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 135^th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING,

11 September 2008.

The one hundred and thirty fifth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 11 September 2008 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9am and closed at 4 pm.

marc members present

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

marc secretariat present

Ms A Cutfield (Advisor, Pharmacovigilance)
Dr J Hart (Senior Advisor, Complementary Medicines, Medsafe)
Mr C James (Pharmacy Advisor/Editor Prescriber Update, Medsafe)
Ms J McNee (MARC Secretary)
K Sheehy (Senior Advisor, Medical, Medsafe)

invited guests and experts

Dr Stewart Jessamine (Group Manger, Medsafe), Dr Susan Martindale (Principal Advisor Regulation, Medsafe) and Dr Alex Bolotovski (Senior Clinical Advisor, Medsafe) attended the meeting during the discussion of minute item 3.4.

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. He welcomed Joanne Hart, Kevin Sheehy and Chris James, who were attending the meeting for the first time. They each gave a brief synopsis of their backgrounds. Apologies were received from Dr F McClure. Assoc. Prof. Frampton left the meeting at 3.15 pm.

1.2 Minutes of the 134th MARC Meeting

The minutes of the 134^th 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 December 2008. The subsequent MARC meetings for 2009 were scheduled for 12 March, 11 June, 10 September and 10 December.

1.4 Potential Conflicts of Interest

Committee members submitted their Conflict of Interest Declaration forms to the Secretary. The Chair reminded the MARC members that, in addition to conflicts disclosed in the declaration forms, members should declare conflicts of interest at the commencement of discussion of any relevant agenda item.

Two members declared potential conflicts of interest. The Committee considered that these potential conflicts of interest would not influence the discussions or decisions of the Committee.

1.5 Prescriber Update

1.5.1 Schedule of Planned Prescriber Update Articles

Discussion

The Committee noted the schedule of planned Prescriber Update articles. The Editor advised that the format of Prescriber Update was being reviewed, to ensure the information was communicated in an optimal and timely manner. The Committee suggested various ideas for these future changes.

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

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
May 2008 minute item 2.1.1, March 2008 minute item 2.1.2, December 2007 minute item 2.1.2, September 2007 minute item 3.2

Issue

In May 2008, the Committee recommended that PHARMAC be contacted to determine the length of time that the Ritalin SR product will be available in New Zealand.

Outcome

PHARMAC has advised that they currently have a stock guarantee agreement in place with Novartis to ensure ongoing supply for those patients funded under Ritalin SR Special Access. Stock is expected to last at least another year or more. PHARMAC are continuing to assess stock needs and are doing all they can to make sure stock continues to be available.

Discussion

The Committee noted the above.

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

Issue

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

In March 2008, 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. Medsafe recommended to the Minister's Delegate that he reject this MARC recommendation because it considered that this issue required further, in depth review before issuing Medsafe advice. Medsafe recommended that this advice be reviewed at the September 2008 meeting of the MARC.

Outcome

Assoc. Prof. Frampton advised that information is being prepared, which will be submitted for publication in the New Zealand Medical Journal.

A report entitled "Suicidality in Adolescents and Children Taking Selective Serotonin Re-uptake Inhibitors (SSRI)" was included in the September dossier.

Discussion

Refer to minute 3.1.

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

Issue

In May 2008, 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.

In May 2008, 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.

Outcome

The Medsafe report on this issue was included in the September dossier.

On 16 July 2008, Bayer provided Medsafe with a data package which included a copy of the original and amended study protocol for the BART study; and a critical assessment by Bayer of the NEJM publication of the BART study.

After reviewing the data provided to them, Bayer raised a number of concerns about the quality of data collection and data analysis in the BART study. These included a number of methodological concerns regarding significant differences between the outcomes and analyses pre-specified in the BART study protocols, and those undertaken and reported in the NEJM publication of the BART study. Although Bayer suggests that the published BART study results do not provide evidence to alter the benefit/risk ratio for aprotinin when used according to its approved indications, Bayer considers that it is not possible to determine what impact the BART study may have on the risk/ benefit profile of aprotinin until the full data set has been reviewed.

At Medsafe's request, Assoc. Prof. Frampton reviewed the data provided by Bayer. He concluded that the NEJM publication of the BART study may have overstated the apparent negative effects of aprotinin treatment and understated the efficacy advantages of aprotinin when compared with the use of tranexamic acid and/or aminocaproic acid. He considered that there were issues to be resolved before a conclusion could be reached regarding the true clinical status of aprotinin.

Bayer informed Medsafe that since the worldwide marketing suspension in November 2007, limited access programmes for aprotinin had been operating in several countries. However, Bayer will no longer be offering a limited access scheme for aprotinin in New Zealand, and has also ceased the limited access scheme that was operating in Australia.

In July 2008, Medsafe sought advice directly from New Zealand cardiac surgeons and anaesthetists, along with other relevant clinicians including paediatric cardiac surgeons, cardiac anaesthetists and perfusionists, and anaesthetists with experience using aprotinin "off-label" in the area of liver, trauma and orthopaedic surgery, regarding the ongoing need for aprotinin in New Zealand.

The feedback received indicated that adult cardiac surgeons and anaesthetists have already changed their practice in light of concerns about the safety of aprotinin; therefore they considered that there was no longer a clinical need for aprotinin in New Zealand. Clinicians involved in liver, orthopaedic and trauma surgery considered that aprotinin can occasionally be useful but its absence was unlikely to result in negative outcomes.

However, clinicians involved in the area of paediatric cardiac surgery considered that there remains a clinical need for aprotinin in New Zealand. They considered that there is good evidence for efficacy in the paediatric population, based on both clinical studies and extensive experience of use in New Zealand, and noted that there is no current evidence that paediatric use is associated with a similar risk to that demonstrated in adult patients. In addition, they noted that there is substantially less data available supporting both the efficacy and safety of the alternative agents in the paediatric population. Medsafe is currently seeking advice from Bayer as to whether or not NZ clinicians will be able to access existing worldwide stocks of aprotinin.

Discussion

The Committee noted the August 2008 Medsafe report, including the feedback received from New Zealand clinicians. They noted that clinicians involved in the area of paediatric cardiac surgery considered that there remained a clinical need for aprotinin in New Zealand. The Committee noted the clinician's comments that there is evidence for efficacy in the paediatric population, and the adverse effect profile had not been demonstrated in the paediatric population. The Committee noted that Medsafe has sought advice from Bayer as to whether or not these clinicians will be able to access stocks of aprotinin, but had not received a response at the time of the meeting.

The Committee thanked the clinicians for their comments. They recommended that a response be sent to each clinician, expressing their gratitude.

The Committee noted Assoc. Prof. Frampton's review and comments that there were significant differences between the outcomes and analyses pre-specified in the BART study protocols, and those undertaken and reported in the NEJM publication of the BART study.

The Committee agreed that in view of the voluntary withdrawal of aprotinin from the New Zealand market, the issue of aprotinin and increased mortality risk should no longer be under formal review by the MARC. They noted that Medsafe will keep the MARC informed of any new developments on this issue.

Recommendations

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

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

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

2.1.4 Symbicort and exacerbation of asthma [death] (75986)
May 2008 minute item 2.1.19, 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.

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.

2.1.5 All adverse reactions to leflunomide (ARCC)
May 2008 minute item 3.1

Issue

In May 2008, the Committee recommended that the issue of all adverse reactions to leflunomide continue as an Adverse Reaction of Current Concern (ARCC).

In May 2008, the Committee recommended that the issue of all adverse reactions to leflunomide be removed from the 'Scheduled Review' list.

Outcome

The NZPhvC advised that it will continue its ongoing attention on leflunomide.

The issue of all adverse reactions to leflunomide has been removed from the 'Scheduled Review' list.

Discussion

The Committee noted the above.

2.1.6 Phosphodiesterase type 5 (PDE-5) inhibitors and sudden hearing loss
May 2008 minute item 3.2

Issue

In May 2008, 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.

Outcome

A paragraph will be prepared for publication in Prescriber Update.

Discussion

The Committee noted the above.

2.1.7 Rituximab and pancytopenia, acute renal failure, pulmonary oedema, respiratory failure, septicaemia [death] (77387)
May 2008 minute item 4.1.1.2

Issue

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

Outcome

The NZPhvC has made the appropriate change to causality.

Discussion

The Committee noted the above.

2.1.8 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)
May 2008 minute items 4.1.1.3, 4.1.1.4, 4.1.1.5, 4.1.1.6

Issue

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

Outcome

This issue is continuing to be investigated.

Discussion

The Committee noted the above.

2.1.9 Flecainide and atrial flutter (78035)
May 2008 minute item 4.2.2.1

Issue

In May 2008, the Committee recommended that NZPhvC seek advice from cardiologists and report back to the MARC at its next meeting.

Outcome

The NZPhvC is in the process of seeking an opinion from a cardiologist.

In addition, the 'Warnings and Precautions' section of the NZ flecainide datasheet has now been updated in line with the Australian Product Information (PI) to include extensive information on the cardiac risks associated with flecainide.

Discussion

The NZPhvC advised that they had received the opinion from a cardiologist, who considered that flecainide was contraindicated in atrial flutter, due to the risk of 1:1 conduction occurring. He would consider the use of flecainide in patients with atrial fibrillation who did not have structural heart disease, however if a bolus dose was not effective, an intravenous infusion would not be given. He noted that flecainide was to be used under specialist supervision in his particular area.

The Committee recommended that a paragraph be published in Prescriber Update highlighting the potential risk and possible mechanism of action of the cardiac risks associated with flecainide.

Recommendation

The Committee recommended that a paragraph be published in Prescriber Update highlighting the potential risk and possible mechanism of action of the cardiac risks associated with flecainide.

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

Issue

At the May 2008 meeting of the MARC, a member highlighted two recently published studies regarding the risk of atrial fibrillation in association with oral bisphosphonates. The Committee recommended that this issue be placed on the agenda to be discussed at a subsequent MARC meeting.

Outcome

This issue will be placed on the agenda for the December 2008 MARC meeting.

Discussion

The Committee noted the above.

2.1.11 Clozapine and neutropenia, lymphopenia, anaemia [death] (76419)
May 2008 minute item 2.1.2, 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.

Outcome

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

Discussion

The Committee noted the above.

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

Issue

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

Outcome

The Chair has 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 was provided with a draft copy of Prof. Maling's letter to BPAC. They suggested some minor alterations, and noted that the letter was scheduled for publication in their next edition of the BPAC publication, due at the end of September 2008.

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

Issue

The Committee recommended that the NZ datasheet 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 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 NZ sponsor of Avandia has made the above-mentioned changes to the datasheet.

The NZPhvC has carefully considered this proposal. It would be useful to study pioglitazone, as compared with rosiglitazone; there is no evidence as yet that pioglitazone increases the risk of myocardial infarction. While it is likely that enough patients could be accrued given the estimated increased risk of myocardial infarction with rosiglitazone, the NZPhvC has decided, after discussion with the MARC at the May meeting, that such a study would not be feasible or appropriate for the following reasons:

The difficulty of finding a comparator. Rosiglitazone users were too few, and the actual number of prescriptions unknown, to make a comparison with pioglitazone.

Diabetic patients not taking pioglitazone could be control patients, but there are a large number of risk factors for cardiac events that would be difficult to control for in current systems. An alternative would be to use patients as their own controls but increased risk of myocardial infarction over time may confound the analysis, especially as this would be difficult to quantify.

It is likely that pioglitazone and myocardial infarction are already undergoing pharmacoepidemiological investigation in other countries with larger databases.

With regards to the future, it is possible that data-mining of linked databases may be useful in this situation prior to embarking on more formal studies. This would investigate if there is a signal for a causal association between pioglitazone and myocardial infarction, in databases not subject to the biases of spontaneous reporting.

Discussion

The Committee noted the above.

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

Issue

In March 2008, 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.

Background

On 31 January 2008, the United States Food and Drug Administration (FDA) informed US healthcare professionals that the Agency had analysed reports of suicidality (suicidal behavior 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 antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were reported to be 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.

US Healthcare Professionals were advised to closely monitor all patients currently taking or starting any antiepileptic medicine for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression.

The issue was to be further discussed at a meeting of the FDA's Expert Advisory Committee.

In February 2008, Medsafe distributed a "Dear Health Professional" letter to all New Zealand prescribers informing them of the FDA's alert regarding the increased risk of suicidal thoughts and behaviours occurring in patients taking anti-epileptic medicines. Patients taking anti-epileptic medicines were advised not to make any changes without first consulting their doctor.

Medsafe also contacted the sponsors of all anti-epileptic medicines approved for use in New Zealand, requiring them to update their datasheets to include the recent information. The datasheets for all lamotrigine products and most generic anti-epileptic drugs (AEDs) have been updated as requested. However, Medsafe agreed to requests to defer updating innovator datasheets until final wording has been agreed to with the FDA.

In March 2008, the MARC noted the action taken by the FDA and Medsafe and agreed that more detail was required in order to determine if this information altered the overall risk profile of anti-epileptic drugs. They recommended that Medsafe provide the MARC with a copy of the full results of the FDA's meta-analysis when it became available.

In June 2008 the FDA published briefing documents for their 10 July 2008 advisory committee meeting to discuss AEDs and suicidality. These documents included both a statistical and a clinical review of the meta-analysis of placebo controlled trials of 11 AEDs conducted by the FDA.

The meta-analysis review concluded that anti-epileptic drugs are associated with an increased risk of suicidality relative to placebo in randomised placebo-controlled trials. The effect appears consistent among the group of 11 drugs. There are 1.9 per 1000 (95% CI 0.6, 3.9) more anti-epileptic drug patients than placebo patients who experienced suicidal behaviour or ideation. In terms of adjusted risk estimates for the treatment groups, 0.43% of the drug patients experience suicidal behaviour or ideation compared to 0.24% of the placebo patients.

The clinical review concluded that future research using prospective data is necessary to evaluate the risk of AEDs and suicidal behaviour or ideation without the limitations of adverse event data. Also, further development of validated methods to assess suicidality was required. Other areas for additional research included characterising potential underlying mechanisms of increased risk of suicidal behaviour or ideation with AEDs, and also research on whether certain patient subgroups were at particular risk.

The FDA's Expert Advisory Committee was also asked to advise on the type of information it considered appropriate for inclusion in the prescribing information for all AEDs.

Although the minutes of the advisory committee meeting were not publicly available at the time of the Medsafe report, media reports have stated that the Committee agreed that the data provided by the FDA supported a class effect for suicidality associated with all AEDs. However, although the Committee recommended that a warning be included in the datasheets for all AEDs (including those not included in the FDA's meta-analysis), they did not consider that a Black Box warning was warranted.

The MARC was asked whether or not the data provided sufficient evidence to conclude that the AEDs as a class were associated with an increased risk of suicidality and suicidal behaviour.

Outcome

A Medsafe report on this issue was included in the September dossier.

Discussion

The Committee noted the August 2008 Medsafe report.

The Committee considered that the conclusions of the FDA analysis should be interpreted with caution. They noted that 75% of the data included in the FDA analysis was from psychiatric or "other" indication studies, rather than for an indication of epilepsy, and therefore the estimate of risk of suicidality in association with anti-epileptic drugs was difficult to estimate. They noted that while the FDA analysis included eleven AEDs, when the individual AEDs were analysed only two were associated with a statistically significant increased rate of suicidality. A further five AEDs were associated with an increased rate of suicidality that was not significant, and two AEDs had a possible protective effect, though this was not statistically significant. The Committee agreed that it was therefore difficult to extrapolate these results to a class effect, rather than an effect of individual medicines. They agreed that while suicide was very rare, this was a difficult area to obtain definitive answers through clinical studies. They considered that this may be a signal, and was important to consider as a risk factor when prescribing these medicines and counselling patients.

The MARC considered that an underlying mechanism of a class effect would be difficult to postulate as anti-epileptic agents work by various mechanisms. They considered that there was insufficient evidence at this time to conclude that the AEDs as a class were associated with an increased risk of suicidality and suicidal behaviour. The Committee noted that the issue of antiepileptic drugs and the risk of suicidality is scheduled for review in March 2009. They noted that, if further significant information became available in the interim, it would be brought to the MARC's attention immediately.

The Committee agreed that the outcome of negotiations between the sponsors of innovator AEDs and other international regulators should be awaited before a final decision is made on the wording of warning statements to be included in New Zealand AED datasheets.

Recommendation

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

2.1.15 Venlafaxine and serotonin syndrome, rhabdomyolysis, multiple organ failure, drug interaction [death] (76686)
May 2008 minute item 2.1.12, 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. Information not received by September 2008 and item removed from Standing Agenda list.

Discussion

The Committee noted the above.

2.1.16 Sodium valproate, topiramate and hyperammonaemia, drug interaction (76527)
May 2008 minute item 2.1.13, 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 made the requested datasheet changes.

Discussion

The Committee noted the above.

2.1.17 Lamotrigine and mania (77337,77338)
May 2008 minute item 2.1.14, March 2008 minute items 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 Reactions 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 Reactions section.

Discussion

The Committee noted the above.

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

In May 2008, the Committee noted the above change in causality in the CARM case report. At the September 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'.

Recommendation

The Committee recommended that the Committee member forward this communication to the NZPhvC, for further review.

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

Medsafe has received the international information and will report back to the MARC when the review is complete. The NZPhvC has initiated an analysis of the WHO database for etanercept uveitis and will report back to the MARC.

Discussion

NZPhvC advised that they have completed an analysis of the WHO database for cases of uveitis (uveitis, iritis, iridocyclitis) attributed to etanercept and compared them with adalimumab and infliximab. There were occasional reports in the WHO database of uveitis in association with etanercept, and this combination had a positive IC value. In NZ, two children with juvenile rheumatoid arthritis developed uveitis while taking etanercept, one of whom improved when a change was made to adalimumab. NZPhvC advised that the proportion of total reports with the ADR term uveitis in the WHO database is greater with etanercept (0.32%) than for adalimumab (0.06%) and infliximab (0.12%). These reports were not confined to patients with underlying disease that predisposed to uveitis. These WHO reports reflect the findings of a registry-based study published in October 2007 which concluded that etanercept therapy was associated with a significantly greater number of reported uveitis cases when compared with adalimumab and infliximab. They suggested that this is drug specific and not related to TNF inhibitors as a whole. The report found that the number of patients who developed uveitis with etanercept was greater that expected, even after patients with indications that predispose to uveitis were excluded. This was not the case for infliximab and adalimumab. The Committee noted that this data would be combined with the international information obtained by Medsafe, and reviewed at a subsequent MARC meeting.

Recommendation

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

2.1.20 The safety and efficacy of cough and cold medicines for use in children
May 2008 minute item 2.1.17, 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

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

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

Discussion

The Committee noted that before 1 May 2009, information will be provided to pharmacies advising them of the new product labelling requirements. They suggested that further background information regarding the decision to contraindicate cough and cold medicines in children under two years be disseminated at this time, both directly to pharmacies, and via appropriate pharmaceutical publications.

2.1.21 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 when received.

Discussion

NZPhvC advised that the post mortem report has been received, and it was considered that the death was likely to be related to an epileptic convulsion.

2.1.22 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.

2.1.23 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 2007, the Committee noted the report from Assoc. Prof. [..] and recommended that Medsafe contact [..] for further comment on the issues raised.

Outcome

After further consultation with [..], 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.

3. pharmacovigilance issues

3.1 SSRI ANTIDEPRESSANTS AND INCREASED SUICIDALITY IN CHILDREN AND ADOLESCENTS

References

Goren JL, (2008) Antidepressants use in pediatric populations, Expert Opinion on Drug Safety 7(3), 223 - 5
Mamdani MM, (2008) Health advisories: when good intentions go bad, Canadian Medical Association Journal 178(8), 1025 - 6
Medsafe, (October 2004) The use of SSRI antidepressants in children and adolescents, Dear Healthcare Professional Letter
Medsafe, (March 2004) The use of SSRI antidepressants in children and adolescents, Dear Healthcare Professional Letter
Ministry of Health. 2007. Suicide Facts: 2005 - 2006 data. Wellington: Ministry of Health
FDA, (2004) Suicidality in children and adolescents being treated with antidepressant medications
FDA, (2007) FDA proposes new warnings about suicidal thinking, behaviour in young adults who take antidepressant medications
EMEA, (2005) European Medicines Agency finalises review of antidepressants in children and adolescents
MHRA, (2005) Selective Serotonin Reuptake Inhibitors (SSRIs): Overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents including a summary of available safety and efficacy data
TGA, (2005) Suicidality with SSRIs: adults and children Australian Adverse Drug Reactions Bulletin 24(4):14
Royal Australian and New Zealand College of Psychiatrists, (2005) Clinical guidance on the use of antidepressant medications in children and adolescents
New Zealand Guidelines Group, (2008) Identification of common mental disorders and management of depression in primary care Wellington: Ministry of Health 23 - 53
Dunnachie B, (2007) Evidence - based age - appropriate interventions - A guide for child and adolescent mental health services (CAMHS) Auckland: The Werry Centre for Child And Adolescent Mental Health Workforce Development 9 - 25
Merry S, (2008) Should antidepressants be used to treat depression in children and adolescents (BPAC)
Wohlfarth TD, Van Zwieten BJ, Lekkerkerker FJ, Gispen-de-Wied CC, Ruis JR, Elferink AJA, StorosumJG, (2008) Antidepressant use in children and adolescents and the risk of suicide European Neuropsychopharmacology 16, 79 - 83
Usala T, Clavenna A, Zuddas A, Bonati M, (2008) Randomised controlled trials of selective serotonin reuptake inhibitors in treating depression in children and adolescents: A systematic review and meta-analysis European Neuropsychopharmacology 18, 62 - 73
Katz LY, Kozyrskyj AL, Prior HJ, Enns MW, Cox BJ, Sareen J, (2008) Effect of regulatory warnings on antidepressant prescription rates, use of health services and outcomes among children, adolescents and young adults Canadian Medical Association Journal 178(8), 1005 - 1011
Medsafe (2008) The use of SSRI antidepressants in children and adolescents, Proposed Dear Healthcare Professional Letter

Issue

Medsafe provided a report for the MARC on the issue of SSRI antidepressants and increased suicidality in children and adolescents.

At its December 2007 meeting, the Committee were advised of recent publications regarding the effects of regulators previous suicidality warnings on SSRI prescriptions and suicide in children and adolescents. They recommended that the issue of SSRIs and the risk of suicidality in children and adolescents be placed on the agenda for the next meeting of the MARC.

At its March 2008 meeting, the Committee discussed recent publications in more detail and agreed it was important to provide prescribers with a current summary of advice. They recommended that a Prescriber Update article be written; advising that the MARC advice issued in 2004 entitled "SSRI antidepressants in children and adolescents" remained valid in light of the recent/current evidence. The Committee recommended that the key messages to be contained in this article be discussed by the MARC before publication.

The Committee did not believe the new information reviewed in March 2008 altered the risk:benefit profile of the risk of suicide when SSRI antidepressant medicines are used in children and adolescents. They maintained that the current NZ SSRI datasheets adequately warn prescribers of the potential risks associated with the use of these medicines, and the need to carefully monitor patients for the emergence or worsening of suicidal thoughts or behaviours, particularly during the initial stages of treatment. The Committee considered the proposed Prescriber Update article would provide a summary of current advice.

The purpose of the September 2008 report was to review the recent literature regarding the risk of suicidality with SSRI antidepressants in children and adolescents along with recent New Zealand and international guidelines on the treatment of depression in children and adolescents. The MARC was asked whether the available evidence continues to support the Committee's advice issued in October 2004. They were asked to consider whether the current advice for prescribers to use SSRI antidepressants in the treatment of depression in children and adolescents only in consultation with a child and adolescent psychiatrist, should be extended to include in consultation with a child and adolescent psychiatrist or an adult psychiatrist due to the lack of child and adolescent psychiatrists to meet current demand. They were also asked to review Medsafe's proposed communication on this issue.

Discussion

The Committee noted the 2008 Medsafe report. They noted the two recently published meta-analyses, by Wohlfarth et al and Usala et al, but considered that these did not add any further information. They discussed the Katz et al paper, which looked at the effect of regulatory warnings on antidepressant prescription rates, use of health services and outcomes among children, adolescents and young adults in the nine years before, and the two years after the Health Canada warning. The Katz paper concluded that the data suggested an increase in the number of completed suicides in the two years following the warning. The MARC noted however, that there was a peak in New Zealand at the same time of youth suicides, and there can be a strong year-to-year variation in suicide deaths.

The Committee noted that in New Zealand, the number of fluoxetine, citalopram and venlafaxine prescriptions to children and adolescents have increased or remained constant subsequent to the MARC warnings in 2004. The number of paroxetine prescriptions to children and adolescents has reduced subsequent to the MARC warnings in 2004.

The Committee reviewed the draft Dear Healthcare Professional Letter and recommended some changes. They did not consider that the current advice for prescribers to use SSRI antidepressants in the treatment of depression in children and adolescents only in consultation with a child and adolescent psychiatrist, should be extended to include 'adult psychiatrists' and suggested that this be amended to 'other appropriate psychiatrists or paediatricians'. They recommended that the amended letter be published in Prescriber Update.

The Committee noted that Medsafe will assess New Zealand and international data, along with any new literature on SSRI prescriptions to children and adolescents and completed suicide on a 12- monthly basis, and report back to the Committee as necessary.

Recommendation

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.

3.2 BLACK COHOSH AND HEPATOTOXICITY

References

Workshop on the Safety of Black Cohosh in Clinical Studies. Sponsored by the National Centre for Complementary and Alternative Medicines, NIH. November 2004. pp 22-6
Chow E C-Y, Teo M, Ring JA & Chen JW (2008) Liver failure associated with the use of black cohosh for menopausal symptoms. Medical Journal of Australia 188(7): 420-2

Issue

Medsafe provided a report for the MARC on the issue of black cohosh and hepatotoxicity. At its May 2008 meeting, the Committee noted a paper by Chow et al, which described an Australian case report of a patient who developed liver failure after taking black cohosh to treat menopausal symptoms. The Committee recommended that this issue be further discussed at the next meeting.

Black cohosh is a perennial herb, the root and rhizomes of which are used medicinally most commonly for symptoms of menopause, but also for premenstrual syndrome, dysmenorrhoea, and the induction of labour in pregnant women. Its use appears to have gained in popularity over recent years, following safety concerns over the use of conventional hormone replacement therapy.

Very rare, idiosyncratic hepatotoxic reactions have been reported with black cohosh, including abnormal or elevated liver function test results, hepatitis and hepatic failure, sometimes requiring liver transplantation. In some of the cases the strength of evidence for a casual association is tenuous, due to the presence of confounding factors such as other concomitant hepatotoxic medicines or lack of verification of the botanical constituents. Additionally, the demographics of patients with idiopathic hepatitis are similar to those of most black cohosh users i.e. women in their fifties. In the serious cases however, there is a lack of other identifiable causal substances or detectable viral infections. Serious reactions have occurred with use for less than a month.

Four case studies describing black cohosh use and serious hepatotoxic reactions were examined in detail at the 'Workshop on the Safety of Black Cohosh in Clinical Studies' hosted by the US NIH in 2004. Two were Australian cases and two American cases; three of these patients required liver transplant. A third Australian case report of liver failure requiring liver transplantation associated with black cohosh is described in Chow et al. This report was considered by the Australian Adverse Drug Reactions Advisory Committee in August 2006 and included in the review conducted by the TGA's Black Cohosh Expert Advisory Group in November 2006 along with 15 other Australian adverse reaction reports. As a result of this review, warning statements on Australian product labels were strengthened.

Pathological examinations of the excised livers of transplant patients have identified features consistent with drug-induced hepatitis, displaying massive and sub-massive necrosis. In one liver however, features consistent with drug-induced autoimmune hepatitis were observed.

Mechanisms underlying the hepatotoxicity of black cohosh, including the identification of the causative constituent(s), remain unknown.

In New Zealand, there are no registered medicines containing black cohosh but there are a significant number of dietary supplements available directly to consumers containing the herb; the majority of which are marketed for the relief of menopausal symptoms. Dietary supplements are regulated under the Dietary Supplements Regulations 1985 and administered by the New Zealand Food Safety Authority (NZFSA) under the Food Act 1981. Dietary supplements do not undergo any pre-market assessment and are not required to be registered with NZFSA. To date, no regulatory action has been taken by NZFSA regarding black cohosh in dietary supplements.

The Committee was asked whether the concern regarding black cohosh use and hepatotoxicity is sufficient to warrant warning prescribers, complementary healthcare practitioners and/or consumers of the risk given the very rare but life-threatening hepatotoxic reactions that have been reported with the herb.

Discussion

The MARC noted the May 2008 Medsafe report.

NZPhvC advised that to date, CARM has received three spontaneous adverse reaction reports for products containing black cohosh as the sole active ingredient, however none indicated hepatic reactions.

Another eleven reports were retrieved from the CARM database in which adverse reactions were described for multi-ingredient products in which black cohosh was an ingredient; three of these reports described hepatic reactions. One report has been considered previously by the MARC.

The Committee noted that in Australia products such as black cohosh were governed by regulations for complementary medicines and compared this with NZ, where black cohosh is not registered as a medicine. It was acknowledged that regulatory options available under the Medicines Act were therefore limited.

The Committee noted that the dosage of black cohosh for the products available in NZ was unclear, but appeared to range from 500 to 1000mg for formulations containing the dried root/ rhizome. They were advised that in Germany, which as a country has a relatively high usage of complementary medicines, the dosage advice is 40mg of the root/rhizome daily. Duration of administration is not recommended for longer than six months.

The Committee agreed that while the risk of hepatotoxicity with black cohosh appeared to be very rare, they considered that the risk:benefit ratio to be such that it was worthwhile to disseminate information regarding this risk. They acknowledged that many of these products contain several different ingredients, in addition to being self-selected by the consumer, rather than via consultation with a practitioner. They recommended that Medsafe consider ways to disseminate this information as widely as possible.

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

Recommendations

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.

The Committee recommended that Medsafe investigate the mechanisms to disseminate the above information as widely as possible.

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

3.3 CONVENTIONAL ANTIPSYCHOTICS AND MORTALITY RISK

References

FDA Alert 6 June 2008
Gill SS, Bronskill SE, Normand S-LT, Anderson GM, Sykora K, Lam K, Bell CM, Lee PE, Fischer HD, Herrmann N, Gurwitz JH & Rochon PA (2007) Antipsychotic drug use and mortality in older adults with dementia. Ann Int Med 146(11): 775-86
Schneeweiss S, Setoguchi S, Brookhart A, Dormuth C & Wang PS (2007) Risk of death associated with use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ 176(5): 627-32
Rochon PA, Normand SL, Gomes T, Gill SS, Anderson GM, Melo M, Sykora K, Lipscombe L, Bell CM & Gurwitz JH (2008) Antipsychotic therapy and short-term serious events in older adults with dementia. Arch Int Med 168(10): 1090-6
Kales HC, Valenstein M, Kim HM, McCarthy JF, Ganoczy D, Cunningham F & Blow FC (2007) Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. Am J Psychiatry 164(10): 1568-76
O'Brien J (2008) Editorials. Antipsychotics for people with dementia BMJ 337: a602

Issue

Medsafe and NZPhvC provided reports for the MARC on the issue of conventional antipsychotics and mortality risk. This followed a release by the United States Food and Drug Administration (FDA) on 16 June 2008, informing US prescribers of an increased risk of death in elderly patients treated for dementia-related psychosis with conventional antipsychotics.

In April 2005, the FDA released a Public Health Advisory informing prescribers there was an increased risk of mortality in elderly patients with dementia treated with atypical antipsychotics, requiring a black-box warning and bolded paragraph at the start of the Warnings section be included in the datasheets of all atypical antipsychotics. The FDA concluded that the increase in mortality was likely to be related to the pharmacologic effect of the atypical antipsychotics and not due to the individual chemical structures of these agents. At this time the FDA also indicated it was considering including this warning in the datasheets of all conventional antipsychotics.

The MARC considered the increased risk of mortality in elderly patients with dementia treated with atypical antipsychotics at its June 2005 meeting. The Committee noted that there were a limited number of treatment options available to the majority of patients with dementia, and the only atypical antipsychotic approved in NZ for use in the treatment of the behavioural and psychological symptoms of dementia was risperidone. At this time, the Committee considered that the risperidone datasheet contained adequate information of the associated mortality risk, and supported the continued availability of risperidone for use in patients with dementia.

The FDA indicated the June 2008 release regarding the conventional antipsychotics was based on the overall weight of the available evidence, which included two published observational epidemiological studies (Gill et al. 2007 and Schneeweiss et al. 2007), in which it was stated that the conventional antipsychotics share the increased risk of death in elderly patients with dementia-related psychosis that has been observed for atypical antipsychotics. The FDA required datasheets for all antipsychotic drugs to include the same information as for the atypical antipsychotics, namely a black-box warning and a bolded paragraph in the Warnings section.

The Committee was asked to evaluate the information provided and determine if any further regulatory action was required.

Discussion

The Committee noted the August 2008 Medsafe and NZPhvC reports.

NZPhvC advised that the CARM database includes a small number of reports of deaths in association with antipsychotics.

The MARC noted that it had considered the issue of increased risk of mortality in elderly patients with dementia treated with atypical antipsychotics at its June 2005 meeting. They noted that the only atypical antipsychotic approved in NZ at that time for use in the treatment of the behavioural and psychological symptoms of dementia was risperidone, and had supported the continued availability of risperidone for use in these patients.

The Committee noted that in New Zealand, zuclopenthixol (Clopixol) is the only conventional antipsychotic approved specifically for use in the treatment of the behavioural and psychological symptoms of dementia. Haloperidol (Haldol) and trifluoperazine (Stelazine) are approved for use in the treatment of senile psychosis.

The Committee noted that the recently published studies concluded that the risk of death associated with conventional antipsychotics in elderly patients with dementia may be greater than that with atypical antipsychotics. They noted that the Gill et al study found that, compared with no antipsychotic use, there was a relative risk of death at 30 days of 1.3 with antipsychotic use, and that this risk seemed to persist to 180 days. The authors noted however, that there were unmeasured confounders, which could affect associations.

The Committee noted that while there was some evidence that risperidone produced some limited benefits, there was little evidence that the conventional antipsychotics were of benefit. They noted that antipsychotics were only used in advanced cases of dementia, and considered that there were a limited number of treatment options available to the majority of patients with dementia, and that practical issues were important in the decision making process. The MARC considered that the diagnosis was important, and that it was important to exclude delirium before commencing treatment with antipsychotics.

The Committee noted the recent editorial article by O'Brien in the British Medical Journal on the topic of antipsychotics for people with dementia which recommended that antipsychotic use for dementia patients should be reserved for severe and distressing symptoms after careful assessment of risk and benefit. It suggested that non-pharmacological approaches should be considered first, and possible alternatives such as cholinesterase inhibitors for apathy and psychosis, and carbamazepine for aggression should be considered. The author acknowledged the lack of suitable evidence-based alternatives to antipsychotics, and that the decision making process was complex. This advice is consistent with the National Institute of Clinical Excellence-Social Care Institute for Excellence guidelines endorsed by the British Royal College of Psychiatrists.

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

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.

Recommendations

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

3.4 ELTROXIN FORMULATION CHANGE ADVERSE REACTIONS

References

Medsafe. Eltroxin (levothyroxine) - June 2008. Dear Dr Letter sent by GlaxoSmithKline.
Medsafe. Eltroxin (levothyroxine) - Patient resource issued to Healthcare Professionals by GSK. June 2007.
Medsafe. Eltroxin (levothyroxine) - June 2008. Dear Dr Letter sent by Medsafe.
Vaidya B, Pearce S H S (2008) Management of hypothyroidism in adults British Medical Journal 337: 284-9.

Issue

Medsafe and NZPhvC provided reports to inform the MARC of investigations undertaken into the safety and efficacy of the new formulation of Eltroxin tablets. This was identified as an emerging issue at the May 2008 MARC meeting following an increase in the number of adverse reaction reports received by the Centre for Adverse Reactions Monitoring (CARM).

In July 2007, the manufacturer (GlaxoSmithKline, GSK) introduced a new formulation of Eltroxin tablets in New Zealand, and stopped manufacturing the previous formulation. The new formulation contains an identical active ingredient, made in the same manufacturing site. The excipients in the new formulation were changed; however these are all commonly used in other medicines and are controlled to pharmacopoeial standards. The manufacturer also removed the tablet breakline and advised that the tablets should not be halved or crushed. Consequently, dosage regimens in some patients changed; instead of halving tablets, patients were instructed to take whole tablets on alternate days.

Prior to the distribution of the new formulation, GSK submitted data to Medsafe to gain consent to market the new formulation. Medsafe evaluated this data and concluded that the product met all internationally accepted criteria for quality, safety, and bioequivalence. Medsafe required the company to notify all New Zealand GPs and pharmacies of the new formulation prior to its distribution, and this occurred in June 2007.

Discussion

The MARC noted the August 2008 Medsafe and NZPhvC reports.

The Centre for Adverse Reactions Monitoring (CARM) received the first report of an adverse reaction to the new formulation on 8 October 2007. Prior to October 2007 CARM had received a total of 14 adverse reaction reports where thyroxine was the suspect medicine. Between 8 October 2007 and 8 July 2008, CARM received approximately 40 additional adverse reactions associated with the change in formulation. Following media coverage in June 2008, the rate of reporting increased markedly, and at the time of the meeting CARM had received 810 reports. Over 40% of the reports have been received from patients, with the remainder from prescribers and pharmacists. The reports describe largely three groups of symptoms, those describing hypothyroid-type symptoms accounting for the largest proportion of reports since the formulation change. Other symptoms could be broadly grouped into categories of headache, associated with eye pain and visual disturbances, and allergic-type symptoms. There were occasional reports of hyperthyroid symptoms. Some recent reports have included blood test results, and the majority of these have demonstrated thyroid levels within the normal limits. In some cases baseline thyroid levels were available, and some patient's levels have increased from base line, while still remaining in the normal range. Some patients have had markedly elevated TSH levels.

NZPhvC advised that reports had been received from across New Zealand. They noted that while the distribution approximately reflected that of the population, the Southland area reflected a disproportionate excess considering the relatively smaller population in that region. The mean age of patients reporting adverse reactions was 61 years, and over 90% were female.

NZPhvC advised that in reports where patients have discontinued medication, they have reported that the headache and allergic groups of symptoms have improved; however, the hypothyroid group of symptoms have not changed. Some have described improvement in hypothyroid symptoms after discontinuing the new formulation, while others have reported no improvement after discontinuation. Some patients found their hypothyroid symptoms have resolved after adjustments in dose of the new formulation.

In response to the increased number of adverse reaction reports in New Zealand, in June 2008 Medsafe reassessed the change in formulation and confirmed that all international criteria for quality, safety, and bioequivalence were satisfactorily met.

The new Eltroxin was launched in Germany in July 2006, the Netherlands in December 2007, and in Singapore in April 2007. GSK intends to roll out the new formulation globally. GSK informed Medsafe that no significant increase in adverse reactions linked to the new formulation of Eltroxin have been reported in Germany and the Netherlands to date. However, this may be due to under reporting or the availability of alternative brands and formulations in these countries. Medsafe also contacted Singapore and was informed that they also did not see an increase in reporting of adverse drug reactions following the introduction of the new formulation.

NZPhvC advised they had contacted the 83 countries on the WHO adverse reactions monitoring scheme, seeking information on adverse reaction patterns for levothyroxine. There were no reports of increased rates of adverse reactions to the GSK brand of Eltroxin. However, Australia and the United Kingdom, countries in which the GSK brand is not available, advised that they have reports of adverse reactions of a similar nature to all three classes of adverse reactions described above with the various levothyroxine products registered in their countries, and also when patients changed brands or formulations of levothyroxine.

Also in June 2008, Medsafe requested that GSK supply further quality data on the specific batches of the new formulation supplied to the New Zealand market. The Medsafe Compliance Team reviewed this and considered that there was no obvious quality or manufacturing reason for the increased number of adverse reaction reports to the new formulation. The Good Manufacturing Practice (GMP) status of the finished product manufacturing site was also confirmed by the Medsafe Compliance Team.

Medsafe advised the Committee of the results of the independent testing it had initiated. Four batches of the new Eltroxin formulation that had been supplied into New Zealand were tested, including a 'complaint batch' returned by a patient who had reported adverse reactions to CARM following the switch to the new formulation. The manufacturer conducted testing simultaneously on each batch of the new formulation that had been supplied into New Zealand. A Medsafe review of GSK's test results found that there was no evidence to suggest the reported adverse effects were attributable to a quality problem with the changed formulation. Preliminary results from the independent testing carried out for Medsafe also suggested that all drug product expiry specifications have been met. Results were comparable with those provided to Medsafe by GSK. The active ingredient in the reformulated product is produced by the same manufacturer, using the same method as the previous formulation. An assay of active ingredient was well within specification. With the introduction of the new formulation, GSK upgraded the product specifications. These new specifications were more complicated than the previous formulation, and included a number of identified impurities. Testing showed the same impurities were present in both formulations at acceptable levels. No contaminants were identified. Dissolution testing also met the defined specifications. Medsafe was awaiting the final report.

Medsafe advised that the excipients in the reformulated product are very common, and are widely used, and do not offer any explanation for the adverse effects that have been reported. Investigations to date have revealed nothing to suggest that the reported adverse effects are due to a batch or manufacturing related problem.

Medsafe consulted expert endocrinologists in June 2008 and again in August 2008, to discuss the adverse reactions reported to CARM. The specialists advised that the patients they have seen have normal TSH levels, within the appropriate range, with levels in a few patients only altering to the extent that dose adjustments were required. They were not able to explain the range of side effects that have been reported. The issue of visual symptoms were discussed with the endocrinologists at length and they were unable to provide any explanation for the symptoms reported, with the possible exception in the case of patients with a past history of Graves disease. Following the advice received from the endocrinologists, in June 2008, Medsafe issued advice to all healthcare professionals emphasising the importance of thyroid function monitoring, patient compliance, and how to adjust the dose if necessary.

On 29 June 2007, GSK again notified all New Zealand GPs and pharmacies of the change in formulation. This second letter reiterated the advice on dose regimen and administration and also included a resource so patients could identify the new and the old tablets.

Medsafe directed GSK to advise healthcare professionals for a third time of the change in formulation and to provide advice on switching patients to the new formulation. GSK also advised the public directly via national newspapers.

In addition to the Medsafe advice, an article was published in the Best Practice Journal (August edition) in conjunction with BPAC. The article provided further information on the Eltroxin formulation change and how to access unapproved medicines using provisions in the Medicines Act 1981 (Sections 25 and 29).

The Committee noted that there was no specific medical, physiological, or pharmacological explanation for the increase in adverse reaction reports, and noted that similar situations had occurred in the past following brand switches.

The Committee noted that Eltroxin is the only brand of levothyroxine tablets with Ministerial consent for distribution in New Zealand, and this has been the case for several years. The previous formulation is no longer manufactured, and therefore the company are unable to supply this. Eltroxin is the only brand of levothyroxine subsidised by PHARMAC. PHARMAC have unsuccessfully tendered for an alternative product since 2001.

A review of the adverse reaction reports submitted to CARM suggests there is some evidence of a decreased therapeutic effect in some cases. Medsafe considers the majority of adverse reactions reported to CARM to be related to thyroid dysfunction, caused by a loss of thyroid hormone control following the formulation change. Following consultation with endocrinologists, Medsafe believes that appropriate thyroid function monitoring and, if necessary, dose re-titration will resolve these symptoms. However, Medsafe considers that there is a need for an alternative supply of levothyroxine tablets in patients experiencing hypersensitivity type reactions. Similarly patients exhibiting intolerance or short onset non-specific symptoms, as described in the NZPhvC report, that are not readily attributable to thyroid dysfunction may also require an alternative levothyroxine formulation. Details of dechallenge improvement and recurrence on rechallenge in a small number of these cases has added weight in support of a causal association with the new formulation of Eltroxin. Medsafe and PHARMAC are working to encourage another brand of levothyroxine to be supplied in New Zealand, however, the decision to market a product in NZ is not within either Medsafe's or PHARMAC's control. One application had been received to date, with another likely in the near future. The Committee noted that with any brand change of thyroxine, patients will need to be monitored and doses adjusted as necessary, and adverse reaction reports are likely to continue.

The Committee noted the clinical review paper published in the BMJ by Vaidya and Pearce entitled "Management of hypothyroidism in adults". The authors reported that a cross sectional survey of patients treated with levothyroxine have shown that between 40% and 48% are either under-treated or over-treated. They stated that one of the unanswered questions regarding the management of hypothyroidism was why some patients continued to feel unwell, despite being treated with levothyroxine.

The Committee discussed if the change in dosage regimen introduced with the new formulation could be a possible explanation for some of the adverse effects reported. CARM advised that they had carried out an analysis of the reports of patients receiving a single tablet daily, against those on complex regimes, and found no differences between the two groups.

The Committee noted that information was to be published on the Medsafe website following the media conference later in the day, and agreed that it was important to keep people informed of the ongoing action and progress. They agreed that due to the long half life of levothyroxine, it was necessary to continue to emphasise the time period of six weeks between dose monitoring and any necessary adjustments.

Recommendations

The Committee recommended that Medsafe continue to work with PHARMAC to encourage an alternative brand to be approved and supplied in New Zealand.

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

Secretary's note: The Medsafe media release and information may be found on

www.medsafe.govt.nz/downloads/eltroxin-media-conference-information.doc (This is a 98KB Microsoft Word document)

www.medsafe.govt.nz/hot/media/2008/EltroxinSept2008.asp

3.5 INHALED LABAS AND THE RISK OF FATAL AND NON-FATAL ASTHMA EXACERBATIONS - SCHEDULED REVIEW

References

Salpeter et al. (2006). Meta-analysis: Effect of long-acting β-agonists on severe asthma exacerbations and asthma-related deaths. Annals of Internal Medicine. 144: 904-912
PHARMAC usage data
CARM data
MHRA alerts:
1. Long-acting β₂ agonists for asthma: review. MHRA. January 2008 - Drug Safety Update. Volume 1(6): 9.
2. Reminder: Salmeterol (Serevent) and formoterol (Oxis, Foradil) in asthma management. MHRA. February 2008.
Cates CJ, Cates MJ. (2008). Regular treatment with salmeterol for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews. Issue 3
Gustavo et al (2008). Safety of long-acting β-agonists in stable COPD: A systematic Review. Chest. 133: 1079-1087
Bateman et al. (2008). Meta-analysis: Effects of adding salmeterol to inhaled corticosteroids on serious asthma-related events. Annals of Internal Medicine. 149(1): 33 - 42
Walters et al. (2007). Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid. Cochrane Database of Systematic Reviews. Issue 1

Issue

Medsafe provided a report for the MARC's Scheduled Review on the issue of inhaled long-acting beta-agonists (LABAs) and the risk of fatal and non-fatal asthma exacerbations. The purpose of the report was to provide the Committee with the results of the UK Medicines and Healthcare products Regulation Agency's (MHRA) review of the risks and benefits of salmeterol and formoterol use, and to inform the Committee of recent data and regulatory action regarding the safety of LABAs.

The MARC reviewed the safety of LABAs in the treatment of asthma at their meeting in September 2006. At that time, the MARC reviewed the final results of the SMART trial, a meta-analysis by Salpeter et al (2006), and were informed of recent regulatory action undertaken in New Zealand and internationally to manage the identified risks of fatal and non-fatal asthma exacerbations in patients receiving LABA therapy (predominantly in the absence of inhaled corticosteroid therapy).

At the next review in September 2007, the Committee was advised that the MHRA was conducting a review of the risks and benefits of formoterol and salmeterol use in the treatment of asthma and chronic obstructive pulmonary disease. The Committee noted that recent literature had not added significantly to the body of evidence previously reviewed by MARC in September 2006. They noted that the LABA datasheets had been updated and contained adequate information on the risk of asthma exacerbations occurring in association with the use of LABAs and the need to ensure that LABAs are only used in combination with anti-inflammatory therapy. They noted that this information was disseminated to New Zealand prescribers in a BPAC article in December 2006 and would be included in the next issue of Prescriber Update (published in November 2007). The Committee recommended that the issue of LABAs and non-fatal asthma exacerbations be placed on the 'Scheduled Review' list for a 12-monthly review, until the results of the MHRA's review of the risks and benefits of salmeterol and formoterol use became available.

In January 2008, the MHRA advised that they had completed their review of the use of LABAs in the treatment of asthma. The MHRA reviewed the following:

The pharmacology of salmeterol and formoterol, and combination products of the two.
The current position of research into the β₂adrenoreceptor genotype.
The epidemiology of asthma in relation to the introduction of LABAs.
An overall assessment of the benefits and risks of LABAs in the treatment of asthma.

The conclusions from the review were:

Epidemiological data show that since the introduction of LABAs, there has been a decrease in asthma-related hospitalisations in adolescents and a decrease in asthma-related mortality in all ages.
Data from randomised controlled clinical trials do not suggest a similar safety concern to that shown in post-marketing studies, probably because of more consistent use of concomitant inhaled corticosteroids in randomised controlled settings. The data support the use of LABAs in conjunction with inhaled corticosteroids in the treatment of moderate to severe asthma.
To aid compliance with the concomitant use of inhaled corticosteroids and LABAs, a combination inhaler should be used when appropriate.

The MHRA also advised that further epidemiological studies are under way to assess the relation between adverse outcomes and use of LABAs, the results of which are expected before the end of 2008.

In February 2008, the MHRA issued further advice to Healthcare Professionals, reminding them that:

Patients given salmeterol or formoterol should always be prescribed an inhaled corticosteroid.
Patients with acutely deteriorating asthma should not be initiated on salmeterol or formoterol.
Patients should be monitored closely during the first 3 months of treatment.
It is not clear if underlying genetic variations are responsible for the differences observed between African-American and Caucasian patients.

The Committee was asked to evaluate the information provided and determine if any further regulatory action was required.

Discussion

The MARC noted the August 2008 Medsafe report.

The Committee noted that following a request by Medsafe in 2005, the NZ datasheets for Foradil, Oxis, Symbicort, and Serevent were updated to contain the following information:

LABAs must only be prescribed in combination with anti-inflammatory therapy such as inhaled corticosteroids (ICS). LABAs must never be prescribed as monotherapy.
LABAs must not be used to treat acute asthma exacerbations. Short acting beta agonists must always be available to be used as rescue medication.
LABAs must not be initiated or the dose increased during an episode of significant worsening or acute deterioration in asthma control.
Patients must be advised to seek medical treatment immediately if their asthma deteriorates suddenly.

The Committee noted the MHRA's conclusions from their review of the use of LABAs in the treatment of asthma as detailed above. They noted that aside from the recommendation that in order to aid compliance with the concomitant use of inhaled corticosteroids and LABAs, a combination inhaler should be used when appropriate, the results of the MHRA's initial review of the risks and benefits of salmeterol and formoterol use did not draw any new conclusions that have not already been addressed in New Zealand.

They noted the study by Cates CJ and Cates MJ, which concluded that, in comparison with placebo, there was an increased risk of serious adverse events with regular salmeterol, and an increased risk of asthma-related mortality in patients not using inhaled corticosteroids. The authors stated that although the increase in asthma-related mortality was smaller in patients taking inhaled corticosteroids at baseline, the confidence interval was wide and so it could not be concluded that the inhaled corticosteroids abolished the risks of regular salmeterol.

The Committee noted the study by Gustavo et al, which reviewed the safety of long-acting β-agonists in stable chronic obstructive pulmonary disease (COPD). The authors concluded that LABAs may not be associated with an increased risk of respiratory deaths in adults with COPD, and that tiotropium decreased the incidence of severe COPD exacerbations, compared with LABAs. The Committee noted however, that this study focused on COPD, rather than asthma.

The Committee noted the Bateman meta-analysis which examined whether the incidence of severe asthma-related events differed in patients receiving salmeterol plus ICS, compared with ICS alone. The main conclusion gained showed that there were two asthma-related adverse events in patients receiving salmeterol plus ICS therapy, and no events in patients receiving ICS alone, suggesting that there may be additional risks with the use of LABAs compared with placebo, when added to ICS therapy.

The Committee noted the Nannini study which reviewed the use of combined inhalers (ICS plus LABA) as a single inhaler versus LABAs alone for the treatment of COPD. This study found the exacerbation rates with combined inhalers were reduced in comparison with LABAs alone, however pneumonia occurred more commonly with combined inhalers. A member commented that a recent publication had suggested that the use of combined inhalers resulted in patients receiving a higher dose of ICS, when compared with patients using two separate inhalers, and queried if this could affect immune suppression. The Committee considered that this was a possibility if the combined inhalers were used inappropriately.

The Committee noted the systematic Cochrane review by Walters et al, which looked at the use of LABAs for chronic asthma in adults and children where background therapy contained varied or no ICS. One conclusion from this paper indicated an absolute increase in asthma-related mortality consistent with an increase of around one per 1250 patients treated with a LABA for six months, however, the confidence intervals were wide. The Committee considered that this was a high number needed to harm (NNH) figure. The review also suggested that African-Americans and those not on inhaled ICS were at particular risk of death or a life-threatening asthma event, and a suggestion of an increased exacerbation rate in children.

The Committee noted that in NZ, the use of single inhalers was higher than that of combined inhalers. They noted that BPAC is currently reviewing the ratio of LABA and ICS prescribing, in order to inform prescribers, with a 1:1 ratio being optimal. BPAC are also undertaking an education programme in order to optimise usage of the various inhalers in the treatment of asthma.

Medsafe considered that the current literature supports previous conclusions and recommendations made by the MARC. They advised that the question of the risk of the rare event of asthma-related deaths in patients treated with LABAs is altered by the concomitant use of ICS remains unanswered. In this context, the Medical Research Institute of NZ (MRINZ) has proposed undertaking a meta-analysis of data relating to salmeterol and asthma-related death, using all of the data in the GlaxoSmithKline clinical trial database. This data also offers the potential for a sub-group analysis of patients using concomitant ICS, in order to provide a more accurate assessment whether this risk is mitigated by concomitant use of ICS. The MRINZ has recently completed a meta-analysis on the risk of mortality associated with formoterol, and this has been submitted for publication. The MRINZ propose to follow the same methodology for the meta-analysis of the mortality risk with salmeterol, in order to generate conclusions which can be reliably compared. Medsafe requested that the MARC consider if an independently funded meta-analysis of the entire GSK database on salmeterol treatment of asthma would provide important information about the risk of mortality associated with LABAs. The Committee agreed that while in principle this information would be valuable, the MARC did not currently have enough information to make any recommendation to Medsafe regarding funding.

The Committee agreed that the new information provided did not alter the current risk-benefit profile of inhaled long-acting beta-agonists. They considered that the current NZ datasheets for inhaled LABAs adequately warn prescribers of the potential risks associated with the use of these medicines, and the need to prescribe in combination with inhaled corticosteroids.

The Committee agreed that the issue of inhaled long-acting beta-agonists and risk of fatal and non-fatal asthma exacerbations remains important; however, it no longer required specific annual review and recommended the issue be removed from the Scheduled Review list. They 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 the issue of inhaled long-acting beta-agonists and risk of fatal and non-fatal asthma exacerbations 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 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 Fleet oral preparation and renal failure, hyperphosphataemia [death] (79049)

Discussion

NZPhvC advised that follow-up information stated that the preparation includes monobasic and dibasic sodium phosphate. The reporter stated that recent nephrological literature revealed adverse effects related to the products high phosphate content, which may lead to acute hyperphosphataemia, acute hypocalcaemia, acute renal failure, worsening of chronic renal failure, and nephrocalcinosis. One centre in the United States performing 500 colonoscopies each year had detected 15 cases of acute phosphate neuropathy in 12 months. The US FDA issued an alert in May 2006.

NZPhvC advised that in addition to the report of APN described above, they have received one other report similar to this case, while the other reports to Fleet oral preparation described electrolyte disturbances, diarrhoea, and dehydration.

The product datasheet indicates that hyperphosphataemia may occur, along with dehydration, low sodium and potassium levels, and renal failure, and that these may be more likely in patients taking medicines to treat hypertension, or those which may result in dehydration. Advice is included about cautious use in the elderly, the frail and debilitated. The NZPhvC noted that other bowel preparations can also cause dehydration and electrolyte disturbances.

The Committee queried if these problems could be dose related and suggested that it would be useful to reiterate the general advice about the risks of dehydration and electrolyte disturbance during bowel preparation in predisposed individuals.

The causal association with Fleet oral preparation was considered to be 'probable' for renal failure, hyperphosphataemia.

Recommendation

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.

4.1.1.2 Ketoprofen, dextropropoxyphene/paracetamol and intracranial haemorrhage [death] (78488)

Discussion

NZPhvC advised that the CARM database does not include any reports of intracranial or cerebral haemorrhage with either medicine; however, the WHO database does include reports of haemorrhage with ketoprofen.

The NZ datasheet for Oruvail (ketoprofen) includes reference to thrombotic stroke and cardiovascular events. The Paradex datasheet (dextropropoxyphene/paracetamol) does not include reference to cerebral bleeding or intracranial haemorrhage.

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

The causal association with ketoprofen, dextropropoxyphene/paracetamol was considered to be 'unclassified' for intracranial haemorrhage.

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

4.1.1.3 Flucloxacillin and anaphylactic reaction [death] (78269)

Discussion

NZPhvC advised that there are reports in the CARM database of anaphylaxis and anaphylactoid reactions with flucloxacillin. The NZ datasheets for both oral and intravenous forms of flucloxacillin list the possibility of occasional fatal hypersensitivity reactions.

The Committee noted that this was a recognised potentially unpredictable rare event, and that previous tolerance to beta-lactam antibiotics did not necessarily predict future safety. They noted that while the change from oral to intravenous administration could increase the allergenic load, it would be useful to review the post-mortem report to obtain further background information.

The causal association with flucloxacillin was considered to be 'certain' for anaphylactic reaction.

Recommendation

The Committee recommended that further information be brought back to the MARC once the post-mortem has been received.

4.1.1.4 Piperacillin / tazobactam (Tazocin), ciprofloxacin, doxycycline and fluconazole and hepatic necrosis, renal failure, encephalopathy,disseminated intravascular coagulation [death] (78866)

Discussion

NZPhvC advised that the reporter suggested the outcome was due to a fatal drug hypersensitivity to Tazocin. While these events have been associated with Tazocin both in datasheets and literature, they could have equally been attributed to a number of the other medicines the patient was receiving. The sequence of medications was not clear and further information has been requested.

The Committee considered the causal association with piperacillin / tazobactam (Tazocin), ciprofloxacin, doxycycline to be 'probable' for hepatic necrosis, renal failure, encephalopathy, disseminated intravascular coagulation.

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

4.1.1.5 Amsacrine and ventricular tachycardia, agranulocytosis [death] (78367)

Discussion

NZPhvC advised that there are no similar events with amsacrine listed in the CARM database. The WHO database includes one report of agranulocytosis and 31 reports of arrhythmias in association with amsacrine.

The Committee noted that this medicine was imported into NZ under Section 29 of the Medicines Act 1981, and the patient had been involved in the decision making process leading to the use of amsacrine.

The Committee considered the causal association with amsacrine was 'certain' for ventricular tachycardia and 'possible' for agranulocytosis.

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

4.1.1.6 Capecitabine and renal failure, hepatic failure, diarrhoea [death] (78831)

Discussion

NZPhvC advised that the CARM database includes reports of diarrhoea, liver and hepatic abnormalities in association with capecitabine. The product datasheet for capecitabine lists diarrhoea as a common and often severe adverse drug reaction, and provides detailed recommendations for dealing with the various grades.

The product datasheets indicate that there are no clinically significant interactions between capecitabine and oxaliplatin, and that the incidence of diarrhoea is the same with mono- or dual-therapy.

NZPhvC advised that there is a small amount of evidence that capecitabine can rarely cause hepatic failure, and no indication that it directly causes renal failure. It was possible that the severe diarrhoea and dehydration may have led to renal failure. The hepatic and renal failure may have also been due to end stage metastatic colorectal cancer.

The Committee considered the causal association with capecitabine to be 'unclassified' for renal failure and hepatic failure, and 'possible' for diarrhoea.

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

4.1.1.7 Trastuzumab, vinorelbine and coronary artery occlusion, intestinal ischaemia, intestinal necrosis, pulmonary embolism, pneumonia [death] (78289)

Discussion

NZPhvC advised that of the reports for trastuzumab in the CARM database, one is of a cardiac condition. There are no similar reports in association with vinorelbine. In the WHO database, reports for hypotension, pulmonary embolism, and pneumonia in association with trastuzumab are statistically significant. There are no reports of intestinal ischaemia, necrosis or gangrene in association with trastuzumab.

The product datasheet for trastuzumab includes hypotension as a serious adverse effect with treatment. NZPhvC advised that this could have led to a myocardial infarction. However, myocardial infarction has been reported with vinorelbine. Subsequent events suggested that she experienced multiple thromboembolic events. Her malignancy was an alternative explanation for the thromboembolic events.

The causal association with trastuzumab, vinorelbine was considered to be 'possible' for coronary artery occlusion, intestinal ischaemia, intestinal necrosis, pulmonary embolism, pneumonia.

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

4.1.1.8 Enoxaparin and haemorrhage stroke [death] (78673)

Discussion

NZPhvC advised that reports of haemorrhage in association with enoxaparin were recorded in both the CARM and WHO databases.

The Committee noted that this was a recognised adverse event with this medicine. They noted however that there were insufficient details provided in this case report to determine if the medicine or another underlying condition contributed to the final outcome.

The causal association with enoxaparin was considered to be 'possible' rather than 'probable' for haemorrhage stroke.

Recommendation

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

4.1.1.9 Atorvastatin and cardiac arrest [death] (78895)

Discussion

NZPhvC advised that the CARM and WHO databases include myocardial events in association with atorvastatin.

The Committee noted that there was limited information provided, but in view of the longstanding risk factors, it was unlikely that this event was related to atorvastatin.

The causal association with atorvastatin was considered to be 'unlikely' for cardiac arrest.

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

4.1.1.10 Acitretin and hepatic function abnormal, INR elevated, leukopenia, consciousness decreased [death] (78280)

Discussion

The NZPhvC advised that both the CARM and WHO databases include reports of abnormal hepatic function in association with acitretin. The datasheet recommends that hepatic function is monitored and the literature includes occasional reports of hepatic reactions in association with acitretin.

The causal association with acitretin was considered to be 'possible' for hepatic function abnormal, INR elevated, leukopenia, consciousness decreased.

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

4.1.1.11 Human menopausal gonadotrophin, human chorionic gonadotrophin, buserelin and cerebral infarction, thrombosis, pleural effusion, ovarian hyperstimulation, cyst [death] (78674)

Discussion

NZPhvC advised that the CARM database does not include any reports for any of the medicines. The WHO database includes reports of OHSS in association with both chorionic gonadotrophin and buserelin. The NZ datasheets for both medicines refer to the possibility of OHSS.

The Committee expressed their sympathy and noted that OHSS is a rare complication of IVF.

The causal association with human menopausal gonadotrophin, human chorionic gonadotrophin, buserelin was considered to be 'probable' for cerebral infarction, thrombosis, pleural effusion, ovarian hyperstimulation, cyst.

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

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

Discussion

NZPhvC advised that the possibility of serious infection occurring with leflunomide and adalimumab had been discussed at previous meetings.

NZPhvC advised that the CARM database includes two other reports of cerebral haemorrhage in association with both adalimumab and leflunomide. One patient reported aggravated hypertension some time after discontinuation of the medicines. The other patient developed hypertension while taking leflunomide, which was then discontinued and blood pressure treatment commenced. Four months later, the patient collapsed with an intracranial haemorrhage after one or two doses of adalimumab. The WHO database also indicates that hypertension is prominent for both adalimumab and leflunomide, but the IC values for both medicines are negative for cerebral haemorrhage.

NZPhvC advised that further information received stated that the patient's blood pressure was normal on admission, and lower while in Intensive Care, but as he was improving, gradually increased (at this stage he was no longer receiving any disease modifying antirheumatic drugs (DMARDs), and leflunomide had been washed out), with a peak two days before the intracerebral bleed.

NZPhvC advised that the NZ product datasheets for both adalimumab and leflunomide include references to hypertension as an adverse reaction.

NZPhvC advised of a recent study which reviewed the prevalence of cardiovascular disease in patients with rheumatoid arthritis, and its association with other factors, including the use of DMARDs. This data indicated that the hypertensive effects of leflunomide do not have a major effect on the risk of stroke and myocardial infarction. Adalimumab was not analysed separately.

It is possible that in this case report the hypertension and cerebral haemorrhage were a result of multi-organ failure. However, the Committee agreed that NZPhvC continue to monitor leflunomide combination therapy, including the co-prescription of adalimumab and leflunomide, and the prescribing of either with other medicines that can increase blood pressure.

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

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

Recommendation

The Committee recommended that NZPhvC add prednisone and naproxen to the suspect medicines in this report.

4.1.1.13 Lenalidomide and thrombosis venous deep, granulocytopenia, pneumonia, disease progression (78536)

Discussion

NZPhvC advised that Drugdex information includes deep vein thrombosis, neutropenia and pneumonia as recognised serious adverse effects of lenalidomide.

The causal association with lenalidomide was considered to be 'possible' for thrombosis venous deep, granulocytopenia, pneumonia and 'unlikely' for disease progression.

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

4.1.1.14 Allopurinol and exfoliative dermatitis, hepatocellular damage, renal failure acute aggravated, hepatic failure, pancreatitis, hypersensitivity [death] (78171)

Discussion

NZPhvC advised that the CARM database includes reports of exfoliative dermatitis, and hypersensitivity, hepatic, and haematologic reactions in association with allopurinol.

The product datasheet lists serious allergic reactions, including skin reactions, in the Adverse Reactions section. It states that skin reactions may be delayed and rarely have been followed by severe hypersensitivity reactions which may be fatal. It recommends that allopurinol be withdrawn immediately if a rash or other signs of allergy occur. The datasheet includes information about hypersensitivity reactions, which have occurred occasionally, including a generalised hypersensitivity vasculitis which can lead to renal and hepatic damage. These hypersensitivity reactions may be severe and life-threatening, and may occur more frequently in patients with renal impairment and / or taking thiazide diuretics.

The Committee noted that a rheumatology research group has been formed in NZ, and an analysis of cases of allopurinol hypersensitivity syndrome is to be conducted in the near future to investigate possible risk factors.

The causal association with allopurinol was considered to be 'possible' for exfoliative dermatitis, hepatocellular damage, renal failure acute, hepatic failure, pancreatitis, hypersensitivity.

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

4.1.1.15 Rocuronium, suxamethonium and respiratory failure [death] (78416)

Discussion

NZPhvC advised that neither of the product datasheets for rocuronium or suxamethonium specifically mention motor neurone disease as a precaution. However, neuromuscular disease is listed as a precaution for rocuronium.

In this case report the patient's condition was not evident when she was anaesthetised.

The causal association with rocuronium, suxamethonium was considered to be 'probable' for respiratory failure.

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

4.1.1.16 Clozapine and intestinal obstruction, deep vein thrombosis, renal failure chronic aggravated [death] (78976)

Discussion

NZPhvC advised that the CARM database includes reports of gastro-intestinal hypomotility in association with clozapine, and that these cases have been discussed in an article published in the Journal of Clinical Psychiatry in 2008.

The product datasheet includes anticholinergic effects on the bowel in the Special Warnings and Precautions section. An increased risk of thromboembolism in immobilised patients is also stated.

NZPhvC advised that further information has been requested but not yet received.

The causal association with clozapine was considered to be 'possible' for intestinal obstruction, deep vein thrombosis, renal failure chronic aggravated.

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

4.1.1.17 Olanzapine and suicide [death] (78207)
Case Report

Discussion

NZPhvC advised that both the IMMP and WHO databases include reports of suicide and suicidal ideation in association with olanzapine.

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

The Committee noted that this case will be reviewed when further details have been received and agreed that no further regulatory action was required at this time.

4.1.2 Alimentary

4.1.2.1 Omeprazole and hypomagnesaemia, hypocalcaemia (77999)

Discussion

NZPhvC advised that there were few relevant reports in the CARM database, while some were included in the WHO database. Hypocalcaemia and hypomagnesaemia are not listed as adverse reactions in the product datasheets.

NZPhvC advised there is a small amount of evidence in the literature of a casual relationship between proton pump inhibitors and hypocalcaemia, hypomagnesaemia. However, in some cases diarrhoea or renal impairment are alternative explanations, or may have contributed.

The causal association with omeprazole was considered to be 'probable' for hypocalcaemia, hypomagnesaemia.

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

4.1.2.2 Omeprazole and hypomagnesaemia, hypocalcaemia (78532)

Discussion

Refer to minute item 4.1.2.1.

The causal association with omeprazole was considered to be 'probable' for hypocalcaemia, hypomagnesaemia.

4.1.3 Hormones

4.1.3.1 Drospirenone/ethinyloestradiol (Yasmin) and embolism pulmonary, pulmonary infarction (78261)

Discussion

NZPhvC advised that Yasmin is not currently funded in NZ. They advised that both the CARM and WHO databases include reports of pulmonary embolism in association with Yasmin, with the majority of the CARM reports being received in the past year. The NZ Yasmin datasheet includes contraindications and precautions to reduce the risk of venous and arterial thromboembolism, in common with other combined oral contraceptives.

The Committee noted that the product datasheet includes an interim estimation of the rates of venous thromboembolism and arterial thromboembolism from the European Active Post Marketing Surveillance (EURAS) study. This study was conducted to compare the risks of adverse cardiovascular and other events associated with the use of drospirenone-containing oral contraceptives with two groups of established oral contraceptives- those containing levonorgestrel, and 'others'.

The Committee was provided with a copy of the final results of the EURAS study, by Dinger et al published in 2007. This study concluded that the risks of cardiovascular and other serious events in users of drospirenone-containing oral contraceptives are similar to those associated with the use of the other oral contraceptives groups with which it was compared.

The causal association with drospirenone/ethinyloestradiol (Yasmin) was considered to be 'probable' for embolism pulmonary, pulmonary infarction.

4.1.3.2 Drospirenone/ethinyloestradiol (Yasmin) and cerebral infarction (78908)

Discussion

NZPhvC advised that the EURAS study suggested that the rate of arterial-thromboembolic events appeared to be lower with drosperidone containing oral contraceptives, when compared with the other oral contraceptives in the study; however, this was not statistically significant.

Refer to minute item 4.1.3.1.

The causal association with drospirenone/ethinyloestradiol (Yasmin) was considered to be 'possible' for cerebral infarction.

4.1.4 Other Reports

The Committee noted the following case reports:

4.1.4.1 Etoricoxib (78235)
4.1.4.2 Ezetimibe (78677)
4.1.4.3 Leflunomide, ibuprofen (78413)
4.1.4.4 Leflunomide (78961)
4.1.4.5 Leflunomide, adalimumab (78407)
4.1.4.6 Pioglitazone (78966)

4.2 Quarterly Reports from CARM as at March 2008

Discussion

NZPhvC presented the report. They noted that PHARMAC are now funding more than one brand of product for both pantoprazole and omeprazole, and that the brand switch reports continue for all brands of these medicines. No reports for methylphenidate have been received since the previous brand was made available to those experiencing adverse effects.

The Committee noted the quarterly reports from CARM as at June 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.

Brune K, et al. (2008) N-Terminal Pro-B-Type Natriuretic Peptide Concentrations Predict the Risk of Cardiovascular Adverse Events from Antiinflammatory Drugs: A Pilot Trial. Clinical Chemistry ; 54:7: 1149 -1157
Fea A. (2008) Medicine and Mental Health- the Isotretinoin Issue. NZ Clinical Psychologist Journal ; Vol 18(1): 8-14
Darwish T. (2008) Ciprofloxacin-induced seizures in a healthy patient. NZMJ; 121(1277): 104 - 105
Record of the Pharmacology and Therapeutics Advisory Committee Meeting held on 21 and 22 February 2008
Record of the Pharmacology and Therapeutics Advisory Committee Meeting held on 8 and 9 May 2008

6. New Zealand pharmacovigilance-related activities

DHBNZ Safe and Quality Use of Medicines Group. 2008. Newsletter. Volume 4, Number 2

DHBNZ Safe and Quality Use of Medicines Group. 2008. Newsletter. Volume 4, Number 3

7. international pharmacovigilance-related Activities

7.1 United Kingdom

Medicines and Healthcare products Regulatory Agency (MHRA). 2008. Drug Safety Update. Volume 1, Issue 11
Medicines and Healthcare products Regulatory Agency (MHRA). 2008. Drug Safety Update. Volume 1, Issue 12
Medicines and Healthcare products Regulatory Agency (MHRA). 2008. Drug Safety Update. Volume 2, Issue 1

7.2 United States

Food and Drug Administration (FDA). 2008. Drug Safety Newsletter. Volume 1, Issue 3

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.

9. ANY OTHER business

9.1 Report from Health and Disability Commissioner

The Chair raised a report from the Heath and Disabilities Commissioner relating to medicine safety issues, in particular the NHI alert system. The Chair requested that NZPhvC review the report and report back to the MARC.

9.2 Eltroxin correspondence

The Committee discussed the correspondence that some of the members had received. They agreed that the Chair would respond on behalf of the members, including the following points:

The Committee had taken great care in reviewing all of the available New Zealand and international evidence at their most recent meeting
The Committee was concerned about the difficulties patients had experienced
The MARC members understand the significance of the symptoms patients have experienced
The MARC supports Medsafe and PHARMAC in their efforts to obtain an alternative supply of levothyroxine for those patients experiencing allergic or intolerant reactions to the new formulations of Eltroxin
The Committee was pleased to hear the announcement today that an application for an alternative product has been received by Medsafe, and that funding is being considered by PHARMAC.

9.3 PHARMAC consultation on removing specialist restriction from retinoids

The Committee raised concerns regarding the PHARMAC proposal to remove the specialist restriction on the prescribing of oral retinoid products isotretinoin and tretinoin. Currently, these products require a specialist prescription in order to obtain Government subsidy. The Committee considered that the removal of this requirement for a specialist prescription would increase prescribing, while other countries are taking steps to reduce prescribing due to safety concerns. The Chair agreed to discuss a submission with Committee members via email.

There being no further business, the Chair thanked members and the secretariat for their attendance and closed the meeting at 4pm.

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

Committees