 2070-2080.
Wilcox R, Kupfer S and Erland E on behalf of the PROactive study investigators. 2008. 'Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: Results from PROspective pioglitazone Clinical Trial in macro Vascular Events (PROactive 10)' Am Heart J 155: 712-7.
Winkelmayer WC et al. 2008. 'Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy'. Arch Intern Med 168: 2368-2375.

Issue

Medsafe provided a report for the MARC's 'Scheduled Review' on the issue of all adverse reactions to rosiglitazone and pioglitazone, particularly fracture/bone density. This issue was placed on the Adverse Reaction of Current Concern (ARCC) list in March 2006.

Since the Committee first reviewed this issue, the NZ data sheets for both Actos (pioglitazone) and Avandia (rosiglitazone) have been extensively updated with respect to safety issues, including cardiovascular warnings and the risk of bone fractures. A Prescriber Update article entitled 'Glitazones: fluid retention, cardiac failure and macular oedema' was published in November 2007.

In March 2008, the Committee recommended that the data sheet for Avandia be further updated to bring it in line with the Australian Product Information (PI) regarding cardiovascular risks. They also recommended that an article be published in Prescriber Update reminding prescribers of the association between rosiglitazone and myocardial infarction, and that pioglitazone may have the same effect. An article entitled 'Myocardial infarction with glitazones' was published in the June 2008 edition of Prescriber Update.

The purpose of the February 2009 report was to update the Committee on regulatory actions and new information regarding adverse reactions with rosiglitazone and pioglitazone that have arisen in the previous 12 months.

The Committee was asked to evaluate the information provided and to determine whether the risk-benefit profile of rosiglitazone and pioglitazone had changed as a result of this new information; and if so, recommend appropriate risk management.

Discussion

The Committee noted the 2009 Medsafe report.

The Committee noted that previously identified adverse reactions of concern related to the glitazones were cardiovascular (fluid retention, cardiac failure, myocardial infarction), liver disorders, bone density, and macular oedema.

The Committee noted that rosiglitazone is not funded in New Zealand, and NZPhvC has few reports of adverse reactions in association with rosiglitazone. Pioglitazone is funded under Special Authority criteria, and so usage in this country was likely to be low. There have only been a small number of reports for both rosiglitazone and pioglitazone to CARM since the last review in 2008.

NZPhvC provided an analysis of the WHO database. Early signals of cardiac failure and myocardial infarction have been investigated in formal studies and reporting of these disorders was not re-evaluated. It was also concluded that formal studies were of more value in evaluating osteoporosis and fractures.

The combinations of pioglitazone or rosiglitazone with mitral insufficiency are statistically disproportionate in the WHO database and evaluation of reports indicates a signal. This signalled adverse drug reaction and those previously identified by CARM for pleural and pericardial effusion and pulmonary hypertension are considered due to fluid retention. These observations are in keeping with the published case histories of reversible mitral regurgitation and pleural effusion in the literature survey.

There was no new data in the WHO database to indicate that pancreatic and hepatic neoplasms, bile duct disorder and retinal haemorrhage, identified in 2008 as statistically disproportionate, were signals of a direct adverse effect of the medicines.

The Committee noted that a number of papers have been published on the effects of the thiazolidinediones (TZDs) in the last year, including results of clinical trials, observational studies, case reports, reviews and opinions. Many papers detailing the results of small (10-20 subjects) trials with surrogate end points have been published in the last year. Papers containing information in relation to the adverse events of interest in clinical trials, observational studies (of reasonable size) and case reports were reviewed by the Committee.

The Committee discussed the paper by Wilcox et al which analysed the PROactive study. The PROactive study was a randomised, double-blind placebo controlled study involving the use of pioglitazone in patients with type 2 diabetes and an established history of macrovascular disease. The primary composite end point included death, myocardial infarction, acute coronary syndrome, stroke, coronary and leg revascularisation. The PROactive study showed a 10% risk reduction in the pioglitazone group, compared with the placebo group for the primary composite end point, but this was not statistically significant. There was a statistically significant 16% risk reduction for the main secondary end point of all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke. The Wilcox analysis presented the results of commonly evaluated composite end points of major adverse cardiovascular events (MACEs). There was an approximate 20% reduction in time to the MACE end points in subjects taking pioglitazone compared to control. This was considered important by the authors since it was independent of presenting vascular disease and was achieved on top of existing standard management with cardiovascular medication. The Committee considered that although the study indicated a reduction in risk with pioglitazone, the results were not totally conclusive.

The Committee noted the PERISCOPE trial. They considered that the value of this trial appeared to be minimal; the authors were not convincing that the changes measured were clinically relevant, and the study was conducted over only an 18 month time period.

The Committee noted a study by Giles et al which reported the results of a double-blind randomised multicentre study comparing the effects of pioglitazone and glyburide on cardiac function in patients with type 2 diabetes. The patients also had significant heart failure. The time period for the study was 6 months, with insulin the only allowed rescue medication. The primary end point was time to heart failure. The authors concluded that pioglitazone was associated with a higher incidence of hospitalisation or heart failure without an increase in cardiovascular mortality of worsening cardiac function. The authors did not suggest reasons for this outcome but note that TZD treatment is associated with dose-dependent fluid retention.

The Committee noted the systematic review by Selvin et al, which reviewed publications reporting controlled trials with information on cardiovascular events associated with oral anti-diabetic agents. The authors concluded that their meta-analysis suggested that compared with other oral diabetes agents and placebo, metformin was moderately protective and rosiglitazone possibly harmful, but lack of power precluded firmer conclusions. The authors state that the current evidence based on comparison of specific oral diabetes medications for the risk of cardiovascular morbidity and mortality is inconclusive. There have been few trials longer than 6 months and reporting of cardiovascular adverse events is poor.

The Committee noted the results from a sub-study by Komajda et al looking at blood pressure in subjects enrolled into the RECORD study of rosiglitazone. The RECORD study included patients with type 2 diabetes inadequately controlled on metformin or sulfonylurea monotherapy. While the study showed reductions in blood pressure were greater with rosiglitazone than metformin or sulfonylureas, the Committee noted that the data seemed to have minimal clinical relevance and it wasn't clear whether any differences in blood pressure weren't due to changes in antihypertensive medication alone.

The Committee noted an observational study by Karagiannis et al, the IRIS V study, which was a 12 month multi-centre observational drug monitoring trial looking at biochemical markers, in which patients with mild diabetes were individually observed for about 20 weeks. The subjects received pioglitazone alone or in combination with metformin or a sulfonylurea. All biochemical markers showed significant improvements. However, the clinical significance of the changes appeared to be minimal for many.

The Committee noted the cohort study by Winkelmeyer et al which compared cardiovascular outcomes and mortality between patients initiated on rosiglitazone and pioglitazone therapy. The authors concluded that new users of rosiglitazone experienced higher rates of all-cause mortality and hospitalisation for CHF than pioglitazone users.

The Committee noted the Margolis et al study, which reported a retrospective cohort study of diabetic patients where the primary outcome was serious atherosclerotic vascular disease of the heart. Some potentially confounding variables were addressed. The authors stated that risk increased as total duration of therapy increased for insulin, sulfonylureas and biguanide, but decreased with duration of use for rosiglitazone and pioglitazone. The Committee considered that longer studies may be necessary to determine the risk-benefit profile of the glitazones over other therapies.

The Committee noted that both the ADOPT trial and the Loke meta-analysis confirmed the known fracture risk in women with type 2 diabetes following long-term use of TZDs. The product data sheets for both Actos and Avandia contains a warning regarding the risk of fractures.

The Committee noted a case report by Dorkhan et al which supported a case series presented at the previous MARC review in 2008. This reported the spontaneous resolution of diabetic macular oedema after discontinuation of rosiglitazone.

The Committee noted that no further information was found on salivary gland enlargement, bile duct disorders or retinal haemorrhage, which were previously identified as areas of concern.

The Committee noted that in general the studies were short, and agreed that the long term risks associated with taking these medications have still not been determined.

The Committee agreed that the risk-benefit profile for rosiglitazone and pioglitazone remained unchanged as a result of the new information and that no further regulatory action was required at this time. They noted that the FDA and Health Canada are currently reviewing the hepatic safety of rosiglitazone and pioglitazone. They 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).

Recommendation

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).

3.2 ANTI-EPILEPTICS AND THE RISK OF SUICIDALITY - SCHEDULED REVIEW

References

Levenson M. 23 May 2008. Statistical Review and Evaluation: Anti-epileptic drugs and suicidality. United States Food and Drug Administration.
Quick minutes. Joint meeting of the Peripheral and Central Nervous System Advisory Committee and the Psychopharmacologic Drugs Advisory Committee. 10 July 2008.
PHARMAC usage data: November 2007 - November 2008.
Medsafe. Dear Healthcare Professional Letter. 1 February 2008.
CARM and WHO data provided by the NZPhVC.
EMEA. Anti-epileptics and suicidal behaviour - Final SPC and PIL wording agreed by PhVWP. July 2008.
Suicidal behaviour and ideation and anti-epileptic drugs. FDA website. 16 December 2008.
United States Food and Drug Administration. Letter to sponsors. December 2008
Mula M. and Sander J. 2007. Suicidal ideation in epilepsy and levetiracetam therapy. Epilepsy & Behaviour. 11: 130-132.
Kalinin V. 2007. Suicidality and antiepileptic drugs: Is there a link? Drug Safety. 30(2): 123-142.

Issue

Medsafe provided a report for the MARC's 'Scheduled Review' on the issue of anti-epileptics and the risk of suicidality. This issue was first reviewed by the MARC in March 2008.

In January 2008, the United States Food and Drug Administration (FDA) informed US healthcare professionals that the agency had analysed reports of suicidality (suicidal behaviour or ideation) from placebo-controlled clinical studies of eleven medicines used to treat epilepsy as well as psychiatric disorders, and other conditions. In the FDA's analysis, patients receiving anti-epileptic drugs had approximately twice the risk of suicidal behaviour or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behaviour and suicidal ideation was observed as early as one week after starting the anti-epileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.

There were an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the anti-epileptic treatment groups who experienced suicidal behaviour or ideation than in the placebo groups.

US Healthcare professionals were advised to closely monitor all patients currently taking or starting any anti-epileptic medicine for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression. The FDA indicated that the medicines included in the analyses were: carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide. However, the FDA expected that the increased risk of suicidality was shared by all anti-epileptic medicines and anticipated that these recommendations will be applied to all anti-epileptic drugs.

In February 2008, Medsafe required New Zealand product sponsors to update their data sheets for anti-epileptic medicines with this new information. The data sheets for lamotrigine products and most generic anti-epileptic medicines were updated as requested. However, Medsafe agreed to requests to defer updating innovator data sheets until final wording had been agreed to by the FDA. Medsafe also distributed a Dear Healthcare Professional letter to New Zealand prescribers informing them of the FDA's alert.

In March 2008, the Committee agreed that more detail was required in order to determine if this information altered the overall risk profile of anti-epileptics. They recommended that Medsafe provide the MARC with a copy of the full results of the FDA's statistical review and evaluation of anti-epileptics and suicidality (meta-analysis) when it became available.

Following a review of the FDA's meta-analysis in September 2008, the MARC 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 data sheets.

The purpose of this report was to provide the Committee with an update on the New Zealand situation and to inform the Committee of recent data and regulatory action regarding the risk of suicide in association with the use of anti-epileptic medicines.

The Committee was asked to evaluate the information provided, and to determine whether the actions taken by Medsafe were sufficient and whether this issue needed to remain on the 'Scheduled Review' list.

Discussion

The MARC noted the February 2009 Medsafe report.

The Committee considered that although the FDA's analysis showed clear differences between the different anti-epileptic medicines, the FDA concluded the risk of suicidality with these medicines to be a class effect. They noted however, that some trials involved too few patient numbers to be able to draw conclusions.

Medsafe advised that the final wording for inclusion in the prescribing information for all anti-epileptics has been decided and such changes have been required by international regulators including the FDA and Therapeutic Goods Administration (TGA).

The Committee noted that Medsafe will require the sponsors of the remaining anti-epileptic drugs to update their data sheets with the information as originally requested, and considered that there was no further action to be taken on this issue at this time.

The MARC noted that Medsafe will continue to monitor and evaluate international regulatory activity and safety-related data as it arises, and will report back to the MARC as necessary. The Committee recommended that the issue of anti-epileptics and suicidality be removed from the 'Scheduled Review' list.

Recommendation

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

3.3 OESTROGEN AND KIDNEY FUNCTION LOSS IN THE ELDERLY

References

Ahmed SB et al. 2008. Oral estrogen therapy in postmenopausal women associated with loss of kidney function. Kidney Int 74:370-376.

Issue

Medsafe provided a report for the MARC on the issue of oestrogen and kidney function loss in the elderly. This followed a report in Reactions Weekly in September 2008 of a signal of loss of kidney function in association with oral oestrogen therapy in postmenopausal women.

The signal originated from a publication by Ahmed et al (2008). This reported the results from a cohort of women over 66 years of age who had at least two serum creatinine measurements taken during the two year study period. The authors suggested that in elderly women use of oestrogen only hormone therapy may increase age-related decline in renal function and increase the risk of rapid loss of kidney function.

The Committee was asked to consider the strength and clinical relevance of this signal, and if any further investigation of the signal was required.

Discussion

The Committee noted the November 2008 Medsafe report.

The Committee noted that the Ahmed paper suggested that in elderly women use of oestrogen-only hormone therapy may increase age-related decline in renal function and increase the risk of rapid loss of kidney function. However, they noted that there were several confounding factors which the authors could not control, and the data presented in this paper were inconclusive. The Committee agreed that there was little additional evidence in the published literature on this issue, and that the spontaneous reports did not suggest that adverse effects of oestrogen on the kidney have been recognised to date.

The Committee considered that no regulatory action was required at this time, but would review further literature as it became available.

3.4 METHYLPHENIDATE SR (RUBIFEN SR) BRAND SWITCH-AGGRESSIVE AND DEFIANT BEHAVIOURAL REACTIONS- SCHEDULED REVIEW

References

PHARMAC Notification. Funding Approved for ADHD Treatments. 9 December 2008.
EMEA Press Release. European medicines Agency makes Recommendations for Safer Use of Ritalin and other Methylphenidate-containing Medicines in the EU. 22 January 2009.
EMEA Questions and Answers on the Review of Medicines Containing Methylphenidate. 22 January 2009.
CHMP Recommended Elements for Inclusion in Summaries of Product Characteristics for Methylphenidate-Containing Products for the Treatment of ADHD in Children Aged Six years and above and Adolescents. 22 January 2009.
New Zealand data sheet for Rubifen SR.
PHARMAC Report - Ritalin SR Special Access 17 month report

Issue

Medsafe and NZPhvC provided reports for the MARC's 'Scheduled Review' on the issue of methylphenidate SR (Rubifen SR) brand switch-aggressive and defiant behavioural reactions. This issue was brought to the MARC following a number of reports received by CARM following a change in the subsidised brand of methylphenidate from Ritalin SR to Rubifen SR.

On 1 April 2007 Rubifen SR became the only brand of long-acting methylphenidate funded by PHARMAC after Ritalin SR was de-listed from the Pharmaceutical Schedule. Between 8 February 2007 and 31 August 2007 CARM received 78 adverse drug reaction reports for Rubifen SR. A number of reports described the development of aggressive and defiant behaviours, which in many cases were not part of the patient's original Attention Deficit-Hyperactivity Disorder (ADHD) symptoms, and did not occur when the patient was taking Ritalin SR.

The MARC first reviewed the issue of defiant and aggressive behavioural reactions to Rubifen SR at its September 2007 meeting. They recommended that Medsafe:

Write to PHARMAC requesting that they reconsider making the previously subsidised Ritalin SR product available to patients until the issue was investigated further.

Write to the sponsors of Rubifen SR under Section 36 of the Medicines Act 1981 requesting that they provide further data in support of Rubifen SR.

Contact the sponsor of Rubifen SR and request that the data sheet be updated to include information on the risk of aggressive and defiant behaviours.

Report back to the MARC when the results of further testing of the Rubifen SR product were available.

On 27 September 2007, PHARMAC advised that it would fund Ritalin SR on application to PHARMAC for patients who had experienced serious adverse reactions when switching from Ritalin SR to Rubifen SR. This followed from a request by Medsafe to reconsider making Ritalin SR available until the issue was fully investigated.

At its December 2007 meeting, Medsafe advised the MARC that the sponsor of Rubifen SR had provided the data requested under Section 36 of the Medicines Act 1981. Medsafe advised that these data were evaluated by its Evaluation Team and were found to have been acceptable, with all batches tested meeting agreed specifications. There was no evidence of a manufacturing or pharmaceutical chemistry fault which could explain the unusual adverse reactions experienced by some patients taking Rubifen SR. The Committee noted that the new information did not provide any pharmacokinetic data suggestive of dose dumping which could have explained the aggressive and defiant behavioural reactions experienced by some patients while taking Rubifen SR.

At the March 2008 MARC meeting, the NZPhvC advised the MARC that the frequency of reports received had decreased since PHARMAC agreed to make the previously subsidised Ritalin SR product available to affected patients. It was noted that the pattern of reports for Rubifen SR remained essentially unchanged. Medsafe advised that the data sheet for Rubifen SR was being updated to bring it in line with the Ritalin datasheet, by including information on the risk of aggressive and defiant behaviours occurring.

The purpose of the report was to update the Committee about developments regarding this issue since it was last considered by the MARC in March 2008. The Committee was asked to consider whether any further regulatory action is needed on this issue.

Discussion

The Committee noted the February 2009 Medsafe and NZPhvC reports.

The Committee noted that PHARMAC had advised that Ritalin SR, Ritalin and Ritalin LA, will be funded from 1 July 2009. Ritalin SR and Ritalin will be listed under the same Special Authority criteria applicable to Rubifen SR and Rubifen.

The Committee considered that the methylphenidate SR brand-switch issue has effectively been resolved through the PHARMAC re-listing of Ritalin SR allowing access to patients who have experienced aggressive and defiant behaviour upon changing to Rubifen SR, and 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.

Medsafe advised of a recent European Medicines Agency (EMEA) press release, in which recommendations made for the safer use of Ritalin and other methylphenidate-containing medicines in the European Union (EU) were outlined. This was the result of a Committee for Medicinal Products of Human Use (CHMP) review of methylphenidate due to concerns over cardiovascular and cerebrovascular risks. The CHMP also considered the risk of psychiatric disorders, the effect of methylphenidate on growth and sexual maturation, and the effects of long-term treatment. Following its review of the data, the CHMP concluded there was no need for an urgent restriction on the use of methylphenidate-containing medicines, but new recommendations on the prescribing, and on pre-treatment screening and monitoring of patients were needed to maximize the safe use of these medicines. The CHMP concluded information about the safety of methylphenidate-containing medicines was not consistent across the EU, and that the Summaries of Product Characteristics for these medicines should contain specific core information. The CHMP also requested that further risk minimisation measures be put in place, including educational material for doctors. A need for further studies was identified, particularly into the long-term effects of methylphenidate.

The Committee noted that Medsafe has requested a copy of the risk-benefit review that was presented to the CHMP. They considered that the issues identified in the CHMP risk-benefit review of methylphenidate-containing products warranted further investigation. They recommended that Medsafe reviews the CHMP risk-benefit review for methylphenidate-containing medicines and reports back to the MARC.

Recommendation

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.

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

3.5 LIPID-LOWERING AGENTS AND PSYCHIATRIC ADVERSE REACTIONS - SCHEDULED REVIEW

References

PHARMAC Usage Data
CARM and WHO data provided by the NZPhVC
Feng L., Tan C., Merchant R., Ng T. 2008. Association between depressive symptoms and use of HMG-CoA Reductase Inhibitors (Statins), Corticosteroids and Histamine H2 Receptor Antagonists in Community-Dwelling Older Persons - Cross-Sectional Analysis of a Population-Based Cohort. Drugs Aging. 25(9): 795-805.
Tuccori M. et al. 2008. Statin-Associated Psychiatric Adverse Events: A Case/Non-Case Evaluation of an Italian Database of Spontaneous Adverse Drug Reaction Reporting. Drug Safety. 31: 1115-1123.
Peters J., Garwood C., Lepczyk M. 2008. Behavioral changes with paranoia in an elderly woman taking atorvastatin. The American Journal of Geriatric Pharmacotherapy. 6: 28-32.
Tatley M. and Savage R. 2007. Psychiatric adverse reactions with statins, fibrates and ezetimibe: implications for the use of lipid-lowering agents. Drug Safety. 30(3): 195-201.
Parale G., Baheti N., Kulkarni P., Panchal N. 2006. Effects of atorvastatin on higher functions. European Journal of Clinical Pharmacology. 62: 259-265.
Galatti L., Giovanni P., Francesco S., Marcello R., Aurelio S., Edoardo S. 2006. Short-Term Memory Loss Associated with Rosuvastatin. Pharmacotherapy. 26: 1190-1192.
Golomb B., Kane T., Dimsdale J. 2004. Severe irritability associated with statin cholesterol-lowering drugs. QJM. 97: 229-235.
King D., Wilburn A., Wofford M., Harrell T., Lindley B., Jones D. 2003. Cognitive impairment associated with atorvastatin and simvastatin. Pharmacotherapy. 23(12): 1663-7.
Manfredini R., Caracciol S., Salmi R., Boari B., Tomelli A., Gallerani M. 2000. The association of low serum cholesterol with depression and suicidal behaviours: New hypotheses for the missing link. The Journal of International Medical Research. 28: 247-257.

Issue

Medsafe and NZPhvC provided reports for the MARC's 'Scheduled Review' on the issue of the risk of psychiatric adverse reactions occurring in association with the use of lipid-lowering agents. This issue was placed on the 'Scheduled Review' list in December 2005 following CARM case reports observing a pattern of psychiatric events, including well documented cases of aggressive reactions observed in patients on statin therapy.

In December 2005, the Committee agreed that the NZPhvC investigate publishing an article on the psychiatric adverse effects of statins internationally and then subsequently in Prescriber Update. In June 2006, the MARC recommended that ezetimibe be included in the list of monitored lipid-lowering agents.

Since the June 2006 MARC recommendations were made, an article titled "Psychiatric adverse reactions with statins, fibrates and ezetimibe: implications for the use of lipid-lowering agents" was prepared by the NZPhvC and published in Drug Safety. A subsequent watching brief article was included in the November 2006 edition of Prescriber Update.

In September 2007, the MARC recommended that Medsafe contact the sponsors of all lipid-lowering agents and request that information regarding depression and amnesia be added to the Adverse Effects section of the data sheets for all lipid-lowering agents. Medsafe reported back to the MARC at the March 2008 meeting, and advised that some sponsors had declined to include the wording requested by Medsafe in their data sheets. The Committee expressed concern regarding the sponsors' decisions not to include the requested information in their data sheets in the context of public safety.

The purpose of this report was to provide the Committee with an update on the New Zealand situation and to inform the Committee of recent data and regulatory action regarding the risk of psychiatric adverse reactions occurring in association with the use of lipid-lowering agents.

The Committee was asked to evaluate the information provided, and to consider whether this issue needs to remain on the 'Scheduled Review' list.

Discussion

The MARC noted the February 2009 Medsafe and NZPhvC reports. The Committee noted that there were some recently published papers which suggested a potential signal of insomnia in association with lipid-lowering agents. They noted that results were awaited from a specific clinical review of the statins by Golomb. The MARC considered that the risk:benefit ratio of the statins remained unchanged as a result of the new information. They noted that Medsafe and NZPhvC will continue to monitor and evaluate international regulatory activity and safety-related data as it arises, including the results of the Golomb study, and will report back to the MARC as necessary.

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

Recommendation

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

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 Fluorouracil and coronary artery disorder, fibrillation ventricular [death] (81331)

Discussion

NZPhvC advised that the CARM database includes reports of cardiovascular events in association with fluorouracil and irinotecan, but not with leucovorin. The product data sheet for fluorouracil includes reference to cardiotoxicity, while the irinotecan data sheet includes references to thromboembolic cardiovascular adverse effects.

NZPhvC noted that cardiac adverse effects in association with fluorouracil usually occurred early after the start of treatment, and in this case, the cardiac event occurred late in the course of treatment.

The causal association with fluorouracil was considered to be 'possible' for coronary artery disorder, fibrillation ventricular.

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

4.1.1.2 Fludarabine, cyclophosphamide and haemolytic autoimmune anaemia, hyperkalaemia, acute renal failure, cardiac arrest [death] (81915)

Discussion

NZPhvC advised that there are no reports of similar reactions to either fludarabine or cyclophosphamide in the CARM database; however, there are reports in the WHO database. All reactions reported in this case history except cardiac arrest are IC positive for fludarabine. All reactions except hyperkalaemia are IC positive for cyclophosphamide.

The causal association with fludarabine, cyclophosphamide was considered to be 'probable' for haemolytic autoimmune anaemia, hyperkalaemia, acute renal failure, and cardiac arrest.

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

4.1.1.3 Tenecteplase and cardiac arrest [death] (82319)

Discussion

NZPhvC advised that the CARM and WHO databases include reports of cardiac events in association with tenecteplase. Warnings about arrhythmias and cardiac disorders are included in the product datasheet.

The causal association with tenecteplase was considered to be 'unclassifiable' for cardiac arrest.

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

4.1.1.4 Intragam, tranexamic acid and myocardial infarction, renal failure acute, cognitive deterioration, vomiting, hypertension aggravated [death] (81333)

Discussion

The Committee noted that there were insufficient details to assign causality in this case.

The Committee considered the causal association with Intragam, tranexamic acid to be 'unclassifiable' for myocardial infarction, renal failure acute, cognitive deterioration.

The Committee considered the causal association with Intragam, tranexamic acid to be 'possible' for vomiting, hypertension aggravated.

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

4.1.1.5 Diclofenac and intestinal perforation, sepsis, multiple organ failure [death] (82166)

Discussion

NZPhvC advised that the CARM database includes reports of intestinal perforation in association with diclofenac, one of which was life-threatening. There are also reports of ulcerative and necrotic conditions in association with diclofenac, and a small number of similar reports with other non-steroidal anti-inflammatory agents (NSAIAs). The risk of serious gastrointestinal effects, including ulcers, bleeding, and perforation is included in product data sheets for all NSAIAs.

The Committee noted that an article entitled 'NSAIAs can cause lower GIT damage' was published in Prescriber Update in May 2001.

The Committee suggested that this patient may have had an underlying medical condition which contributed to the rapid progression of the ulcer and recommended that NZPhvC seek further details about this case.

The Committee considered the causal association with diclofenac was 'possible' for intestinal perforation, sepsis, multiple organ failure.

Recommendation

The Committee recommended that NZPhvC seek further details about this case.

4.1.1.6 Aripiprazole, olanzapine and myocardial ischaemia [death] (81944)

Discussion

NZPhvC advised that olanzapine had been included in the Intensive Medicines Monitoring Programme (IMMP), and the assessments to date include reports of sudden death and cardiac events in association with olanzapine. There were no related reports included in the CARM database for aripiprazole. The WHO database includes reports of myocardial ischaemia in association with both olanzapine and aripiprazole.

The Committee noted that there were insufficient details to allow causality assessment, and that the patient had significant medical history which could be closely associated with cardiovascular disorders. The Committee considered that the medical history itself could also be attributable to the antipsychotic therapy.

The Committee considered the causal association with aripiprazole, olanzapine to be 'unclassified' for myocardial ischemia.

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

4.1.1.7 Clozapine and cardiomyopathy [death] (82098)

Discussion

NZPhvC advised that clozapine is associated with myocarditis, and more rarely with cardiomyopathy, and this was discussed in an article entitled 'Clozapine and Achy Breaky Hearts (myocarditis and cardiomyopathy)' in the June 2008 edition of Prescriber Update.

The Committee noted that other possible causes of cardiomyopathy in this patient had been excluded and considered that the causal association with clozapine was 'probable' rather than 'possible' for cardiomyopathy.

Recommendation

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

4.1.1.8 Budesonide, felodipine, valproate sodium, zopiclone and pulmonary infiltration [death] (82120)

Discussion

NZPhvC advised that the CARM database does not include any reports of pulmonary infiltration, pneumonitis or related terms in association with budesonide, sodium valproate, felodipine, or zopiclone. The WHO database includes a very small number of similar reports, with negative IC values.

The causal association with budesonide, felodipine, valproate sodium, zopiclone was considered to be 'unlikely' for pulmonary infiltration.

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

4.1.1.9 Infanrix-hexa, Prevenar and sudden death [death] (82290)

Discussion

NZPhvC advised that this case is currently being reviewed by the Coroner, and further details will be provided when this report has been received.

The causal association with Infanrix-hexa, Prevenar was considered to be 'unclassifiable' rather than 'unclassified' for sudden death.

Recommendations

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

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

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

Discussion

NZPhvC advised that the CARM database includes another report of oligohydramnios attributed to trastuzumab. The WHO database includes a small number of reports of oligohydramnios in association with trastuzumab, with a positive IC value. There are no reports to note of oligohydramnios in association with tamoxifen.

The Committee noted that it was reported that the moderate to severe chronic lung disease was considered to be due to pulmonary hypoplasia complicating oligohydramnios, and suggested there may have been a pre-existing renal condition. They recommended that NZPhvC seek further information, including ultrasound information if available.

The causal association with trastuzumab, tamoxifen was considered to be 'probable' for renal disorder NOS, respiratory infection in the infant.

The causal association with trastuzumab, tamoxifen was considered to be 'probable' for oligohydramnios, and 'certain' for pregnancy exposure in the mother.

Recommendation

The Committee recommended that NZPhvC seek further information, including ultrasound information if available.

4.1.2 Cardiovascular

4.1.2.1 Acipimox and rash, pruritis, muscle cramp (82041)

Discussion

NZPhvC advised that the CARM database includes one report of a muscle reaction in association with acipimox, and the product data sheet includes musculoskeletal disorders as an adverse reaction.

The Committee noted that this was a report of another class of hypolipidaemics which appeared to be associated with muscle disorders.

The causal association with acipimox was considered to be 'probable' for rash, pruritus, muscle cramp.

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

4.1.3 Neurological

4.1.3.1 Sodium valproate, topiramate, levetiracetam and hyponatraemia, cerebral infarction, peripheral oedema (81286)

Discussion

NZPhvC advised that this was one of an increasing number of reports to CARM of hyponatraemia, with more medicines being implicated.

The CARM database includes reports of hyponatraemia in associated with sodium valproate, and this association is IC positive in the WHO database.

A literature search showed four published case histories of hyponatraemia attributed to sodium valproate, but none for either topiramate or levetiracetam.

The Australian Adverse Drug Reactions Advisory Committee (ADRAC) has recently published an article on drug-induced hyponatraemia. This indicated that the medicines most often implicated in severe, life-threatening or neurologically damaging hyponatraemia were hydrochlorothiazide, indapamide, carbamazepine, paroxetine, venlafaxine, and sertraline, with 26% of reports associated with more than one medicine. The CARM reports for the last two years support these findings.

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

The causal association with sodium valproate, topiramate, levetiracetam was considered to be 'possible' for hyponatraemia, peripheral oedema and 'unclassified' for cerebral infarction.

Recommendation

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

4.1.4 Vitamins

4.1.4.1 Vitamin D and renal failure, hypervitaminosis D, medication error (81804)

Discussion

The Committee recommended that this event be followed up through Medsafe.

The causal association with vitamin D was considered to be 'certain' rather than 'probable' for medication error.

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

Recommendations

The Committee recommended that this event be followed up through Medsafe.

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

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

4.1.5 Pharmaceutical Company death reports

The Committee noted the following case reports:

4.1.5.1 Capcitabine, oxaliplatin (81186)
4.1.5.2 Clozapine (82287)
4.1.5.3 Enoxaparin (81312)
4.1.5.4 Insulin aspart, felodipine, frusemide, doxycycline, omeprazole (82077)
4.1.5.5 Tenecteplase (81182)
4.1.5.6 Tenecteplase (81650)
4.1.5.7 Tenecteplase (81651)
4.1.5.8 Tenecteplase (82099)
4.1.5.9 Tenecteplase (82100)
4.1.5.10 Tenecteplase (82281)
4.1.5.11 Thalidomide (82032)
4.1.5.12 Thalidomide (82046)
4.1.5.13 Thalidomide (82237)

4.1.6 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.

4.1.6.1 Dianeal (81218)
4.1.6.2 Dianeal (81219)
4.1.6.3 Dianeal (81220)
4.1.6.4 Dianeal (81221)
4.1.6.5 Dianeal, Icodextran (81222)
4.1.6.6 Dianeal (81223)
4.1.6.7 Dianeal (81272)
4.1.6.8 Dianeal (81273)
4.1.6.9 Dianeal, Icodextran (81584)
4.1.6.10 Dianeal (81585)
4.1.6.11 Dianeal (81586)
4.1.6.12 Icodextran (82323)
4.1.6.13 Icodextran (82324)

4.1.7 Other Reports

The Committee noted the following case reports:

4.1.7.1 Pioglitazone, glipizide, simvastatin, felodipine, omeprazole, metoprolol, quinapril (81169)
4.1.7.2 Rosiglitazone (81325)
4.1.7.3 Rosiglitazone, lactulose (81739)
4.1.7.4 Alendronate, atenolol, furosemide, aspirin, losartan, amitriptyline (81838)
4.1.7.5 Tenecteplase (82101)
4.1.7.6 Salbutamol/ ipratropium, budesonide/eformoterol, salbutamol, prednisone, omeprazole (82103)
4.1.7.7 Lithium, tadalafil (82163)

4.2 Quarterly Reports from CARM as at December 2008

Discussion

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

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 31 January 2009. The Committee noted that the reports received were in line with the adverse reactions detailed in the product data sheet, and were not unexpected.

4.4 Proton pump inhibitor reports

Discussion

NZPhvC advised that the reports received by CARM following brand changes of proton pump inhibitors followed a similar pattern to previous brand switches.

The Committee noted the proton pump inhibitors report from NZPhvC for the period 1 June 1990 to 31 January 2009.

4.5 Norfloxacin and tendon rupture

Medsafe and NZPhvC provided reports for the MARC on the issue of tendinopathy in association with norfloxacin. This followed a cluster of three reports of tendon disorders attributed to norfloxacin received by CARM in the third quarter of 2008.

Medsafe advised that all fluoroquinolone data sheets were reviewed in 2008 and warnings about the adverse events of tendon rupture and tendonitis improved.

The Committee noted that an article entitled 'Tendon disorders with quinolone antibiotics' was published in the November 2007 edition of Prescriber Update, reminding prescribers of the risk of tendinopathy associated with fluoroquinolone use. The Committee considered that this message should be widely disseminated and recommended that Medsafe request that BPAC include information in their publication.

Indications for norfloxacin

The Committee was also advised that in July 2008, the European Medicines Agency (EMEA) recommended the removal of the indication of treatment of complicated urinary tract infection for norfloxacin. This was based on the Agency's Committee for Medicinal Products for Human Use (CHMP) review, which concluded that efficacy had not been adequately demonstrated for this type of infection and therefore the risk-benefit ratio was unfavourable. Medsafe advised that it will review this data once it is received from sponsors and report back to the MARC if necessary.

Recommendation

The Committee recommended that Medsafe request that BPAC include information in their publication regarding the risk of tendinopathy associated with fluoroquinolone use.

4.6 Intensive Monitoring of varenicline tartrate (Champix)

NZPhvC presented an overview of the interim Intensive Medicines Monitoring Programme (IMMP) results for the first year of intensive monitoring of varenicline tartrate up to January 2009.

NZPhvC advised that the average age of patients at the time of their first varenicline prescription was 49 years, with between 3 - 4% being 70 years of age or older. There were some gender differences, with varenicline prescriptions most commonly being prescribed to women in their fifties, and men in their forties.

The number of new patients prescribed varenicline has increased gradually over the first year of marketing in NZ. Of note were the prescribing patterns, which showed that 90% of patients received the starter pack for their first prescription. This starter pack gradually increases the dose up to 2mg daily over two weeks. The Champix data sheet advises that this 2mg daily dosage should then continue for another 10 weeks. An analysis of the number of days treatment showed that 34% of patients were dispensed 14 days treatment, however, only 4% of patients were dispensed the complete 12 weeks of treatment.

NZPhvC advised that the most common adverse effects reported were psychiatric events, including depression, suicidal ideation, sleep disorders, anxiety disorders and withdrawal symptoms. With the exception of withdrawal symptoms, this is consistent with the emerging international safety profile of varenicline. At this time in NZ, there is no suggestion of a high number of accidents causally related to varenicline as has been reported in the United States. The IMMP has also been carefully monitoring deaths identified in patients prescribed varenicline. From initial assessments, the majority of the deaths in NZ patients who have received a prescription for varenicline appear to be unrelated to the medicine.

NZPhvC advised of a report of a patient with blood tests showing mild renal impairment after beginning varenicline. There was no previous history of renal disease, and blood tests returned to normal after stopping varenicline. The WHO database includes reports of renal disorders in association with varenicline, and the Committee considered it would be useful if the IC value of this association could be determined. Medsafe advised that it would further investigate this possible association with other international regulators. In addition, Medsafe will review the Champix periodic safety update report (PSUR), focusing particularly on any reports involving renal abnormalities.

The Committee was advised of a recent FDA analysis of adverse event reporting system reports which compared cases of suicidality associated with the use of varenicline and bupropion. This postmarket review showed that cases of suicidality had been reported among patients with and without a prior psychiatric history with both varenicline and bupropion. This is included in the Warning section of the US varenicline label, and as a Boxed Warning in the US bupropion label.

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.

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

Recommendations

The Committee recommended that the next IMMP report for varenicline be presented to the MARC at the December 2009 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.

Summary of Medsafe Signal Detection and Evaluation, February 2009
Gislason GH, Rasmussen JN, Abildstrom SZ, et al. 2009. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med 169:141-149
Philippe J, Raccah D. 2009. Treating type 2 diabetes: how safe are current therapeutic agents? Int J Clin Pract 63 (2):321-332
Record of the Pharmacology and Therapeutics Advisory Committee Meeting held on 6 and 7 November 2008

6 New Zealand pharmacovigilance-related activities

DHBNZ Safe and Quality Use of Medicines Group. 2008. Newsletter. Volume 4, Number 5.

DHBNZ Safe and Quality Use of Medicines Group. 2009. Newsletter. Volume 5, Number 1.

7 international pharmacovigilance-related Activities

7.1 Australia

Minutes of the 311^th meeting of the Adverse Drug Reactions Advisory Committee (ADRAC) held on 24 October 2008
ADRAC. 2009. Australian Adverse Drug Reactions Bulletin. Volume 28, Number 1

7.2 Canada

Canadian Adverse Reaction Newsletter. 2009. Volume 19, Issue 1

7.3 United Kingdom

Medicines and Healthcare products Regulatory Agency (MHRA). 2008. Drug Safety Update. Volume 2, Issue 5
Medicines and Healthcare products Regulatory Agency (MHRA). 2009. Drug Safety Update. Volume 2, Issue 6
Medicines and Healthcare products Regulatory Agency (MHRA). 2009. Drug Safety Update. Volume 2, Issue 7

7.4 United States

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

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

9.1 Safety Concerns

Following the recent decision by PHARMAC to broaden access to oral retinoid treatments, the Committee expressed its concern about the potential safety issues arising from similar changes which may occur in the future. The Committee considered that there had been inadequate time allowed to ensure risk management strategies were in place before the decision was implemented and recommended that the Chair write to PHARMAC, highlighting the issues which have arisen in this instance.

Medsafe advised that it was not possible under the current Medicines Act 1981 to restrict the prescribing of particular medicines to defined specialist groups. This is a professional issue, falling within the Health Practitioners Competence Assurance Act, which requires that health practitioners do not practice outside their scope of practice.

Recommendation

The Committee recommended that the Chair write to PHARMAC, highlighting the issues which have arisen following their recent decision to broaden access to oral retinoids.

The Chair thanked members and the secretariat for their attendance and closed the meeting at 3.40pm.

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

Committees