Revised: 20 May 2013

Committees

Minutes of the 132nd Medicines Adverse Reactions Committee Meeting - 13 December 2007

Preface:

In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.

Names of individuals have also been deleted where that person's contribution is not in the public domain, or will not shortly be so. For example, the names of those to be approached to write an article are deleted, but the names of those who have contributed to a draft article are not usually deleted. In addition, names are not usually deleted when a contribution has been made in an official capacity.

The material listed as being considered on an issue is not intended to be exhaustive.

The Recommendations of the Committee are in bold typeface.

Minutes:

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

1 MATTERS OF ADMINISTRATION

2 STANDING AGENDA ITEMS

3 PHARMACOVIGILANCE ISSUES

4 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

5 PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

6 INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

6.1 UNITED KINGDOM

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

8 OTHER BUSINESS

8.1 INTERNATIONAL NON-PROPRIETARY NAMES (INN) FOR ACTIVE INGREDIENTS

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Minutes of the 132nd Medicines Adverse Reactions Committee Meeting
13 December 2007

The one hundred and thirty second meeting of the Medicines Adverse Reactions Committee (MARC) was held on 13 December 2007 at the Sunderland Room, Wellington Airport Conference Centre, Wellington, New Zealand. The meeting commenced at 8:30 am and closed at 2.30 pm.

MARC MEMBERS PRESENT

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

MARC SECRETARIAT PRESENT

Dr A Forde (Acting Principal Technical Specialist, Medsafe)
Ms S Von Afehlt (Senior Pharmacy Advisor/Editor of Prescriber Update, Medsafe)
Ms A Cutfield (Advisor, Pharmacovigilance)
Ms J McNee (MARC Secretary)

1. MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Dr M Tatley.

1.1.1 MARC membership

Discussion

The Committee noted that Dr Ruth Savage has been appointed as an alternate member to Dr Michael Tatley.

1.2 Minutes of the 131st MARC Meeting

The minutes of the 131st MARC meeting were not reviewed at this time. It is the intention of Medsafe that the minutes of the 131st meeting be ratified out of session.

1.2.1 Report to the Minister's Delegate

The Secretary advised that there had been a formalisation of the process when the Committee recommended that action be taken urgently regarding a particular issue. In such instances, the Chair is to be provided with the minute of the discussion in draft form and asked to confirm in writing that the minute is accurate. Following this, a report is to be sent to the Minister's Delegate, asking for approval to action the Recommendation.

The complete minutes, once finalised, are to be ratified by the Chair before being sent to the Minister's Delegate, asking for approval to action the Recommendations of the MARC.

The Committee noted that one Recommendation from the 131st MARC meeting, regarding minute item 3.9 Amiloride/ hydrochlorothiazide, hypnonatraemia and hyperkalaemia, had been rejected by the Minister's Delegate on the advice of Medsafe (see minute item 2.1.7 ). The Committee agreed to provide further information in support of this Recommendation.

1.3 Dates of Future MARC Meetings

The date for the next MARC meeting was confirmed as being Thursday 20 March 2008. The subsequent MARC meeting dates for 2008 were scheduled for 12 June, 11 September and 11 December.

1.4 Potential Conflicts of Interest

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

There were no potential conflicts of interest considered to influence the Discussions or decisions of the Committee.

1.5 Prescriber Update

1.5.1 Schedule of Planned Prescriber Update Articles

Discussion

The Committee noted the schedule of planned Prescriber Update articles.

1.5.2 Prescriber Update. Volume 28, Number 1. November 2007

Discussion

The Committee noted the latest edition of Prescriber Update.

Professor Ellis advised that a paper entitled 'Clozapine: Fatal 'constipation' more common than fatal agranulocytosis' , to which he and members of the Intensive Medicines Monitoring Programme (IMMP) had contributed, had been accepted for publication in the Journal of Clinical Psychiatry.

2 STANDING AGENDA ITEMS

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

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

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

2.1.1 Lumiracoxib and liver toxicity
September 2007 minute item 3.1

Issue

In September 2007, the Committee recommended that Medsafe contact the Best Practice Advocacy Centre (BPAC) and ask they disseminate the MARC's monitoring advice.

The Committee recommended that Medsafe request that Novartis forward all New Zealand reports regarding adverse hepatic reactions to lumiracoxib to NZPhvC.

The Committee recommended that Medsafe contact Novartis to further investigate the establishment of a patient registry, to establish the prevalence of disordered liver function tests.

The Committee recommended that NZPhvC should seek further information about the CARM case report (76287) and report back to the MARC.

The Committee recommended that Medsafe obtain usage data for lumiracoxib in six months time and report back to the MARC.

The Committee recommended that the issue of lumiracoxib and liver toxicity should be placed both on the standing agenda list, and scheduled for review in 12 months.

Outcome

Medsafe has asked BPAC to disseminate the MARC's monitoring advice for patients taking lumiracoxib.

Medsafe is in the process of contacting Novartis regarding the establishment of a patient registry to determine the prevalence of disordered liver function tests in association with lumiracoxib use.

Medsafe has requested that Novartis forward all reports of adverse hepatic reactions to NZPhvC regardless of the severity of the reports.

The NZPhvC will collate reports and relevant data in preparation for the review and bring any important observations to the committee's attention at an earlier time if warranted.

Discussion

See minute item 3.1.

2.1.2 Rubifen SR (methylphenidate SR) brand switch – aggressive and defiant behavioural reactions
September 2007 minute item 3.2

Issue

In September 2007, the Committee recommended that Medsafe write to PHARMAC requesting that they reconsider making the previously subsidised Ritalin SR product available to patients until this issue is investigated further.

The Committee recommended that Medsafe write to the sponsors of Rubifen SR under Section 36 of the Medicines Act 1981 requesting that they provide further data in support of Rubifen SR.

The Committee recommended that Medsafe contact the sponsor of Rubifen SR and request that the data sheet is updated to include information on the risk of aggressive and defiant behaviours.

The Committee recommended that Medsafe report back to the MARC when the results of further testing of the Rubifen SR product are available.

Outcome

Medsafe has written to PHARMAC, who have agreed to fund the Ritalin SR brand for patients who have experienced serious adverse reactions following the switch to Rubifen SR.

Medsafe will provide a verbal report regarding the Outcome of the Discussions with the sponsor of Rubifen SR at the time of the meeting.

Discussion

Medsafe advised that the sponsor of Rubifen SR had provided the data requested under Section 36 of the Medicines Act 1981. This data has been evaluated by the evaluation section of Medsafe and been found to have been acceptable, with all batches tested meeting agreed specifications.

The Committee noted that the new information did not provide any pharmacokinetic data which explained the aggressive and defiant behavioural reactions experienced by some patients while taking Rubifen SR.

Recommendation

The Committee recommended that Medsafe and NZPhvC provide the MARC with an update on Rubifen SR (methylphenidate SR) brand switch – aggressive and defiant behavioural reactions at its next meeting.

2.1.3 Lipid-lowering agents and psychiatric adverse reactions: Active Monitoring Review
September 2007 minute item 3.3

Issue

In September 2007, the Committee recommended that Medsafe contact the sponsors of all lipid-lowering agents and request the above-mentioned datasheet changes.

Outcome

The sponsors have been contacted and requested to add memory loss and depression to their data sheets. Medsafe is awaiting responses.

Discussion

The Committee noted the above.

2.1.4 Statins, neuromuscular degenerative disease and amyotrophic lateral sclerosis-like syndrome
September 2007 minute item 3.4

Issue

In September 2007, the Committee recommended that the issue of statins, neuromuscular degenerative disease and amyotrophic lateral sclerosis-like syndrome be placed on the 'scheduled review' list for a 12-monthly review.

Outcome

The issue of statins, neuromuscular degenerative disease and amyotrophic lateral sclerosis-like syndrome has been placed on the 'scheduled review' list for a 12-monthly review.

Discussion

The Committee noted the above.

2.1.5 Oral terbinafine and serious adverse reactions (blood dyscrasias, heptatotoxicity and dermatological reactions ) –Active Monitoring Review
September 2007 minute item 3.5

Issue

In September 2007, the Committee recommended that Medsafe contact the Best Practice Advocacy Centre (BPAC) and ask they include a paragraph in their publication regarding the appropriate prescribing of oral terbinafine.

The Committee recommended that NZPhvC bring back case reports to the MARC in six months time.

The Committee recommended that the issue of oral terbinafine and serious adverse reactions (blood dyscrasias, heptatotoxicity and dermatological reactions) should be placed on the 'scheduled review' list for 12-monthly review.

Outcome

Medsafe has asked BPAC to include a paragraph in their publication regarding the appropriate prescribing of oral terbinafine.

The issue of oral terbinafine and serious adverse reactions (blood dyscrasias, heptatotoxicity and dermatological reactions) has been placed on the 'scheduled review' list for 12-monthly review.

Discussion

The Committee noted the above.

2.1.6 Inhaled LABAs and risk of fatal and non-fatal asthma exacerbations – Watching Brief Review
September 2007 minute item 3.7

Issue

In September 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 becomes available.

Outcome

This issue has been placed on the ''scheduled review' list for a 12-monthly review.

Discussion

The Committee noted the above.

2.1.7 Issues monitored by the MARC, Medsafe and NZPhvC as at June 2007
September 2007 minute item 3.9, June 2007 minute item 1.6

Issue

In June 2007, the Committee recommended that NZPhvC review the reports in the CARM and WHO databases regarding Amizide, and bring these back to the MARC.

The Committee recommended that Medsafe seek information on the current usage of Amizide in New Zealand.

The Committee recommended that the issue of Amizide, hyponatraemia, and hyperkalaemia be placed on the Agenda for the September 2007 MARC meeting.

Outcome

Medsafe and the NZPhvC presented reports to the MARC at the September 2007 meeting on amiloride/hydrochlorothiazide, hyponatraemia, and hyperkalaemia.

Medsafe recommended to the Minister's Delegate that he reject the MARC Recommendation from the September 2007 meeting that "Medsafe write to the sponsors of Amizide, asking them to justify why their product contains 50mg hydrochlorothiazide when similar medicines generally contain 12.5mg hydrochlorothiazide" because Medsafe considered that there was insufficient evidence of harm to justify contacting the product sponsor, given the absence of reported adverse drug reactions for this medicine in the past seven years.

Discussion

Refer to minute item 1.2.1.

2.1.8 Amiodarone and interstitial lung disease [death] (75626)
September 2007 minute item 4.1.1.1

Issue

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

Outcome

Although further information was received it adds no further insight into the approximately 6 month lag between discontinuation of amiodarone and the onset of progressive respiratory symptoms – an unusual but reported occurrence in association with amiodarone. In addition the notes also suggest that there may have been ongoing respiratory compromise whilst also indicating that the patient had sufficient endurance to undertake a bush walk. In the light of these diverse factors, the relationship although suggesting an underlying possibility of association given its long term use with at least some respiratory compromise, is recommended that it is at best still unclassifiable.

Discussion

The Committee noted the above.

2.1.9 Diclofenac and duodenal ulcer haemorrhagic, oesophagitis [death] (74905)
September 2007 minute item 4.1.1.3

Issue

In September 2007, the Committee recommended that NZPhvC analyse the CARM reports of renal failure with diclofenac further, and that these should be included in the standing agenda item review of non-specific NSAIDs and cardiovascular adverse effects, including congestive heart failure, at the December 2007 MARC meeting.

Outcome

The report on renal failure with diclofenac and non-specific NSAIDS has been postponed to the March 2008 meeting.

Discussion

The Committee noted the above.

2.1.10 Salmeterol and bronchospasm aggravated (death) (75086)
September 2007 minute item 4.1.1.11

Issue

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

Outcome

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

Discussion

The Committee noted the above.

2.1.11 Ezetimibe and pancreatitis, pancreas cyst, diabetes mellitus (74993)
September 2007 minute item 4.1.1.13

Issue

In September 2007, the Committee recommended that a paragraph be published in Prescriber Update, advising prescribers that ezetimibe can cause drug-induced pancreatitis.

Outcome

Medsafe and NZPhvC will liaise regarding the writing of this article.

Discussion

The Committee noted the above.

2.1.12 Citalopram, Codral Cough and Flu preparation and serotonin syndrome, drug interaction (75084)
September 2007 minute item 4.1.1.16

Issue

In September 2007, the Committee recommended that a paragraph be published in Prescriber Update, advising prescribers that it would be prudent to monitor patients receiving SSRIs who are also taking dextromethorphan-containing preparations.

Outcome

Medsafe and NZPhvC will liaise regarding the writing of this article.

Discussion

The Committee noted the above.

2.1.13 Schedule of Planned Prescriber Update Articles
September 2007 minute item 2.2.1, June 2007 minute item 1.5.1

Issue

In June 2007, the Committee reviewed a draft Prescriber Update article on "Glitazones: Fluid Retention, Cardiac Failure, and Macular Oedema". Due to the emergence at that time of further issued around the use of glitazones and their place in treatment, the Committee recommended that an additional, separate Prescriber Update article be written to focus on the other emerging adverse reactions of the glitazones.

Outcome

The MARC has previously recommended a Prescriber Update article about the non-cardiovascular adverse drug reactions of the glitazones. This article will most likely be authored by NZPhvC.

Discussion

The Committee noted the above.

2.1.14 Adverse reactions to rosiglitazone & pioglitazone: active monitoring review
September 2007 minute item 2.1.3, June 2007 minute item 2.1.5; March 2007 minute item 4.1

Issue

In June 2007, the Committee recommended that the issue of the effects of the glitazones on bone density be included in the Active Monitoring review to be discussed at the March 2008 MARC meeting.

The Committee recommended that Medsafe contact the sponsors of Actos for comment on the cardiac safety of pioglitazone.

Outcome

The issue of fracture/bone density has been added to the Scheduled Review of all adverse effects to rosiglitazone and pioglitazone, to be carried out in March 2008.

Both the Actos (pioglitazone) and Avandia (rosiglitazone) datasheets have been revised with cardiovascular warnings and contraindications.

Discussion

The Committee noted the above.

2.1.15 Golimumab, amoxycillin/clavulanic acid, isoniazid, and diarrhoea, vomiting, colitis, septic shock, cardiac arrest [death] (73358)
September 2007 minute item 2.1.4, June 2007 minute item 2.1.7; March 2007 minute item 4.3.1.2

Issue

In June 2007, the Committee recommended that NZPhvC discuss the issue of making reporters aware of patient's rights with respect to ACC and report back to the Committee.

Outcome

The current ACC mechanism of informing Medsafe would be extended to include CARM.

Discussion

The Committee noted the above.

2.1.16 Adverse reactions to leflunomide: active monitoring review
September 2007 minute item 2.1.5, June 2007 minute item 3.1

Issue

In June 2007, the Committee recommended that an article concerning pancytopenia, hepatic reactions, and pneumonitis in combination with methotrexate be written for publication in Prescriber Update. The article should also include a reminder about peripheral neuropathy and infection such as tuberculosis.

The Committee recommended that Medsafe contact the sponsors of leflunomide to request the above mentioned data sheet revisions.

The Committee recommended that the issue of adverse reactions to leflunomide should remain on the active monitoring review list.

Outcome

The Prescriber Update article will be authored by NZPhvC.

The issue of all adverse reactions to leflunomide has been placed on the 'scheduled review' list for a 12 monthly review.

Discussion

The Committee noted the above.

2.1.17 Lamotrigine and convulsion [death] (74826)
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

The Committee noted the above.

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

Issue

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

Outcome

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

Discussion

The Committee noted the above.

2.1.19 Tiotropium and cardiac failure [death] (74591), Tiotropium and headache [death] (74756), Tiotropium and sudden death [death] (74759), Tiotropium and sudden death [death] (74760) Tiotropium and sudden death [death] (74838)
September 2007 minute item 2.1.11, June 2007 minute items 4.1.1.6, 7, 8, 9, 10

Issue

In June 2007, the Committee recommended that NZPhvC seek further case details from the company about these reports involving tiotropium (74591, 74756, 74759, 74760, 74838) and bring the information back to the MARC.

In September 2007, a verbal report was presented to the MARC, summarising the details which had been received from the company to date. The Committee recommended that NZPhvC prepare a summary of these reports involving tiotropium for the December MARC meeting.

Outcome

A report was included in Section 4 of the dossier.

Discussion

See minute item 4.3.

2.1.20 Clozapine and haematological malignancies
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

In March 2007, 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.

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

Issue

In March 2007, the Committee recommended that Medsafe write to the Pharmacy Council of New Zealand and the Pharmaceutical Society of New Zealand (Inc) asking that they remind pharmacists about the adverse reactions of oral terbinafine.

Outcome

The Pharmaceutical Society published an article on their website in September 2007, which will also be included in the next print version of their newsletter scheduled for November 2007.

A response is still awaited from the Pharmacy Council.

Discussion

The Committee noted the above.

2.1.22 Aprotinin and cardiovascular, renal & cerebrovascular adverse reactions: watching brief review
September 2007 minute item 2.2.3, June 2007 minute item 2.1.3; March 2007 minute item 3.1

Issue

In March 2007, the Committee recommended that Medsafe bring back to the MARC any data that arises from the BART study, and continue to monitor international regulatory activity and report back to the MARC as appropriate.

The Committee agreed with Medsafe's suggested revisions for the NZ Trasylol data sheet.

Outcome

The revised data sheet was published on the Medsafe website in October 2007.

See minute item 3.3 for further information on this issue.

Discussion

The Committee noted the above.

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

Issue

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

Outcome

The NZPhvC will bring further information to MARC when received.

Discussion

The Committee noted the above.

2.1.24 COX-2 Inhibitors: Active Monitoring Review
September 2007 minute item 2.2.8, June 2007 minute item 2.2.2; March 2007 minute item 2.1.5; December 2006 minute item 3.1

Issue

In September 2007, Medsafe advised that the COX-2 inhibitor data sheets have been reviewed and the gastrointestinal safety warnings compared against those in the Australian Product Information (PI).

The Committee recommended that Medsafe write to sponsors to request the inclusion of the additional statements in the New Zealand data sheets.

Outcome

The sponsors have been contacted and have responded to Medsafe's requests. The New Zealand data sheets are in the process of being updated.

Discussion

The Committee noted the above.

2.1.25 Non-selective NSAIDs: Active Monitoring Review
September 2007 minute item 2.2.9, June 2007 minute item 2.2.3; March 2007 minute item 2.1.6; December 2006 minute item 3.2

Issue

In December 2006, the members recommended that non-selective NSAID product information amendments recommended by the ADEC in Australia be adopted in New Zealand.

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

The Committee recommended that the information in Prescriber Update form the basis of a Dear Healthcare Professional letter.

Outcome

Medsafe has written to the sponsors of the non-selective NSAIDs to request datasheet changes. All sponsors have revised their datasheets to Medsafe's satisfaction with respect to gastrointestinal, skin and cardiac safety warnings.

A Dear Healthcare Professional letter has been drafted, and will be included in the next issue of Prescriber Update.

Discussion

The Committee noted the above. A draft of the letter was included in the December 2007 dossier and members made some suggestion for changes.

2.1.26 Candesartan and palpitations (73162)
September 2007 minute item 2.2.13, June 2007 minute item 2.2.7; March 2007 minute item 2.1.11; December 2006 minute item 4.1.8.1

Issue

In December 2006, the Committee recommended that Medsafe review the Australian and International data sheets for candesartan and palpitations, and update the New Zealand data sheet if warranted.

Outcome

Medsafe has contacted AstraZeneca to request that the Atacand data sheet be updated to list palpitations as an adverse reaction. The data sheet has been updated to include: "Although causality to candesartan has not been established, palpitation has been very rarely reported as an adverse event during post-marketing surveillance."

Discussion

The Committee noted the above.

2.1.27 Quinine, Nocturnal Leg Cramps and Thrombocytopenia
June 2007 minute item 2.2.8; March 2007 minute item 2.2.2; December 2006 minute item 2.1.3; September 2006 minute item 3.1; June 2006 minute item 4.1.3.1

Issue

In September 2006, the Committee recommended that Medsafe pursue removal of the indication "prophylaxis and treatment of nocturnal recumbency leg muscle cramps, including those associated with arthritis, diabetes, varicose veins, thrombophlebitis, arteriosclerosis and static foot deformities" from quinine products.

In September 2006, the Committee recommended that, following resolution of the above, Medsafe write an article for publication in Prescriber Update informing prescribers of the change to the indications for quinine.

Outcome

The data sheets of the quinine products (Apotex and Pacific brands) currently available in New Zealand have been updated and published on the Medsafe website.

The Prescriber Update article was published on the Medsafe website in October 2007, and in the November 2007 hard-copy issue of Prescriber Update, which was distributed to health professionals in mid November 2007.

Discussion

The Committee noted the above. The editor of Prescriber Update informed the Committee that correspondence had been received from some general practitioners, expressing concern about how to manage their patients who relied on quinine, now that quinine was no longer indicated for leg cramps.

2.1.28 SSRIs and Use in Pregnancy: Watching Brief Review
September 2007 minute items 2.2.16 and 3.6, June 2007 minute item 2.2.10; March 2007 minute item 2.2.4; December 2006 minute item 2.1.5; September 2006 minute item 3.3; June 2006 minute item 2.2.8; March 2006 minute item 2.2.7; December 2005 minute item 2.1.7; September 2005 minute item 3.5

Issue

In September 2006, the Committee recommended that Medsafe consider publishing an article in Prescriber Update alerting prescribers and lead maternity carers (LMCs) to the risks associated with the use of SSRIs in pregnancy.

In September 2006, the Committee recommended that Medsafe ask all sponsors of SSRIs to update the data sheets as per the Aropax data sheet to describe the potential risk of persistent pulmonary hypertension in the newborn (PPHN) following foetal exposure.

In September 2006, the Committee recommended that Medsafe ask the sponsors of Apo-Fluoxetine (Apotex) and Plinzene (Douglas) to update the data sheets to describe the risk of neonatal withdrawal following foetal exposure.

In September 2006, the Committee recommended that Medsafe ask the sponsor of Apo-Paroxetine (Apotex) to amend the data sheet categorisation of risk during pregnancy from Australian Drug Evaluation Committee category B3 to category C.

Outcome

A draft Prescriber Update article was included in the September 2007 MARC dossier.

With the following exceptions, all datasheets have been updated as requested:

Lundbeck (Cipramil, Lexapro) and Eli Lilly (Prozac) did not consider the inclusion of PPHN justified at this time. At the March 2007 meeting, the MARC accepted the reasoning provided by these companies.

Pfizer have now agreed to update the data sheet for Zoloft as requested.

Discussion

The Committee noted the above.

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

Issue

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

Outcome

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

Discussion

The Committee noted the above.

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

Issue

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

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

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

Outcome

Medsafe will draft a Prescriber Update article and seek input from [..].

Discussion

The Committee noted the above.

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

Issue

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

Outcome

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

Discussion

The Committee noted the above.

2.1.32 Diclofenac/ibuprofen/prednisone and gastric ulcer, duodenal ulcer, intestinal ulceration, haematemesis, hypoproteinaemia (CARM case 71906)
September 2007 minute item 2.2.20, June 2007 minute item 2.2.14; March 2007 minute item 2.2.9; December 2006 minute item 2.1.12; September 2006 minute item 4.1.3.1

Issue

In September 2006, the Committee recommended that Medsafe review the NSAID product data sheets with respect to the risk of lower gastrointestinal adverse effects and then request the product sponsors to update the data sheets as warranted.

Outcome

This Recommendation has been actioned as part of the Outcomes arising from the MARC review of the safety of the non-selective NSAIDs at the December 2006 MARC meeting – see item 2.1.25.

Discussion

The Committee noted the above.

2.1.33 2.3.1 Low Molecular Weight Heparins (LMWHs) in Renal Impairment.
December 2005 minute item 2.2.12; September 2005 minute item 2.2.6; June 2005 minute item 2.2.11; September 2004 minute item 2.1.6; June 2004 minute item 2.1.4; March 2004 minute item 2.1.8; December 2003 minute item 4.1.1.5

issue

In June 2005, the Committee recommended that Medsafe should contact the DHBNZ Safe Use of Medicines Group to enquire on the progress of the development of a protocol for the safe use of LMWHs in patients with severe renal impairment.

Outcome

The DHBNZ Safe Use of Medicines Group responded to Medsafe in October 2005. Medsafe was informed that an alert was currently being developed to advise prescribers on the required enoxaparin dosage adjustment for patients with renal impairment (creatinine clearance <50mL/min). In view of a lack of data for other LMWHs this advice would not be extrapolated to the other LMWHs available in New Zealand. After consultation throughout New Zealand the Safe Use of Medicines Group determined that there was only limited ability to perform anti-Xa monitoring in New Zealand and therefore monitoring could not be recommended routinely.

In December 2005, the Committee noted the above and agreed that Medsafe should bring the DHBNZ Safe Use of Medicines Group protocol to the MARC once it was finalised.

In August 2007, the DHBNZ Safe Use of Medicines Group advised that the protocol was in its final stages of development and would be sent out for consultation to relevant parties before publication.

Discussion

The Committee noted the above.

3 PHARMACOVIGILANCE Issues

3.1 LUMIRACOXIB AND LIVER TOXICITY

References

• MHRA Drug Safety Information: Lumiracoxib – Suspension of UK licenses with immediate effect. 19 November 2007. http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2033074&ssTargetNodeId=364
• Novartis Pharmaceuticals. Latest cumulative update on severe hepatic cases until 15 November 2007.
• Novartis Pharmaceuticals. Latest Prexige approval and launch list. 21 November 2007.

Background

Medsafe provided a report for the MARC on the issue of lumiracoxib (Prexige) and liver toxicity. This item was placed on the standing agenda list in September 2007, following the review by the Australian Adverse Drug Reactions Advisory Committee (ADRAC) on 10 August 2007 which resulted in the cancellation of the registration of all dosage forms of lumiracoxib in Australia. This was in response to 8 reports of serious liver toxicity associated with the use of lumiracoxib, including two deaths from liver failure, and two patients requiring liver transplant, that had occurred in Australia since February 2007.

On Tuesday 14 August 2007, Medsafe convened a meeting of the Medicines Adverse Reactions Committee (MARC) by teleconference. At this meeting, the MARC recommended that:

• The consent for Prexige 200mg and 400mg tablets be revoked in New Zealand, under Section 35(1)(a) of the Medicines Act 1981.
• Prexige 100mg tablets should remain available in New Zealand for the chronic treatment of osteoarthritis only, with a number of restrictions including the requirement that liver function tests (LFTs) be performed at baseline and monthly thereafter.
• Prescribers should be advised to report any liver function test abnormalities to CARM.

On 21 August 2007, Novartis distributed a "Dear Healthcare Professional" letter to New Zealand prescribers and pharmacies to disseminate this information. The Prexige New Zealand data sheet was also updated to include this new information.

On 23 August 2007, the UK Medicines and Healthcare products Regulatory Agency (MHRA) issued interim information and advice concerning the hepatic safety of lumiracoxib. A "Dear Health Professional letter" was distributed to inform UK prescribers of the following information:

• Novartis had received reports of serious liver toxicity including cases resulting in death of liver transplantation in patients taking lumiracoxib, mostly with doses higher than 100mg daily.
• Lumiracoxib was now contraindicated in the following patients:
  • Patients with any current hepatic disease;
  • Patients with prior drug-induced significant (>3xULN) elevations of transaminases;
  • Patients with liver transaminases >1.5xULN before treatment, or >3xULN during treatment (see below); or
  • Patients taking other medicines associated with clinically significant hepatotoxicity.
• Liver function tests (LFTs) should be performed at baseline and monthly where treatment is needed for longer than 1 month. Prescribers were advised to stop treatment if transaminases >3xULN and to repeat in 7 days if transaminases are >2xULN. It was also advised that LFTs should be performed in any patients reporting any systemic illness whilst taking lumiracoxib.
• Patients should be informed of possible signs and symptoms of hepatic injury including nausea, vomiting, anorexia, malaise, fatigue, dark urine, right upper abdominal pain as well as itching and jaundice.

In August 2007, Health Canada advised that they were currently reviewing the hepatic safety of lumiracoxib in light of the TGA's decision. In the interim, prescribers were advised to use the lowest effective dose of lumiracoxib for the shortest possible duration.

At this time, lumiracoxib had not been approved for use in the United States.

At its September 2007 meeting, Medsafe provided the MARC with an update on the national and international regulatory action undertaken subsequent to the special MARC meeting in August 2007. The Committee noted that no other regulators apart from the Australian Therapeutic Goods Administration (TGA) had withdrawn the 100mg strength of lumiracoxib and considered the action taken in New Zealand had been appropriate. The MARC considered that while the risk:benefit ratio for the 100mg strength in the treatment of osteoarthritis remained favourable at that time, this could change as further information became available. The Committee agreed that no further regulatory action was required at that time and recommended that the issue of lumiracoxib and liver toxicity be placed on the standing agenda list, and scheduled for review in 12 months.

In September 2007, the FDA issued a 'non-approvable' letter for lumiracoxib 100mg tablets.

On 3 October 2007, Health Canada announced that Novartis had agreed to cease sales and marketing of lumiracoxib in Canada. This request had been made after Health Canada concluded that the risk of serious hepatotoxicity associated with the use of Prexige could not be safely and effectively managed.

On 19 November 2007, the MHRA announced that the license for lumiracoxib 100mg tablets was being suspended, effective immediately, due to concerns regarding an increase in reports of serious hepatic adverse effects associated with the 100mg dose. This decision was made on the advice of the MHRA's independent expert advisory committee - the Commission on Human Medicine (CHM). The CHM noted that although there was some evidence that the risk of hepatotoxicity may be related to dose and duration of exposure, cases of serious hepatotoxicity have been identified following exposure to the licensed 100mg dose, and after short duration of treatment (less than one month in some cases). CHM therefore concluded that the risk minimisation measures implemented in the UK in August/September (baseline and monthly liver function test monitoring, and contraindications for patients with current or previous hepatic dysfunction) to manage the identified risks of hepatotoxicity could not be relied upon to guarantee patient safety, and further restrictions were unlikely to be practical. Media reports indicated that similar action had been taken in Germany and Austria.

The purpose of the November 2007 Medsafe report was to:

• To update the MARC on national and international regulatory action undertaken subsequent to the September 2007 MARC meeting.
• To seek the MARC's opinion as to whether or not further regulatory action is required to address the potential risk of hepatotoxicity associated with the use of lumiracoxib 100mg.

Discussion

The Committee noted the November 2007 Medsafe report.

The Committee noted that the data supplied by Novartis indicated that up to 15 November 2007, there had been nine reports of severe hepatic reactions associated with lumiracoxib 100mg. Severe cases were defined as hepatic failure; confirmed Hy's cases (ie ALT or AST >3 x ULN and bilirubin 2 x ULN); or cases resulting in transplant or death. In addition, there were three serious reports of hepatitis/hepatic failure and seven reports of serious jaundice or hepatic enzyme elevation in patients taking lumiracoxib 100mg.

NZPhvC advised that up until 20 November 2007, CARM had received 18 reports of adverse reactions to Prexige, three of which were hepatic reactions. All three hepatic reactions were determined to be non-serious, and the onset of symptoms occurred prior to the dissemination of advice to prescribers on 21 August 2007.

The Committee noted that lumiracoxib data provided by Novartis indicated that in September 2007, sales of Prexige 100mg in New Zealand had fallen significantly compared to sales in July 2007.

The Committee discussed the difficulties of ascertaining if the risk management strategies implemented in New Zealand in August 2007 to manage the potential risk of hepatotoxicity associated with the 100mg dose had been successful or not. It was noted that the three ADR reports to CARM indicated that LFT monitoring had been utilised appropriately as per the MARC's advice in August. However, it was not yet possible to determine whether monthly LFT monitoring would prevent the occurrence of serious or severe hepatotoxicity occurring with the 100mg dose, particularly as the number of patients taking Prexige in New Zealand is very low.

The Committee noted that the licence for lumiracoxib 100mg had now been suspended or withdrawn in Australia, Canada, the UK, Germany, Austria, Turkey and Aruba.

They also noted that a full regulatory review of the risks and benefits of lumiracoxib within Europe was currently being conducted. Medsafe advised that the CHMP, the EMEA's advisory committee, was meeting on the 13th December 2007 to discuss the risk:benefit analysis for lumiracoxib.

The MARC agreed that the new information on spontaneous reports of adverse hepatic reactions in association with lumiracoxib 100mg has altered the risk:benefit ratio of this medicine. However, the MARC agreed there was no current evidence that the risk management strategy implemented in August 2007 had been unsuccessful. The Committee recommended that no further regulatory action was required at this time but that regulatory action be reconsidered once the Outcome of the EMEA's full regulatory review of the risks and benefits of lumiracoxib are available.

Recommendation

The Committee recommended that regulatory action be reconsidered once the Outcome of the EMEA's full regulatory review of the risks and benefits of lumiracoxib became available.

Secretary's note:

Following the Outcome of the EMEA's full regulatory review, the consent for Prexige 100mg tablets was revoked in New Zealand by Medsafe on 20 December 2007. A pharmacy-level recall of available stock was instigated and a letter was issued to health professionals to explain that the benefits of lumiracoxib no longer outweighed the risks of harm.

3.2 NON-SPECIFIC NSAIDs AND CARDIOVASCULAR ADVERSE EFFECTS, INCLUDING CONGESTIVE HEART FAILURE – SCHEDULED 12 MONTHLY REVIEW

References

• Table of prescription non-selective NSAIDs currently registered in New Zealand.
• Draft Prescriber Update article – Dear Healthcare Professional Letter.
• CARM and WHO data provided by NZPhvC
• EMEA Press Release: European Medicines Agency recommends restricted use for piroxicam.
• US FDA - Information for Healthcare Professionals regarding the concomitant use of ibuprofen and aspirin.
• Hawkey et al (2006). Increased risk of myocardial infarction as first manifestation of ischaemic heart disease and nonselective nonsteroidal anti-inflammatory drugs. British Journal of Clinical Pharmacology. 61(6): 730-737
• Knights et al (2006). Non-selective nonsteroidal anti-inflammatory drugs and cardiovascular events: is aldosterone the silent partner in crime? British Journal of Clinical Pharmacology. 61(6): 738-740.
• Morrison et al (2007). Systematic review of trials of the effect of continued use of oral non-selective NSAIDs on blood pressure and hypertension. Current Medical Research and Opinion. 23(10): 2395-2404.
• Farkouh et al (2007). Cardiovascular Outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. Ann Rheum Dis. 66: 764-770.

Issue

Medsafe and NZPhvC provided reports for the MARC's Scheduled Review of non-specific NSAIDs and cardiovascular adverse effects, including congestive heart failure. In April 2005, an announcement was made by the FDA stating that there was sufficient evidence to suggest that the use of non-selective NSAIDs might increase cardiovascular risk. At its September 2005 meeting, the Committee concluded that the available evidence did not justify regulatory action and recommended that Medsafe and the MARC continue to monitor and review all new information as it became available. The issue was placed on the Active Monitoring (now Scheduled Review) list for annual review in December 2005.

In December 2006, the MARC carried out the first active monitoring review and concluded that, while the risk-benefit profile for non-selective NSAIDs remained favourable, it was important that risk management advice regarding the risk of cardiovascular events be disseminated to New Zealand prescribers and consumers. The Committee agreed that the key messages were:

• The lowest effective dose of NSAID should be prescribed for the shortest time necessary for control of symptoms.
• The need for long-term treatment should be reviewed periodically.
• Prescribing should be based on the safety profiles of individual NSAIDs and on individual patient risk profiles (e.g., gastrointestinal and cardiovascular).
• Prescribers should not switch between NSAIDs without careful consideration of the overall safety profile of the products, a patient's individual risk factors, and patient preference.

In conveying the key messages above, the Committee also agreed that no distinction should be made between prescription-only and over-the-counter NSAIDs in terms of the risk management advice given; nor should a distinction be made between individual NSAIDs and dosages in terms of the risk management advice given. This information was to be conveyed via a Prescriber Update article, a Dear Healthcare Professional letter, and changes to the data sheets of the non-selective NSAIDs available in New Zealand.

The purpose of the December 2007 reports from Medsafe and NZPhvC was to inform the Committee of recent data and regulatory action regarding the cardiovascular adverse effects, including congestive heart failure of non-selective NSAIDs. The Committee was asked to evaluate the information provided and to determine whether the risk-benefit profile of non-selective NSAIDs has changed as a result of this new information. If the risk-benefit profile was deemed to have changed, the Committee was asked to recommend appropriate risk management.

Discussion

The MARC noted the November 2007 Medsafe and NZPhvC reports. They noted that the datasheets for all non-selective NSAIDs have now been updated in line with the non-selective NSAID Product Information changes recommended by the MARC, which were based on those recommended by the Australian Drug Evaluation Committee (ADEC).

The Committee noted that in September 2006, the US FDA released new information for Healthcare Professionals, outlining the potential of ibuprofen to interfere with the anti-platelet effect of low dose aspirin, potentially rendering aspirin less effective when used for cardioprotection and stroke prevention. Healthcare Professionals were provided with a number of Recommendations, regarding concomitant use of aspirin and ibuprofen, by the US FDA. They noted that the EMEA and the UK have not taken regulatory action on this issue at this time.

The Committee noted that in June 2007, the European Medicines Agency (EMEA) recommended restrictions on the use of piroxicam-containing products due to the risk of gastrointestinal side effects and serious skin reactions. They noted that Medsafe has contacted the three sponsors of piroxicam-containing products approved in New Zealand, requesting a response to the European decision. One of the product sponsors has updated their data sheets in line with the Recommendations, and also sent out a "Dear Healthcare Professional" letter to inform prescribers of restrictions on the use of piroxicam due to the risk of gastrointestinal and serious skin adverse effects. One other sponsor discontinued the registration of their products in New Zealand. The Committee noted that Medsafe will continue to follow up with the remaining company which has not yet made the requested changes.

NZPhvC advised that New Zealand data from the CARM database supported the association of an increased risk of skin reactions with piroxicam, when compared with other NSAIDs. The Committee agreed that information about piroxicam and serious skin reactions should be added as a separate box to the draft Prescriber Update article about non-selective NSAIDs.

The Committee noted that the New Zealand data sheets for non-selective NSAIDs have now been updated, although the warnings regarding cardiac failure are mild. The Committee agreed that changes be made to the Prescriber Update article to highlight the increased risk of cardiac failure with the non-selective NSAIDs.

The Committee agreed that the new information provided did not alter the current risk-benefit profile of non-selective NSAIDs. They considered that the amended New Zealand non-selective NSAID data sheets adequately warn prescribers of the potential risks associated with the use of these medicines, and the need to carefully consider whether the benefit of non-selective NSAID use outweighs the risk. The Committee noted that the Prescriber Update article that has been drafted will further communicate the issue to prescribers.

Recommendation

The Committee recommended that the issue of non-selective NSAIDs and the risk of cardiovascular adverse effects, including congestive heart failure be removed from the Scheduled Review list.

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

References

NZPhvC report re: use of cough and cold medicines in children.
FDA Briefing information:

• Schiffenbauer J. Executive Summary to FDA briefing information.
• Roy P. Division of Clinical Pharmacology 2. Clinical Pharmacology Review. For Cough/Cold Advisory Committee meeting Oct 18-19 2007.
• Lopez LA. Medical Officer's Review: Cold and Cough Products for Over-The-Counter (OTC) Use. July 24 2007.
• Akhavan-Toyserkani G, Chang YJ and Ahmad SR. Division of Drug Risk Evaluation. Postmarketing safety review of serious adverse events in children less than 6 years of age associated with the use of cough and cold medications. 17 September 2007
• Akhavan-Toyserkani G, Division of Drug Risk Evaluation. Infant mortality associated with the use of cough and cold medications. 6 February 2007
• Abate R. Postmarketing Safety Review of Medication Errors Involving Over-the-Counter Cold Products in Paediatric Patients (Newborn to Five Years). 14 September 2007

Other references

• FDA Public Health Advisory. Non-prescription Cough and Cold Medicine Use in Children. 15 August 2007. http://www.fda.gov/cder/drug/advisory/cough_cold.htm
• Health Canada Advisory. Recommendations for the Appropriate Use of Cough and Cold Products in Children. 11 October 2007.  http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2007/2007_147_e.html
• Classification status of the active ingredients approved for use in cough and cold medicines in New Zealand.
• Review of the classification definitions for controlled drugs in New Zealand

Issue

Medsafe provided the MARC with a report on the safety and efficacy of cough and cold medicines for use in children. This followed a release by the United States Food and Drug Administration (FDA) of a Public Health Advisory announcing that, in October 2007, the Non-prescription Drugs Advisory Committee (NDAC) would be discussing the safety and effectiveness of cough and cold medicines used in children. This was in response to published reports of serious adverse events, including death, in children receiving cough and cold medicines; and a Citizen's Petition expressing concern about the safety and efficacy of cough and cold medicines used in children less than 6 years of age.

In January 2007, the Centre for Disease Control (CDC) published a report describing three deaths of infants less than 6 months of age for which cough and cold medications were determined to be the underlying cause of death. All three infants had high levels of pseudoephedrine in post-mortem blood samples. In March 2007, a Citizen's Petition provided evidence to support their request that the FDA adjust the product labelling for cough and cold medicines to state that these products have not been found to be safe or effective in children less than 6 years of age for the treatment of cough and cold; and should not be used in this age group.

In September 2007, briefing documents prepared by the FDA to inform the NDAC's decision making, were published on the FDA's website. Medsafe provided the MARC with a review of these documents (as summarised below) as well as a review of the New Zealand experience of the use of cough and cold medicines in children.

Clinical Pharmacology

Dosage advice

In the United States (US), paediatric dosage advice for cough and cold medicines has been determined by extrapolation from the adult dose. An expert advisory committee convened in 1976 determined that this was appropriate based on the assumption that the pathophysiology of the common cold, and the clinical response to the pharmacologic intervention are likely to be sufficiently similar in adults and children. The following doses are recommended in the US:

Table 1: Paediatric dosage Recommendations for cough and cold medicines

Age of child	Fraction of adult dose
6-12 years	½ of adult dose
2 - 6 years	¼ of adult dose
Under2 years	Ask a doctor

Although dosage advice for children aged less than 2 years is available in some paediatric handbooks, it is not clear how these instructions were determined.

Pharmacokinetics

There is very limited paediatric pharmacokinetic (PK) data available for the majority of the ingredients in cough and cold medicines. During the first two years of life, physiological and biochemical processes governing drug absorption (eg gastric pH), distribution (eg quantity of body water and fat), metabolism and excretion (eg renal excretion and/or CYP-mediated hepatic elimination) undergo significant maturation. In addition, environmental factors (such as exposure to other medicines) and dietary factors (eg breast fed versus bottle fed) can affect the PK of medicines in young children. Thus extrapolating adult PK data to children may not achieve an equivalent pharmacological effect, particularly in children less than 2 years.

Therefore the FDA's expert committee concluded that paediatric dosing cannot always be obtained by simply applying weight or surface area based calculations to the adult dose. The limited PK data available for pseudoephedrine and chlorpheniramine suggests that larger doses than those currently recommended may be required to produce equivalent systemic exposure in children as in adults.

Evidence for efficacy and safety from the published literature

A literature search identified eleven clinical trials involving the use of cough and cold medicines in children, and seven articles reporting individual case reports or case series.

After reviewing the available published literature in children (6 weeks to 18 years old), it was concluded that there was no convincing evidence of efficacy of cough and cold medications when used to treat symptoms of the common cold in this population. However, it was noted that there were issues with the design of the studies including inadequate power to detect a drug-placebo difference that may have affected the ability of any of the studies to show efficacy. In addition, it was noted that although possible, paediatric clinical studies are more difficult to conduct because children are less verbal or are unable to express their symptoms well; therefore, one has to rely on the caregiver for assessment of symptoms.

Review of reports to the FDA's Adverse Event Reporting System (AERS) associated with the use of cough and cold medicines in children

Reports of infant mortality associated with the use of pseudoephedrine, phenylephrine, ephedrine, diphenhydramine, brompheniramine and chlorpheniramine

The AERS data base was searched for reports of fatalities in children aged less than 6 years of aged between 1969 and September 13 2006, associated with the use of decongestants and antihistamines.

54 fatalities associated with the use of decongestants were identified: pseudoephedrine 46; phenylephrine 4; and ephedrine 4. 43 of 54 cases were reported in children aged less than 1 year, 2 in children aged 1- 2 years and 9 in children aged 2-6 years. Most deaths occurred within five days of initiating treatment. Overdose and/or drug toxicity were the most common adverse events reported in these cases. The reasons given for the overdose occurring included use of multiple cough/cold products, medication errors, accidental exposures and intentional overdoses.

69 fatalities associated with the use of antihistamines were identified: diphenhydramine 33; brompheniramine 9 and chlorpheniramine 27. 41 of 69 cases occurred in children aged less than 2 years and 28 in children aged 2-6 years. Overdose and drug toxicity were commonly reported adverse events in these cases with similar reasons for overdose as identified with the decongestants.

It was concluded that the AERS cases demonstrate that the administration of cough and cold medicines to children aged less than 2 years could result in fatal overdoses. The identified factors that contributed to the risk of unintentional overdoses include:

• Medication error due to lack of proper dosage guidelines may be contributing to overdose in children aged less than 2 years of age.
• Parents and caregivers being unaware of the risk of overdose when using multiple cough and cold medicines.
• Parents may be misinformed that medicines for children aged more than 6 years are also safe in younger children.
• Age based dosing may be inappropriate for infants who are less than average weight or were born premature.

Postmarketing review of serious adverse events in children aged less than 6 years of age associated with the use of cough and cold medications

The AERS database was searched for reports of serious adverse events in children aged less than 6 years associated with pseudoephedrine, chlorpheniramine, diphenhydramine, and dextromethorphan between 1/1/2002 and 11/5/2007.

Serious adverse event (SAE) reports were identified for pseudoephedrine (150), dextromethorphan (105), diphenhydramine (83) and chlorpheniramine (63). Over 50% of SAE reports for pseudoephedrine occurred in children aged less than 2 years. Drug overdoses accounted for approximately 48% of the SAEs reported. Convulsions were reported more commonly in children aged 2 years and older and were more common outside of the setting of overdose. Serious cardiac and respiratory events were most commonly reported in the setting of overdoses but also occurred where the dosage did not exceed the labelled dose.

It was concluded that cough and cold medications used in children aged less than 6 years of age have been associated with serious adverse events including death.

Review of Medication Errors involving over-the-counter (OTC) cough and cold products in paediatric patients (newborn to 5 years)

36 cases of medication errors involving cough and cold medicines used in children aged less than 6 years were identified. 22 of these cases involved children aged less than 2 years. Of note 14 cases of medical error occurred after a parent had sought medical advice. 9 cases involved death – 7 of those were in children less than 2 years. The majority of errors involved improper dosing.

It was determined that the following factors contributed to the medical errors identified: concurrent use of medicines containing the same active ingredient, or ingredients from the same therapeutic class; errors related to misinterpretation of directions for use or appropriate measuring devices; and confusion regarding products with similar names to other products with different active ingredients.

It was concluded that the above data indicates that unintentional overdoses occur in children aged less than 6 years using OTC cough and cold products.

Expert opinions sought by the FDA

American Academy of Pediatrics (AAP)

The AAP considered that there is sufficient available data from paediatric studies to conclude that cough and cold medicines are ineffective in children. In addition, the AAP noted that although these medicines are generally safe when used according to the product labelling there are two situations that potentially put children at risk of serious adverse events or death when exposed to cough and cold medicines - notably:

1. Inappropriate dosing of cough and cold medicines. The AAP considers that the available of multiple multi-ingredient preparations that may contain the same active ingredients contributes to this risk.
2. Complete lack of data to support current dosing regimens for paediatric patients. In addition, the lack of information available to physicians when the product labelling recommends consulting a physician for dosage advice. The AAP is also concerned that children less than 2 years appear to have a greater sensitivity to the potentially fatal effects of some of the ingredients in cough and cold medicines.

The AAP considered that extrapolation of adult efficacy data for children is not justifiable as there is available paediatric data that does not support the efficacy of these medicines. In addition, there is significant age related developmental variability in both pharmacokinetics and pharmacodynamics in children such that it is clear that adults and children handle and respond to drugs differently.

The AAP expressed considerable concern at that demonstrable lack of efficacy, evidence for considerable misuse, lack of rational basis for dosing, and apparent increased sensitivity to toxicity of these preparations in children less than 6 years of age. The AAP recommended that unless clear, evidence-based paediatric dosing guidelines are available for all ages, then these products should not be available for OTC use in these age groups.

New Zealand Experience

Currently there are more than 100 cough and cold products available in New Zealand. The following active ingredients are approved for use in OTC cough and cold medicines in New Zealand:

• Expectorants: guaifenesin
• Decongestants: pseudoephedrine, phenylephrine
• Mucolytics: bromhexine
• Cough suppressants: pholcodine, dextromethorphan
• Sedating antihistamines: doxylamine, brompheniramine, chlorpheniramine, tripolidine, promethazine and diphenhydramine (Note: this is also a cough suppressant)

Currently in New Zealand the sedating antihistamines are only available on prescription for use in children aged less than 2 years.

Reports to CARM

CARM has not received any reports of serious adverse reactions occurring in children receiving cough and cold medicines.

Reports to the National Poisons Centre

The National Poisons Centre has received 154 calls regarding children at or below the age of 2 years who required medical observation and/or intervention following overdoses of cough and cold preparations. The majority of calls involved sedating antihistamines.

International Regulatory Action

Both the US FDA and Health Canada have issued general advice to parents and caregivers regarding the safe use of cough and cold medicines in children.

The following advice was issued by Health Canada in October 2007:

Children under 2 years of age

• Do not use cough and cold products, including drugs and natural health products, in children under 2 years of age unless instructed to do so by a healthcare practitioner.
• Even if the cough and cold products are labelled for use in children under 2 years of age (for example, they use the word "infant" in their name or have dosing instructions for infants) it is still preferable to discuss the use of these products with your healthcare practitioner before giving them to any young child.

Children of all ages

• If it is necessary to give a cough and cold product to a child, make sure that you read all labels and instructions before doing so. If the product does not contain dose information for children, then it should not be used in children.
• Do not give a child a larger dose than is recommended or use the product more frequently than is recommended in the labelling and instructions.
• Take note of the medicinal ingredients in the product, particularly if you may be giving more than one product to a child. Be aware that many products contain the same medicinal ingredient(s) and combined use could lead to overdose. Some herbs used in cough and cold medications and some over-the-counter medications used to control fever may also have medicinal ingredients similar to those in other cough and cold products.
• Because cough and cold medications often contain multiple ingredients, it is advised not to give more than one cough and cold product to a child.
• Talk to your healthcare practitioner if you have questions about the proper use of these products, dosing and administration information, or the medicinal ingredients in the products you are using.
• There is no cure for the common cold. Children will usually recover from coughs and colds in time on their own. The common cold is a mild, viral infection that can be managed by rest, sufficient fluid intake and comfort measures.
• In young children and babies, it is sometimes important to rule out serious illnesses (for example, pneumonia or other infections) which may present with cold-like signs and symptoms; this is especially important if symptoms persist or if the child's condition deteriorates.
• If you are concerned about the child's health, the child should be brought to a healthcare practitioner for medical evaluation.

The purpose of the November 2007 Medsafe report was to:

• Provide the MARC with a review of the briefing documents prepared by the FDA for their expert advisory committee's review of the safety and efficacy of cough and cold medicines available for use in children.
• Provide the MARC with a review of the ingredients approved for use in cough and cold medicines in New Zealand including their current classification, any restrictions on their use, whether or not use is recommended in children aged less than 2 years, and current international dosing Recommendations.
• Seek the MARC's opinion as to whether the available data is adequate to determine the risk-benefit profile of cough and cold medicines used in children; and to seek the MARC's advice as to whether or not regulatory action is required for children aged less than 2 years and/or above 2 years of age.

Discussion

The MARC noted the Medsafe report summarised above.

The MARC noted that after reviewing the data, the overall conclusions of the FDA's expert advisory committee review was that there was no evidence of efficacy for the use of cough and cold medicines in children, however, fatalities had been reported. In the main, the reports of fatalities appear to be associated with inappropriate use, either in a particularly young age group, with multiple ingredient preparations or inappropriately high dosing. The Expert Advisory Committee recommended against licensing these preparations for use in children less than 2 years of age, and the majority of the Committee recommended against the use of these preparations in children less than 6 years of age. The MARC noted that the FDA had not yet announced whether these Recommendations will be accepted.

The MARC noted that the CARM database includes no reports of deaths associated with these preparations. It was noted that in New Zealand, cough and cold preparations are largely scheduled as pharmacy-only medicines and only able to be sold in a pharmacy. This contrasts with the US, where the preparations are available for general sale in any retail outlet. The US also allows for different labelling and promotion.

The Committee agreed that the determination of paediatric doses based on extrapolation from adult doses is unlikely to be appropriate due to differences in pharmacokinetics and pharmacodynamics in paediatric patients, particularly in children aged less than two years.

The Committee noted that currently in New Zealand, the labelling for most cough and cold medicines indicate that they should not be used in children less than 2 years except upon medical advice. In addition, most products do not contain any dosage advice for children less than 2 years. Sedating antihistamines are no longer available over-the-counter for children aged less than 2 years in New Zealand.

The MARC discussed whether rescheduling the medicines from pharmacy only medicines to pharmacist only medicines may help to prevent inappropriate use.

The Committee concluded that there is very limited evidence for efficacy, an absence of evidence- based dosage advice for the use of cough and cold medicines in children aged less than 2 years, and evidence of significant toxicity in overdose in this age group. They considered that the risk-benefit profile for the use of cough and cold medicines in children under 2 years is currently unfavourable. Therefore, the MARC considered that they should be contraindicated in this age group.

Children over the age of two years

Athough there is an absence of clear evidence for efficacy in children over 2 years, the Committee considered that there is some evidence that cough and cold medicines are well tolerated in this age group when administered according to current dosage Recommendations.

The Committee agreed that the main concern with the use of cough and cold medicines in children over the age of 2 years was inappropriate use. They agreed that the advice issued by Health Canada was helpful in avoiding inappropriate use and recommended that Medsafe disseminate similar advice in New Zealand.

The MARC considered that further information was required before a decision could be made as to whether regulatory action was required for children over two years. Therefore, they agreed to seek further information and expert advice from different professional bodies such as the Paediatric Society, the College of General Practitioners and the College of Physicians.

The Committee noted that many of the cough and cold products contained ingredients with conflicting actions, such as a cough suppressant plus an expectorant in the same preparation. They agreed it would be helpful if there was a move towards single ingredient products.

The Committee agreed that a public education campaign was a key issue regarding the safe use of cough and cold products in children.

Recommendation

The Committee recommended that all cough and cold medicines be contraindicated in children under two years of age.

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.

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.

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.

Secretary's note:

The minutes of the Medicines Classification Committee meeting held on 8 December 2007 are available on the Medsafe web site at www.medsafe.govt.nz/profs/class/mccMin14Dec2007.htm.

3.4 APROTININ AND INCREASED MORTALITY RISK

References

• Early Communication about an Ongoing Safety Review Aprotinin Injection (marketed as Trasylol). 25 October 2007. http://www.fda.gov/cder/drug/early_comm/aprotinin.htm
• Medsafe Alert. Aprotinin – Increased caution is warranted. 26 October 2007. www.medsafe.govt.nz/hot/alerts/aprotinin.asp
• Bayer Healthcare. Important Safety Information. Trasylol (aprotinin injection). 5 November 2007.
• Correspondence from Bayer re Recommendation from DSMB of BART study
• Minutes of the 129th MARC meeting March 2007.
• Minutes of the 125th MARC meeting March 2006.
• Henry DA et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion (Review). The Cochrane Library 2007, Issue 4.

Issue

Medsafe provided the MARC with a report on aprotinin and increased mortality risk following the temporary suspension of the worldwide marketing of aprotinin by product sponsor Bayer on 5 November 2007.

The issue of aprotinin and increased mortality risk was placed on the watching brief list in March 2006. This followed the publication of an article in the New England Journal of Medicine by Mangano et al, which reported an association between the use of aprotinin in coronary bypass graft surgery (CABG) with cardiopulmonary bypass and the development of serious renal and cardiovascular adverse reactions.

At the time of the March 2006 meeting, antifibrinolytic agents Trasylol (aprotinin) and Cyclokapron (tranexamic acid) were registered and available in New Zealand. Only aprotinin was approved for use in cardiopulmonary bypass surgery. Information obtained at that time from specialist anaesthetists in New Zealand indicated that, due to cost, tranexamic acid was the more commonly used product. Aprotinin was reserved for use in complicated cases, or in cases where bleeding was considered to be more likely to occur. Data from the product sponsor indicated that approximately 1,500 patients per annum in New Zealand may be treated with aprotinin for a number of different indications, including during CABG surgery.

On 8 February 2006, the United States Food and Drug Administration (FDA) issued a public health advisory based on the Mangano et al paper. The FDA advised clinicians of an apparent increase in risk of complications associated with use of aprotinin, and recommended that clinicians monitor patients exposed to aprotinin for episodes of toxicity to the kidneys, heart and central nervous system. In addition, they advised that physicians should consider limiting use of aprotinin to situations where the clinical benefit of reduced blood loss was essential to patient management and outweighed the potential risks.

At its March 2006 meeting, the MARC considered that the Mangano et al study did not provide definitive answers on the issue. They noted that the product sponsor, Bayer, was conducting product trials and an integrated safety analysis, which would be brought to the MARC in due course.

At its March 2007 meeting, the Committee reviewed the data package provided by Bayer. They noted that the New Zealand data sheet for Trasylol had been updated – the most significant amendment was the alignment of the indications with global labelling. They agreed that the datasheet should be further amended to include a tightened indication, strengthened information on anaphylactic reactions, and strengthened information on renal dysfunction. The Committee noted that there was a double blind, randomised controlled trial (the BART study - Blood conservation using antifibrinolytics) looking at the relative efficacy of commonly used anti-fibrolytic agents in high-risk cardiac surgical patients being conducted in Canada. The results of this trial were expected in 2008.

On 19 October 2007, the FDA released an early communication announcing that the Data Safety Monitoring Board (DSMB) for the BART study had recommended that enrolment in the aprotinin arm of the study should be stopped. This was in response to preliminary findings that patients in the aprotinin arm of the study had an excess mortality compared to patients receiving aminocaproic acid or tranexamic acid.

The limited information available from the interim analysis performed by the DSMB found that:

• The 30 day mortality in the aprotinin group had nearly reached statistical significance compared to aminocaproic acid and tranexamic acid
• There had been a trend toward increased mortality in the aprotinin arm throughout the study
• The use of aprotinin was associated with less serious bleeding than either aminocaproic acid or tranexamic acid

The FDA noted that these findings support the findings from observational studies that also suggested increased risks for mortality when aprotinin was compared to other antifibrinolytic drugs.

The FDA indicated that they would be working with the sponsor of the BART study and the manufacturer of aprotinin to fully evaluate the risks and benefits associated with the use of aprotinin. However, in the interim prescribers were advised to consider the known risks and benefits of aprotinin, and the accumulating data suggesting aprotinin administration increases the risk for death compared to other antifibrinolytic drugs, before prescribing aprotinin.

On 26 October 2007, based on the information provided in the FDA's communication, Medsafe disseminated an alert to anaesthetists, cardiothoracic and other surgeons, haematologists, and transfusion specialists informing them of the suspension of the BART study. Medsafe's interim advice was that clinicians should consider each patient on an individual basis to determine whether aprotinin is appropriate for that patient, taking into account the accumulating data suggesting aprotinin increases the risk for death compared to other antifibrinolytic drugs.

On 29 October 2007, Bayer provided Medsafe with a copy of the letter from the DSMB to the BART study invesitigators recommending that patient entry into the aprotinin treatment arm should be stopped immediately. The DSMB noted that although "the evidence that aprotinin decreases serious post-operative haemorrhage is stronger than the evidence that it increases mortality…..because all cause mortality is a much more serious Outcome than serious post-operative bleeding, we believe that it is unlikely that clinicians will consider aprotinin to be an appropriate treatment for the vast majority of patients".

On 3 November 2007 Medsafe was informed that the FDA had requested, and the sponsor had agreed to, the temporary suspension of marketing of aprotinin in the US; until the final data from the BART study are available and a more robust assessment of the benefit/risk profile of aprotinin can be made.

On 5 November 2007, Medsafe was informed that Bayer intended to temporarily suspend the worldwide marketing of aprotinin until final results of the BART study are available. Medsafe supported this decision and approved the distribution of a "Dear Healthcare Professional" letter by Bayer to New Zealand prescribers. Prescribers were informed that once the complete BART dataset are available, Bayer will work with regulatory authorities to determine the benefit-risk assessment for aprotinin and the marketing suspension will be re-evaluated at that time. Medsafe agreed that in the interim, it may be appropriate for Bayer to continue supplying aprotinin to individual prescribers in exceptional circumstances.

The purpose of the November 2007 Medsafe report was to inform the Committee of recent data and regulatory action regarding the safety of aprotinin.

Discussion

The Committee noted the November 2007 Medsafe report.

The Committee noted that a trend towards an increase in mortality in the aprotinin-treated patient group has been present throughout most of the trial. They noted that the increase in mortality in the aprotinin group had almost reached conventional statistical significance for 30 day mortality compared with the other agents in the trial.

The MARC considered that no further regulatory action is required pending the availability of the final results of the BART study. The Committee noted that Medsafe will provide the MARC with a copy of the BART trial results when available and at that time the MARC will be asked to consider the most appropriate risk management strategy to manage any identified risks associated with the use of aprotinin. As a result, the March 2008 Scheduled Review of aprotinin and cardiovascular, renal and cerebrovascular adverse reactions is deferred.

Recommendation

The Committee recommended that the Issue of aprotinin and increased mortality risk be reviewed once the final results of the BART study are available.

4 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

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

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 http://www.who-umc.org/. These designations (certain, probable, possible, unlikely, unclassified and unclassifiable) refer to the degree of certainty about the relationship between the medicine and the adverse event. The terms should not be understood literally. For example, "certain" means that the appropriate elements are present to match the international definition. It does not mean there is absolute certainty that the medicine caused the adverse event.

Explanations of the terms used by CARM and MARC can be accessed by hyperlink at each causality designation.

4.1.1 Deaths

4.1.1.1 Alteplase and haemorrhage intracranial [death] (75765)

Discussion

NZPhvC advised that the CARM database contains one report of is a death due to intracranial haemorrhage and another of a death due to cerebral haemorrhage with alteplase.

The New Zealand data sheet lists the risk of severe and fatal haemorrhage in the "Warnings and Precautions" section.

The Committee noted that the information provided was not adequate to allow a further assessment at this time.

The causal association with alteplase was considered to be 'possible' for haemorrhage intracranial.

Recommendation

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

4.1.1.2 Simvastatin, enalapril and pancreatitis [death] (76148)

Discussion

NZPhvC advised that the CARM database included six reports of pancreatitis associated with the statins and the lipid lowering agent ezetimibe, and this combination is statistically disproportionate in the WHO database. NZPhvC advised that in both the CARM and WHO databases the number of reports of pancreatitis compared with the total number of reports for ezetimibe is greater than for simvastatin and it is therefore possible that the risk of pancreatitis is greater with ezetimibe than with the statins. The Committee noted that ezetimibe/statin combination products are now being marketed.

The Committee noted that the patient was also being treated with enalapril, which can also be associated with pancreatitis and agreed that enalapril should be added as a suspect medicine in this case.

The Committee noted that an article on ezetimibe and pancreatitis is to be published in Prescriber Update.

The causal association with simvastatin was considered to be 'possible' for pancreatitis.

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

Recommendation

The Committee recommended that NZPhvC add enalapril as a suspect medicine in this case.

4.1.1.3 Insulin glargine and sudden death [death] (75949)

Discussion

NZPhvC advised that the CARM database contains five reports for insulin glargine, none of which are deaths. They noted that it has a prolonged duration of action of 24 hours. The product datasheet states that this prolonged action may delay recovery from hypoglycaemia and that the warning symptoms of hypoglycaemia may be less pronounced when there has been a marked improvement in blood glucose levels.

The Committee noted that while nocturnal hypoglycaemia was relatively common in diabetic patients, it did not commonly cause death. They noted that there were several possible explanations, however, the cause of death was unknown.

The Committee noted that NZPhvC were seeking more information about this case and any information would be brought to the MARC.

The causal association with insulin glargine was considered to be 'unclassified' for sudden death.

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

4.1.1.4 Peginterferon Alfa 2a and pneumonia [death] (76001)

Discussion

NZPhvC advised that the CARM database includes nine reports for peginterferon alfa 2a, of which one is for infection in a patient also receiving treatment with ribavirin. The CARM database includes five reports in association with the combination of peginterferon alfa 2a and ribavirin. The WHO database includes reports of infection, including pneumonia, with peginterferon alfa 2a.

The product data sheet describes pulmonary symptoms that have been reported during therapy with peginterferon alfa 2a alone or in combination with ribavirin, and states that treatment should be discontinued if there is evidence of persistent or unexplained pulmonary infiltrates or pulmonary function impairment.

The Committee noted that the details of this case were limited and that a coroner's report may be forthcoming.

The Committee considered the causal association with peginterferon alfa 2a was 'possible' for pneumonia.

Recommendation

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

4.1.1.5 Adalimimab and cerebral haemorrhage [death] (75961)

Discussion

NZPhvC advised that of the 24 reports for adalimumab in the CARM database, one is for cerebrovascular haemorrhage in a patient with uncontrolled hypertension, who was also taking leflunomide. The WHO database includes 47 reports for cerebrovascular disorder, with no specific reports of cerebral haemorrhage.

The product data sheet includes references only to haemorrhage, but not specifically cerebral haemorrhage.

The Committee noted that further information has been requested but not yet received.

The Committee considered the causal association with adalimimab was 'unclassified' for cerebral haemorrhage.

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

4.1.1.6 Thalidomide and disease progression [death] (76186)

Discussion

The Committee agreed that it was possible that the patient had multi-organ failure before beginning thalidomide treatment and it was likely that the cause of death was disease progression.

The causal association with thalidomide was considered to be 'unlikely' for disease progression.

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

4.1.1.7 Clozapine and neutropenia, lymphopenia,anaemia [death] (76419)

Discussion

NZPhvC advised that both the CARM and WHO databases contain reports of neutropenia with clozapine. The IC value for agranulocytosis with clozapine in the WHO database is strongly positive.

The Committee noted that the product datasheet for Clozaril contains a boxed warning regarding agranulocytosis and it is a well recognised adverse effect of clozapine.

The Committee noted that the patient did recover, however, there was a close temporal association with the clozapine treatment and evidence of neutropenia.

The Committee noted that BPAC has recently published an article discussing the use of antipsychotics in the treatment of dementia. They agreed it would be useful to contact the College of Psychiatrists to determine how often clozapine is used to treat some of the features of dementia, and whether usage appears to be increasing.

The causal association with clozapine was considered to be 'probable' for neutropenia, 'possible' for lymphopenia, and 'possible' for anaemia.

Recommendation

The Committee recommended that the College of Psychiatrists be contacted to determine how often clozapine is used to treat some of the features of dementia, and whether usage appears to be increasing.

4.1.1.8 Olanzapine and liver injury, urinary retention,acute, renal impairment [death] (76420)

Discussion

NZPhvC advised that the IMMP database contains reports of hepatic reactions and acute renal failure with olanzapine. The WHO database shows positive IC values for hepatic reactions and urinary retention, but not for acute renal failure.

The Committee noted that urinary retention does occur with the antipsychotics with an anticholinergic action.

The causal association with olanzapine was considered to be 'possible' for liver injury, urinary retention, acute, renal impairment.

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

4.1.1.9 Paroxetine, quetiapine, zopiclone and suicide, depression aggravated [death] (75725)

Discussion

NZPhvC advised that the CARM database includes reports of suicide or suicide attempt with both paroxetine and zopiclone, but none for quetiapine. They noted that the paroxetine datasheet contains extensive warnings about the risk of suicidal behaviour in young adults and the need to monitor all patients for suicidal ideation. They noted however, that this patient was not a young adult and he had a previous history of suicidal ideation.

The Committee noted that in June 2007 it had reviewed the latest literature regarding the risk of suicidality in association with the SSRIs, and the MARC considered the warnings in the SSRI datasheets remained adequate. The MARC also noted that Dear Healthcare Professional letters regarding suicidality with SSRIs in children and adolescents were sent to prescribers in 2004. A Prescriber Update article was published in 2002 indicating that in a small number of patients who become restless and agitated soon after staring SSRIs, suicidality may be attributable to the medicines.

A recent analysis examined time trends in suicide attempts between 90 days prior and 180 days following treatment initiation with antidepressants or psychotherapy and found that the incidence of suicide attempts was highest in the month before treatment initiation and next highest in the month following treatment initiation. Another analysis showed that patients who received SSRIs alone or with other antidepressants had a significantly lower suicide attempt rate that those receiving other antidepressants or no antidepressants.

The Committee agreed that a high degree of involvement with the patient by the mental health service and/or general practitioner around the time of commencing antidepressants is appropriate.

One member described an editorial by Lackman about the adverse effects of zopiclone.

The causal association with paroxetine, quetiapine, zopiclone was considered to be 'possible' for suicide, depression aggravated.

Recommendation

The Committee recommended that the Issue of SSRIs and suicidality be placed on the agenda for the next meeting of the MARC.

4.1.1.10 Risperidone and consciousness loss, stroke [death] (75848)

Discussion

NZPhvC advised that risperidone is included in the Intensive Medicines Monitoring Programme and reports of stroke, transient ischaemic attack and cerebrovascular disease have been recieved. There are no CARM reports for cerebrovascular events with procyclidine. The WHO data indicates a low level of statistical disproportionality for cerebrovascular disorder with risperidone.

The Committee noted that the cause of death was assumed as a stroke, and that there was insufficient information, particularly on the duration of risperidone use, to properly assess the causality with risperidone.

The Committee noted that NZPhvC were seeking more information about this case including a post mortem report and any further information would be brought to the MARC.

The causal association with risperidone was considered to be 'unclassified' for consciousness loss, stroke.

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

4.1.1.11 Levomepromazine (methotrimeprazine) and hypothermia, cardiac arrest [death] (75865)

Discussion

NZPhvC advised that of eleven reports for levomepromazine in the CARM database, there is one report of cardiac arrest, in a patient who was also being treated with tranylcypromine.

The product datasheet for levomepromazine states that it has a hypotensive effect and should be used with caution in the elderly and in patients with cardiac disease, and notes that overdose symptoms include hypothermia.

The causal association with levomepromazine (methotrimeprazine) was considered to be 'possible' for hypothermia, cardiac arrest.

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

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

Discussion

NZPhvC advised that both the CARM and WHO databases includes reports of bronchospasm and dyspnoea. The Symbicort product datasheet states that treatment should not be stopped abruptly.

The Committee agreed it was important to obtain as many details about this case as possible. They discussed the difficulties of obtaining complete details of reported cases. A member advised that a national mortality review process for those patients under 24 years of age had been developed and the Committee agreed to investigate this further in order to communicate relevant information between agencies.

The causal association with budesonide/formoterol (Symbicort) was considered to be 'unclassified' for exacerbation of asthma.

Recommendation

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.

4.1.2 Alternative Medicines (CAM)

4.1.2.1 Chromium picolinate, metformin and aspirin and hypoglycaemia, drug interaction (76105)

Discussion

NZPhvC advised that there were no reports for chromium picolinate in the CARM database and one report for hypoglycaemia in the WHO database.

The Committee noted that the mechanism and actions of chromium are well documented in the literature and would appear to support the clinically observed hypoglycaemia in this patient, including the additive effect of the aspirin.

The Committee noted that chromium has different clinical properties and toxicity depending on the valency and it would be useful to obtain more information about this case.

The causal association with chromium picolinate, metformin and aspirin was considered to be 'possible' for hypoglycaemia, drug interaction.

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

4.1.3 Analgesics

4.1.3.1 Tramadol and drug dependence (narcotic) (75728)

Discussion

NZPhvC advised that there were reports regarding tramadol in the CARM database, of which none listed withdrawal syndrome and one listed dependence. The product datasheet refers to dependence as a precaution and states that no clinical studies regarding the safety and efficacy of tramadol after more than six months of therapy are available.

The Committee agreed it would be useful to further investigate the issue of tramadol and dependency and recommended that NZPhvC review the literature and report back to the MARC.

The causal association with tramadol was considered to be 'probable' for drug dependence (narcotic).

Recommendation

The Committee recommended that NZPhvC review the literature regarding the Issue of tramadol and dependency, and report back to the MARC.

4.1.4 Anti-epileptics

4.1.4.1 Lamotrigine and therapeutic response inadequate, brand switch, convulsions grand mal (76045)

Discussion

NZPhvC advised that the CARM database includes two reports of inadequate therapeutic response leading to loss of seizure control following lamotrigine brands switches (see also minute 4.1.4.2). Both patients had been seizure free and developed seizures within a month of the brand switch. After returning to the Lamictal brand, both patients again became seizure free.

The New Zealand Regulatory Guidelines for Medicines indicate that medicines with a narrow therapeutic index, including anti-epileptics, are not interchangeable, however, it is not clear if lamotrigine has a narrow therapeutic index.

The causal association with lamotrigine was considered to be 'probable' for therapeutic response inadequate, brand switch, convulsions grand mal.

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

4.1.4.2 Lamotrigine and depression, therapeutic response inadequate, brand switch, convulsions grand mal (76046)

Discussion

See minute item 4.1.4.1.

The causal association with lamotrigine was considered to be 'probable' for depression, therapeutic response inadequate, brand switch, convulsions grand mal.

4.1.5 Anti-infectives

4.1.5.1 Clotrimazole, warfarin and INR increased, drug interaction (75825)

Discussion

NZPhvC advised that there were no reports of drug interactions with clotrimazole in the CARM database, in PubMed, or in any other standard ADR databases. The product datasheet notes that interactions are not reported with topical forms of clotrimazole.

The Committee agreed that INR variation could be a natural change or a co-incidence due to other factors.

The causal association with clotrimazole was considered to be 'possible' for INR increased, drug interaction.

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

4.1.6 Anti-inflammatories

4.1.6.1 Lumiracoxib and hepatocellular damage (76287)

Discussion

See minute item 3.1.

The causal association with lumiracoxib was considered to be 'probable' for hepatocellular damage.

4.1.6.2 Lumiracoxib and hepatic enzymes increased, renal function abnormal (76405)

Case Report

A 64-year-old male received lumiracoxib 400mg for the treatment of gout. The gout was described as unresponsive to prednisone, and the patient had received diclofenac in the past. Other medical conditions were myocardial infarction, hearth failure, atrial fibrillation, prostate cancer and renal transplant. He took three doses of lumiracoxib, 17 and 21 days apart. Following the third dose, abnormal renal function and liver function tests were recorded. The patient's hepatic and renal function had been monitored regularly since the renal transplant, and were normal. A repeat liver function test showed levels were improving following the cessation of lumiracoxib, but the patient had not recovered at the time of reporting.

Discussion

See minute item 3.1.

The causal association with lumiracoxib was considered 'probable' for hepatic enzymes increase, renal function abnormal.

4.1.7 Dermatologicals

4.1.7.1 Isotretinoin and tiredness, Crohns disease (76152)

Discussion

NZPhvC advised that inflammatory bowel diseases with isotretinoin were reported in both the CARM and WHO databases.

The Committee noted that there are increasing reports in the literature suggesting a possible association between isotretinoin and inflammatory bowel disease. The Committee queried if the use of isotretinoin could trigger a predisposition for Crohns disease and this case may add further weight to a possible association. They noted however that the age group for the diagnosis of both Crohns disease and acne were the same and this may be a coincidential occurrence.

The causal association with isotretinoin was considered 'possible' for tiredness, Crohns disease.

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

4.1.7.2 Terbinafine and parotid enlargement (76151)

Discussion

NZPhvC advised that there are no reports for parotid disorders associated with terbinafine in the CARM database, and only one report in the WHO database. One report was found on a literature search.

The Committee noted that this could be possible further evidence for a very rare event.

The causal association with terbinafine was considered 'probable' for parotid enlargement.

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

4.1.8 Vaccines

4.1.8.1 Influenza vaccine and myelitis transverse, encephalitis (76080)

Discussion

NZPhvC advised that the product datasheet for the current influenza vaccine refers to the possibility of post vaccination disorders following immunisation and that in particular conditions such as encephalopathy, neuritis and Gullain Barre Syndrome have been observed very rarely.

The causal association with influenza vaccine was considered 'unlikely' for myelitis transverse, encephalitis.

Recommendation

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

4.1.8.2 MeNZB vaccine and encephalomyelitis, demyelination (75151)

Discussion

NZPhvC advised that there is one report of demyelination in association with the MeNZB vaccination, which had previously been reviewed by the MARC and considered to be attributable to the progression of an existing demyelination condition. There is no specific literature evidence for MeNZB in association with demyelination or encephalitis, however papers on vaccination in general and the risk of CNS demyelinating diseases report that no association is observed.

The Committee noted that the duration to onset in this case was long, six to nine months, making the causal link unlikely.

The causal association with MeNZB was considered 'unlikely' for encephalomyelitis, demyelination.

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

4.1.9 Other Reports

The Committee noted the following case reports:

4.1.2.1 Trastuzmab, docetaxel (76194)

4.1.2.2 Rosiglitazone, Accuretic, simvastatin, metformin (76228)

4.1.2.3 Leflunomide (76431)

4.2 Quarterly Reports from CARM as at 30 September 2007

Discussion

NZPhvC presented the report. They noted that the reports for methylphenidate were continuing, along with reports of withdrawal reactions associated with paroxetine. NZPhvC advised that brand switch reports involving lamotrigine would be summarised for the next quarterly report and discussed at the next meeting if warranted.

The Committee noted the quarterly reports from CARM as at 30 September 2007.

4.3 Tiotropium – Summary of recent CARM case reports

Discussion

NZPhvC presented the report. They concluded that these case reports did not constitute a signal of a causal association between tiotropium and unexpected death.

The Committee registered its concern regarding the quality of the data contained in some of the reports submitted to the Pharmacovigilance Centre.

4.4 Paradex – Drug Utilisation Study

[..]

The report presented to the MARC was an interim analysis of prescription data identified from the Pharmaceuticals Data Mart (Pharms) database for the calendar month of July 2007.

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.

• Goodyer I, et al. 2007. Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behaviour therapy in adolescents with major depression: randomised controlled trial. BMJ 335: 142-146.
• Leckman JF, King RA. 2007. Editorial: A developmental perspective on the controversy surrounding the use of SSRIs to treat paediatric depression. Am J Psychiatry 164 (9): 1304-1306.
• Gibbons RD, et al. 2007. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 164 (9): 1356-1362.
• Hetrick SE et al. 2007. Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents (Review). The Cochrane Library 4.
• Brent D. 2007. Antidepressants and suicidal behaviour: cause or cure? Am J Psychiatry 164: 989-991 (7).
• Simon GE, et al. 2007. Suicide attempts among patients starting depression treatment with medications or psychotherapy. Am J Psychiatry 164: 1029-1034 (7).
• Gibbons RD, et al. 2007. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration Data Sets. Am J Psychiatry 164: 1044-1049 (7).
• Perlis RH, et al. 2007. Association between treatment-emergent suicidal ideation with citalopram and polymorphisms near cyclic adenosine monophosphate response element binding protein in the STAR*D Study. Archives of General Psychiatry 64: 698-697 (6).
• Ly J, et al. 2007. Colchicine prescribing and safety monitoring in patients with gout. The New Zealand Medical Journal 120: 1265

6 INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

6.1 United Kingdom

• Medicines and Healthcare products Regulatory Agency (MHRA). 2007. Drug Safety Update. Volume 1, Issue 3.
• Medicines and Healthcare products Regulatory Agency (MHRA). 2007. Drug Safety Update. Volume 1, Issue 4.

7 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.

8 OTHER BUSINESS

8.1 International Non-proprietary Names (INN) for active ingredients

A member raised the issue of International Non-proprietary Names (INN), which are increasingly being used in New Zealand in place of British approved names (BAN) as the generic name for medicines. Concern was expressed that the name changes created potential for confusion amongst prescribers, pharmacists and patients.

Medsafe advised that the INN system is administered by the World Health Organisation (WHO) and began in 1953. The aim of the INN system is to provide health professionals with a unique and universally available designated name to identify each pharmaceutical substance. According to the WHO, the existence of such a nomenclature assists in the clear identification, safe prescription and dispensing of medicines to patients.

Increasingly, countries with large markets (due to their population size) are requiring medicine manufacturers to adopt the INN when labelling their medicines. As New Zealand is a small market, the medicines supplied here are often batches of product produced or packaged for a larger or international market. If that other market is in a country that requires medicines to be labelled as INNs, then the medicines supplied to the NZ market will be labelled using the INN nomenclature.

Medsafe advised that it has published information on its website about INNs in order to clarify that the adoption of INNs in NZ is not a new or changed regulatory policy. Medsafe reminded the Committee that health professionals have a professional and ethical responsibility to accurately identify the medicine prescribed, whether it be a new active ingredient, a change of brand name, or a different spelling or nomenclature for an active ingredient. Lack of familiarity with a medicine name is not an acceptable reason for dispensing errors to occur.

There being no further business, the Chair thanked members and the secretariat for their attendance and closed the meeting at 2.30pm.

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