Revised: 20 May 2013

Committees

Minutes of the 131^st Medicines Adverse Reactions Committee Meeting - 13 September 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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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.

Secretary's note:

The recommendation regarding minute item 3.9 Amiloride/ hydrochlorothiazide, hypnonatraemia and hyperkalaemia, was been rejected by the Minister's Delegate on the advice of Medsafe. Refer to minute item 2.1.7 of the minutes of the 131st MARC Meeting for further information- www.medsafe.govt.nz/profs/adverse/Minutes131.htm

Minutes:

TABLE OF CONTENTS

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

1. MATTERS OF ADMINISTRATION

2. ACTIONS ARISING

3. PHARMACOVIGILANCE ISSUES

3.1 LUMIRACOXIB AND LIVER TOXICITY
3.2 RUBIFEN SR (METHYLPHENIDATE SR) BRAND SWITCH – AGGRESSIVE AND DEFIANT BEHAVIOURAL REACTIONS
3.3 LIPID-LOWERING AGENTS AND PSYCHIATRIC ADVERSE REACTIONS: ACTIVE MONITORING REVIEW
3.4 STATINS, NEUROMUSCULAR DEGENERATIVE DISEASE AND AMYOTROPHIC LATERAL SCLEROSIS-LIKE SYNDROME
3.5 ORAL TERBINAFINE AND SERIOUS ADVERSE REACTIONS (BLOOD DYSCRASIAS, HEPTATOTOXICITY AND DERMATOLOGICAL REACTIONS ) – ACTIVE MONITORING REVIEW
3.6 SSRI ANTIDEPRESSANTS AND USE IN PREGNANCY (INCLUDING DEVELOPMENTAL DELAY) – WATCHING BRIEF REVIEW
3.7 INHALED LABAS AND RISK OF FATAL AND NON-FATAL ASTHMA EXACERBATIONS – WATCHING BRIEF REVIEW
3.8 MENINGOCOCCAL B VACCINE AND CHRONIC FATIGUE
3.9 AMILORIDE/HYDROCHLORTHIAZIDE, HYPONATRAEMIA AND HYPERKALAEMIA

4. MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 CENTRE FOR ADVERSE REACTIONS MONITORING (CARM) SPONTANEOUS CASE REPORTS

4.1.1 Deaths
4.1.2 Other Reports

4.2 IMMP UPDATE FOR THE MARCE SEPTEMBER 2007
4.3 QUARTERLY REPORTS FROM CARM AS AT 30 JUNE 2007 31

5. PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

6. NEW ZEALAND PHARMACOVIGILANCE-RELATED ACTIVITIES

7. INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

7.1 AUSTRALIA
7.2 UNITED KINGDOM
7.3 WORLD HEALTH ORGANISATION (WHO)

8. SUMMARY LISTINGS OF CASE REPORTS CONSIDERED BY MARC (1997-2006)

9. OTHER BUSINESS

9.1 AUSTRALIA AND NEW ZEALAND THERAPEUTICS PRODUCTS AUTHORITY (ANZTPA) - POSTPONEMENT

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MINUTES OF THE 131^st MEDICINES ADVERSE REACTIONS COMMITTEE MEETING,
13 SEPTEMBER 2007.

The one hundred and thirty first meeting of the Medicines Adverse Reactions Committee (MARC) was held on 13 September 2007 at the Sunderland Room, Wellington Airport Conference Centre, Wellington, New Zealand. The meeting commenced at 9:00 am and closed at 3:50 pm.

marc members present

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

marc secretariat present

Dr S Jessamine (Principal Technical Specialist/ Interim Manger, 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 Honorary Associate Professor M Rademaker and Professor P Ellis.

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 129^th MARC Meeting

Members agreed that the minutes of the 130^th MARC meeting were a true and accurate record of the meeting. The Chair subsequently ratified the minutes.

1.2.1 Report to the Minister's Delegate

Members noted that all of the recommendations made at the 130^th MARC meeting had been accepted by the Minister's Delegate.

1.3 Dates of Future MARC Meetings

The date for the next MARC meeting was confirmed as being Thursday 13 December 2007. The subsequent MARC meeting dates for 2008 were scheduled for 20 March, 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.

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

1.5 Prescriber Update

1.5.1 Schedule of Planned Prescriber Update Articles

Discussion

The Committee was asked to review one draft Prescriber Update article.

'SSRI use in pregnancy - Collaborative decision-making is key'

The first draft of the Prescriber Update article 'SSRI use in pregnancy - Collaborative decision-making is key' was reviewed. The Committee suggested some changes, including advice that prescribers and lead maternity carers consider seeking an expert opinion in this situation. It was suggested that the article could be more specific in terms of abnormalities as this could direct practitioners to particular tests to be carried out. MARC agreed it was important to make midwives aware of this issue, and suggested that the New Zealand College of Midwives be approached to publish the article in their Journal.

1.6 Issues monitored by the MARC, Medsafe and NZPhvC as at June 2007

1.6.1 Revised definitions for MARC monitored issues

At the June 2007 MARC meeting, Medsafe agreed to revise the current definitions for the pharmacovigilance issues that the MARC recommends are monitored.

The previous system defined three categories:

Standing agenda item

High-level monitoring. Medsafe and NZPhvC should actively monitor the issue, and all new data should be reported to the MARC at every meeting, including information on case reports in the CARM and WHO databases, recently published literature and international regulatory action. Adverse Reactions of Current Concern should be included in this category. A decision should be made at each meeting of whether to maintain standing agenda item status, or to demote the issue to active monitoring or watching brief status.

Active monitoring (with formalised review)

Intermediate-level monitoring. Medsafe and NZPhvC should actively monitor the issue and provide an annual report to the MARC. In addition to information on case reports in the CARM and WHO databases, there should be a review of the recently published literature and international regulatory actions. If concerns emerged prior to the annual review the issue should be brought back to the MARC at the next meeting. Active monitoring status could be demoted to watching brief status after one year if the issue had been resolved, or if deemed necessary the issue could be promoted to standing agenda item status.

Watching brief

Low-level monitoring. Medsafe and NZPhvC should monitor the issue and provide a brief annual report to the MARC including information on case reports in the CARM and WHO databases. If concerns emerged prior to the annual review the issue should be brought back to the MARC at the next meeting. The watching brief should expire in one year if there were no further concerns, or if deemed necessary the issue could be promoted to active monitoring or standing agenda item at that time.

The proposed system defined two categories:

• Standing agenda items - these would comprise of issues that arise from previous MARC meetings and are reported back to the MARC at subsequent meetings as "matters (or actions) arising from previous meetings". When Medsafe/NZPhvC report back to MARC on either the progress or resolution of these matters, any new information that has arisen about the issue (such as published papers, or international regulatory actions) will be included. Once the issues have been resolved (i.e. the MARC recommendations implemented and completed), they will be removed as Standing Agenda Items.
• Scheduled review - consists of conducting a 12-monthly, 15-monthly or 18-monthly review of a specified medicine safety issue. The frequency of the review is to be determined on a case-by-case basis, taking into consideration the seriousness of the safety concerns and the anticipated availability of further data. The Scheduled Review is to include CARM & WHO data, published literature, and a summary of international regulatory action.

The Committee agreed to implement the proposed new system.

2. actions arising

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

2.1 Report on Actions Arising from the 130^th MARC Meeting, 14 June 2007

Please refer to the minutes of the 130^th MARC meeting, held on 14 June 2007, available on the Medsafe website at www.medsafe.govt.nz/profs/adverse/Minutes130.htm for background information on these issues.

2.1.1 Schedule of Planned Prescriber Update Articles

June 2007 minute item 1.5.1

Issue

In June 2007, the Committee recommended that an additional, separate Prescriber Update article be written to focus on the other side effects of the glitazones.

Outcome

The NZPhvC is preparing an article for Prescriber Update.

Discussion

The Committee noted the above.

2.1.2 Issues monitored by the MARC, Medsafe and NZPhvC as at June 2007

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 Amizide, hyponatraemia, and hyperkalaemia be placed on the Agenda for the next MARC meeting.

Outcome

Medsafe and CARM have both produced a report on this issue which was included in the September 2007 dossier.

Discussion

Please refer to minute item 3.9 for the discussion on the issue of Amizide, hyponatraemia, and hyperkalaemia.

2.1.3 Adverse reactions to rosiglitazone & pioglitazone: Active Monitoring Review

June 2007 minute item 2.1.5; March 2007 minute item 4.1

Issue

In June 2007, the Committee recommended that 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

A letter asking Eli Lilly to provide comment on the cardiac safety of pioglitazone was sent by Medsafe in August 2007. The letter noted that while much of the data surrounding the cardiac safety of thiazolidinedione focuses on rosiglitazone, there is no robust evidence to suggest that pioglitazone does not have similar cardiac effects.

In addition, the letter requested that a number of amendments be made to the NZ Actos datasheet, unless evidence-based justification is provided to the contrary. These amendments included:

1. Strengthened precautions regarding congestive heart failure
2. A contraindication for NYHA class III and IV cardiac status
3. A change to the indications whereby insulin may be added to established pioglitazone monotherapy; however, pioglitazone may not be commenced as add-on therapy to patients already receiving insulin - this is due to a possible increased risk of heart failure and myocardial infarction in this group.
4. Possible risk of bone fracture

Medsafe requested that comment on the cardiac safety of pioglitazone, together with a draft updated ACTOS datasheet and any other proposed risk management action, be provided by Tuesday 21 August 2007.

Discussion

The Committee noted the above.

2.1.4 Golimumab, amoxycillin/clavulanic acid, isoniazid, and diarrhoea, vomiting, colitis, septic shock, cardiac arrest [death] (CARM case report 73358)

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 NZPhvC has initiated discussions with the ACC in order to consider what options may be appropriate and how the NZPhvC could contribute to awareness of bringing relevant cases to ACC's attention.

Discussion

The Committee agreed that the transfer of case information between ACC and the pharmacovigilance centre should be as efficient as possible. This could be a direct transfer of information from Medsafe to NZPhvC, otherwise a formal process should be initiated to transfer information between ACC and NZPhvC. The Committee suggested that Medsafe explore options to allow NZPhvC access to relevant ACC cases.

Recommendation

The Committee recommended that Medsafe explore options for allowing NZPhvC access to relevant ACC cases.

2.1.5 Adverse reactions to leflunomide: Active Monitoring Review

June 2007 minute item 3.1

Issue

In June 2007, the Committee recommended that an article concerning pancytopenia, hepatic reactions, and pneumonitis in association 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

Medsafe has contacted the sponsors of leflunomide (AFT-Pharmaceuticals and Sanofi-Aventis) to request the data sheet revisions. Both sponsors have formally submitted these to Medsafe and they were currently being reviewed.

Discussion

The Committee noted the above.

2.1.6 Lamotrigine and convulsion [death] (CARM case report 74826)

June 2007 minute item 4.1.1.3

Issue

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

At the time of the September 2007 MARC meeting, no further information had been received.

Discussion

The Committee noted the above.

2.1.7 Quetiapine, paroxetine, and neuroleptic malignant syndrome, pneumonia inhalation [death] (CARM case report 74373)

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

At the time of the September 2007 MARC meeting, no further information had been received.

Discussion

The Committee noted the above.

2.1.8 Tiotropium and cardiac failure [death] (CARM case report 74591), Tiotropium and headache [death] (CARM case report 74756), Tiotropium and sudden death [death] (CARM case report 74759), Tiotropium and sudden death [death] (CARM case report 74760), Tiotropium and sudden death [death] (CARM case report 74838)

June 2007 minute items 4.1.1.6, 7, 8, 9, 10

Issue

In June 2007, the Committee recommended that the 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.

Outcome

The sponsor company has been contacted requesting further case or reporter details, which when received will be collated for reporting to MARC.

Discussion

NZPhvC provided a verbal report, summarising the details which had been received from the company to date. The eight reports were coded as sudden death as there was no cause of death included in the report. Further information showed that of these, 4 reports stated that there was no autopsy carried out. The causes of death were listed as terminal chronic pulmonary obstructive disease, myocardial infarction, dyspnea, and cardiac failure/pneumonia respectively. From the details provided, it was not possible to show an association between tiotropium and these deaths. The results of an autopsy on one patient showed death from coronary artery disease. Further details on the remaining three reports have not yet been received.

The Committee agreed that a summary of these reports should be prepared and included in the dossier for the December MARC meeting.

Recommendation

The Committee recommended that NZPhvC prepare a summary of these reports involving tiotropium for the December 2007 MARC meeting.

2.1.9 Red Rice Yeast Extract, Saw Palmetto, CoQ10, Multivitamins, and myalgia, CK elevated, LFTs abnormal, chest pain (CARM case report 74641)

June 2007 minute item 4.1.4.1

Issue

In June 2007, the Committee recommended that a paragraph be published in Prescriber Update to illustrate the pharmacologically active nature of some complementary medicines.

Outcome

A suitable paragraph is being prepared for Prescriber Update.

Discussion

The Committee noted the above.

2.1.10 Imiquimod and pigmentation abnormal (CARM case report 74330), Imiquimod and application site oedema, bullous eruption, headache, myalgia, hypotension, nausea, epistaxis, diarrhoea, arthralgia, hypertension (CARM case report 74656)

June 2007 minute items 4.1.5.2, 4.1.5.3

Issue

In June 2007, the Committee recommended that an article about imiquimod be published in Prescriber Update informing prescribers of its adverse effects of skin depigmentation and influenza-like symptoms.

Outcome

Medsafe is preparing an article forPrescriber Update.

Discussion

The Committee noted the above.

2.2 Report on Actions Arising from Previous Meetings of the Medicines Adverse Reactions Committee (MARC)

2.2.1 Clozapine and haematological malignancies

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 Associate Professor Frampton, explore developing 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 and asked to be kept informed of the outcome.

2.2.2 Oral Terbinafine Serious Adverse Reactions

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

A letter was sent to the Pharmacy Council and the Pharmaceutical Society in September 2007. Medsafe is awaiting a response.

Discussion

The Committee noted the above.

2.2.3 Aprotinin and cardiovascular, renal & cerebrovascular adverse reactions: Watching Brief Review

June 2007 minute item 2.1.3; March 2007 minute item 3.1

Issue

In March 2007, the Committee recommended that the issue of aprotinin and cardiovascular, renal and cerebrovascular adverse reactions remain on the watching brief list.

In March 2007, the Committee recommended that Medsafe bring back to the MARC any data that arises from the BART study (expected in 2008), and continue to monitor international regulatory activity and report back to the MARC as appropriate.

In March 2007, the Committee agreed with Medsafe's suggested revisions to the NZ Trasylol data sheet.

Outcome

The company has submitted a revised data sheet to Medsafe for review.

Discussion

The Committee noted the above.

2.2.4 Adverse reactions to rosiglitazone & pioglitazone: Active Monitoring Review

June 2007 minute item 2.1.5; March 2007 minute item 4.1

Issue

In March 2007, the Committee recommended that Medsafe seek an expert opinion on an appropriate measure of bone turnover that might indicate reduced bone density in thiazolidinedione treated patients.

In March 2007, the Committee recommended that all adverse reactions to rosiglitazone and pioglitazone should remain on the active monitoring list for annual review.

In March 2007, the Committee recommended that Medsafe contact the sponsors of rosiglitazone and pioglitazone to request datasheet revisions.

Outcome

An expert opinion regarding an appropriate measure of bone turnover that might indicate reduced bone density in glitazone-treated patients was provided and discussed at the June 2007 MARC meeting. The Committee agreed that a particular point should be made to further review information around fractures and bone loss as part of the next standing agenda (previously active monitoring) item review of the glitazones in March 2008.

A letter requesting amendments to the NZ datasheet for Avandia was sent to GSK in May 2007. An updated Avandia datasheet was submitted to Medsafe in July 2007. This update did not include cardiac-related safety amendments as further discussions surrounding cardiovascular safety were underway. The datasheet update also did not include the following text: "It is recommended that patients treated with Avandia undergo periodic monitoring of liver enzymes. Liver function tests should be performed at baseline, every two months for the first twelve months, and periodically thereafter".

GSK has informed Medsafe that the above recommendation for liver function test monitoring during treatment with Avandia has been removed from the core company text, and is not included in the US or EU prescribing information documents.

The deletion of this recommendation is based on long-term safety data available from the ADOPT trial - these data were submitted to the Medsafe Evaluation division in March 2007 and a Medsafe evaluation report dated May 2007 concludes the following:

"The incidence of hepatic related safety events was similar across treatment groups."

Hepatic safety events	RSG	GLIB	MET
On-therapy AEs	3.2%	4.4%	6.1%
On-therapy SAEs	0.1%	0.1%	0.3%
On therapy AEs leading to withdrawal	0.4%	0.9%	1.1%

Notable changes in ALT (X3 ULN) occurred in 1.0% of RSG v 0.8% of GLIB and 1.1% of MET exposed patients. Similarly for ALP the values were 0.2% v 0% v 0.2% and for AST 0.6% v 0.4% v 0.4%.

Generally these support the hepatic safety of rosiglitazone.

A further cardiac safety-related datasheet update for Avandia was submitted to Medsafe in August 2007. The update contained the following key messages:

1. Strengthened precautions regarding congestive heart failure
2. A contraindication for NYHA class III and IV cardiac status
3. A change to the indications whereby insulin may be added to established rosiglitazone monotherapy; however, rosiglitazone may not be commenced as add-on therapy to patients already receiving insulin - this is due to a possible increased risk of heart failure and myocardial infarction in this group.

A Dear Healthcare Professional letter advising NZ prescribers of these changes was disseminated by GSK in August 2007.

Discussion

The Committee noted the above.

2.2.5 Tenecteplase and sudden death [death] (CARM case report 74192)

June 2007 minute item 2.2.5; 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 the report back in the event that further information on the cause of death is received.

Discussion

The Committee noted the above.

2.2.6 Tamoxifen and retinal deposits (CARM case report 73804)

June 2007 minute item 2.1.9; March 2007 minute item 4.3.4.1

Issue

In March 2007, the Committee recommended that a reminder article be published in Prescriber Update informing prescribers of retinopathy with tamoxifen.

Outcome

Medsafe will author this article.

Discussion

The Committee noted the above.

2.2.7 Candesartan and palpitations (73162)

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

A letter requesting the inclusion of palpitations in the NZ datasheet for Atacand (candesartan) was sent to AstraZeneca in May 2007. Medsafe is awaiting a response.

Discussion

The Committee noted the above.

2.2.8 Infliximab/methotrexate/prednisone and secondary sepsis, dural abscess, tooth abscess, headache, coma [death] (CARM case report 72110)

June 2007 minute item 2.2.1; March 2007 minute item 2.1.1; December 2006 minute item 2.1.9; September 2006 minute item 4.1.1.5

Issue

In December 2006, the Committee recommended that an article be written for publication in Prescriber Update, raising the awareness of a possible association between anti-TNF agents and dental cavity abscess, and describing the CARM case reports.

Outcome

A Prescriber Update article, including information about the possibility of infection in general with anti-TNF agents, is being prepared by Dr Ruth Savage.

Discussion

The Committee noted the above.

2.2.9 Non-selective NSAIDs: Active Monitoring Review

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 Committee recommended that non-selective NSAID product information amendments recommended by the ADEC in Australia be adopted in New Zealand.

In December 2006, 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

Following liaison with the TGA to ensure consistency of product information updates between the two countries, Medsafe requested that the New Zealand sponsors of the non-selective NSAIDs update their data sheets to include the latest Australian PI information.

As at August 2007, Medsafe had received and reviewed the proposed updated datasheets for all but two non-selective NSAID products (Roche will be submitting proposed datasheets for their Naproxen products in September 2007). Sponsors are now in the process of formally submitting the amended datasheets to Medsafe as Self Assessable Change Notifications.

As a result of the Medsafe datasheet update request, some sponsors took the opportunity to discontinue product registration in New Zealand - these products included: Diclax EC, Oraflam, Candyl-D, Panafen, Apo-Sulindac, Apo-Tiaprofenic, and Ibucare.

A Prescriber Update article and 'Dear Health Professional' letter will now be drafted.

Discussion

The Committee noted the above.

2.2.10 Omeprazole and headache (CARM case report 72715)

June 2007 minute item 2.2.10; March 2007 minute item 1.2, 2.1.8; December 2006 minute item 4.1.2.1

Issue

In December 2006, the Committee recommended that an article be written for publication in Prescriber Update informing prescribers of headaches as a possible adverse effect of omeprazole.

Outcome

Medsafe will liaise with NZPhvC to draft a Prescriber Update article informing prescribers of headaches as an adverse effect of omeprazole in children.

Discussion

The Committee noted the above.

2.2.11 Roxithromycin, warfarin, and decreased prothrombin (CARM case report 73165)

June 2007 minute item 2.2.11; March 2007 minute item 2.1.9; December 2006 minute item 4.1.4.2

Issue

In December 2006, the Committee recommended that an article be written for publication in Prescriber Update informing prescribers of the interaction between roxithromycin and warfarin, and to include erythromycin.

Outcome

A Prescriber Update article will be authored by Medsafe.

Discussion

The Committee noted the above.

2.2.12 Sodium valproate and foetal valproate syndrome (CARM case report 73289)

June 2007 minute item 2.2.6; March 2007 minute item 2.1.10; December 2006 minute item 4.1.5.1

Issue

In December 2006, the Committee recommended that an article be written for publication in Prescriber Update on anticonvulsants and risk of congenital malformations, and the importance of pre-pregnancy counselling for all women of child-bearing age taking anti-convulsants.

Outcome

A Prescriber Update article will be authored by Medsafe.

Discussion

The Committee noted the above.

2.2.13 Candesartan and palpitations (CARM case report 73162)

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

A letter requesting the inclusion of palpitations in the NZ datasheet for Atacand was sent to AstraZeneca in May 2007. The company has submitted a revised data sheet to Medsafe, which has been approved.

Discussion

The Committee noted the above.

2.2.14Quinine, 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 have been published on the Medsafe website.

The Prescriber Update article is in the process of being drafted by Medsafe.

Discussion

The Committee noted the above.

2.2.15 Inhaled Long-Acting Beta-Adrenoceptor Agonists (LABAs) and the Risk of Fatal and Non-Fatal Asthma Exacerbations

June 2007 minute item 2.2.9; March 2007 minute 2.2.3; December 2006 minute item 2.1.4; September 2006 minute item 3.2

Issue

In September 2006, the Committee recommended that Medsafe again ask AstraZeneca to update the Oxis Turbuhaler and Symbicort data sheets to include warnings on the risk of serious asthma exacerbations.

In September 2006, the Committee recommended that Medsafe consider publishing an article in Prescriber Update summarising the changes to the LABA data sheets.

Outcome

The data sheets for Oxis Turbuhaler and Symbicort have been updated as requested.

The Prescriber Update article has been finalised and published on the Medsafe website. It will also be included in the next published hard copy edition of Prescriber Update.

Discussion

The Committee noted the above.

2.2.16 SSRIs and Use in Pregnancy: Watching Brief Review

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 to the risks associated with the use of selective serotonin reuptake inhibitors (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 has been written, which was included in the September 2007 dossier.

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

Lundbeck, the sponsor of Cipramil (citalopram) and Lexapro (escitalopram) and Eli Lilly, the sponsor of Prozac (fluoxetine) 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. Please refer to minute item 1.5 for discussion on the Prescriber Update article.

2.2.17 Clozapine and myocarditis, heart failure, arrhythmia [death] (CARM case report 66578)

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 the 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 has requested the post-mortem report and follow-up re-assessment and will bring the results back to the MARC in due course.

Discussion

The Committee noted the above.

2.2.18 Clozapine and Myocarditis

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.

Outcome

Expert opinion was sought and received from [..], cardiologist, and was included in the September 2007 dossier. Medsafe suggested that [..] advice be incorporated into the Prescriber Update reminder article.

Discussion

The Committee noted the report from [..] They agreed it was a comprehensive report and asked that their appreciation be passed on [..]. The report gave some suggestions for routine cardiac monitoring of clozapine patients, but did not specify who would undertake this monitoring. The Committee agreed it would be necessary to maintain flexibility about who was responsible for the monitoring but that continuity of care was key to managing the risks. They noted that the report did not include recommendations about what monitoring and/or how frequent monitoring should occur after the initial 7 - 14 day period of clozapine treatment and agreed that it would be useful to seek further clarification around this. The Committee noted that the measurement of troponin I or T levels was recommended but the sensitivity and specificity of these tests for the diagnosis of myocarditis have not been established. The MARC agreed that troponin levels are very low in the general population and therefore any abnormal levels would suggest a change in cardiac status. They noted that there are six tests listed in the Australian diagnostic criteria for clozapine-induced myocarditis, of which troponin is one, however, abnormalities in any of these would be significant. The Committee suggested it would be useful to obtain further comment from [..] around the significance of troponin levels, particularly their negative predictive value, and to comment on the ADRAC criteria for diagnosing myocarditis.

Recommendation

The Committee recommended that Medsafe contact [..] for further comment on the issues raised above.

2.2.19 Influenza vaccine and sudden death (CARM case report 71269)

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 still awaiting the post-mortem report and will bring the report back to MARC once this has been received.

Discussion

The Committee noted the above.

2.2.20 Diclofenac/ibuprofen/prednisone and gastric ulcer, duodenal ulcer, intestinal ulceration, haematemesis, hypoproteinaemia (CARM case report 71906)

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 2.2.8.

Discussion

The Committee noted the above.

2.2.21 Tramadol-Drug Interactions and Serious Reactions

June 2007 minute item 2.2.15; March 2007 minute item 2.2.11; December 2006 minute item 2.2.4; June 2006 minute item 2.1.14; March 2006 minute item 4.2.1

Issue

In March 2006, the Committee recommended that Dr Savage write two Prescriber Update articles on tramadol. The first should be on increased International Normalised Ratio (INR) when tramadol is administered with warfarin and/or other medicines known to increase INR. The second article should be on serious adverse effects of tramadol, specifically serotonin syndrome and convulsions.

Outcome

The first article has been completed and published on the Medsafe website. The second article is almost finalised.

Discussion

The Committee noted the above.

2.3 Report on Unresolved Actions Arising from Recommendations of the MARC

The following list is of recommendations made by the MARC that have yet to be resolved. Prescriber Update articles are not included, as they are listed in the Schedule of Planned Prescriber Update Articles (see minute item 1.5.1). Nor are actions arising from the last MARC meeting included, as they are listed in the Report on Actions Arising from the 130^th Meeting of the MARC (see minute item 2.1).

2.3.1 Low Molecular Weight Heparins (LMWHs) in Renal Impairment.

June 2007 minute item 2.3.1; March 2007 minute item 2.3.1; December 2006 minute item 2.3.1; 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 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

• Lee WM. 2003. Drug -Induced Hepatotoxicity. NEJM 349(5): 474-485
• Lewis JH. 2006. 'Hy's Law', the 'Rezulin Rule', and other predictors of severe drug-induced hepatotoxicity: putting risk-benefit into perspective. Pharmacoepidemiology and Drug Safety 15: 221-229
• Teoh NC and Farretll GC. 2003. Hepatotoxicity associated with non-steroidal anti-inflammatory drugs. Clin Liver Dis 7: 401-413.
• Chitturi S and George J. 2002. Hepatoxicity of Commonly Used Drugs: Nonsteroidal Anti-Inflammatory Drugs, Antihypertensives, Antidiabetic Agents, Anticonvulsants, Lipid-Lowering Agents, Psychotropic Drugs. Seminars in Liver Disease 2: 169-183
• Goldkind L and Laine L. 2006. A systemic review of NSAIDs withdrawn from the market due to hepatoxicity: lessons learned from the bromfenac experience. Pharmacoepidemiology and Drug Safety 15: 213-220.
• Boelsterli UA. 2002. Mechanisms of NSAID-Induced Hepatotoxicity. Focus on Nimesulide. Drug Safety 25(9): 633-648.

Issue

Medsafe provided a report for the MARC on the issue of lumiracoxib (Prexige) and liver toxicity, following a 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.

On Tuesday 14 August 2007, Medsafe convened a meeting of the Medicines Adverse Reactions Committee (MARC) by teleconference. The MARC reviewed the Australian case reports of severe hepatic toxicity in association with lumiracoxib, the draft ADRAC minutes, WHO and CARM data and Novartis' expert evaluation report.

After reviewing the available evidence, Medsafe and the MARC concluded that there was evidence of a signal that lumiracoxib carried a risk of severe hepatotoxicity, but that the strength of this association could not be defined at that time. The Committee noted that the data supported a clear association with higher doses of lumiracoxib (200mg and 400mg) and the development of hepatotoxicity. In addition, the MARC considered that there was no demonstrable clinical advantage for the use of high doses of lumiracoxib compared to alternative treatments for the treatment of acute pain. Therefore the risk:benefit ratio for the 200mg and 400mg doses was considered to be unfavourable.

Medsafe and the MARC noted that the 100mg dose of lumiracoxib had been used in the UK and Europe for many years without any reports of serious liver damage associated with its use, and therefore it was not possible to determine whether the 100mg dose carried the same risk of hepatotoxicity as the higher strength tablets. It was also noted that there appeared to be a clinical niche for the 100mg dose for patients with osteoarthritis who had not found other treatments to be effective. Therefore, the MARC concluded that the risk:benefit ratio for lumiracoxib 100mg remained favourable at that time.

At the conclusion of the 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.

Subsequent to this meeting, Novartis informed Medsafe that they would supply Medsafe with monthly global monitoring data for lumiracoxib.

On 21 August 2007, Novartis distributed a "Dear Healthcare Professional" letter to New Zealand prescribers and pharmacies and updated the New Zealand data sheet to disseminate this information.

The purpose of the August 2007 Medsafe report was to update the Committee on national and international regulatory action undertaken subsequent to the TGA's decision to withdraw all dosage forms of lumiracoxib from the Australian market, and to provide some recent literature on drug-induced hepatotoxicity in association with NSAID use.

Discussion

The Committee noted that no other regulators apart from the TGA have 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 remains favourable at this time, this may change as further information becomes available.

The Committee discussed the importance of monthly monitoring of liver function tests (LFTs) and the need for this to continue whilst the patient was receiving lumiracoxib treatment. The MARC recommended that Medsafe contact the Best Practice Advocacy Centre (BPAC) and ask them to include an article in their publication, reiterating this advice. Prescribers should be advised to forward any abnormal LFT results to CARM. Prescribers should also be reminded to dispose of any 400mg sample stock they may have, and remove references to the 400mg strength from their computer systems.

The Committee discussed the possibility of a patient registry being established by Novartis, in order to establish the prevalence of disordered LFTs in association with lumiracoxib. They agreed that this would be of value and recommended that Medsafe contact Novartis to further explore this option.

NZPhvC advised that the first report of a hepatic reaction to lumiracoxib had been received. This report was of a 63-year-old female who took lumiracoxib between 100 mg and 400 mg daily for foot pain. Two months later, it was noted that her alkaline phosphatase was mildly elevated but the rest of her hepatic function was normal. After a further three months of taking lumiracoxib (five months altogether) LFTs were markedly elevated, indicating a hepatocellular reaction. Lumiracoxib was discontinued and after a week there was marked improvement in the LFTs. No other suspect or concomitant medicines were listed but asthma and hypertension were listed under other medical conditions. The Committee agreed it would be useful to obtain more details about this case, in particular, any other medications the patient was taking, and clarifying the dose of lumiracoxib she was taking for the majority of the time.

NZPhvC noted that the "Dear Healthcare Professional letter" sent by Novartis indicated that any cases of serious or unexpected adverse reactions, or abnormal LFTs in patients receiving Prexige should be reported to Novartis or CARM. The Committee recommended that Medsafe confirm with Novartis that all New Zealand reports regarding hepatic adverse drug reaction reports to lumiracoxib be forwarded to CARM, rather than only those that are unusual or unexpected.

The Committee agreed that no further regulatory action was required at this time and recommended that the issue of lumiracoxib and liver toxicity be placed on the standing agenda list, for a 12 month review. They noted that any new information should be brought to the Committee as appropriate in the interim and recommended that it would be of value if usage data of the 100mg strength of lumiracoxib be brought to the Committee in six months time.

Recommendation

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.

3.2 RUBIFEN SR (METHYLPHENIDATE SR) BRAND SWITCH - AGGRESSIVE AND DEFIANT BEHAVIOURAL REACTIONS

References

• Medsafe. 2005. Evaluation report on the Administrative, Chemical, Pharmaceutical and Bioavailability Data of Rubifen SR.
• Medsafe. 2003. Supplementary report: Methylphenidate.
• Psychiatric Adverse Events Associated with Drug Treatment of ADHD: Review of Post-marketing Safety Data http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210b_11_01_AdverseEvents.pdf
• Minutes - March 22, 2006 FDA Paediatric Advisory Committee
• http://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-210m_Minutes%20PAC%20March%2022%202006.pdf
• AFT Pharmaceuticals. Rubifen SR data sheet: www.medsafe.govt.nz/profs/Datasheet/r/rubifentabsrtab.htm
• What is bioequivalence? 2007. Best Practice Journal Special edition
• Wolraich ML and Doffing MA. 2004. Pharmacokinetic Considerations in the Treatment of Attention-Deficit Hyperactivity Disorder with Methylphenidate. CNS Drugs 18 (4): 243-250

Issue

Rubifen SR (methylphenidate) was granted ministerial consent for marketing in New Zealand in September 2005. Rubifen SR had been fully subsidised by PHARMAC since November 2006. However, from 1 November 2006 to 1 January 2007, both Rubifen SR and Ritalin SR were fully subsidised. From 1 January 2007 to 1 April 2007 Ritalin SR received only a partial subsidy from PHARMAC and from 1 April 2007 the PHARMAC subsidy was removed from Ritalin SR. Thus from 1 April 2007 Rubifen SR became the only brand of long-acting methylphenidate funded by PHARMAC.

NZPhvC advised that between 8 February 2007 and 31 August 2007, CARM received 79 reports of adverse reactions in patients following the change from Ritalin SR to Rubifen SR. The rate of reporting had slowed, but had now maintained a steady pattern of three to five new reports each week, which was a higher rate than would normally be expected. The reports included details of a reduced therapeutic effect, which was not unexpected at the time of a brand-switch. A number of reports, however, described patients developing very unusual serious and severe side effects following changing to Rubifen SR. These reports included the emergence of aggressive behaviour, as well as other unusual psychiatric events including mood disorders, irritability, hallucinations and unusual behaviours that were obstructive, defiant or extremely disruptive. Some reports detailed children engaging in aggressive risky behaviour such as intentionally riding a bicycle against the traffic flow, speaking of suicidal ideas or threatening self harm or harm to others. Whilst the majority of reports were for children under the age of 17 years, reports were also received from adult patients. Adult patients largely reported reduced therapeutic effect, but similarly reported experiences of aberrant psychiatric reactions. The reports of aggressive or psychiatric adverse effects accounted for close to 50% of the total number of reports received for children.

Concern was raised with Medsafe that these unusual brand-switch reports may indicate a pharmaceutical manufacturing problem or a bioequivalence issue that may have resulted in dose-dumping of the slow-release product.

To investigate these concerns Medsafe convened a meeting of the Medsafe Evaluation Team who assessed the bioequivalence of Rubifen SR and Ritalin SR, the Medsafe Pharmacovigilance Team, CARM and Dr David Reith. At this meeting, the biostudies that were used to assess bioequivalence were reviewed. It was noted that the biostudies consisted of a single dose, five period crossover bioequivalence study conducted in Ireland. There was no evidence in the bioequivalence studies that may have indicated a problem with dose-dumping in some patients. The pharmaceutical chemistry assessments of both Ritalin SR and Rubifen SR were deemed to be acceptable.

The purpose of the August 2007 reports from Medsafe and NZPhvC were to:

• Review the ADR reports for Rubifen SR received by CARM since the Ritalin SR to Rubifen SR brandswitch
• To summarise Medsafe's evaluation of the bioequivalence and pharmaceutical chemistry of Rubifen SR
• To review the information on the risk of aggressive and defiant behaviours contained in New Zealand and international product information for methylphenidate products
• To seek the MARC's opinion as to what the cause of these unexpected brand-switch reactions may be and to advise Medsafe whether any regulatory action is required on this issue.

Discussion

The Committee noted the Medsafe and NZPhvC reports.

The NZPhvC advised that the majority of reports claimed that these behaviours were not part of the patient's original ADHD symptoms, did not occur when the patient was taking Ritalin SR and settled when the patient was transferred back to Ritalin SR. In some instances, the dose of Rubifen SR was increased, but no difference in behaviour was noted. The Committee discussed the earlier brand switch from Ritalin Immediate Release (IR) to Rubifen IR which produced a number of reports of loss of effect, but none of aggressive or psychiatric type adverse events. A review of CARM reports of adverse reports to Ritalin 10mg found no reports of aggression or psychiatric disturbance.

The Committee agreed that there was reasonable observational evidence for a temporal relationship between the change in brand and the change in the stability of the patient.

The disproportionate number of these reports was of concern to the Committee, particularly in light of the severity of the aggressive and unusual behaviours described. The aggressive behaviours, which appeared to be more prominent in children, were generally not part of the patient's pre-morbid condition and have resulted in some children becoming completely unmanageable.

The Committee noted that Medsafe had already reviewed the formulation, manufacturing process, and bioequivalence testing of Rubifen SR and agreed with Medsafe's conclusions that there was no evidence of dose dumping within the bioequivalence data. They noted that Medsafe was conducting further testing of Rubifen SR to confirm that potency and dose uniformity are acceptable.

The Committee noted the Wolraich and Doffing (2004) article, which stated that there was a clinical impression that some children did not respond as well to the generic immediate release form of methylphenidate as to the brand name product. A study comparing the two products found that although it met all the criteria to be considered bioequivalent, there was more intersubject variation in plasma concentration-time measurements for the generic product. There did appear to be more interindividual variation with the generic product, which could mean that it does not work as well in some patients.

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 noted that the Ritalin SR datasheet includes the risk of aggressive and defiant behaviours in the 'Warnings and Precautions' section. The Rubifen SR datasheet includes no information on psychiatric, psychotic or aggressive reactions in this section. The Committee agreed that the Rubifen SR datasheet should be updated to include these warnings.

The Committee noted that reports of aggression, behavioural disturbance and psychiatric adverse events have been reported overseas for a range of products containing methylphenidate. The Committee discussed an FDA report which identified that these side effects can occur at any dose of methylphenidate and in most cases the emergent behaviours were not part of the patient's pre-morbid condition.

The MARC considered that this was an important safety issue which needed to be addressed urgently in order to prevent harm, either by patients harming themselves or causing harm to others.

Medsafe advised that there was provision under Section 36 of the Medicines Act 1981 to require a company to supply Medsafe with further information regarding a medicine if there are reasons to believe it may be unsafe or ineffective for the therapeutic purpose for which it is has consent for marketing. This information must be provided in order to address these safety or efficacy concerns within a certain time frame. 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.

Recommendation

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.

3.3 LIPID-LOWERING AGENTS AND PSYCHIATRIC ADVERSE REACTIONS: ACTIVE MONITORING REVIEW

Issue

Medsafe and NZPhvC provided reports for the MARC's annual active monitoring review of the risk of psychiatric adverse reactions occurring in association with the use of lipid lowering agents. This issue was placed on the active monitoring list in December 2005 following CARM case reports observing a pattern of psychiatric events, including well documented cases of aggressive reactions observed in patients on statin therapy. At that time, it was agreed that NZPhvC should investigate publishing an article on this issue internationally, and then subsequently in Prescriber Update.

In September 2006, the MARC carried out the first active monitoring review and concluded that the evidence at this review had not added substantially to the information considered by the Committee in December 2005. They agreed that the issue of lipid-lowering agents and psychiatric adverse reactions should remain on the active monitoring list but that no regulatory action was required at that time.

The purpose of the August 2007 reports from Medsafe and NZPhvC was to inform the Committee of recent data and regulatory actions regarding lipid-lowering agents and psychiatric adverse reactions. The Committee was asked to evaluate the information provided and if determine whether or not regulatory action was required.

Discussion

The Committee noted the Medsafe and NZPhvC reports. They noted that an article entitled "Psychiatric reactions with cholesterol-lowering agents" was published in Prescriber Update in November 2006 and the NZPhvC paper "Psychiatric Adverse Reactions with Statins, Fibrates and Ezetimibe - implications for lipid-lowering agents" was published in Drug Safety in January 2007.

NZPhvC noted that they have continued to receive reports of a variety of psychiatric reactions, not only with the statins, but also with ezetimibe, which would indicate that is an effect of the lipid lowering, rather than a class effect. Observations in the WHO database support an increasing disproportionality (increasing IC value) of psychiatric reactions with lipid lowering agents including ezetimibe and further strengthen the signal.

NZPhvC discussed the paper by Lalovic et al entitled "Cholesterol content in brains of suicide completers" published in the International Journal of Neuropsychopharmacology in 2007. They noted that those who completed violent suicides were found to have significantly lower levels of cholesterol compared with non-violent suicides, however the data was sparse.

The Committee noted that while the mechanism of action was unknown, there appeared to be a strong signal linking lipid-lowering agents with psychiatric reactions.

The Committee agreed that there was sufficient evidence to request information regarding depression and amnesia being added to the Adverse Effects sections of the datasheets for all lipid-lowering agents.

The Committee noted that NZPhvC were to commence a study, reviewing case reports which have described psychiatric events, and looking at background and current cholesterol levels in these patients. This study will be presented to the MARC when it is completed.

Recommendation

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

The Committee recommended that the issue of lipid-lowering agents and psychiatric adverse reactions be removed from the active monitoring review list.

3.4 STATINS, NEUROMUSCULAR DEGENERATIVE DISEASE AND AMYOTROPHIC LATERAL SCLEROSIS-LIKE SYNDROME

Reference

• Edwards R, Star K and Kiuru A. 2007. Statins, Neuromuscular Degenerative Disease and an Amyotrophic Lateral Sclerosis-Like Syndrome. An Analysis of Individual Case Safety Reports from Vigibase. Drug Safety 30(6):515-525

Issue

Medsafe provided the MARC with a report informing them of a recently published paper from the WHO Uppsala Monitoring Centre which identified a potential signal of neuromuscular degenerative disease and an amyotrophic lateral sclerosis (ALS)-like syndrome in association with statin use. The Committee was asked to evaluate the information provided and to advise whether or not regulatory action is required.

Discussion

The Committee noted the Medsafe report. They noted the paper by Edwards et al (2007), which concluded that the issue of statins and neuromuscular damage was likely to be a class effect and was an emerging signal. The authors expressed concern that the long term and broad use of these agents may lead to them being overlooked as a potential cause of neuromuscular events.

The Committee agreed that the association between statin use and the development of an ALS-like syndrome is an early signal that requires further investigation.

Recommendation

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

3.5 ORAL TERBINAFINE AND SERIOUS ADVERSE REACTIONS (BLOOD DYSCRASIAS, HEPATOTOXICITY AND DERMATOLOGICAL REACTIONS) - ACTIVE MONITORING REVIEW

References

• Perveze Z et al. 2007. Terbinafine-induced hepatic failure requiring liver transplantation. Liver Transpl 13(1):162-4.
• Paredes A, Lewis J. 2007. Terbinafine-induced autoimmune hepatitis in the setting of hepatititis B virus infection. Ann Pharmacother 41(5):880-4.
• Kim B et al. 2007. Generalized pustular psoriasis and hepatic dysfunction associated with oral terbinafine therapy. J Korean Med Sci 22(1):167-9.

Issue

Medsafe and NZPhvC provided reports for the MARC's annual active monitoring review on the issue of oral terbinafine and serious adverse reactions (blood dyscrasias, hepatotoxicity and dermatological reactions). This issue was brought to the MARC following a review of oral terbinafine and blood dyscrasias by the Australian Adverse Drug Reactions Advisory Committee (ADRAC) in February 2006. ADRAC recommended that the sponsor of the innovator product (Novartis) be requested to provide information on the number of worldwide reports of these serious adverse reactions, in order to assess the adequacy of the product information (PI) and consumer medicine information (CMI).

In September 2006, Medsafe reviewed the data sheets for oral terbinafine products available in New Zealand and compared them with the Australian Generic Tablet Product Information. The data sheets were found to contain insufficient warnings about the haematological, hepatic and dermatological serious adverse effects. Data sheet changes were subsequently made, and the MARC considered that if amendments to the Australian Product Information were made as a result of the ADRAC review, the New Zealand data sheets should then be equivalently updated. The Committee agreed that the issue of oral terbinafine and serious adverse reactions (blood dyscrasias, hepatotoxicity and dermatological reactions should be placed on the active monitoring list.

The purpose of the August 2007 review was to inform the Committee of recent data and regulatory actions. The Committee was asked to evaluate the information provided and determine whether the risk-benefit profile of oral terbinafine has changed as a result of the recent information; and if so, recommend appropriate regulatory action.

Discussion

The Committee noted the Medsafe and NZPhvC reports.

NZPhvC noted that the reports to CARM continue to show that oral terbinafine causes serious adverse reactions. As well as Stevens-Johnson syndrome and epidermal necrolysis, the reports indicate that acute generalised exanthematous pustulosis (AGEP) may also be a serious adverse effect of oral terbinafine. The liver and skin disorders may be more important than the haematological disorders originally highlighted.

The Committee noted that an article entitled "Terbinafine: serious hepatic and haematological reactions" was published in the November 2006 edition of Prescriber Update. They felt it was important to disseminate this information as widely as possible and suggested that the Best Practice Advocacy Centre (BPAC) should be approached and asked to include a paragraph in their publication about the appropriate prescribing of oral terbinafine.

The Committee agreed that this issue was of ongoing concern and should continue to be monitored. They recommended that the issue of oral terbinafine and serious adverse reactions (blood dyscrasias, hepatotoxicity and dermatological reactions) be placed on the scheduled review list for 12-monthly review.

Recommendation

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, hepatotoxicity and dermatological reactions) should be placed on the 'scheduled review' list for 12-monthly review.

3.6 SSRI ANTIDEPRESSANTS AND USE IN PREGNANCY (INCLUDING DEVELOPMENTAL DELAY) - WATCHING BRIEF REVIEW

References

• Wogelius, et al. 2006. Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations. Epidemiology 17(6): 701-704.
• Louik, et al. 2007. First-trimester use of selective serotonin reuptake inhibitors and the risk of birth defects. The New England Journal of Medicine 356(26): 2675-83.
• Alwan, et al. 2007. Use of selective serotonin reuptake inhibitors in pregnancy and the risk of birth defects. The New England Journal of Medicine 356(26): 2684-92.

Issue

Medsafe provided a report for the MARC's annual watching brief review on the issue of selective serotonin reuptake inhibitor (SSRI) antidepressants and use in pregnancy (including developmental delay). This issue was placed on the watching brief review list in September 2005, when the Committee considered that the data available at that time were insufficient to determine whether there was a causal association between paroxetine use in pregnancy and the development of congenital abnormalities.

In September 2006, the Committee considered that the risk of neonatal withdrawal was well known amongst lead maternity carers and paediatricians, but that the risks of congenital abnormalities and persistent pulmonary hypertension of the newborn were less well-known. They recommended that an article be published in Prescriber Update, advising of the risks associated with the use of SSRIs in pregnancy. The Committee also recommended that some inconsistencies in the SSRI data sheets regarding the risks of use in pregnancy be addressed. The Committee agreed that the issue of SSRIs and use in pregnancy should remain on the watching brief list. They also agreed that developmental delay should be added to the issue.

The purpose of the August 2007 Medsafe report was to inform the Committee of recent data and regulatory actions. The Committee was asked to evaluate the information provided and determine whether the risk-benefit profile of SSRI antidepressant use during pregnancy has changed as a result of the recent information; and if so, recommend appropriate regulatory action.

Discussion

The Committee noted the Medsafe report. They considered that while neonatal withdrawal from SSRIs was well known in paediatrics, this was not the case in obstetrics and midwifery. They noted that the withdrawal syndrome was not as severe as with other agents such as opioids, and was not life-threatening. The risk of PPHN was very low, but it is a serious condition and can be life-threatening.

They noted the study by Louik et al (2007), which concluded that there was not a clear association with cardiac defects but also said there was a statistically significant increased risk of right ventricular defects with paroxetine. The Committee queried whether there could be a link between pulmonary hypertension and right ventricular outflow tract obstruction. This paper also showed a clear increased risk of neural tube defects and club foot with paroxetine. The Committee noted that this study had a high drop-out rate and hence was vulnerable to potential selection bias.

Members noted the Alwan et al (2007) paper, which showed an increased odds ratio for birth defects with paroxetine, with the defects reported being neural type defects.

The Committee noted that the risk of birth defects with SSRI use was very small, and this needed to be balanced against the risk of not treating the depression. They considered that a specialist consultation would be helpful to aid in the decision making process.

The Committee noted that the article advising of the risks associated with the use of SSRIs in pregnancy is to be included in the next issue of Prescriber Update.

The Committee agreed that the information provided does not alter the current risk-benefit profile of the SSRI antidepressants. They agreed that the current New Zealand data sheets adequately warn prescribers of the potential risks associated with the use of these medicines during pregnancy, and the need to carefully consider whether the benefit of SSRI use for the mother outweighs the risk to the foetus. They noted that the Prescriber Update article will further communicate this issue.

Recommendation

The Committee recommended that the issue of SSRI antidepressants and use in pregnancy should be removed from the 'watching brief' list.

3.7 INHALED LABAs AND RISK OF FATAL AND NON-FATAL ASTHMA EXACERBATIONS - WATCHING BRIEF REVIEW

References

• MHRA. 2007. Review of formoterol and Salmeterol in asthma and chronic obstructive pulmonary disease.
• MHRA. 2006. Asthma: Long-acting b2 agonists.
• Reid J. 2006. Update on the use of LABAs for the treatment of Asthma. Best Practice Journal
• Currie GP, Lee DKC and Lipworth BJ. 2006. Current Opinion: Long-Acting b2-Agonists in Asthma - Not so SMART? Drug Safety 29 (8): 647-656

Letters to the Editor:

• Sears MR, Nelson HS and Dorinsky PM. 2006. The Salmeterol Multicenter Asthma Research Trial. Chest 130(3): 928-929
• Currie GP, Nelson HS and Dorinsky PM. 2006. Why SMART About Second-Line Treatment When First-Line Treatment Is Being Ignored? Chest 130(3): 929
• Williams C, Nelson HS and Dorinsky PM. 2006. Cause of Death in the SMART Trial. Chest 130(3): 929-930
• Seymour SM, Sullivan EJ, Chowdhury BA, Meyer RJ, Davi RC, Nelso HS and Dorinsky PM. 2006. Comments on the Salmeterol Multicenter Asthma Research Trial. Chest 130(3): 930-931
• Nelson HS, Dorinsky PM, Lindberg MJ, Ryan D, Stoloff SW and Currie GP. 2006. Safety of Long-Acting b-Agonists. Annals of Internal Medicine 145(9):706-709
• Salpeter SR. 2006. Response to: Safety of Long-Acting b-Agonists. Annals of Internal Medicine 145(9): 708-710
• Glassroth J. 2006. Use of Long-Acting b-Agonists and Inhaled Corticosteroids. Annals of Internal Medicine 145(9): 710
• Bell A and McIvor RA. 2006. SMART therapy. CMAJ 175(3): 276
• Weinberger M and Abu-Hasan. 2006. Life-Threatening Asthma during Treatment with Salmeterol. NEJM 355(8): 852-853
• Perspectives:
• Ernst P et al. 2006. Safety and Effectiveness of Long-Acting Inhaled b-Agonist Bronchodilators When Taken with Inhaled Corticosteroids. Ann Intern Med 145:692-694

Issue

Medsafe provided a report for the MARC's annual watching brief review on the issue of inhaled long acting beta agonists (LABAs) and non-fatal asthma exacerbations. This issue was placed on the watching brief review list in September 2006, when the MARC reviewed the safety of LABAs in the treatment of asthma. The final results of the SMART trial, a meta-analysis by Salpeter SR et al (2006) were reviewed, and the Committee informed of recent regulatory action undertaken, in New Zealand and internationally, to manage the identified risks of fatal and non-fatal asthma exacerbations in patients receiving LABA therapy (predominantly in the absence of inhaled corticosteroid therapy).

The purpose of the August 2007 Medsafe report was to inform the Committee of recent data and regulatory actions. The Committee was asked to evaluate the information provided and determine whether the risk-benefit profile of LABAs has changed as a result of the recent information; and if so, recommend appropriate regulatory action.

Discussion

The Committee noted the Medsafe report.

Medsafe advised that the MRHA is currently conducting a review of the risks and benefits of formoterol and salmeterol use in the treatment of asthma and chronic obstructive pulmonary disease. It was not known when this review would be completed although product sponsors were required to provide data to the MHRA by 31 March 2007.

The Committee noted that recent literature has not added significantly to the body of evidence previously reviewed by MARC in September 2006. They noted that the LABA data sheets have been updated and contain adequate information on the risk of asthma exacerbations occurring in association with the use of LABAs and the need to ensure that LABAs are only used in combination with anti-inflammatory therapy. This information has been disseminated to New Zealand prescribers by way of a BPAC article published in December 2006 and further information on this issue will be published in the next issue of Prescriber Update.

They agreed that no further regulatory action is required at this time and that the issue of LABAs and the risk of fatal and non-fatal asthma exacerbations should 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.

Recommendation

The Committee recommended that the issue of LABAs and non-fatal asthma exacerbations should 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.

3.8 MENINGOCOCCAL B VACCINE AND CHRONIC FATIGUE

Issue

NZPhvC provided a report for the MARC on the issue of prolonged fatigue-like conditions following the MeNZB immunisation.

The purpose of the August 2007 NZPhvC report was to review the cases of prolonged fatigue-like conditions following the MeNZB immunisation reported to the Centre for Adverse Reactions Monitoring (CARM).

The MeNZB vaccine was rolled out in a national immunisation campaign from July 2004 to June 2006 for epidemic control in under 20-year-olds and has been the subject of media and community attention as perceived concerns about its safety were raised in the public arena. In particular, there was heightened concern following the screening of a Norwegian documentary that focused on patients who were reported to have developed Chronic Fatigue following the administration of the Norwegian variant of the vaccine. Following the screening, CARM received reports from parents concerned that previously unexplained fatigue-like conditions that children had developed were likely to be attributable to the MeNZB vaccine they had received.

Discussion

The Committee noted the NZPhvC report. NZPhvC advised that subsequent to the documentary being screened on television, CARM had received 13 reports of 'prolonged fatigue-like conditions'. This is a new category, as NZPhvC acknowledged that chronic fatigue is a difficult and nebulous condition to deal with and none of the cases reported truly fitted the generally accepted definition of chronic fatigue.

NZPhvC advised that the average age of the patients was 12.7 years, and the majority were boys. Many patients had other potential explanations for the symptoms they were experiencing, while other reports contained insufficient information to allow any relationship between the immunisation and the symptoms to be assessed.

NZPhvC advised that studies have suggested that there is a background incidence of chronic fatigue of 0.18% and 0.7% of the population. If the cases reported to CARM were considered to be a variant of Chronic Fatigue Syndrome, they would have to be considered in the context of the natural background incidence of these fatigue-like conditions. In addition, studies have shown that Chronic Fatigue Syndrome has been linked to a diverse range of precipitating and perpetuating factors and no clear understanding has been reached to determine risk factors. Under these circumstances, NZPhvC considered that it was difficult to substantially attribute causality to a single factor.

The Committee considered that there was insufficient evidence to show an association between chronic fatigue and the MeNZB vaccine.

The Committee noted that a review of the Norwegian cases included in the documentary programme is due to be released in the near future and that the outcome of this would be brought back to the MARC.

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

3.9 AMILORIDE/HYDROCHLORTHIAZIDE, HYPONATRAEMIA AND HYPERKALAEMIA

Issue

At the June 2007 MARC meeting, concern was expressed about the safety of amiloride/hydrochlorothiazide combination product (Amizide®) in light of anecdotal reports of patients experiencing severe electrolyte abnormalities such as hyponatraemia and hyperkalaemia.

The purpose of the Medsafe and NZPhvC August 2007 reports was to review the risk of severe electrolyte disturbances such as hyponatraemia and hyperkalaemia in patients receiving amiloride/hydrochlorothiazide and to determine whether this issue warrants regulatory action.

Discussion

The Committee noted the Medsafe and NZPhvC reports. They noted that while usage of Amizide in New Zealand has decreased over the last three years, it is used mainly in elderly patients, who were at risk of hospital admissions when electrolyte imbalances occurred. NZPhvC advised that reports of hyponatraemia with amiloride/hydrochlorothiazide diuretics were received sporadically between 1980 and 2000, with no reports in the last seven years.

The Committee agreed that there was insufficient recent reported evidence to alter the risk profile of Amizide, but that the benefits of this product has lessened in light of current best practice and the alternative products that were now available. A member provided an anecdotal report of a case of hypokalaemia in a patient taking Amizide which proved to be fatal. The Committee agreed that the electrolyte disturbances in association with Amizide could be significant and that the risk:benefit profile of this combination had changed over time.

The Committee considered that the side effect profile of the product might be reduced if the dose of hydrochlorothiazide was reduced. They recommended that Medsafe contact the sponsor of Amizide, and ask them to justify why their product contains 50mg hydrochlorothiazide when similar medicines generally contain only 12.5mg.

Recommendation

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

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 Amiodarone and interstitial lung disease [death] (75626)

Discussion

NZPhvC noted that the connection between interstitial lung disease and amiodarone was recognised in both the CARM and WHO databases, where it has a strong positive IC value. It is also well described in the product datasheet. A Prescriber Update article entitled "Keep an eye on Amiodarone patients" was published in February 2005.

Medsafe advised that further information regarding this case may have been reported to them. The Committee agreed that it would be useful to collate the information to further investigate this case.

The causal association with amiodarone was considered to be 'unclassifiable' for interstitial lung disease.

Recommendation

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

4.1.1.2 Cholecalciferol and stroke [death] (75121)

Discussion

NZPhvC advised that the recommended dose in the data sheet for moderate to severe vitamin D deficiency was one tablet daily for ten days as a loading dose, then one tablet per month as a maintenance dose. For mild to moderate deficiency, the recommended dose was one tablet per month. In this case, the patient's Vitamin D level was considered to be at an intermediate level, and the Calciferol was prescribed for five days. Cardiovascular adverse effects, which are listed on the product datasheet generally occur with high doses and prolonged time period and therefore it was considered unlikely that the dose prescribed would have caused this patients CVA.

The causal association with cholecalciferol was considered to be 'unlikely' for stroke.

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

4.1.1.3 Diclofenac and duodenal ulcer haemorrhagic, oesophagitis [death] (74905)

Discussion

NZPhvC noted that the CARM database includes reports for duodenal ulcer, duodenal ulcer haemorrhagic, and oesophagitis with diclofenac. Since January 2006, eight reports have been received by CARM of perforation or haemorrhage of gastric or duodenal ulcers, or of gastrointestinal bleeding. Five of these patients were taking the maximum recommended daily dose of diclofenac, and two others were also taking other NSAIDs. They noted that there is some evidence in the literature suggesting that gastroduodenal reactions to NSAIDs are dose-related. Notably, this patient was taking the maximum daily dose. While the risk of duodenal and gastric ulceration is higher in elderly patients, the history of alcoholism may have contributed in this patient.

In addition, NZPhvC noted that a recent analysis of case reports for diclofenac have highlighted reports of renal failure. Further investigation of these reports showed that many of these patients were taking the maximum recommended daily dose. The Committee noted that the issue of NSAIDS and cardiovascular adverse effects was to be discussed at the December MARC meeting and agreed that the reports of renal failure with diclofenac should be further analysed and included in this review.

The Committee noted that gastroduodenal ulceration and bleeding are well documented in the data sheets for diclofenac, and that oesophageal disorders are listed as rare adverse reactions.

The causal association with diclofenac was considered to be 'probable' for duodenal ulcer haemorrhagic, oesophagitis.

Recommendation

The Committee recommended that NZPhvC should 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.

4.1.1.4 Fluconazole and foetal death[death] (75091)

Discussion

NZPhvC noted that there are no reports of foetal effects with fluconazole in the CARM database, The WHO database contains seven reports of foetal death with fluconazole. The datasheet states that there have been reports of multiple congenital abnormalities in infants whose mothers were being treated with high doses of fluconazole for long periods, however, this case was neither a high dose nor a long time period. NZPhvC noted a study by Jick SS "Pregnancy outcomes after maternal exposure to fluconazole" suggested that fluconazole exposure in the first trimester of pregnancy does not materially increase the risk of congenital disorders in infants. The Committee agreed that there was insufficient information to support an association between the fluconazole treatment and the spontaneous abortion.

The Committee considered the causal association with fluconazole was 'unclassified' for foetal death.

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

4.1.1.5 Losartan, salbutamol/ipratropium and sudden death [death] (75645)

Discussion

The Committee noted that there were several possible reasons for this sudden death, including the underlying disease, a tachyarrhythmia induced or exacerbated by bronchodilators in the presence of cardiomyopathy, an anaphylactic reaction to Combivent or losartan, or hyperkalaemia.

The Committee considered the causal association with losartan, Combivent was 'possible' for sudden death.

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

4.1.1.6 Olanzapine and embolism pulmonary [death] (74721)

Discussion

NZPhvC advised that there were two reports in the IMMP database, one of pulmonary embolism which resulted in death, and another of deep venous thrombosis. Both cases had other factors which may have contributed. There are also some reports in the WHO database and in the published literature. The olanzapine datasheet lists venous thromboembolism as a very rare adverse effect.

The Committee noted that atypical antipsychotics are associated with an increased risk of venous thromboembolism. The patient's past history of breast cancer was a potential confounding factor in this case.

The causal association with olanzapine was considered to be 'possible' for embolism pulmonary.

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

4.1.1.7 Quetiapine and cardiomyopathy, embolism pulmonary [death] (75057)

Discussion

NZPhvC advised that there are three other cases of cardiomyopathy in the IMMP database, and none for pulmonary embolism with quetiapine. The WHO database included nine reports of cardiomyopathy with quetiapine; there was an increasing IC value for the association of quetiapine and pulmonary embolism. Neither cardiomyopathy nor pulmonary embolism are listed as adverse reactions in the quetiapine datasheet.

The Committee noted that the post-mortem report has been requested but not yet received. The reporting doctors were preparing a case report for publication or discussion and the Committee agreed it would also be useful if a copy of this report could be sent to CARM.

The causal association with quetiapine was considered to be 'possible' for cardiomyopathy, embolism pulmonary.

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

4.1.1.8 Quetiapine and overdose [death] (75399)

Discussion

NZPhvC noted that the pathologist did not comment on the concurrent administration of paroxetine, which may have increased serum levels of quetiapine by CYP2D6 inhibition. The involvement of alcohol and other medicines made it difficult to determine if the overdose was accidental or intentional. NHI data showed previous hospital admissions for overdose and alcohol toxicity.

The causal association with quetiapine was considered to be 'possible' for overdose.

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

4.1.1.9 Peg interferon alpha-2a, ribavirin and leukocytosis, thrombocytopaenia, GI haemorrhage, confusion, medication error [death] (75149)

Discussion

NZPhvC noted that when the patient began treatment, his neutrophil count was within the parameters specified on the product datasheet. The level at which the patient was told to discontinue treatment was that specified on the datasheet, however, in this case the patient continued treatment. The cause of death is not clear, the gastrointestinal bleeding was probably due to the thrombocytopenia, and he may have also had oesophageal varices due to his hepatic disease. The change from a low to very high neutrophil count suggests there may have also been sepsis.

The causal association with peg interferon alpha-2a, ribavirin was considered to be 'possible' for leukocytosis, thrombocytopaenia, GI haemorrhage, confusion and 'certain' for medication error.

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

4.1.1.10 Rituximab, methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone and coma, cardiac arrest,convulsion, hemiparesis [death] (75575)

Discussion

NZPhvC noted that there were no related reports in the CARM database. The WHO database showed positive IC values for coma, chest pain and myocardial infarction with rituximab. The Mabthera datasheet refers to various neurological and cardiovascular events. NZPhvC noted that there was a delay from the discontinuation of rituximab to the onset of the symptoms, but the datasheet suggests that some neurological events have been reported for several months after the completion of therapy. The WHO database contains some reports with the term coma in association with rutiximab, but details are lacking, and the Committee agreed that it was not possible to establish a causal association in this case.

The causal association with rituximab, methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone was considered to be 'unclassified' for coma, cardiac arrest, convulsion, hemiparesis.

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

4.1.1.11 Salmeterol and bronchospasm aggravated [death] (75086)

Discussion

The Committee agreed it would be useful to find out if the patient was taking any complementary medicines, in order to clarify if this was an allergic type response in an asthmatic patient. It was noted that there were no details about past history of asthma control and it would be useful to have more background information.

The causal association with salmeterol was considered to be 'possible' for bronchospasm aggravated.

Recommendation

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

4.1.1.12 Tiotropium and chronic obstructive airways disease, disease progression [death] (75038)

Discussion

The Committee noted that the MARC had reviewed a cluster of company reports of tiotropium deaths at the last meeting in June 2007. They noted that the company had been contacted to seek additional details from reporters in other reports of 'sudden death' that may assist in understanding more about the association with tiotropium, and that these would be reviewed by the MARC when this information became available.

The causal association with tiotropium was considered to be 'unclassified' for chronic obstructive airways disease, disease progression.

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

4.1.1.13 Ezetimibe and pancreatitis, pancreas cyst, diabetes mellitus (74993)

Discussion

NZPhvC noted that pancreatitis is included in the product datasheet under postmarketing reports. They noted that there were no relevant publications in the literature. However, in the December 2006 Australian Adverse Drug Reactions Bulletin, ezetimibe was included in a list of medicines reported most frequently as suspected causes of pancreatitis. Similarly, in 2005 Health Canada and the manufacturer provided new safety information that included pancreatitis in a list of serious adverse disorders reported rarely with ezetimibe, with or without a statin.

NZPhvC advised that there is one report of pancreatitis for ezetimibe in the CARM database. The WHO database indicates an emerging adverse effect. The IC value is positive, and increasing.

NZPhvC noted that there is emerging evidence that ezetimibe can cause pancreatitis which can be severe. There is also evidence that statins can cause pancreatitis. Reports in the CARM database indicate that there are proportionately more reports of pancreatitis with ezetimibe than with the statins.

The Committee agreed that a paragraph adding ezetimibe to the list of medicines likely to cause drug-induced pancreatitis should be published in Prescriber Update, referring back to the article published in December 2005.

The causal association with ezetimibe was considered to be 'possible' for pancreatitis, pancreas cyst, diabetes mellitus.

Recommendation

The Committee recommended that a paragraph is published in Prescriber Update, advising prescribers that ezetimibe can cause drug-induced pancreatitis.

4.1.1.14 Pioglitazone and pleural effusion (75471)

Discussion

NZPhvC advised that the CARM database includes one report of pleural effusion with rosiglitazone, but none for pioglitazone. The WHO database shows a strongly positive and increasing IC value. The datasheet includes no mention of pleural effusion. There is only one published case report, despite the reports in the WHO database.

The Committee discussed whether the glitazones were unusual, compared with other medicines that cause fluid retention, in causing compartmental oedema.

The causal association with pioglitazone was considered to be 'possible' for pleural effusion.

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

4.1.1.15 Leflunomide, prednisone and abscess pulmonary, bronchiectasis (75123)

Discussion

NZPhvC advised that the CARM database includes reports of pneumonia with leflunomide, but none of lung abscess or bronchiectasis. In total there are seven reports of serious infection. The WHO database includes six reports of bronchiectasis, with a strong positive IC value. The product datasheet mentions pneumonia, but no indication of the severity or nature of these pneumonias.

The causal association with leflunomide, prednisone was considered to be 'probable' for abscess pulmonary, bronchiectasis.

The Committee noted that a paragraph to be prepared by NZPhvC for publication in Prescriber Update will include information about the early recognition and treatment of infection in patients taking leflunomide.

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

4.1.1.16 Citalopram, Codral Cough and Flu preparation and serotonin syndrome, drug interaction (75084)

Discussion

NZPhvC advised that there are no reports of serotonin syndrome with SSRIs and dextromethorphan combinations in the CARM database, however, there are some reports in the WHO database. The Cipramil datasheet refers to the possibility of serotonin syndrome. A paper has been published describing serotonin-like syndrome in a few patients taking SSRIs, specifically fluoxetine and paroxetine, with dextromethorphan.

The Committee noted that the full product name was Codral Cough, Cold & Flu, and that the product contained a number of other ingredients, including pseudoephedrine. They agreed that it was potentially a common combination of medicines and queried how well recognised the possible interaction between them was. They considered it would be useful to obtain further details about this case to aid in the writing of a paragraph in Prescriber Update to highlight this potential interaction.

The causal association with citalopram, Codral Cough and Flu preparation was considered to be 'possible' for serotonin syndrome, drug interaction.

Recommendation

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

4.1.1.17 Salmeterol and bronchospasm aggravated, respiratory arrest (75236)

Discussion

NZPhvC advised that the patient had previously had asthma, but never had experienced a precipitous attack before.

The causal association with salmeterol was considered to be 'probable' for bronchospasm aggravated, respiratory arrest.

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

4.1.1.18 ADT vaccine, Vivaxim vaccine and myelitis transverse (75119)

Discussion

NZPhvC noted that the CARM database includes three reports of transverse myelitis, but these have been attributed to the influenza vaccine. The WHO database also includes reports for myelitis with the influenza vaccine, and also for Twinrix (Hepatitis A and B). Both have positive IC values.

The datasheets for ADT and Vivaxim both include a broad statement regarding neurological disorders. The literature includes case reports suggesting that some neurological entities have a temporal association with immunisation.

The Committee noted that herpes zoster is a well-recognised risk factor for transverse myeltis and agreed that the symptoms were more likely to be associated with this than the vaccines.

The causal association with ADT vaccine, Vivaxim vaccine was considered to be 'unlikely' for myelitis transverse.

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

4.1.1.19 Influenza virus vaccine and transverse myelitis (75478)

Discussion

NZPhvC advised that the product datasheet refers to the possibility of post-vaccination disorders following immunisation and that in particular conditions such as encephalopathy, neuritis and Guillain Barre Syndrome (GBS) have been observed rarely. The literature is more supportive of the link between neurological conditions and immunisation and possible mechanisms of action, however, this is based on indirect and theoretical evidence.

The Committee agreed that it was unable to exclude the possibility that there may be a causal association with influenza immunisation and transverse myelitis.

The causal association with Fluvax was considered 'possible' for transverse myelitis.

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

4.1.2 Other Reports

The Committee noted the following case reports:
4.1.2.1 Adalimumab (75287)
4.1.2.2 Etoricoxib (75004)
4.1.2.3 Etoricoxib (75295)
4.1.2.4 Quinine (75083)
4.1.2.5 Terbinafine (75567)

4.2 IMMP Update for the MARC September 2007

The Committee noted the report.

4.3 Quarterly Reports from CARM as at 30 June 2007

Discussion

NZPhvC presented the report. They noted that the main issue of methylphenidate had previously been discussed at this meeting. The other emerging issue was for paroxetine and the brand switch from Aropax to Loxamine. These reports documented reduced effect and/or symptoms possibly consistent with withdrawal effects.

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

• Kerr D et al. Rofecoxib and Cardiovascular Adverse Events in Adjuvant Treatment of Colorectal Cancer. The New England Journal of Medicine. 357, 26 July 2007.
• Risk of fracture with alendronic acid. Reactions Weekly; Vol. 1151,12 May 2007.
• Harrison-Woolrych M et al. Safety and Usage of Atypical Antipsychotic Medicines in Children. Drug Safety; 2007; 30 (7); 569 - 579.

6 new zealand pharmacovigilance-related activities

Record of the Pharmacology and Therapeutics Advisory Committee Meeting held on 9 and 10 May 2007.

7 international pharmacovigilance-related Activities

7.1 Australia

• Minutes of the 300th meeting of the Adverse Drug Reactions Advisory Committee held on 11 May 2007.
• Minutes of the 301st meeting of the Adverse Drug Reactions Advisory Committee held on 15 June 2007.

7.2 United Kingdom

• Drug Safety Update. Vol. 1; No.1. August 2007.

7.3 World Health Organisation (WHO)

• The Uppsala Monitoring Centre. Signal - Analyses of Adverse Reaction Reports in the WHO database. June 2007.

8 Summary listings of case reports considered by the MARC (1997-2006)

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

9 OTHER BUSINESS

9.1 Australia and New Zealand Therapeutics Products Authority (ANZTPA) - postponement

The Committee was advised that the establishment of the Australia and New Zealand Therapeutics Products Authority has been postponed due to insufficient parliamentary support.

There being no further business, the Chair thanked members, guests and the secretariat for their attendance and closed the meeting at 3:50pm.

 

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