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 134TH
MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
29 May 2008

The one hundred and thirty forth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 29 May 2008 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9am and closed at 2.45pm.

marc members present

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

marc secretariat present

Ms A Cutfield (Advisor, Pharmacovigilance)
Ms J McNee (MARC Secretary)

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Dr H Kingston.

1.2 Minutes of the 133^rd MARC Meetings

The minutes of the 133^rd meeting of the Committee were accepted as a true and accurate record of the meeting.

1.3 Dates of Future MARC Meetings

The date for the next MARC meeting was confirmed as being 11 September 2008. The subsequent MARC meeting date for 2008 was scheduled for 11 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.

One member declared a potential conflict of interest. The Committee considered that this potential conflict of interest would not influence the discussions or decisions of the Committee.

1.5 Prescriber Update

1.5.1 Schedule of Planned Prescriber Update Articles

Discussion

The Committee noted the schedule of planned Prescriber Update articles.

1.5.2 Prescriber Update. Volume 29, Number 1. June 2008

Discussion

The Committee noted the latest issue of Prescriber Update.

2. STANDING AGENDA ITEMS

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

The Committee noted that there were outstanding items on the 'Standing Agenda Item' list, for which further information had been awaited for some time but had not been received to date. The Committee agreed that if the information being sought, with the exception of Coroner's Reports, was not received by the time of the next MARC meeting, then that outstanding item should be removed from the 'Standing Agenda Item' list. The rationale is that the reason the information being sought had not been supplied was probably due to the information not being available, and as a result, the Committee would be unable to consider the matter further. However issues of significant importance can be kept active with further information being brought to the committee when it arrives.

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 Rubifen SR (methylphenidate SR) brand switch - aggressive and defiant behavioural reactions
March 2008 minute item 2.1.2, December 2007 minute item 2.1.2, September 2007 minute item 3.2

Issue

In March 2008, the Committee recommended that PHARMAC be contacted to determine the length of time that the Ritalin SR product will be provided to affected patients.

In March 2008, the Committee recommended that the issue of Rubifen SR (methylphenidate SR) brand switch - aggressive and defiant behavioural reactions be placed on the 'Scheduled Review' list for 12-monthly review.

Outcome

PHARMAC advised Medsafe that unless advice is received from the MARC to the effect that there is no longer a safety concern with Rubifen SR, the funding for the Ritalin SR brand for affected patients would need to be indefinite. The Committee expressed its concern that the manufacturer may not continue to supply the product and recommended that PHARMAC be contacted to determine the length of time that the Ritalin SR product will be available in New Zealand.

The issue of Rubifen SR (methylphenidate SR) brand switch - aggressive and defiant behavioural reactions has been placed on the 'Scheduled Review' list for a 12-monthly review.

Recommendation

The Committee recommended that PHARMAC be contacted to determine the length of time that the Ritalin SR product will be available in New Zealand.

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

Issue

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.

In March 2008, the Committee recommended that a short Prescriber Update article on the use of clozapine in the elderly be published.

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.

A paragraph entitled "Use of clozapine in older people requires extra care" was published in the June 2008 issue of Prescriber Update.

Discussion

The Committee noted the above.

2.1.3 Lipid-lowering agents and psychiatric adverse reactions: Active Monitoring Review
March 2008 minute item 2.1.13, December 2007 minute item 2.1.3, September 2007 minute item 3.3

Issue

In March 2008, the Committee recommended that Medsafe provide a summary of the data sheet changes regarding depression and memory loss that have been made to be brought to the next meeting.

In March 2008, the Committee recommended that the issue of lipid-lowering agents and psychiatric adverse reactions be placed on the 'Scheduled Review' list for 12-monthly review.

Outcome

A report entitled "Lipid-lowering agents and Psychiatric Adverse Reactions" was included in the May 2008 dossier.

A paragraph entitled "Memory loss and depression with lipid-lowering agents" was published in the June 2008 issue of Prescriber Update.

The issue of lipid-lowering agents and psychiatric adverse reactions has been placed on the 'Scheduled Review' list for 12-monthly review.

Discussion

The Committee expressed concern that not all of the product sponsors had updated their data sheets regarding depression and memory loss and noted that the issue of lipid-lowering agents and psychiatric adverse reactions would again be reviewed in March 2009. Various mechanisms for telling prescribers about changes requested in data sheets but not completed were discussed.

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

Issue

In September 2007, the Committee recommended that Medsafe write to the sponsors of Amizide, asking them to justify why their product contains 50mg hydrochlorothiazide when similar medicines generally contain 12.5mg hydrochlorothiazide.

In December 2007, the Committee noted that this recommendation had been rejected by the Minister's Delegate on the advice of Medsafe.

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

Outcome

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

Discussion

The Committee noted the above.

2.1.5 SSRI antidepressants and the risk of suicidality
March 2008 minute item 3.1

Issue

The Committee recommended that the issue of SSRI antidepressants and the risk of suicidality be placed on the 'Scheduled Review' list for 12-monthly review.

The Committee recommended that a Prescriber Update article be written, advising that the MARC advice issued in 2004 still remained valid in light of the recent/current evidence. The Committee recommended that the key messages to be contained in this article be discussed at the next meeting of the MARC.

Outcome

The issue of SSRI antidepressants and the risk of suicidality has been placed on the 'Scheduled Review' list for 12-monthly review.

Medsafe recommended to the Minister's Delegate that he reject the MARC recommendation that "a Prescriber Update article be written, advising that the MARC advice issued in 2004 still remained valid in light of the recent/current evidence. The Committee recommended that the key messages to be contained in this article be discussed at the next meeting of the MARC" because it considered that this issue requires further, in depth review before issuing Medsafe advice. Medsafe recommended that this advice be reviewed at the September 2008 meeting of the MARC.

Discussion

Associate Professor Frampton provided the Committee with a report on the published paper by Kirsch et al.2008 "Initial Severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration" published in PLOS Medicine. He noted that this study had received considerable public attention and the conclusions, particularly relating to the overall efficacy of antidepressant medicines, had been widely disseminated as if representing a definitive summary of the efficacy of antidepressant medicines. He noted that the study contained a number of flaws, including the methodology used and therefore the conclusions obtained in light of this were invalid. The Committee were appreciative of this analysis and agreed that the public attention generated by the study had created uncertainty in patients. They recommended that Assoc Prof Frampton prepare information to be submitted for publication in the New Zealand Medical Journal.

Recommendation

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

2.1.6 All adverse reactions to rosiglitazone and pioglitazone (ARCC*), particularly fracture/bone density
March 2008 minute item 3.2

Issue

The Committee recommended that the issue of all adverse reactions to rosiglitazone and pioglitazone, particularly fracture/bone density remain on the 'Scheduled Review' list for 12-monthly review.

The Committee recommended that the NZ data sheet for Avandia (rosiglitazone) be further updated to bring it in line with the information about ischaemic heart disease recently added to the Australian PI, i.e.:

Use of rosiglitazone is not recommended in patients with known ischaemic heart disease, particularly in those taking nitrates; and that rosiglitazone has been shown to be associated with an increased risk of myocardial ischaemia (angina, infarction) in pooled short-term clinical studies, particularly in those who needed several antidiabetic drugs or nitrates.

The Committee recommended that an article be published in Prescriber Update, suggesting that the risk of myocardial infarction seen with rosiglitazone may also occur with pioglitazone, and the adverse effect profile should be considered before prescribing these medicines.

The Committee recommended that NZPhvC examine the Vigibase reports for rosiglitazone and pioglitazone in order determine individual IC values for the two medicines.

The Committee recommended that NZPhvC prepare a proposal for consideration for a NZ data-linkage study, to evaluate adverse events with the glitazones, with particular focus on cardiac events.

Outcome

The issue of all adverse reactions to rosiglitazone and pioglitazone, particularly fracture/bone density remained on the 'Scheduled Review' list for 12-monthly review.

The NZ sponsor of Avandia has been contacted and requested to make the above-mentioned changes to the datasheet.

A paragraph entitled "Myocardial infarction with glitazones" has been published in the June 2008 issue of Prescriber Update.

A table of the IC values for the glitazones was included in the May 2008 dossier.

The NZPhvC has examined the literature for studies already completed that address pioglitazone cardiac adverse effects and was preparing a protocol for a record linkage study for consideration.

Discussion

The Committee noted the above. NZPhvC advised that it will keep the Committee informed of progress regarding the proposed CARM study.

2.1.7 Tamoxifen and retinal deposits (73804)
September 2007 minute item 2.2.6, June 2007 minute item 2.1.9; March 2007 minute item 4.3.4.1

Issue

The Committee recommended that a reminder article be published in Prescriber Update informing prescribers of the risk of retinopathy with tamoxifen.

Outcome

A paragraph entitled "Tamoxifen and visual changes - investigate promptly" was published in the June 2008 issue of Prescriber Update.

Discussion

The Committee noted the above.

2.1.8 Infliximab/methotrexate/prednisone and secondary sepsis, dural abscess, tooth abscess, headache, coma [death] (CARM case 72110)
September 2007 minute item 2.2.7, June 2007 minute item 2.2.1; March 2007 minute item 2.1.1; December 2006 minute item 2.1.9; September 2006 minute item 4.1.1.5

Issue

The Committee recommended that an article be written for publication in Prescriber Update, raising the awareness of a possible association between anti-TNFα agents and dental cavity abscess, and describing the CARM case reports.

Outcome

An article entitled "Tumour necrosis factor (TNF) inhibitors - recognise and treat infection promptly" was published in the June 2008 issue of Prescriber Update.

Discussion

The Committee noted the above.

The recently published paper by Dixon WG, et al. "Serious Infection Following Anti-Tumor Necrosis Factor α Therapy in Patients With Rheumatoid Arthritis" was included in the dossier for member's information. This paper was an extended analysis of the study by the same authors "Rates of serious infection, including site specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register" published in 2006 and reviewed at the September 2006 MARC meeting. The original study examined rates of serious infection in rheumatoid patients receiving anti-tumour necrosis factor (anti-TNFα) therapy and concluded that the overall risk of severe infection was not increased in patients taking anti-TNFα therapy when compared with those patients receiving only traditional disease modifying antirheumatic drugs (DMARDs). NZPhvC advised that this appeared to conflict with the reports received by CARM. The authors noted that this was an observational study, and the data obtained was subject to a number of important biases relating to selection factors for the timing of starting and stopping therapy, and that infection risk was also likely to vary with duration of therapy.

The extended analysis published in 2007 was intended to examine the influences of these biases and of the method of analysis on the risk of infection. When the data were reanalysed, an increased rate of infection in the first 90 days was shown.

2.1.9 All adverse reactions to complementary and alternative medicines (ARCC).
March 2008 minute item 3.3

Issue

The Committee 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.

Outcome

NZPhvC will 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.

Discussion

The Committee noted the above.

2.1.10 Anti-epileptics and the risk of suicidality
March 2008 minute item 3.4

Issue

The Committee recommended that Medsafe provide the MARC with a copy of the full results of the FDA's meta-analysis when it is available.

The Committee recommended that the issue of anti-epileptic medicines and the risk of suicidality be placed on the Scheduled Review list for 12-monthly review.

Outcome

Medsafe will provide the MARC with a copy of the full results of the FDA's meta-analysis when it is available.

The issue of anti-epileptic medicines and the risk of suicidality has been placed on the 'Scheduled Review' list for 12-monthly review.

Discussion

The Committee noted the above.

2.1.11 Clozapine and sudden death, heart failure acute and flu-like illness [death] (76714)
March 2008 minute item 4.1.1.8

Issue

The Committee recommended that NZPhvC further study the causes of sudden death in young patients taking clozapine and other atypical antipsychotics.

Outcome

As from 31 March 2008, the atypical antipsychotic medicines (clozapine, risperidone, olanzapine and quetiapine) were no longer monitored by the IMMP. The IMMP cohorts for clozapine and the other atypical antipsychotic medicines remain available for further studies of sudden death or other serious adverse outcomes.

Discussion

The Committee noted the above.

2.1.12 Venlafaxine and serotonin syndrome, rhabdomyolysis, multiple organ failure, drug interaction [death] (76686)
March 2008 minute item 4.1.1.12

Issue

The Committee recommended that NZPhvC seek further information about this case and report back to the MARC.

Outcome

The reporter has been requested to provide further feedback relating to the medication received by the patient.

Discussion

The Committee noted the above.

2.1.13 Sodium valproate, topiramate and hyperammonaemia, drug interaction (76527)
March 2008 minute item 4.1.3.1

Issue

The Committee recommended that the Epilim datasheet be amended to include the same advice about the co-administration of topiramate as the Topamax datasheet has for valproate.

Outcome

The NZ sponsor of Epilim has been contacted and requested to amend the Epilim datasheet to include the same advice about the co-administration of topiramate as the Topamax datasheet has for valproate.

Discussion

The Committee noted the above.

2.1.14 Lamotrigine and mania (77337,77338)
March 2008 minute item 4.1.3.2, 4.1.3.3

Issue

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

Outcome

The NZ sponsors of lamotrigine have been contacted and requested to amend the datasheets to include references to mania in the post-marketing reports of the Adverse Effects section.

Discussion

The Committee noted the above.

2.1.15 Methylene Blue, Tramadol, Fentanyl, paroxetine and serotonin syndrome (77178)
March 2008 minute item 4.1.4.1

Issue

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

Outcome

The CARM database has been amended to reflect the change.

Discussion

The Committee noted the above.

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

Issue

The Committee recommended that Medsafe obtain international information regarding uveitis in association with etanercept.

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.

Outcome

The NZPhvC has initiated an analysis of the WHO database for etanercept and uveitis and will report back to the MARC. The sponsor has been contacted and requested to provide Medsafe with a report of ophthalmic adverse events with Enbrel, including a review of international cases received.

Discussion

The Committee noted the above.

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

Issue

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

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

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

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

Outcome

Medsafe was in the process of actioning the other recommendations of the December MARC meeting. In addition, Medsafe intended 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.

A paragraph was published in the June 2008 issue of Prescriber Update, informing health professionals that MARC considers the risk-benefit profile of cough and cold medicines to be unfavourable in children under 2 years of age; and that the safety of these products in children over 2 years of age is under review.

Discussion

The Committee noted the above.

2.1.18 Aprotinin and increased mortality risk
March 2008 minute item 2.1.4, December 2007 minute item 3.4

Issue

In December 2007, the Committee recommended that the issue of aprotinin and increased mortality risk be reviewed once the final results of the BART study are available.

Background

The BART study (Blood conservation using antifibrinolytics: A randomised trial in a cardiac surgery population) was a multi-centre triple blind randomised controlled trial designed to test the hypothesis that aprotinin was superior to aminocaproic acid and tranexamic acid in reducing the incidence of massive bleeding associated with cardiac surgery. On 19 October 2007, it was announced that the Data Safety Monitoring Board (DSMB) for the BART study had recommended that enrolment in the aprotinin arm of the study should be stopped. This was in response to preliminary findings that patients in the aprotinin arm of the study had an excess mortality compared to patients receiving aminocaproic acid or tranexamic acid.

On 5 November 2007 following the publication of the preliminary results of the BART study, the product sponsor Bayer announced the temporary suspension of worldwide marketing of aprotinin, until the final data from the study were available. At that time, Medsafe agreed that in the interim, it was appropriate for Bayer to continue supplying aprotinin to individual prescribers in exceptional circumstances.

Outcome

On 14 May 2008, Bayer notified Medsafe that the final results of the BART study would be published online in the New England Journal of Medicine on 14 May 2008. Medsafe was also provided with an advanced copy of the publication entitled "A Comparison of Aprotinin and Lysine Analogues in High-Risk Cardiac Surgery". This paper, along with the editorial entitled "The Aprotinin Story- Is BART the Final Chapter" were provided to the MARC as a late addition to the dossier.

The published study results showed that there were no statistically significant differences in the risk of massive bleeding between the three agents, aprotinin, aminocaproic acid and tranexamic acid. However, aprotinin use was associated with a statistically significant increased risk of death (relative risk 1.53; 95% confidence interval, 1.06 to 2.22) compared to tranexamic acid and aminocaproic acid combined, but did not reach statistical significance against either agent alone. Further analysis indicated that the excess deaths were due to cardiac causes.

Bayer indicated that their preliminary assessment of the study was that it did not contain any additional information to that reported by the BART investigators in November 2007. Medsafe was informed that Bayer was in the process of obtaining the full data set of the BART study from Health Canada, and that it intended to evaluate this data and provide a report to Health Authorities once completed. In addition, Bayer intends to provide regulators with the full data set to enable them to make their own assessment of the data.

Subsequent to the publication of the BART study, the US FDA announced that all remaining stocks of aprotinin would be recalled in the US. Health professionals were informed that Trasylol would continue to be available to US patients under a 'limited use agreement', which limited use to certain patients who are at increased risk of blood loss and transfusions during coronary artery bypass graft surgery, and have no acceptable alternative therapy.

Health Canada informed Canadian prescribers that they are continuing to review the available safety information on Trasylol, and they will include the findings of the newly published BART study as part of this review.

In November 2007 following the preliminary results, the EMEA announced that after reviewing all available evidence, the CHMP had concluded that the benefits of aprotinin no longer outweighed the risks and therefore, recommended that the marketing authorisations for all systemic medicines containing aprotinin be suspended in all European Union and European Economic Area markets.

[..]

Medsafe was informed that in May 2008, there were approximately 300 units of aprotinin remaining in New Zealand hospitals. Bayer informed Medsafe that they would be recalling these remaining stocks of aprotinin from the NZ market and that from this time onwards, aprotinin would only be available to NZ patients under the same conditions as the limited access agreement now operating in the US.

Discussion

The MARC noted that the published results of the BART study were consistent with the preliminary results reviewed by the Committee in December 2007. They noted that although the study found a trend to increased mortality in association with aprotinin use compared to the use of tranexamic acid or aminocaproic acid, the result was only statistically significant when aprotinin was compared to tranexamic acid and aminocaproic acid combined. In addition, the confidence intervals were relatively wide suggesting that the study was underpowered to show a mortality difference. The MARC also noted that analysis of secondary endpoints suggested that the majority of the mortality difference was due to cardiovascular deaths including myocardial infarction and ischaemic stroke. The BART study also found that aprotinin reduced the risk of serious haemorrhage compared to the other two agents, which was consistent with other published studies.

The Committee noted that since the limited access scheme for aprotinin was introduced by Bayer in November 2007, Bayer had received very few requests for aprotinin. However, it was noted that this scheme was likely to limit use to high risk patients in whom the BART study had demonstrated a clear increased mortality risk.

The Committee considered that based on the results of the BART study the risk:benefit ratio of aprotinin appeared to be unfavourable. However, the MARC considered that more information was required, including the analysis of the full BART study data set, as well as consultation with relevant prescribers, before a final assessment of the risk:benefit profile could be made. Therefore a final decision on the most appropriate risk management strategy could not be made at this time.

The Committee recommended that Medsafe seek assurance from the sponsor that active marketing of aprotinin will not resume until Medsafe and the MARC have had the opportunity to review the full study report for the BART study. The Committee recommended that Medsafe consult with cardiac surgeons and/or anaesthetists as appropriate to determine whether or not there remained a clinical need for aprotinin in NZ. In the meantime, they recommended that the limited access scheme for aprotinin should continue.

Recommendations

The Committee recommended that Medsafe consult with cardiac surgeons and/or anaesthetists as appropriate to determine whether or not there remained a clinical need for aprotinin in NZ. In the meantime, they recommended that the limited access scheme for aprotinin should continue.

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

Issue

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.

Outcome

Assoc. Prof. Reith was continuing to investigate this issue.

Discussion

Assoc. Prof. Reith advised that there are privacy issues involved in the sharing of this information.

Recommendation

The Committee recommended that Medsafe further investigate possible ways of sharing relevant information.

2.1.20 Oral terbinafine and serious adverse reactions (blood dyscrasias, heptatotoxicity and dermatological reactions ) - Active Monitoring Review
March 2008 minute item 2.1.14, December 2007 minute item 2.1.5, September 2007 minute item 3.5

Issue

In September 2007, the Committee recommended that NZPhvC bring back case reports to the MARC in six months time.

Outcome

The NZPhvC will revisit this issue again in preparation for the December 2008 MARC meeting.

Discussion

The Committee noted the above.

2.1.21 Salmeterol and bronchospasm aggravated (death) (75086)
March 2008 minute item 2.1.17, December 2007 minute item 2.1.10, September 2007 minute item 4.1.1.11

Issue

In September 2007, the Committee recommended that NZPhvC seek further information about this case and bring the information back to the MARC.

Outcome

The indirect route by which the report was made to CARM has delayed obtaining further information on other possible allergic factors. However these will be provided when they are received.

Information not received by May 2008 and item removed from Standing Agenda list.

Discussion

The Committee noted the above.

2.1.22 Adverse reactions to leflunomide: active monitoring review
June 2007 minute item 3.1

Issue

The Committee recommended that an article concerning pancytopenia, hepatic reactions, and pneumonitis in combination with methotrexate be written for publication in Prescriber Update. The article should also include a reminder about peripheral neuropathy and infection such as tuberculosis.

Outcome

An article entitled "Leflunomide - update on serious toxicity" was published in the June 2008 issue of Prescriber Update.

Discussion

The Committee noted the above.

2.1.23 Lamotrigine and convulsion [death] (74826)
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

Issue

In June 2007, the Committee recommended that NZPhvC 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 meeting when received.

Discussion

The Committee noted the above.

2.1.24 Quetiapine,paroxetine, and neuroleptic malignant syndrome,pneumonia inhalation [death] (74373)
March 2008 minute item 2.1.19, December 2007 minute item 2.1.18, September 2007 minute item 2.1.10, June 2007 minute item 4.1.1.4

Issue

In June 2008, the Committee recommended that NZPhvC seek further information about this case and bring the information back to the MARC.

Outcome

Further information has been requested and will be brought to a forthcoming MARC meeting when received.

Information not received by May 2008 and item removed from Standing Agenda list.

Discussion

The Committee noted the above.

2.1.25 Imiquimod and pigmentation abnormal (74330)
June 2007 minute item 4.1.5

Issue

The Committee recommended that an article about imiquimod be published in Prescriber Update informing prescribers of the adverse effects of skin depigmentation and influenza-like symptoms.

Outcome

A paragraph entitled "Imiquimod cream - skin pigmentation changes and flu-like symptoms" was published in the June 2008 issue of Prescriber Update.

Discussion

The Committee noted the above.

2.1.26 Non-Selective NSAIDs: Active Monitoring Review
December 2006 minute item 3.2

Issue

The Committee recommended that an article be written for publication in Prescriber Update to inform prescribers of current evidence regarding the safety of NSAIDs and to provide advice for the safe use of these agents.

Outcome

An article entitled "Non-selective NSAIDs - cardiovascular, skin and gastrointestinal risks" was published in the June 2008 issue of Prescriber Update.

Discussion

The Committee noted the above.

2.1.27 Omeprazole and headache (72715)
December 2006 minute item 4.1.2

Issue

The Committee recommended that an article be written for publication in Prescriber Update informing prescribers of headaches as an adverse effect of omeprazole.

Outcome

A paragraph entitled "Omeprazole and headaches" was published in the June 2008 issue of Prescriber Update.

Discussion

The Committee noted the above.

2.1.28 Clozapine and haematological malignancies
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

Issue

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.

2.1.29 SSRIs and Use in Pregnancy: Watching Brief Review
September 2006 minute item 3.3

Issue

The Committee recommended that Medsafe consider publishing an article in Prescriber Update alerting prescribers and lead maternity carers to the risks associated with the use of SSRIs in pregnancy.

Outcome

An article entitled "SSRI use in pregnancy - collaborative decision-making is key" was published in the June 2008 issue of Prescriber Update.

Discussion

The Committee noted the above.

2.1.30 Oral Terbinafine Serious Adverse Reactions
March 2008 minute item 2.1.21, December 2007 minute item 2.1.21, September 2007 minute item 2.2.2, June 2007 minute item 2.1.2; March 2007 minute item 2.2.1; December 2006 minute item 2.1.1; September 2006 minute item; June 2006 minute item 9.2

Issue

The Committee recommended that Medsafe write to the Pharmacy Council of New Zealand and the Pharmaceutical Society of New Zealand (Inc) asking that they remind pharmacists about the adverse reactions of oral terbinafine.

Outcome

The Pharmaceutical Society published an article on their website in September 2007. This article will also be included in the next print version of their newsletter, scheduled for November 2007. A response is still awaited from the Pharmacy Council. Information not received by May 2008 and item removed from Standing Agenda list.

Discussion

The Committee noted the above.

2.1.31 Tenecteplase and sudden death [death] (74192)
March 2008 minute item 2.1.22, December 2007 minute item 2.1.23, September 2007 minute item 2.2.5, June 2007 minute item 2.1.8; March 2007 minute item 4.3.1.6

Issue

In March 2007, the Committee recommended that NZPhvC await more information from the reporter on the cause of death in this case (74192) and bring the results back to the MARC.

Outcome

The NZPhvC will bring further information to MARC when received.

Information not received by May 2008 and item removed from Standing Agenda list.

Discussion

The Committee noted the above.

2.1.32 Roxithromycin, warfarin and decreased prothrombin (73165)
December 2006 minute item 4.1.4

Issue

The Committee recommended that an article be written for publication in Prescriber Update informing prescribers of the interaction between roxithromycin and warfarin, and to include erythromycin.

Outcome

A paragraph entitled "Roxithromycin-warfarin interaction of increased INR" was published in the June 2008 issue of Prescriber Update.

Discussion

The Committee noted the above.

2.1.33 Clozapine and myocarditis, heart failure, arrhythmia [death] (CARM case 66578)
March 2008 minute item 2.1.24, December 2007 minute item 2.1.29, September 2007 minute item 2.2.17, June 2007 minute item 2.2.11; March 2007 minute item 2.2.6; December 2006 minute item 2.1.7; September 2006 minute item 4.1.1.4

Issue

In September 2006, the Committee recommended that NZPhvC await a copy of the post-mortem report in this case (66578), then review the causality assessment and bring the results back to the MARC.

Outcome

The NZPhvC is awaiting a copy of the post mortem report and will bring the findings to a forthcoming MARC meeting when received.

Information not received by May 2008 and item removed from Standing Agenda list.

Discussion

The Committee noted the above.

2.1.34 Clozapine and Myocarditis
March 2008 minute item 2.1.25, December 2007 minute item 2.1.30, September 2007 minute item 2.2.18, June 2007 minute item 2.2.12; March 2007 minute item 2.2.7; December 2006 minute item 2.1.8; September 2006 minute item 4.3.2

Issue

In September 2006, the Committee recommended that Medsafe request expert opinion from a cardiologist on the predictive value of electrocardiograms, echocardiograms and serum cardiac markers for detecting myocarditis in patients treated with clozapine.

In September 2006, the Committee recommended that Medsafe consider publishing a paragraph in Prescriber Update reminding prescribers of the risk of myocarditis with clozapine.

In September 2007, the Committee noted the report from [..] and recommended that Medsafe contact [..] for further comment on the issues raised.

Outcome

An article entitled "Clozapine and achy breaky hearts (myocarditis and cardiomyopathy)" was published in the June 2008 issue of Prescriber Update.

Discussion

The Committee noted the above.

2.1.35 Influenza vaccine and sudden death (CARM case 71269)
March 2008 minute item 2.1.26, December 2007 minute item 2.1.31, September 2007 minute item 2.2.19, June 2007 minute item 2.2.13; March 2007 minute item 2.2.8; December 2006 minute item 2.1.10; September 2006 minute item 4.1.1.6

Issue

In September 2006, the Committee recommended that NZPhvC bring this case (71269) back to the MARC once the post-mortem results were available.

Outcome

The NZPhvC is awaiting a copy of the post mortem report and will bring the findings to a forthcoming MARC meeting when received. Information not received by May 2008 and item removed from Standing Agenda list.

Discussion

The Committee noted the above.

2.1.36 Atorvastatin and aggressive reaction (67166)
June 2006 minute item 1.5.2, September 2005 minute item 4.1.5

Issue

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

Outcome

A paragraph entitled "Memory loss and depression with lipid-lowering agents" was published in the June 2008 issue of Prescriber Update.

Discussion

The Committee noted the above.

3. pharmacovigilance issues

3.1 ALL ADVERSE REACTIONS TO LEFLUNOMIDE (ARCC)

References

NZPhVC review of CARM and WHO data.
Fuerst M, Mohl H, Baumgartel K et al. Leflunomide increases the risk of early healing complications in patients with rheumatoid arthritis undergoing elective orthopedic surgery. Rheumatol Int 2006; 26: 1138-1142
Pieringer H, Stuby U, Biesenbach G. Patients with Rheumatoid Arthritis Undergoing Surgery: How Should We Deal with Antirheumatic Treatment? Semin Arthritis Rheum 2007; 36: 278-286
Donahue KE, Gartlehner G, Jonas DE et al. Systematic Review: Comparative Effectiveness and Harms of Disease-Modifying Medications for Rheumatoid Arthritis. Ann Intern Med 2008; 148: 124-134.
Kremer JM, Genovese MC, Cannon GW et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. Arch Intern Med 2002; 137: 726-733.
Kis E, Nagy T, Jani M et al. Leflunomide and A771726, its metabolite are high affinity substrates of BCRP - implications for drug resistance. Ann Rheum Dis 2008. Prelim abstract on website. Viewed through PubMed April 2008.
The final draft of the Prescriber Update article recommended at the last MARC review.
The current New Zealand Data Sheet for Arava.
The current New Zealand Data Sheet for AFT-Leflunomide.

Issue

Medsafe and NZPhvC provided reports for the MARC's Scheduled Review on the issue of all adverse reactions to leflunomide. These reports were a pharmacovigilance review of the use of leflunomide as monotherapy or in combination therapy for the treatment of rheumatoid arthritis to identify additional findings, including adverse effects, since the previous review in June 2007.

At the last review of adverse reactions to leflunomide in June 2007, the Committee recommended that the warnings in the NZ data sheets be strengthened in line with the Australian Product Information. The product sponsors have now amended their data sheets regarding serious toxicities, especially the increased potential for toxicity when leflunomide is prescribed with other hepatotoxic or other haemotoxic agents, especially methotrexate. The Committee also recommended that an article concerning pancytopenia, hepatic reactions, and pneumonitis in combination with methotrexate be written for publication in Prescriber Update. The article was to include a reminder about peripheral neuropathy and serious infection such as tuberculosis. An article entitled "Leflunomide - update on serious toxicity" was published in the June 2008 issue of Prescriber Update.

The purpose of the May 2008 report was to update the Committee on recent data, literature, adverse reaction reports, and regulatory action regarding leflunomide, particularly when used in combination with other disease-modifying antirheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis and similar disorders. The Committee was asked to evaluate the information provided and to determine whether the risk-benefit profile of leflunomide had changed as a result of this new information. If the risk-benefit profile was deemed to have changed, the Committee was asked to make recommendations about appropriate risk management.

Discussion

The Committee noted the 2008 Medsafe and NZPhvC reports.

NZPhvC provided a review of spontaneous reports and published literature since the last review by the MARC in June 2007. They advised that CARM has continued to receive reports of serious infection in association with leflunomide. Of the new adverse reactions reported to CARM since the last review, those of particular note were bronchiectasis and pulmonary abscess, and pulmonary embolism in association with leflunomide. These combinations had weakly positive IC values in Vigibase. NZPhvC noted that rheumatoid arthritis aggravated had the most positive IC value in the WHO database of all leflunomide adverse reactions, however, this reaction was difficult to separate from the rheumatoid process.

NZPhvC advised that along with rheumatoid arthritis aggravated, hypertension aggravated, and infection (tuberculosis) also had strongly positive IC values in the WHO database.

The WHO database contains reports for leflunomide relating to pregnancy. NZPhvC advised that the product datasheet for leflunomide states that it is contraindicated in pregnancy, and advised that a paragraph may be published in the WHO Pharmaceuticals newsletter reminding prescribers of this.

NZPhvC noted that the IC value for squamous carcinoma in association with leflunomide was higher than that of other cancers, and they would be investigating this further.

NZPhvC provided an overview of the recent literature which reinforced or added information about previously documented adverse reactions, including skin reactions, lung reactions, liver reactions, peripheral neuropathy, infection, and delayed wound healing. This included the recently published study by Uruga et al, describing 11 case reports of infection leading to hospital admission in patients taking leflunomide in Christchurch, which was discussed at the 2007 MARC review. Also at the last review, a paper by Kremer et al (2007) was discussed, which showed an increased rate of post operative wound healing complications following orthopaedic surgery in patients taking leflunomide. A more recent paper by Pieringer et al reviewed the published data on patients with rheumatoid arthritis who underwent surgery. This included a study in which one group of patients ceased leflunomide therapy two weeks before surgery, while the other group did not discontinue therapy. The study concluded that there was no difference between the two groups in the rate of delayed wound healing. However, it was noted that because of the long half life of leflunomide, discontinuation would need to be of longer duration in order to influence the rate of wound healing complications. The authors of the Pieringer paper concluded that while continuation of methotrexate therapy is likely to be safe, more data on the other DMARDs are needed before a recommendation regarding discontinuation prior to surgery could be made.

NZPhvC provided a review of recent published papers on combination DMARD and DMARD/TNF alpha inhibitor therapy which discussed the rationale and benefits of various treatment regimens. Most studies show benefits from both dual and triple therapy. The most comprehensive review, undertaken by Donahue et al, concluded that combination therapy with DMARDs improved response rates where monotherapy had failed, and there was moderate evidence that triple therapy was more effective than dual therapy.

NZPhvC advised that there was only one study by Kremer et al, as previously reviewed by the MARC, which studied the use of leflunomide combination therapy. This study described concluded that leflunomide with methotrexate provided clinical benefit to patients who had not responded to six weeks monotherapy with methotrexate. Spontaneous reports to CARM suggest that this combination appears to be widely used in NZ.

NZPhvC advised that CARM has received two reports of particular concern - one report of intracranial haemorrhage, and one of cerebral haemorrhage involving leflunomide and adalimumab. While there is insufficient data for this to be considered a new signal at present, NZPhvC will continue to monitor any further reports of this type.

The Committee agreed that it was difficult to determine if the new information provided substantially altered the current risk-benefit profile of leflunomide. They recommended that adverse reactions to leflunomide continue to be closely monitored and so remain as an Adverse Reaction of Current Concern (ARCC).

The Committee recommended that the issue of all adverse reactions to leflunomide be removed from the 'Scheduled Review' list.

Recommendations

The Committee recommended that the issue of all adverse reactions to leflunomide continue as an Adverse Reaction of Current Concern (ARCC).

The Committee recommended that the issue of all adverse reactions to leflunomide be removed from the 'Scheduled Review' list.

3.2 PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS AND SUDDEN HEARING LOSS

References

Mukherjee, B. and Shivakumar, T. 2007. A case of sensorineural deafness following ingestion of sildenafil. The Journal of Laryngology & Otology. 121: 395-397.
Timeline of events and regulatory action regarding PDE5-inhibitors.
FDA (United States Food and Drug Administration) Alerts regarding PDE5-inhibitors and sudden hearing loss
- November 2007 - Information for Healthcare Professionals- Sildenafil (marketed as Viagra and Revatio) Vardenafil (marketed as Levitra) and Tadalafil (marketed as Ciaslis).
- October 2007 - FDA News -FDA Announces Revisions to Labels for Cialis, Levitra and Viagra. Potential risk of sudden hearing loss with ED drugs to be displayed more prominently.
Pfizer's Clinical Overview of sudden hearing loss with PDE5-inhibitors - Summary of available data from the updated clinical trial database containing 122 Viagra and 6 Revatio studies.
Information provided by Eli-Lilly regarding Cialis as shared with the FDA.
"Executive Summary: Regulatory response - Hearing loss/hearing impairment. Tadalafil."
Information provided by Bayer regarding Levitra
- "VARDENAFIL (Levitra): Cumulative review of sudden deafness/hearing loss"
Current data sheets for Viagra and Revatio.
CARM and WHO data.

Issue

Medsafe provided a report for the MARC on the issue of phosphodiesterase type 5 (PDE-5) inhibitors and sudden hearing loss. This followed a release by the United States Food and Drug Administration (FDA) on 14 November 2007 informing US healthcare professionals that the Agency had received reports of cases of sudden decrease or loss of hearing following the use of the PDE5-inhibitors; sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis) for the treatment of erectile dysfunction and sildenafil (Revatio) for the treatment of pulmonary arterial hypertension. The alert also advised sudden hearing loss had also been reported in a few patients in clinical trials of these medicines.

The FDA conducted a search of its adverse event reporting system for cases of hearing loss in patients taking PDE-5 inhibitors following the publication of a report in the Journal of Laryngology and Otology in April 2007. This report described the case of a 44 year old male patient with a history of absolute hearing loss 15 days after initiation of sildenafil 50mg per day for erectile dysfunction. The FDA found a total of 29 post-marketing reports of sudden hearing loss, both with and without accompanying ringing in the ears, vertigo, or dizziness in association with PDE-5 inhibitors. In most of the cases, the hearing loss involved one ear. The hearing loss was either a partial or complete loss of usual hearing. In approximately one third of cases, the event was temporary. In the remainder, the hearing loss was ongoing at the time of the report, or the final outcome was not described. Though no causal relationship has been demonstrated, the FDA believed that the strong temporal relationship between the use of PDE5-inhibitors and sudden hearing loss in these cases warranted revisions to the product labelling for the drug class.

On 18 October 2007, the FDA announced that labelling changes would be made to the Precautions, Adverse Effects and Post-marketing surveillance sections of the current labels of all PDE5-inhibitors in the U.S. to address the potential risk of sudden hearing loss and to guide patients on what to do if they experienced sudden problems with their hearing. Corresponding labelling changes have been requested by the European Medicines Agency (EMEA) in Europe and the Therapeutic Goods Administration (TGA) in Australia.

The FDA also advised that patients taking Cialis, Levitra or Viagra who experience sudden hearing loss should immediately stop taking the drug and seek prompt medical attention. Because Revatio is used to treat a potentially life-threatening condition, the FDA did not recommend patients abruptly stop taking this medication but should consult their physician if they experience sudden problems with their hearing.

The Committee was asked to evaluate the information provided, and to determine whether the risk-benefit profile of PDE5-inhibitors had changed as a result of this new information. If the risk-benefit profile was deemed to have changed, the Committee was asked to comment on appropriate risk management and whether or not further regulatory action is required.

Discussion

The MARC noted the May 2008 Medsafe report.

The Committee noted that there was currently no recognised biological mechanism for sudden hearing loss resulting from the use of PDE-5 inhibitors. They noted that reports were rare, but the number of reports was increasing. They noted that hearing loss is very commonly reported in an aging population, especially in patients with risk factors for erectile dysfunction, making it difficult to determine causality. Sudden hearing loss however, is an uncommon event at any age. The Committee commented that intermittent deafness or tinnitus may precede deafness and queried if ceasing treatment with the PDE-5 inhibitor may prevent the onset of deafness. NZPhvC advised that a close temporal relationship had been shown in the reports received by CARM, and in some cases, hearing had not yet returned.

The Committee noted that the New Zealand product datasheets for sildenafil (Viagra, Revatio) contained information regarding sudden hearing loss in the Warnings, Precautions, and/or Adverse Effects section. Medsafe advised that the sponsor of Levitra (vardenafil) is in the process of revising the core datasheet to include information on the risk of sudden hearing loss, and when this is completed, the NZ datasheet will be updated. The sponsor of Cialis (tadalafil) has advised that the NZ datasheet for this product will be updated in line with the proposed Australian Product Information regarding sudden hearing loss. The Committee recommended that a paragraph be published in Prescriber Update to raise awareness of this rare adverse reaction to PDE-5 inhibitors. This should also include advice that prescribers ask if patients reporting any episodes of tinnitus or intermittent deafness had been using PDE-5 inhibitors and to report any cases of hearing problems to CARM.

The Committee 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.

Recommendation

The Committee recommended that a paragraph be published in Prescriber Update to raise awareness of this rare adverse reaction to PDE-5 inhibitors. This should also include advice that prescribers ask if patients reporting any episodes of tinnitus or intermittent deafness had been using PDE-5 inhibitors and to report any cases of hearing problems to CARM.

4. Matters arising from the New Zealand Pharmacovigilance Centre

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

Spontaneous reporting programme

All spontaneous reports presented at the MARC meeting have been assessed by the Centre for Adverse Reactions Monitoring (CARM) and responses have been sent to the reporters. The purpose of these responses is to assist the practitioner to discharge his/her responsibility to patients. These individual replies include as appropriate:

comment about causality;
information about similar suspected adverse reactions reported with the same or related medicines;
prescribing advice;
advice related to the care of the patient, including information that may assist the practitioner to make a risk:benefit assessment for future treatment; and
any specific action being taken by the Centre, including entering the reaction into the National Health Index against the patient's name, presenting the case report to the MARC, etc.

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

4.1.1 Deaths

4.1.1.1 Norfloxacin, prednisone, frusemide and agranulocytosis [death] (77774)

Discussion

NZPhvC advised that both the CARM and WHO databases include reports of blood disorders in association with norfloxacin, prednisone, and frusemide. The product data sheets for norfloxacin and frusemide both refer to agranulocytosis as an adverse reaction. The data sheet for prednisone refers to decreased resistance and inability to localise infection.

NZPhvC advised that although norfloxacin was the most likely suspect medicine on temporal grounds (as both prednisone and frusemide were long term), it was possible that some synergistic effect may have contributed to the septicaemia and agranulocytosis.

The causal association with norfloxacin, prednisone, and frusemide was considered to be 'probable' for agranulocytosis.

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

4.1.1.2 Rituximab and pancytopenia, acute renal failure, pulmonary oedema, respiratory failure, septicaemia [death] (77387)

Discussion

NZPhvC advised that the CARM database includes very few reports of blood disorders and cardiac failure with rituximab. The WHO database includes very little information regarding blood disorders in association with rituximab. The IC value in the WHO database for 'creatinine clearance decreased' and rituximab is negative.

The product datasheet for rituximab includes reference to the possibility of severe infusion-related reactions.

NZPhvC advised that although the cardiac, respiratory, and renal events may not have been directly due to rituximab, it was possible that the effects of fluid overload as well as the sepsis arising from pancytopenia contributed to their exacerbation and the final outcome.

The causal association with rituximab was considered to be 'possible' for acute renal failure, pulmonary oedema, respiratory failure, septicaemia. The causal association with rituximab was considered to be 'probable' rather than 'possible' for pancytopenia.

Recommendation

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

4.1.1.3 Atorvastatin and rhabdomyolysis [death] (77591)

Discussion

This report is one of four reports of statin-associated rhabdomyolysis received by the NZPhvC in the last quarter. However, only one refers to an event that occurred in this period. The other three relate to historical events, some dating back more than one year, that were only submitted to the NZPhvC in this quarter.

NZPhvC advised that the CARM database includes no reports for rhabdomyolysis in association with atorvastatin, however, there are reports for simvastatin.

All statin datasheets refer to the possibility of rhabdomyolysis as a possible adverse effect.

NZPhvC advised that there were insufficient details provided to fully assess causality.

The causal association with atorvastatin was considered to be 'unclassified' for rhabdomyolysis.

Recommendation

See minute item 4.1.1.6.

4.1.1.4 Simvastatin and abdominal pain, rhabdomyolysis, acute renal failure, respiratory failure [death] (76185)

Discussion

See minute item 4.1.1.3.

The causal association with simvastatin was 'probable' for abdominal pain, rhabdomyolysis, acute renal failure, respiratory failure.

Recommendation

See minute item 4.1.1.6.

4.1.1.5 Simvastatin and rhabdomyolysis [death] (77669)

Discussion

See minute item 4.1.1.3.

NZPhvC advised that the creatine kinase level in this case was not particularly high in comparison to other reports of statin-associated rhabdomyolysis and therefore there is a possibility that there may have been other factors which precipitated the rhabdomyolysis.

The Committee considered the causal association with simvastatin was 'possible' for rhabdomyolysis.

Recommendation

See minute item 4.1.1.6.

4.1.1.6 Simvastatin and rhabdomyolysis, creatine kinase increased, hepatic function abnormal, hyperkalaemia, cardiac arrest [death] (78076)

Discussion

See minute item 4.1.1.3.

NZPhvC advised that this issue had been discussed previously by the MARC, resulting in Prescriber Update articles and reminders.

The Committee considered the causal association with simvastatin to be 'probable' for rhabdomyolysis, creatine kinase increased, and 'possible' for hepatic function abnormal, hyperkalaemia, cardiac arrest.

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.

4.1.1.7 Tacrolimus and lymphoma-like disorder [death] (71328)

Discussion

NZPhvC advised that the product datasheet states that patients treated with tacrolimus have been reported to develop Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. A review of the literature revealed that PTLD because of EBV is a major concern following paediatric transplantation, with the greatest risk in patients receiving EBV sero-positive organs.

NZPhvC advised that it was unclear whether this child's PTLD may have been a consequence of EBV and, if so, if this was acquired prior to liver transplantation from a sero-positive organ, or acquired subsequently.

The causal association with tacrolimus was considered to be 'unclassified' for lymphoma-like disorder.

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

4.1.1.8 Pamidronate and fever, confusion, convulsion, renal carcinoma, disease progression [death] (77753)

Discussion

NZPhvC advised that both the CARM and WHO databases include reports of fever, confusion and convulsions in association with pamidronate.

NZPhvC advised that the initial reactions experienced by the patient were in line with the acute phase reactions recognised to occur to varying degrees with intravenous pamidronate.

The causal association with pamidronate was considered to be 'probable' for fever, confusion, convulsion, 'possible' for cardiomyopathy, and 'unlikely' for renal carcinoma, and disease progression.

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

4.1.1.9 Paroxetine and suicide [death] (77838)
Case Report

Discussion

NZPhvC advised that the details in this report are incomplete and it was not possible to determine whether there may be an association with paroxetine. They advised that further details have been requested but had not been received at the time of the meeting.

NZPhvC advised that the CARM database includes reports of suicide and suicide attempts associated with paroxetine. The New Zealand datasheets for paroxetine draw attention to the potentially increased risk of suicidality in depressed patients and the need for closer monitoring in the initial stages of treatment.

The causal association with paroxetine was considered to be 'unclassified' for suicide.

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

4.1.1.10 Baclofen and withdrawal reaction, tetrabenazine, benztropine, dantrolene, clonazepam and dystonia, respiratory failure, hyperthermia, convulsions, hallucination [death] (77867 and 77900)

Discussion

The NZPhvC advised that the initial reactions experienced by the patient were typical of a baclofen withdrawal reaction. They noted that the subsequent events may also have been due to baclofen withdrawal although they persisted over nine days which is unusual.

The Committee noted that the product datasheet for Alpha-Baclofen describes withdrawal symptoms and provides advice about slow reduction in dose.

It was also noted that the product information for tetrabenazine includes dystonia and psychiatric effects as adverse reactions. The benztropine product information includes anhidrosis, which may lead to hyperthermia, as a possible adverse reaction. The dantrolene datasheet includes a caution for use in patients with impaired pulmonary function.

The Committee considered that this patient required complex management, and noted that more information had been sought.

The causal association with baclofen was considered to be 'probable' for withdrawal reaction.

The causal association with tetrabenazine, benztropine, dantrolene, clonazepam was considered to be 'unlikely' for dystonia, and convulsions, and 'possible' for respiratory failure, hyperthermia, hallucination.

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

4.1.2 Cardiovascular

4.1.2.1 Flecainide and atrial flutter (78035)

Discussion

NZPhvC advised that the CARM database includes reports of arrhythmias in association with flecainide and that the doses administered in this case appeared to be in line with those included in the NZ product datasheet for flecainide.

Product datasheets from other regulatory authorities were obtained for comparison. The Australian datasheet states an initial dose of 2mg/kg be given over 10-30 minutes, either as a bolus or intravenous infusion, with no information about further infusions. In addition, there is a prominent warning regarding the risk of converting atrial flutter to 1:1 AV conduction and recommending prophylactic medicines be given. In comparison, this warning in the NZ datasheet is not prominent, and no advice about prophylactic medicines is given. The Japanese datasheet recommends a longer infusion if the arrhythmia reoccurs. The dosage advice in both the UK and South African datasheets are in line with the NZ datasheet.

The Committee discussed if it was appropriate that changes be made to the NZ datasheet, including amending the dosage advice, and making the warning around the risk of 1:1 AV conduction more prominent, in line with the Australian PI. They recommended that specialist advice be sought from cardiologists around these issues, to be considered by the MARC at its next meeting.

The causal association with flecainide was considered to be 'probable' for atrial flutter.

Recommendation

The Committee recommended that NZPhvC seek advice from cardiologists and report back to the MARC at its next meeting.

4.1.3 Dermatological

4.1.3.1 Imiquimod and drug administration error, genital ulceration (78041)

Discussion

The recommended application frequency for this condition is three times weekly. NZPhvC advised that the CARM database includes reports of ulceration associated with imiquimod in association with both normal and excessive application. The product information for Aldara (imiquimod) indicates that erosions are part of the inflammatory reaction that commonly occurs with imiquimod and is part of its pharmacological activity. Deep and painful ulceration is not described.

The Committee noted that ulceration can occur even when the amount and frequency of application are as recommended. They noted that information had been included in the paragraph published in the June 2008 issue of Prescriber Update, stating that in order to avoid unnecessary ulceration, more emphasis may need to be given to instructing patients on the correct use of imiquimod.

The causal association with imiquimod was considered to be 'certain' for drug administration error, genital ulceration.

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

4.1.4 Musculoskeletal

4.1.4.1 Alendronate and osteonecrosis, jaw pain (77351)

Discussion

NZPhvC advised that this is the first report in the CARM database of osteonecrosis in association with alendronate. There are reports in the WHO database and the IC value for avascular necrosis with aledronate in the WHO database is strongly positive.

NZPhvC advised that the datasheet states that localised osteonecrosis of the jaw (ONJ), generally associated with tooth extraction has been reported rarely with oral bisphosphonates.

The Committee noted that few details were provided in this report, and the dose of alendronate was uncertain.

The Committee noted that two articles regarding the management of dental disorders in patients taking alendronate have recently been published in Prescriber Update. One of these, an article by Gibbs et al, discussed risk factors. As well as those listed in the product datasheet, duration of treatment and cumulative dose were also included as risk factors. The Committee noted that the possible greater incidence of ONJ in long term users of alendronate has not yet been measured. They noted a review by Briot et al, which concluded that the use of alendronate for up to four years reduced fracture rates, but there was no firm proof of protection beyond this. They noted that NZPhvC and Medsafe will continue to monitor the issue of long term alendronate and adverse effects on bone, including ONJ, atypical fractures at other sites, and delayed fracture healing, and report back to the MARC as necessary.

A member commented that two recent case control studies had been published regarding the risk of atrial fibrillation in association with oral bisposphonates. The Committee recommended that this issue be placed on the agenda to be discussed at a subsequent MARC meeting.

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

Recommendation

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

4.1.5 Other Reports

The Committee noted the following case reports:

Abciximab (77655)
Estelle (77747)
Citalopram, Valium, ethanol (77922)
Tacrolimus (77998)

4.2 Quarterly Reports from CARM as at March 2008

Discussion

NZPhvC presented the report. They noted that the brand switch reports continue for acetylsalicyclic acid, describing gastrointestinal symptoms, arthralgia, bleeding, and hearing impairment/tinnitus. Reports for paroxetine continue, describing reduced therapeutic effect and symptoms similar to withdrawal reactions as previously reported to the MARC. The reports for methylphenidate continue, although at a low frequency.

An emerging issue was the number of reports received following a formulation change of Eltroxin (levothyroxine) by the manufacturer. The reports have described diverse reactions, some suggesting a change in therapeutic effect, while others have described a range of apparently unrelated events. These problems appear to resolve when patients return to the previous formulation. The Committee noted that the manufacturer of Eltroxin had recently sent a Dear Healthcare Practitioner letter to NZ prescribers, advising that the new formulation of tablets should not be halved, and should be taken on an empty stomach. NZPhvC advised that they will continue to investigate this issue in association with Medsafe, and report back to the Committee as necessary.

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

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.

Dixon WG, et al. 2007. Serious Infection Following Anti-Tumor Necrosis Factor α Therapy in Patients With Rheumatoid Arthritis. Arthritis & Rheumatism 56 (9): 2896-2904.
Chow EC-Y, et al. 2008. Liver failure associated with the use of black cohosh for menopausal symptoms. MJA 188 (7):420-422
Gladding PA, et al. 2007. The Antiplatelet Effect of Six Non-Steroidal Anti-Inflammatory Drugs and Their Pharmacodynamic Interaction With Aspirin in Healthy Volunteers. URL: www.AJConline.org
U.S. Food and Drug Administration. Early Communication about an Ongoing Safety Review of Tiotropium (marketed as Spiriva HandiHaler) URL: www.fda.gov

Discussion

The Committee noted the paper by Chow et al, which described a case report of a patient who developed liver failure after taking black cohosh to treat menopausal symptoms. NZPhvC advised that CARM has received a case report regarding black cohosh, which will be presented at the next meeting. The Committee noted that black cohosh is a complementary medicine in NZ and appears to be widely used to treat the symptoms of menopause. There are limitations to labelling requirements because these drugs are regulated as foods not medicines in NZ. The Committee recommended that the issue of black cohosh and liver failure be placed on the agenda for the next meeting.

Recommendation

The Committee recommended that the issue of black cohosh and liver failure be placed on the agenda for the next meeting.

6. New Zealand pharmacovigilance-related activities

Life-Threatening Clozapine-Induced Gastrointestinal Hypomotility - IMMP Update
1. Palmer SE et al, 2008. Life-Threatening Clozapine-Induced Gastrointestinal Hypomotility: An Analysis of 102 cases. J Clin Psychiatry April 29: e1-e10
2. Ellis PM et al, 2007. Clozapine: Fatal 'constipation' more common that fatal agranulocytosis. Prescriber Update; 28(1):7
DHBNZ Safe and Quality Use of Medicines Group. 2008. Newsletter. Volume 4, Number 1.
NZ Blood. 2007. Annual Haemovigilance Report for 2006. (Cover and contents pages only).

Discussion

The Committee noted the paper entitled "Life-Threatening Clozapine-Induced Gastrointestinal Hypomotility", to which Professor Ellis and members of the Intensive Medicines Monitoring Programme had contributed, had been published in the Journal of Clinical Psychiatry.

7. international pharmacovigilance-related Activities

7.1 United Kingdom

Medicines and Healthcare products Regulatory Agency (MHRA). 2008. Drug Safety Update. Volume 1, Issue 9.
Medicines and Healthcare products Regulatory Agency (MHRA). 2008. Drug Safety Update. Volume 1, Issue 10.

8. Summary listings of case reports considered by the MARC (1997- 2007)

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

There being no further business, the Chair thanked members and the secretariat for their attendance and closed the meeting at 2.45pm.

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

Committees