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Committees

Updated 20 May 2013

Minutes of the 126th Medicines Adverse Reactions Committee Meeting - 15 June 2006

Preface:

In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.

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

The material listed as being considered on an issue is not intended to be exhaustive.
The recommendations of the Committee are in bold typeface.

Minutes:

TABLE OF CONTENTS

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

INVITED GUESTS AND EXPERTS

1. MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies
1.2 Minutes of the 125th MARC Meeting

1.2.1 Report to the Minister's Delegate

1.3 Dates of Future MARC Meetings

1.4 Potential Conflicts of Interest

1.5 Prescriber Update

1.5.1 Prescriber Update. Vol. 27; No. 1. June 2006
1.5.2 Schedule of Planned Prescriber Update Articles

2. ACTIONS ARISING

2.1 Report on Actions Arising from the 125thMARC Meeting, 16 March 2006

2.1.1 Review of Adverse Reactions of Current Concern
2 .1.2 MARC Membership – Vacant Positions
2.1.3 Aprotinin and Risks in Cardiac Surgery
2.1.4 Anti-Tumour Necrosis Factor Alpha (TNFα) Agents and the Risk of Hepatitis B Reactivation
2.1.5 All Serious or Unexpected Adverse Reactions to Rosiglitazone: Standing Agenda Item
2.1.6 Ranitidine / pantoprazole and gynaecomastia (CARM case 69227)
2.1.7 GRINZ party pill and convulsions (CARM case 67975)
2.1.8 Slimfast and fever, neutropenia (CARM case 69406)
2.1.9 Heparin and thrombocytopenia (CARM case 69852)
2.1.10 Tacrolimus / azathioprine / prednisone and skin disorder, pustular rash (CARM case 69948)
2.1.11 Somatropin and enuresis, congenital anomaly, lipoma (CARM case 70008)
2.1.12 Citalopram / fentanyl and neonatal respiratory depression (CARM case 69860)
2.1.13 Venlafaxine and serotonin syndrome (CARM case 69901)
2.1.14 Tramadol - Interactions and Serious Reactions
2.1.15 Selective Serotonin Reuptake Inhibitors (SSRIs) and the Risk of Suicidality
2.1.16 Clozapine and Severe Gastrointestinal Motility Impairment
2.1.17 Clozapine and Haematological Malignancies
2.1.18 Future Arrangements for Pharmacovigilance in New Zealand

2.2 REPORT ON ACTIONS ARISING FROM PREVIOUS MEETINGS OF THE MARC

2.2.1 Venlafaxine and serotonin syndrome (CARM case 59599)
2.2.2 COX-2 Inhibitors and Cardiovascular Safety
2.2.3 The Legacy of Diethylstilboestrol (DES)
2.2.4 Phenytoin, Fluorouracil and Ataxia, Dizziness, Drug Level Increased (CARM case 62606)
2.2.5 Methotrexate, Leflunomide and Respiratory Adverse Effects (CARM cases 63532 and 64391)
2.2.6 Elidel (pimecrolimus) and the Risk of Malignancy
2.2.7 Bisphosphonates and Osteonecrosis of the Jaw
2.2.8 Paroxetine and Use in Pregnancy
2.2.9 Dextropropoxyphene/Paracetamol Combination Products and the Risk of Overdose
2.2.10 Selective Serotonin Reuptake Inhibitors (SSRIs) and Haemorrhage – Watching Brief Review
2.2.11 Selective Serotonin Reuptake Inhibitors (SSRIs) and Withdrawal Reactions – Watching Brief Review
2.2.12 Nitrofurantoin and dyspnoea, cough and pulmonary infiltration (CARM case 67409)
2.2.13 Warfarin/tramadol and purpura, decreased prothrombin (CARM case 67421)

3. PHARMACOVIGILANCE ISSUES

3.1 TOPICAL PIMECROLIMUS AND THE RISK OF MALIGNANCY
3.2 BISPHOSPHONATES AND OSTEONECROSIS OF THE JAW
3.3 TRAMADOL AND HEPATIC REACTIONS: WATCHING BRIEF REVIEW

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 Alternative Medicines
4.1.3 Anti-Malarial Medicines
4.1.4 Cardiovascular Medicines
4.1.5 Endocrine Medicines
4.1.6 Hormones
4.1.7 Immunosuppressive Medicines
4.1.8 Musculoskeletal Medicines
4.1.9 Psychiatric Medicines
4.1.10 Other Reports

4.2  Pharmacovigilance Issues Arising From Reports to CARM

4.2.1 Proton Pump Inhibitors and Interstitial Nephritis

4.3 Quarterly Report from CARM as at 31 MARCH 2006

5. PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

6. NEW ZEALAND PHARMACOVIGILANCE-RELATED ACTIVITIES

7. INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

7.1 Australia

7.2 Canada

7.3 Singapore

7.4 WHO

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

9. OTHER BUSINESS

9.1 FUTURE ARRANGEMENTS FOR PHARMACOVIGILANCE IN NEW ZEALAND
9.2 ORAL TERBINAFINE SERIOUS ADVERSE REACTIONS


Minutes:

The one hundred and twenty-sixth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 15 June 2006 at the De Havilland room, Wellington Airport Conference Centre, Wellington, New Zealand. The meeting commenced at 9:00am and closed at 2:45pm.

marc members present

Assoc. Prof. T. Maling (Chair, 12:00pm until 1:30pm)
Hon. Assoc. Prof. M. Rademaker (Acting Chair)
Dr H. Kingston
Dr F. McClure
Prof. P. Ellis
Dr M. Tatley
Dr S. Sime

marc secretariat present

Ms S. Von Afehlt (Senior Pharmacy Advisor/Editor of Prescriber Update, Medsafe)
Dr K. Moses (Pharmacovigilance Advisor/MARC Secretary, Medsafe)

invited guests and experts

Dr S. Martindale, Team Leader (Business Development and Support), Medsafe attended the meeting for the discussion on the Future Arrangements for Pharmacovigilance in New Zealand (see minute item 9.1).

Assoc. Prof. A. Grey (Endocrinologist at Auckland District Health Board and member of the Osteoporosis Research Group at Auckland University, Faculty of Medicine) and Dr D. Hay (Oral Medicine Specialist, Auckland District Health Board) participated in the meeting by teleconference for the discussion on Bisphosphonates and Osteonecrosis of the Jaw (see minute item 3.2).

Dr C. Cameron (Clinical Pharmacology registrar, Capital and Coast District Health Board) observed the meeting.

1. Matters of Administration

1.1 Welcome and Apologies

The Acting Chair welcomed the attendees to the meeting. Assoc. Prof. T. Maling was only able to attend the meeting from 12:00pm until 1:30pm, and sent his apologies for the remainder of the meeting. Apologies were also received from Prof. D. Skegg.

1.2 Minutes of the 125th MARC Meeting

NZPhvC asked that an amendment be made to the minutes of the 125th MARC meeting, in the discussion for minute item 3.3 All Serious or Unexpected Adverse Reactions to Rosiglitazone: Standing Agenda Item. Members agreed that the sentence "NZPhvC commented that it was now clear that glitazones increase the risk of congestive cardiac failure, alone or in combination with insulin or other oral hypoglycaemic therapies, and the Committee agreed with this assessment." should be amended to read "NZPhvC commented that there was evidence from international spontaneous reports that glitazones increase the risk of congestive cardiac failure, alone or in combination with insulin or other oral hypoglycaemic therapies, and the Committee agreed with this assessment." The Secretary agreed to make that change to the minutes.

Members agreed that the minutes of the 125th MARC meeting were otherwise a true and accurate record of the meeting. The Acting Chair of that meeting subsequently ratified the minutes. The Secretary agreed to also have the minutes ratified by the MARC Chair.

1.2.1 Report to the Minister's Delegate

Members noted that one recommendation from the March 2006 MARC meeting, regarding minute item 3.1, Aprotinin and Risks in Cardiac Surgery, had been rejected by the Minister's Delegate on the advice of Medsafe (see minute item 2.1.3 for further details). The Committee supported this decision. Members also noted that Medsafe's alternate recommendation for the March 2006 minute item 9.1, Future Arrangements for Pharmacovigilance in New Zealand, had been accepted by the Minister's Delegate (see minute item 2.1.18 for further details). The Committee supported this decision.

1.3 Dates of Future MARC Meetings

The date for the next MARC meeting was confirmed as being Thursday 14 September 2006. The subsequent MARC meeting was scheduled for 14 December 2006.

1.4 Potential Conflicts of Interest

Committee members submitted their Conflict of Interest Declaration forms to the Secretary. The Acting 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. The Committee noted potential conflicts declared by two members. The MARC considered that these potential conflicts of interest would not influence the discussions or decisions of the Committee.

1.5 Prescriber Update

1.5.1 Prescriber Update. Vol. 27; No. 1. June 2006

Discussion

The Committee complimented the Medsafe Pharmacovigilance Team on the June 2006 edition of Prescriber Update.

1.5.2 Schedule of Planned Prescriber Update Articles.

Discussion

The Committee noted the schedule of planned Prescriber Update articles.

Members queried whether the scheduled articles on ezetimibe and muscle disorders, and psychiatric adverse effects of the statins would refer to one another. NZPhvC advised that the statins article was to be updated to include information on ezetimibe. Members asked that the ezetimibe article include a reference to the statins article.

Several members agreed to act as MARC peer-reviewers for scheduled Prescriber Update articles. The Editor of Prescriber Update explained that articles were also externally peer-reviewed.

Recommendation

The Committee recommended that the scheduled Prescriber Update article on the psychiatric adverse effects of the statins should include information about ezetimibe

2. Actions Arising

2.1 Report on Actions Arising from the 125th MARC Meeting, 16 March 2006

Please refer to the minutes of the 125th MARC meeting, held on 16 March 2006, available on the Medsafe web site at www.medsafe.govt.nz/Profs/adverse/Minutes125.htm for background information surrounding these issues.

2.1.1 Review of Adverse Reactions of Current Concern

March 2006 minute item 2.1.2; December 2005 minute item 2.1.5; September 2005 minute item 3.3

References
  1. Issues Monitored by Medsafe, NZPhvC and MARC, as at June 2006
  2. Savage R. Method for Developing an Adverse Reaction Profile for a Medicine using National and International Spontaneous Adverse Reaction Reports. May 2006.
Issue

The Committee recommended that Adverse Reactions of Current Concern issues should be moved from the standing agenda item list to the active monitoring list.

Outcome

The Committee were provided with a list of the issues monitored by the MARC, Medsafe and NZPhvC and clarification of the methodology used in reviewing Adverse Reactions of Current Concern issues. The Secretary agreed to include the list of issues monitored, and a list of outstanding actions, in the dossier for every meeting.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.2 MARC Membership – Vacant Positions

March 2006 minute item 2.2.1; December 2005 minute item 2.2.1; September 2005 minute item 2.1.1; June 2005 minute item 1.1.1

Issue

The Committee recommended that Medsafe should investigate appointing a pharmaco-epidemiologist, a paediatrician and a clinical pharmacist to the MARC.

Outcome

Medsafe had initiated the process for nominating an alternate to Prof. Skegg, should he be unable to attend a MARC meeting. Unfortunately, the proposed alternate was unable to attend the June meeting due to prior commitments.

In May 2006, Medsafe wrote to the New Zealand Paediatric Society and the Royal Australasian College of Physicians (Paediatrics and Child Health division) seeking nominees with expertise in paediatrics. The Paediatric Society forwarded the request to members via their list server. Responses had not yet been received.

Medsafe had identified several candidates with expertise in clinical pharmacy and the nomination process was underway.

Discussion

Medsafe informed the Committee of the candidates nominated for MARC membership. Medsafe reminded members that several candidates for each position were required to be provided to the Minister of Health, from which he would choose his preferred candidate.

Members expressed concern that Dr Jessamine (Principal Technical Specialist, Medsafe) was not in attendance at the MARC meeting. As Dr Jessamine was to act as an alternate to Dr Sime as the Ministry of Health ex officio member, the MARC considered that it was imperative that he be available to attend MARC meetings in order to provide a high-level interface with Medsafe, especially regarding the transition to the Australia New Zealand Therapeutic Products Authority (ANZTPA).

Recommendation

The Committee recommended that Dr Jessamine (Principal Technical Specialist, Medsafe) should be requested to be available to attend every meeting of the MARC.

2.1.3 Aprotinin and Risks in Cardiac Surgery

March 2006 minute item 3.1

Issue

The Committee recommended that Medsafe should write to New Zealand's cardiac surgery units, informing them of the findings of recent research on aprotinin in cardiac surgery, and asking for their expert opinion.

The Committee recommended that the issue of aprotinin and the risks of cardiovascular, renal and cerebrovascular adverse reactions in cardiac surgery should be placed on the watching brief list.

Outcome

Medsafe recommended to the Minister's Delegate that he reject the first recommendation above for the following reasons:

This issue was added to the watching brief list and was due to be reviewed in March 2007.

Discussion

The Committee noted the above and supported Medsafe's decision. The Committee agreed that no further regulatory action was required at that time.

2.1.4 Anti-Tumour Necrosis Factor Alpha (TNFα) Agents and the Risk of Hepatitis B Reactivation

March 2006 minute item 3.2

Issue

The Committee recommended that Medsafe should require the sponsors of all three anti-tumour necrosis factor alpha (anti-TNFα) agents to include a consistent warning statement in the data sheets regarding the risk of hepatitis B virus reactivation, including the need to test hepatitis B serology prior to initiating therapy.

The Committee recommended that Medsafe should disseminate a 'Dear Healthcare Professional' letter to all prescribers, once the data sheet changes for the anti-TNFα agents had been finalised.

The Committee recommended that the issue of hepatitis B reactivation with anti-TNFα agents should be placed on the active monitoring list.

Outcome

Medsafe wrote to the anti-tumour necrosis factor alpha (anti-TNFα) sponsors in May 2006 requesting the data sheet updates. Responses had not yet been received.

This issue was added to the active monitoring list and was due to be reviewed in March 2007.

Discussion

The Committee noted the above and asked that Medsafe inform the Committee once responses had been received from the anti-TNFα product sponsors.

2.1.5 All Serious or Unexpected Adverse Reactions to Rosiglitazone: Standing Agenda Item

March 2006 minute item 3.3

Issue

The Committee recommended that Medsafe should ask GlaxoSmithKline to update the Avandia data sheet with the most recent evidence on the risk of congestive cardiac failure with rosiglitazone.

The Committee recommended that the issue of all adverse reactions to rosiglitazone should be removed from the standing agenda item list.

The Committee recommended that all adverse reactions to rosiglitazone and pioglitazone should be placed on the Adverse Reactions of Current Concern (ARCC) list. (Note: All ARCCs are monitored on the active monitoring list.)

Outcome

In a further submission to Medsafe, dated 31 March 2006, GlaxoSmithKline stated that changes to the New Zealand data sheet for Avandia would not be initiated until the results of an epidemiological study were available (expected in May or June 2006). The Core Safety Information, however, had already been updated with respect to congestive cardiac failure.

Medsafe considered that this was unsatisfactory and wrote to GlaxoSmithKline in May 2006 requesting an update to the Avandia data sheet with the current evidence on the risk of congestive cardiac failure. A response had not yet been received.

All adverse reactions to pioglitazone and rosiglitazone were added to the Adverse Reactions of Current Concern list. This issue was due to be reviewed by the MARC in March 2007. The revised list of Adverse Reactions of Current Concern was published in the June 2006 edition of Prescriber Update and the May 2006 issue of MIMS New Ethicals.

Discussion

The Committee noted the above and asked that Medsafe inform the Committee once a response had been received from GlaxoSmithKline.

2.1.6 Ranitidine / pantoprazole and gynaecomastia (CARM case 69227)

March 2006 minute item 4.1.2.1

Issue

The Committee recommended that NZPhvC should contact the reporter in this case (69227) to ask about resolution of the gynaecomastia in this 3-week-old baby.

The Committee recommended that NZPhvC should seek expert advice from a paediatrician on gynaecomastia in newborns.

Outcome

The NZPhvC was seeking the advice of a paediatrician and was following up with the reporter.

Discussion

NZPhvC informed the Committee that a response had been received from the reporter. The child had subsequently been seen by her general practitioner and no record had been made of gynaecomastia.

Additionally, NZPhvC had obtained advice from a paediatrician. He advised that neonatal breast enlargement is common and often presents similarly to this case. He considered that it was possible that ranitidine played a role in this case, but that it was not clear whether pantoprazole could be implicated.

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.7 GRINZ party pill and convulsions (CARM case 67975)

March 2006 minute item 4.1.3.1

Issue

The Committee recommended that, in the future, case reports of adverse reactions to products taken for recreational purposes should not be brought to the MARC.

The Committee recommended that NZPhvC should discuss with the Expert Advisory Committee on Drugs (EACD) the possibility of providing CARM adverse reaction data for party pill products to the EACD.

Outcome

The issue had been communicated to the EACD with a request for advice on how to take the matter further.

Discussion

The Committee noted the above and agreed that NZPhvC should report back to the MARC once a response had bontact experts for advice on this issue.

2.1.8 Slimfast and fever, neutropenia (CARM case 69406)

March 2006 minute item 4.1.3.3

Issue

The Committee recommended that the Medsafe pharmacovigilance team should determine whether Medsafe's compliance team were aware of Slimfast and the therapeutic claims being made.

Outcome

Medsafe's compliance team were aware of this issue. Slimfast was tested in 2005 to confirm that the tablets contained the labelled amount of benzylpiperazine, and did not contain unlabelled ingredients. The results of the testing were acceptable. Additionally, the sponsor was required to remove the therapeutic claims of weight loss from their web site. However, the compliance team were investigating recent information suggesting that the Slimfast web site was no longer compliant.

Discussion

A member passed to the Secretary a recent print-out of the New Zealand web page for Slimfast, containing therapeutic claims for the product. The Secretary agreed to pass the information to the compliance team at Medsafe.

2.1.9 Heparin and thrombocytopenia (CARM case 69852)

March 2006 minute item 4.1.4.2

Issue

The Committee agreed that no further regulatory action was required at that time. However, they asked that NZPhvC report back once experience in other countries was known.

Outcome

Australia and the Netherlands were approached by NZPhvC. Australia had not noticed an association with brand change and, as yet, there had been no response from the Netherlands.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time. However, they asked that NZPhvC report back once experience in the Netherlands was known.

2.1.10 Tacrolimus / azathioprine / prednisone and skin disorder, pustular rash (CARM case 69948)

March 2006 minute item 4.1.5.1

Issue

The Committee recommended that azathioprine and prednisone should be added to the list of suspect medicines in this case (69948) and that the reaction term 'skin malformation' should be changed to 'skin disorder'.

Outcome

The NZPhvC changed the adverse reaction term in the database.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.11 Somatropin and enuresis, congenital anomaly, lipoma (CARM case 70008)

March 2006 minute item 4.1.6.1

Issue

The Committee recommended that CARM should find a more appropriate reaction term than 'congenital anomaly' for this case (70008).

Outcome

The NZPhvC introduced the adverse reaction term 'congenital anomaly – aggravated' and amended the database.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.12 Citalopram / fentanyl and neonatal respiratory depression (CARM case 69860)

March 2006 minute item 4.1.8.1

Issue

The Committee recommended that Medsafe should ask the citalopram product sponsors to update the data sheets with information on the risks to neonates following maternal use.

Outcome

Medsafe wrote to the citalopram sponsors in May 2006 requesting that the data sheets be harmonised with the Australian Product Information sheets with respect to neonatal withdrawal.

Discussion

Medsafe informed the Committee that Pacific Pharmaceuticals had agreed to update the Celapram data sheet as requested. Pharmacy Retailing had responded that the global data sheet for Cipramil was being reviewed and the results would be provided to Medsafe in June 2006. The Arrow-Citalopram brand (Arrow Pharmaceuticals) did not yet have a data sheet published on the Medsafe web site, despite being the fully funded brand of citalopram. Once the data sheet was published pharmacovigilance staff would review it and request changes if necessary.

The Committee noted the above and asked that Medsafe report back once responses had been received.regulatory action was required at that time.

2.1.13 Venlafaxine and serotonin syndrome (CARM case 69901)

March 2006 minute item 4.1.8.5

Issue

The Committee recommended that NZPhvC should contact the reporter again to query what criteria were used for diagnosing serotonin syndrome in this case (69901).

Outcome

The reporter had been contacted to clarify the criteria used in the diagnosis of serotonin syndrome.

Discussion

NZPhvC informed the Committee that a response had been received from the reporter. The signs and symptoms in this case supported the diagnosis of serotonin syndrome. The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.14 Tramadol - Interactions and Serious Reactions

March 2006 minute item 4.2.1

Reference
  1. Boyd I. Tramadol and seizures. MJA. 2005; 182(11): 595-596
Issue

The Committee recommended that NZPhvC should 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 Prescriber Update articles were being prepared in consultation with the Editor.

This issue was discussed at the Singapore/Australia/New Zealand (SANZ) teleconference in April 2006. The Australian Adverse Drug Reactions Unit (ADRU) responded that they had also been concerned about reports of tramadol and convulsions and had written a letter to the Medical Journal of Australia in 2003. They concluded from reports to ADRU that, although tramadol alone could induce seizures, these were more likely to occur in the setting of the concomitant use of other drugs that also have the potential to lower the seizure threshold. ADRU now had 93 such reports and the most suspect concomitant medicines were selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants. The tramadol doses in the ADRU reports ranged from 50 to 1000 mg daily with a median of 200 mg.

The ADRU staff, like NZPhvC, had not found any published lists or guidelines on medicines that might lower the seizure threshold. They thought that opiates could be considered to be seizure threshold-lowering agents as well as tricyclic antidepressants, SSRIs and antipsychotic medicines but were not at this stage offering advice about co-prescription of tramadol with other opiates.

The ADRU only had three reports where seizures occurred in the post-operative setting. NZPhvC also pointed out that hypotension due to a combination of anaesthetic medicines may induce seizures.

The Prescriber Update article on tramadol and seizures would take into account the above observations.

Additionally, at the March 2006 MARC meeting Medsafe agreed to investigate the inconsistency between the maximum intravenous (IV) dose of tramadol in the Tramal data sheet (600mg) and DrugDex 2005 (400mg). Medsafe found that the Australian and Singaporean Product Information sheets stated the maximum IV dose of tramadol to be 400mg. Medsafe wrote to CSL Pharmaceuticals in May 2006 asking them to amend the data sheet unless evidence to support a maximum IV dose of 600mg could be provided. A response had not yet been received.

Discussion

The Committee noted the above and asked Medsafe to report back once a response had been received from CSL Pharmaceuticals.

2.1.15 Selective Serotonin Reuptake Inhibitors (SSRIs) and the Risk of Suicidality

March 2006 minute item 4.4.2

References
  1. GlaxoSmithKline letter to Medsafe. Results from Suicidality Analysis of Adult MDD and non-MDD Paroxetine Clinical Studies. 7 April 2006.
  2. GlaxoSmithKline letter to Medsafe. Attachment 1 – Briefing Document. 7 April 2006. 3. GlaxoSmithKline letter to Medsafe. Attachment
  3. Draft DHCP Letter. 7 April 2006.
  4. Medicines and Healthcare Products Regulatory Agency, Commission on Human Medicines. Dear Healthcare Professional Letter. May 2006.
  5. GlaxoSmithKline. United States Dear Healthcare Professional Letter. May 2006.
Issue

The Committee recommended that severe agitation, severe restlessness/akathisia and/or suicidality with selective serotonin re-uptake inhibitors (SSRIs) should be removed from the Adverse Reactions of Current Concern list.

The Committee recommended that the issues of selective serotonin re-uptake inhibitors (SSRIs) and severe agitation, severe restlessness/akathisia and/or suicidality should be placed on the watching brief list pending the outcome of the United States Food and Drug Administration (FDA) review of the risk of suicidal behaviour in adults taking antidepressants.

Outcome

This issue was removed from the list of Adverse Reactions of Current Concern and added to the watching brief list pending the outcome of the FDA review. The revised list of Adverse Reactions of Current Concern was published in the June 2006 edition of Prescriber Update and the May 2006 issue of MIMS New Ethicals.

In April 2006, GlaxoSmithKline (GSK) informed Medsafe of the completion of a meta-analysis to evaluate the risk of suicidality in adult patients treated with paroxetine. GSK also submitted draft data sheet revisions and a draft Dear Healthcare Professional letter, both of which Medsafe found acceptable.

In May 2006, the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) reminded prescribers of the current advice for monitoring patients prescribed SSRIs, and stated that the new analyses were to be evaluated by the Commission on Human Medicines and the MHRA. Following this evaluation, the prescribing information for Seroxat (paroxetine) would be updated as needed.

In May 2006, GSK informed United States (US) prescribers of the results of the above meta-analysis, and changes to the US Paxil prescribing information.

Discussion

The Committee noted the above and the references provided.

Medsafe informed the Committee that the results of the United States Food and Drug Administration (FDA) review of the risk of suicidal behaviour in adults taking antidepressants were awaited before pursuing data sheet changes for the other SSRI products. Members noted that all SSRI data sheets already contained extensive warnings regarding the risk of suicidality.

Members commented that, in the data provided by GSK, the terminology and grouping of suicide-related events was unclear and inconsistent.

Members agreed that the key advice for New Zealand prescribers, being that patients should be fully informed of the risks and benefits of treatment and monitored carefully, had been adequately communicated through Dear Healthcare Professional letters and data sheet changes.

The Committee agreed that this issue should remain on the watching brief list pending the outcome of the FDA review of the risk of suicidal behaviour in adults taking antidepressants.

2.1.16 Clozapine and Severe Gastrointestinal Motility Impairment

March 2006 minute item 4.5.1

Issue

The Committee recommended that a short paragraph should be written for publication in Prescriber Update on the impairment of gastrointestinal motility with clozapine.

Outcome

The Editor of Prescriber Update was liaising with the author.

Discussion

The Committee noted the above.

2.1.17 Clozapine and Haematological Malignancies

March 2006 minute item 4.5.2

Issue

The Committee recommended that Medsafe should ask the clozapine sponsors to provide further data on the potential association between clozapine and haematological malignancies.

Outcome

Medsafe wrote to the clozapine sponsors in May 2006 requesting further data on the potential association with haematological malignancies. A response had not yet been received.

Discussion

The Committee noted the above and asked that Medsafe report back once responses had been received.

2.1.18 Future Arrangements for Pharmacovigilance in New Zealand

March 2006 minute item 9.2

Issue

The Committee recommended that the MARC Chair should contact the Chair of the Australian Adverse Drug Reactions Advisory Committee (ADRAC) to discuss the future of pharmacovigilance in the ANZTPA.

The Committee recommended that the MARC Chair should write to Medsafe, to highlight the Committee's request, as a Ministerial expert advisory committee, to participate in the development of the Australia New Zealand Therapeutic Products Authority (ANZTPA) pharmacovigilance strategy.

The Committee recommended that the MARC Chair should write to the Minister of Health to emphasise the importance of pharmacovigilance in New Zealand.

The Committee recommended that the Secretary of the MARC should invite the Manager of Medsafe, the Deputy-Director General (Public Health) and the Minister of Health to attend a MARC meeting.

The Committee recommended that the MARC Chair should make a presentation to the Quality Safe Use of Medicines group on pharmacovigilance in New Zealand.

Outcome

Medsafe recommended an alternate recommendation to the Minister's Delegate, that the Delegate "request Medsafe to convene a meeting with the MARC Chair, the Deputy-Director General (Public Health), the Manager of Medsafe, Susan Martindale and Stewart Jessamine to identify appropriate actions to address the Committee's concerns." A letter was sent to the MARC Chair in May 2006 inviting him to meet and discuss these issues.

Unfortunately, the Medsafe Manager and the Deputy-Director General (Public Health) were unable to attend the June 2006 MARC meeting due to prior commitments.

Discussion

See minute item 9.1 for discussion on this issue.

Members queried whether the Minister of Health had been invited to attend a MARC meeting. Medsafe responded that it would be most valuable for the MARC Chair to meet with Medsafe staff to discuss the Committee's concerns prior to extending such an invitation to the Minister of Health. The MARC members explained that the invitation was intended to be a 'meet and greet' rather than to discuss the future arrangements for pharmacovigilance, and asked that an invitation be extended to the Minister to attend a MARC meeting. The Secretary agreed to do so.

2.2 Report on Actions Arising from Previous Meetings of the MARC

2.2.1 Venlafaxine and serotonin syndrome (CARM case 59599)

June 2004 minute item 4.1.2.3; September 2004 minute item 2.1.15

Issue

In June 2004, the Committee recommended that a Prescriber Update article be written to inform and warn prescribers of the potential for interactions to occur between tricyclic antidepressants and SSRI's or SNRI's.

Outcome

A paragraph entitled 'SSRI-TCA interactions and serotonin syndrome' was published in the June 2006 edition of Prescriber Update.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.2 COX-2 Inhibitors and Cardiovascular Safety

December 2005 minute item 2.2.2; September 2005 minute item 2.2.1; June 2005 minute item 2.1.1; March 2005 minute item 3.1.8.1

Issue

In March 2005, the Committee recommended that Medsafe should explore the availability of an alternative, indication-specific, celecoxib product for the treatment of Familial Adenomatous Polyposis (FAP). If such a product is available, the indication for FAP should be removed for the Celebrex brand of celecoxib.

Outcome

Medsafe approved Onsenal (celecoxib 200mg and 400mg capsules) in May 2006 for the sole indication of Familial Adenomatous Polyposis (FAP). Pfizer subsequently applied to have this indication removed from the data sheet for Celebrex. The updated Celebrex data sheet was to be published on Medsafe's web site in June 2006.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.3 The Legacy of Diethylstilboestrol (DES)

March 2006 minute items 1.5.1 and 2.2.2; September 2005 minute item 2.1.3; June 2005 minute item 3.2

Issue

In June 2005, the Committee recommended that the author should be asked to identify and consult with experts in this area, and having done so, write a Prescriber Update article updating prescribers about the current evidence and to remind them about monitoring recommendations.

Outcome

The article entitled Stilboestrol - Gone But Not Forgotten was published on Medsafe's web site in May 2006, and in the June 2006 edition of Prescriber Update.

As suggested by the MARC at their March 2006 meeting, a copy of the published article was sent to the Treatment Injury and Patient Safety Branch of the Accident Compensation Corporation for their information.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.4 Phenytoin, Fluorouracil and Ataxia, Dizziness, Drug Level Increased (CARM case 62606)

March 2006 minute item 2.2.4; December 2005 minute item 2.2.8; September 2005 minute item 2.1.10; June 2005 minute items 4.1.10.1

Issue

In June 2005, the Committee recommended that the data sheet for 5-fluorouracil should be updated to address the interaction with phenytoin.

Outcome

In March 2006, the Committee expressed disappointment that Mayne Pharma had not responded to this request. They asked that Medsafe report back to the MARC once a response had been received.

Medsafe sent a further two requests to Mayne Pharma in March and May 2006. Mayne Pharma Australia informed Medsafe in late May 2006 that the Phenytoin Injection and Fluorouracil Injection data sheets would be updated as requested by the MARC. These changes were submitted to Medsafe in May 2006.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.5 Methotrexate, Leflunomide and Respiratory Adverse Effects (CARM cases 63532 and 64391)

December 2005 minute item 2.2.4; September 2005 minute item 2.1.13; June 2005 minute items 4.2.11.2 and 4.2.11.3.

Issue

In June 2005, the Committee recommended that a brief Prescriber Update article should be written to update prescribers on the respiratory adverse effects of leflunomide.

Outcome

An article entitled 'Leflunomide and pneumonitis' was published in the June 2006 edition of Prescriber Update. This article was a more detailed version of a short article published in the December 2005 issue of Prescriber Update.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.6 Elidel (pimecrolimus) and the Risk of Malignancy

June 2005 minute item 5.1

Issue

In June 2005, the Committee recommended that, once the results of the EMEA-commissioned review were released, Medsafe should ask Novartis to supply information regarding the number of patients using Elidel in New Zealand.

Outcome

Information on the issue of pimecrolimus and the risk of malignancy, including usage of Elidel in New Zealand, was provided to the Committee for the June 2006 MARC meeting.

Discussion

See minute item 3.1 for a full review of this issue.

2.2.7 Bisphosphonates and Osteonecrosis of the Jaw

March 2006 minute item 2.2.6; December 2005 minute item 2.1.4; September 2005 minute item 3.2

Issue

In September 2005, the Committee recommended that the Pamisol (pamidronate) data sheet should be updated in line with the Aredia (pamidronate) and Zometa (zoledronic acid) data sheets. Novartis and Mayne Pharma should highlight osteonecrosis of the jaw as a heading in the 'Warnings and Precautions' sections of their data sheets.

Outcome

In March 2006, the Committee expressed disappointment that Mayne Pharma had not responded to this request. They asked that Medsafe report back to the MARC once a response had been received.

Medsafe sent a further two requests to Mayne Pharma in March and May 2006. Mayne Pharma Australia informed Medsafe in late May 2006 that the Pamisol data sheet would be updated as requested by the MARC. This change was submitted to Medsafe in May 2006.

Discussion

See minute item 3.2 for a full review of this issue.

2.2.8 Paroxetine and Use in Pregnancy

March 2006 minute item 2.2.7; December 2005 minute item 2.1.7; September 2005 minute item 3.5

Issue

In September 2005, the Committee recommended that the data sheets for all paroxetine products should be updated as per the proposed data sheet for Aropax.

Outcome

Medsafe wrote to the sponsor of the Paroxetine brand in April 2006 requesting that the data sheet be updated as per the Aropax data sheet. This data sheet change was received by Medsafe in May 2006.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.9 Dextropropoxyphene/Paracetamol Combination Products and the Risk of Overdose

March 2006 minute item 2.1.3; December 2005 minute item 2.2.7; September 2005 minute item 2.1.2; June 2005 minute item 3.1

Issue

In December 2005, the Committee recommended that the indications in the data sheets for dextropropoxyphene/paracetamol combination products should be updated to limit use to the treatment of chronic pain of moderate severity for patients in whom treatment with therapeutic doses from alternative therapeutic groups, including combination products, had been used and found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient.

In December 2005, the Committee recommended that Medsafe should explore the option of publishing an article in Prescriber Update recommending that dextropropoxyphene/paracetamol combination products should not be used except in appropriate clinical situations, and to increase awareness of the risk of inadvertent overdose with concomitant alcohol use.

Outcome

The data sheets for Capadex and Paradex were updated as requested and submitted to Medsafe in April 2006. A Dear Healthcare Professional letter was disseminated by Healthcare Logistics on 27 April 2006 informing healthcare professionals of the changes to the data sheet for Capadex (indications and dosage) and reminding them of the contraindications and key precautions.

The Prescriber Update article was currently being drafted.

The sponsors had been requested to provide Medsafe with proposals for an industry census of patient use of these products by August 2006, the results of which were to be reviewed by the MARC in December 2007.

Discussion

Members commented that they did not recall having received the Capadex Dear Healthcare Professional letter, and asked that Medsafe investigate to whom the letter had been sent.

Medsafe informed the Committee that PSM Healthcare Ltd (trading as API Consumer Brands) was drafting a Dear Healthcare Professional letter informing prescribers of the changes to the Paradex data sheet and reminding them of the contraindications and key precautions.

Recommendation

The Committee recommended that Medsafe should investigate to whom the Capadex Dear Healthcare Professional letter had been sent.

2.2.10 Selective Serotonin Reuptake Inhibitors (SSRIs) and Haemorrhage – Watching Brief Review

March 2006 minute item 2.1.6; December 2005 minute item 3.1.2

Issue

In December 2005, the Committee recommended that the SSRI data sheets should be updated to adequately address the risk of abnormal bleeding and to be consistent with one another.

In December 2005, the Committee recommended that Medsafe should write a paragraph for publication in Prescriber Update informing prescribers of the risk of abnormal bleeding with SSRIs, and emphasising the risks of co-prescribing NSAIDs/aspirin.

Outcome

Medsafe wrote to the SSRI sponsors in April 2006 requesting updates to the data sheets regarding the risk of abnormal bleeding. Three sponsors (AFT Pharmaceuticals, Douglas Pharmaceuticals and Pacific Pharmaceuticals) had responded agreeing to make the changes as requested. Healthcare Logistics responded that the European data sheets for Cipramil (citalopram) and Lexapro (escitalopram) were being reviewed, including the risk of haemorrhage, and that the results would be available in mid-June 2006. The remaining four sponsors had not responded at the time of this report.

The Prescriber Update paragraph was to be drafted once the data sheet updates were finalised.

Discussion

The Committee noted the above and asked that Medsafe report back once responses had been received.

2.2.11 Selective Serotonin Reuptake Inhibitors (SSRIs) and Withdrawal Reactions – Watching Brief Review

March 2006 minute item 2.1.9; December 2005 minute item 3.1.5

Issue

In December 2005, the Committee recommended that Medsafe should review the evidence regarding the risks of withdrawal reactions with citalopram, and consider asking the product sponsors to update the data sheets.

Outcome

Medsafe wrote to the citalopram sponsors in May 2006 requesting that the data sheets be harmonised with the Australian Product Information sheets regarding the risk of withdrawal reactions. Responses had not yet been received.

Discussion

Medsafe informed the Committee that Pacific Pharmaceuticals had agreed to update the Celapram data sheet as requested. Pharmacy Retailing had responded that the global data sheet for Cipramil was being reviewed and the results would be provided to Medsafe in June 2006. The Arrow-Citalopram brand (Arrow Pharmaceuticals) did not yet have a data sheet published on the Medsafe web site, despite being the fully funded brand of citalopram. Once the data sheet was published pharmacovigilance staff would review it and request changes if necessary.

The Committee noted the above and asked that Medsafe report back once responses had been received.

2.2.12 Nitrofurantoin and dyspnoea, cough and pulmonary infiltration (CARM case 67409)

March 2006 minute item 2.1.12; December 2005 minute item 4.1.3.1

Issue

In December 2005, the Committee recommended that Medsafe should consider publishing a paragraph in Prescriber Update reminding prescribers about the importance of monitoring for respiratory adverse effects of nitrofurantoin and informing patients of the warning symptoms.

Outcome

A paragraph entitled 'Nitrofurantoin – monitor lung function in long-term use' was published in the June 2006 edition of Prescriber Update.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.13 Warfarin/tramadol and purpura, decreased prothrombin (CARM case 67421)

March 2006 minute item 2.1.13; December 2005 minute item 4.1.9.1

Issue

In December 2005, the Committee recommended that Medsafe should ask Pharmaco NZ Ltd to provide assurance that the Zytram data sheet would be updated to address the interaction with warfarin.

Outcome

The Zytram data sheet was updated as requested in April 2006.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

3. pharmacovigilance issues

3.1 Topical Pimecrolimus and the Risk of Malignancy

References
  1. M. Rademaker report for the MARC. June 2006.
  2. Medsafe report for the MARC. June 2006.
    1. EMEA Press Release. European Medicines Agency Recommends Cautious Use of Protopic/Protopy and Elidel. 27 March 2006. http://www.emea.eu.int/pdfs/general/direct/pr/9888206en.pdf
    2. EMEA. Questions and Answers on Protopic/Protopy and Elidel. 23 March 2006. http://www.emea.eu.int/pdfs/general/direct/pr/8027006en.pdf
    1. Novartis. Dear Healthcare Provider letter re. Elidel. 27 January 2006. http://www.fda.gov/medwatch/safety/2006/Elidel_DHCP_%201-27-06.pdf
    2. FDA talk paper. FDA Issues Public Health Advisory Informing Health Care Providers of Safety Concerns Associated with the Use of Two Eczema Drugs, Elidel and Protopic. 10 March 2005. http://www.fda.gov/bbs/topics/ANSWERS/2005/ANS01343.html
    3. FDA Public Health Advisory. Elidel (pimecrolimus) Cream and Protopic (tacrolimus) Ointment. 10 March 2005. http://www.fda.gov/cder/drug/advisory/elidel_protopic.htm
  3. Health Canada Advisory. Safety information about Elidel cream and Protopic ointment. 27 April 2005. http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2005/2005_31_e.html
  4. Berger T et al (2006). The use of topical calcineurin inhibitors in dermatology: Safety concerns. Report of the American Academy of Dermatology Association Task Force. J American Academy of Dermatology 54 (5): 818-823
    1. Novartis NZ Ltd. Elidel 1% Cream data sheet 15 February 2006.
    2. Novartis Pharmaceuticals Corp (US). Elidel 1% Cream Product Information. January 2006.
    3. Novartis (Europe). Elidel 1% Cream Summary of Product Characteristics. Approved 23 March 2006.
Late papers:
Issue

In February 2005, the paediatric sub-committee of the United States Food and Drug Administration (FDA) became concerned over the possible association between various cancers and the use of topical calcineurin inhibitors including pimecrolimus and tacrolimus. This prompted a safety review culminating in notification of a black box warning (finalised in January 2006) and a number of recommendations for prescribers.

The FDA recommendations were largely based on a theoretical risk of harm and evidence from animal studies. Although pimecrolimus is not genotoxic and does not interact directly with DNA, it may have the potential to impair local immunosurveillance. Repeat dose studies conducted with topical application of pimecrolimus in mice demonstrated a dose and treatment dependent development of lymphoma. Carcinogenicity studies conducted with oral administration of pimecrolimus in mice demonstrated a dose dependent development of lymphoma and benign thymoma. Carcinogenicity studies conducted with topical pimecrolimus in rats demonstrated development of follicular cell adenoma of the thyroid. Data from a recently conducted oral nine-month monkey study showed a dose-related increase in virus-associated lymphoma following administration of pimecrolimus. As at December 2004, the FDA had received 10 post-marketing reports of cancer-related events associated with topical Elidel, four of which were in children.

The American Academy of Dermatology conducted a review of the data regarding the risk of malignancy in association with the use of topical calcineurin inhibitors (TCIs) that had been presented at the FDA Paediatric Scientific Advisory Committee meeting in February 2005. (This review was completed prior to changes being made to the United States Product Information for Elidel cream in January 2006). The Academy of Dermatology concluded that:

Up to 17 February 2006, there had been 53 reports worldwide of malignancy in association with topical Elidel (pimecrolimus) use: 27 lymphoma, 15 skin cancers, and seven other organ cancers. Four cases occurred during clinical trials, the remaining were from post-marketing surveillance. Seven of the lymphomas were in children under the age of five. There was considerable variety in types and location of the 27 reported lymphomas. There was skin involvement in six of the eight T-cell non-Hodgkins lymphomas and in two of the nine B-cell lymphomas.

In March 2006, the European Medicines Agency (EMEA) released the findings of the Committee for Medicinal Products for Human Use (CHMP) review of the potential risk of skin cancer and lymphoma in association with topical Elidel (pimecrolimus). The CHMP concluded that, based on the available data, it was not possible to prove or disprove an association between topical Elidel use and the development of skin cancers and lymphomas. However, the Committee concluded that the benefits outweighed the risks of topical Elidel treatment. The CHMP made the following recommendations to prescribers:

In March 2006, Novartis informed Medsafe that the changes to the European Summary of Product Characteristics (SmPC) and Patient Leaflet would not be officially approved by the EMEA until the end of May 2006. Following confirmation of this approval, Novartis intended to update the global Core Data Sheet in line with the changes required in the US and Europe. This process was expected to be completed by the end of July 2006. Novartis proposed to wait until finalisation of the Core Data Sheet before making changes to the New Zealand data sheet for Elidel cream.

Novartis had commissioned several epidemiological studies to assess the risk of malignancies. These included studies to assess the risk of non-melanoma skin cancer, melanoma and systemic cancer (a 10-year follow-up study). In addition, they planned a safety and efficacy trial specifically in immuno-compromised patients. Results from these studies would be provided to Medsafe in due course.

In New Zealand, the indications for Elidel cream at the time of this meeting were: short-term (acute) treatment and long-term management of the signs and symptoms of atopic dermatitis (eczema) in infants (3-23 months), children (2-11 years), adolescents (12-17 years), and adults.

In Australia, the indications for Elidel cream at the time of this meeting were: Patients 3 months of age and older with atopic dermatitis (eczema) for:

Discussion

Members noted that in New Zealand tacrolimus was available in an oral formulation but not in a topical formulation.

The Committee noted that in New Zealand, at the time of this meeting, Elidel cream was not funded by PHARMAC. Novartis sales data showed that Elidel cream usage had decreased between March 2005 and March 2006.

The Committee noted that the expert report stated topical pimecrolimus was probably as clinically effective as topical 1% hydrocortisone but there were some theoretical grounds to consider that it might be more immunosuppressant than hydrocortisone, particularly in association with ultraviolet light exposure.

The Committee noted the expert opinion that there was an increased risk of malignancy associated with atopic eczema. Additionally, there was anecdotal evidence that other immunosuppressant eczema therapies, such as azathioprine, were also associated with an increased risk of lymphoma.

The Committee noted the expert opinion that the development of skin cancers is associated with sun damage and the individual's immune response. Any factor that suppressed the immune system would be permissive in the development of skin cancer. Therefore, topical pimecrolimus was likely to have a slight promotional effect on skin cancer development in previously sun-damaged individuals, particularly with chronic usage and on-going sun exposure.

The Committee considered that the available evidence for an association between topical pimecrolimus and lymphoma was limited. They agreed that it would be appropriate to await the changes to the Elidel cream Core Data Sheet before requesting comparable changes to the New Zealand data sheet with regards to the risk of malignancy.

Members considered that the indications for Elidel cream in Australia better reflected treatment guidelines for atopic dermatitis, in that long-term topical pimecrolimus use should only be on an intermittent basis and when use of topical corticosteroids was not warranted or not advisable. In both the United States and Europe Elidel cream was indicated as second-line therapy after topical corticosteroids for both short-term and long-term treatment. The Committee agreed that the indications for Elidel cream in New Zealand should be harmonised with those in Australia. Members also agreed that a Dear Healthcare Professional letter should be disseminated once the data sheet updates had been finalised and that this issue should be placed on the watching brief list.

Members noted that the indications for Elidel cream in New Zealand were different from those in the United States and the European Union, where use under the age of 2-years-old was not indicated. Medsafe reminded members that in Australia Elidel cream was indicated for patients 3-months of age and older. Members noted that there were other significant differences between the United States Product Information and the New Zealand data sheet for Elidel cream. Members expressed concern that the United States Product Information sheet stated, "the long-term safety and effects of Elidel cream on the developing immune system are unknown". Medsafe reminded the Committee that data on the safety of topical pimecrolimus in under 2-year-olds had not been provided for this meeting. Medsafe informed the Committee that in New Zealand the Medicines Assessment Advisory Committee (MAAC) had assessed the available data for safety and efficacy in paediatric populations as part of the evaluation in March 2002, and had approved topical pimecrolimus for use in infants aged 3 to 23-months. The Committee asked to be provided with the relevant minute item from MAAC, and asked that Medsafe request data from Novartis on the safety of Elidel cream use in under 2-year-olds and bring these back to the Committee.

Recommendations

The Committee recommended that Medsafe should request that Novartis update the New Zealand data sheet for Elidel 1% cream in line with the Core Data Sheet, once updated. The following changes would be required at a minimum:

The Committee recommended that Novartis should disseminate a Dear Healthcare Professional letter (following update of the data sheet) advising New Zealand prescribers of the available evidence regarding topical pimecrolimus and the risk of malignancy; the relevant changes to the Elidel cream data sheet and; that they should advise patients of the need for appropriate sun protective measures during Elidel cream use.

The Committee recommended that the issue of topical pimecrolimus and the risk of malignancy should be placed on the watching brief list.

The Committee recommended that Medsafe should obtain the Medicines Assessment Advisory Committee (MAAC) meeting minute regarding the approval of topical pimecrolimus for use in paediatric populations between 3 and 23-months of age. This should be provided to the MARC at the next meeting.

The Committee recommended that Medsafe should ask Novartis to provide general safety data for the use of Elidel 1% cream in under 2-year-olds and subsequently bring these data back to the MARC.

3.2 Bisphosphonates and Osteonecrosis of the Jaw

References
  1. Medsafe report for the MARC. June 2006.
  2. Woo S-B et al. Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws. Annals of Internal Medicine 2006;144:753-761
  3. Novartis Pharmaceutical Corp. Expert Panel Recommendations for the Prevention, Diagnosis and Treatment of Osteonecrosis of the Jaws: June 2004.
  4. Hay K and Bishop P. Association of osteonecrosis of the jaws and bisphosphonate pharmacotherapy: Dental implications. NZ Dental Journal 2006; 102(1): 4-9.
  5. Marx R et al. Bisphosphonate-Induced Exposed Bone (Osteonecrosis/ Osteopetrosis) of the Jaws: Risk Factors, Recognition, Prevention and Treatment. J Oral and Maxillofac Surg 2005; 63: 1567-1575.
  6. Migliorati C et al. Managing the care of patients with bisphosphonate-associated osteonecrosis. An American Academy of Oral Medicine position paper. JADA 2005; 136:1658-1668.
  7. Melo M and Obeid G. Osteonecrosis of the jaws in patients with a history of receiving bisphosphonate therapy. Strategies for prevention and early recognition. JADA 2005; 136:1675-1681. 8
  8. Cheng A et al. The dental implications of bisphosphonates and bone disease. Australian Dental Journal Medications 2005; 50 Suppl 2: S4-S13.
  9. Reid I. Osteonecrosis of the Jaw. Prescriber Update 27(1): June 2006.
Late papers:
Issue

At their September 2005 meeting, the MARC reviewed the available evidence for an association between the use of bisphosphonates and the development of osteonecrosis of the jaw (ONJ) (see www.medsafe.govt.nz/Profs/adverse/Minutes123.htm for details). The Committee concluded that there was evidence of an association between the use of the intravenous bisphosphonates pamidronate and zoledronic acid and the development of ONJ. However, due to the presence of a number of potential confounding factors a casual association could not yet be proven. The MARC also concluded that the available data were inadequate to determine the prevalence of ONJ in patients who had received the intravenous bisphosphonates, but it was likely that this was a very rare association.

At the September 2005 MARC meeting, members commented that, although there had been a small number of international case reports of ONJ in association with the oral bisphosphonates alendronate and risedronate, the available data were inadequate to determine whether or not the oral bisphosphonates were likely to be associated with a similar risk of ONJ as the intravenous agents. However, the MARC noted that, in view of the recent changes to funding of alendronate in New Zealand, it was likely that there would be an increase in usage of alendronate for the treatment of osteoporosis. Therefore, in September 2005, the MARC recommended that Medsafe continue to monitor the available literature on this issue, with a view to distributing advice to prescribers by way of a Prescriber Update article as the data on this issue became clearer.

Prior to the September 2005 MARC meeting, the New Zealand bisphosphonate data sheets were updated at Medsafe's request to include information on the risk of ONJ. In addition, two Dear Healthcare Professional letters were distributed to New Zealand doctors and dentists to inform them of the risks of ONJ in association with the use of the intravenous bisphosphonates. The MARC considered that the advice provided had been appropriate.

In October 2005, Merck Sharp & Dohme (MSD) updated the global prescribing information for Fosamax (alendronate) to include the following information:

Localised osteonecrosis of the jaw (ONJ), generally associated with tooth extraction and/or local infection with delayed healing, has been reported rarely with oral bisphosphonates (see Adverse Effects, Post-Marketing Experience). Most reported cases of bisphosphonate-associated ONJ have been in cancer patients treated with intravenous bisphosphonates. Known risk factors for ONJ include a diagnosis of cancer, concomitant therapies (e.g., chemotherapy, radiotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., pre-existing dental disease, anaemia, coagulopathy, infection). Patients who develop ONJ should receive appropriate care by an oral surgeon.

At the December 2005 MARC meeting, members recommended that bisphosphonate-associated ONJ should be placed on the active monitoring list and should undergo formal review in September 2006 or earlier if required (this issue was subsequently brought forward to the June 2006 meeting).

At the time of this meeting, the following bisphosphonates were approved for use in New Zealand (in order of potency):

Bisphosphonate Route of administration Date approved Pre-clinical antiresorptive potency (relative to etidronate)6 Nitrogen-containing?
Clodronate Oral 1991
(since discontinued)
? No
Etidronate Oral and intravenous 1979
(IV since discontinued)
1 No
Tiludronate Oral 1997
(not marketed)
10 No
Pamidronate Intravenous 1991 100 Yes
Alendronate Oral 1995 100-1,000 Yes
Risedronate Oral 2001
(not marketed)
1,000-10,000 Yes
Ibandronate Oral and intravenous 1998
(not marketed)
1,000-10,000 Yes
Zoledronic acid Intravenous 2004 >10,000 Yes


At the time of this meeting, the New Zealand Pharmacovigilance Centre (NZPhvC) had received four reports of ONJ in association with intravenous bisphosphonate therapy. There had not been any reports of ONJ in association with the oral bisphosphonates.

The prescribing of bisphosphonates for the treatment of osteoporosis in New Zealand was largely determined by PHARMAC funding arrangements. At the time of this meeting, both etidronate and alendronate were funded by PHARMAC with no restrictions on their duration of use. Etidronate was fully funded for the treatment of osteoporosis with no prescribing restrictions listed in the pharmaceutical schedule. Funding of alendronate required a Special Authority application, with the initial application made by a specialist or vocationally registered general practitioner. Approvals were valid without further renewal for applications meeting the following criteria:

  1. History of one significant osteoporotic fracture demonstrated radiologically and documented bone mass density (BMD) >= 2.5 standard deviations below the mean normal value in young adults (i.e. T-Score <= -2.5); or
  2. History of one significant osteoporotic fracture demonstrated radiologically and the patient is either over 75 years of age or is too frail to undergo a bone mass density scan; or
  3. History of two significant osteoporotic fractures demonstrated radiologically; or
  4. Documented T-Score <= -3.0.

Since the MARC's last review of bisphosphonate-associated ONJ in September 2005, there had been a substantial amount of literature published on this issue. However, the majority of data were observational in nature and there remained an absence of high quality controlled data to inform decision-making. Most experts agreed that the available data supported an association between the use of intravenous, nitrogen-containing bisphosphonates and the development of ONJ. However, an association with the use of nitrogen-containing oral bisphosphonates was less clear.

There was widespread agreement that the following factors increased the risk of developing ONJ: use of nitrogen-containing bisphosphonates; intravenous route of administration; increasing duration of use and cumulative dose of bisphosphonate; an underlying diagnosis of multiple myeloma and/or malignancy and; a preceding history of invasive dental procedures, periodontal trauma or infection.  Although it had been suggested that known risk factors for osteonecrosis of other bones (e.g. corticosteroids, chemotherapy, head and neck radiotherapy, female gender, an underlying coagulopathy, blood dyscrasia, arthritis or vascular disorder, alcohol abuse, smoking or malnutrition) would also increase the risk of ONJ, further research was required to determine the influence of these factors.

Although attempts had been made to determine the prevalence of ONJ in cancer patients receiving intravenous bisphosphonates, methodological issues had limited the reliability of the results. However, most authors considered that ONJ was a very rare complication of intravenous bisphosphonate therapy. Although it was not possible to estimate the prevalence of ONJ in patients receiving alendronate, most experts agreed that in view of the low reporting rate despite widespread use of alendronate worldwide, the prevalence was likely to be substantially less than that associated with the intravenous bisphosphonates. There was no evidence to associate the non-nitrogen containing bisphosphonates with the development of ONJ.

Most experts agreed that the risk:benefit ratio for patients receiving intravenous bisphosphonates for the treatment of multiple myeloma or complications of malignancy remained favourable despite the recognition of ONJ as a rare complication of bisphosphonate therapy. However, some authors suggested that, as there were an absence of data supporting the use in multiple myeloma patients beyond two years, continuation for more than two years should only be considered after a careful risk:benefit assessment. Anecdotal reports from New Zealand oncologists suggested the multiple myeloma treatment protocols now reflected this advice.

As the available data suggested that the risk of ONJ in association with nitrogen-containing oral bisphosphonates such as alendronate was very low, the risk:benefit ratio for the treatment of osteoporosis was unlikely to be altered. However, it was less clear whether the risk:benefit ratio was altered when used to prevent osteoporosis. As New Zealand prescribing restrictions limited the use of alendronate to the treatment of patients at high risk of osteoporotic fractures the risk:benefit ratio for most New Zealand patients was considered to remain favourable.

However, Medsafe acknowledged that there was considerable concern both nationally and internationally regarding the potential for the number of cases of ONJ associated with the nitrogen-containing oral bisphosphonates such as alendronate to increase substantially as more people were prescribed alendronate for long-term use. This was likely to become more of a problem as the population aged and the population prevalence of both osteoporosis and dental comorbidities increased. Medsafe considered that osteoporosis experts would need to balance the potential for ONJ to occur with the significant morbidity and mortality associated with osteoporotic fractures when developing osteoporosis prevention and treatment guidelines.

Current advice on the prevention and management of intravenous bisphosphonate-associated ONJ was based largely on expert opinion due to the absence of data to support an evidence-based approach. Recent literature largely supported the guidelines issued by Novartis in 2004, although debate continued regarding whether or not bisphosphonate therapy should be discontinued in patients who develop ONJ. Due to the rarity of the condition it was likely that management of patients with ONJ should be co-ordinated by expert oral medicine specialists or oral and maxillofacial surgeons.

Controversy remained regarding what ONJ prevention advice to offer to patients currently receiving or due to initiate oral bisphosphonate therapy. Although there was agreement that all patients should be advised to maintain good oral hygiene, and to seek advice if dental problems develop, it was less clear whether patients should be advised to undergo a dental review and/or preventative dentistry prior to initiating alendronate therapy. As it appeared that nitrogen-containing oral bisphosphonate-associated ONJ generally did not occur until a threshold level of exposure occurred, it was unclear whether preventative dentistry months or years in advance would have any effect on preventing the development of ONJ.

Discussion

Members welcomed the invited experts, Dr Hay and Assoc. Prof. Grey, who participated in the discussion on this agenda item by teleconference. The following discussion was limited to those bisphosphonates approved and marketed in New Zealand at the time of this meeting; intravenous zoledronic acid (Zometa), intravenous pamidronate (Pamisol and Aredia), oral alendronate (Fosamax) and oral etidronate (Etidrate).

Members noted the late paper on alendronate (subsequently published in the New Zealand Dental Association News), and considered that the advice was balanced and appropriate.

Members noted that, regarding the intravenous bisphosphonates, the evidence was strong for an increase in risk of ONJ, but that because these agents were used to treat life-threatening conditions the risk:benefit profile remained favourable. Members noted that the intravenous bisphosphonate data sheets had been updated with warning statements on the risk of ONJ, two Dear Healthcare Professional letters had been disseminated in New Zealand, and there had also been a number of papers published in the national and international literature. Medsafe considered that a good level of awareness had been achieved among prescribers. The experts informed the Committee that a lot of information had been disseminated to dentists on this issue and that a good level of awareness had been achieved. In addition, most oncologists and haematologists were aware of this issue.

The Committee discussed the use of nitrogen-containing oral bisphosphonates, such as alendronate, for the treatment and prevention of osteoporosis. Members noted that, at the time of this meeting, alendronate was only funded for the treatment of osteoporosis and prevention of osteoporotic fractures in high-risk patients, and therefore alendronate was unlikely to be used in low-risk patients. Medsafe informed the Committee that PHARMAC prescribing data showed a trend of increasing usage of alendronate between January 2005 and March 2006.

Members asked the invited experts about the evidence for efficacy and optimal duration of treatment with alendronate for osteoporosis. They responded that the evidence for efficacy in patients at high-risk of fracture was strong, and that the morbidity and mortality related to osteoporotic fractures in this patient group was significant. For example, hip fracture carried a 25% risk of mortality within six months. The experts advised that the evidence for the optimal duration of alendronate therapy was limited and that studies were ongoing. There was some evidence that five years of treatment with alendronate, followed by an alendronate-free period of five years, resulted in maintenance of spine bone density, although values at the hip tended to fall after cessation of therapy. The experts advised that prescribers should discuss the risks and benefits of treatment with osteoporosis patients prior to prescribing alendronate, and plan for an initial treatment period of five years. At the end of this period the patient should be reviewed for bone density and fracture risk. A clinical decision could then be made on whether to continue treatment, to have an alendronate-free period, to reduce the alendronate dose, or to discontinue treatment.

Members noted that there was some evidence for an increased risk of ONJ with nitrogen-containing oral bisphosphonates, such as alendronate. The invited experts informed the Committee that the risk associated with these agents was very low and that, therefore, strict guidelines on the prevention and monitoring of patients' oral health were not necessary. The experts noted that it was important that a clear distinction be drawn between the risk associated with the use of intravenous and oral bisphosphonates. Members noted that data from Merck Sharp & Dohme (sponsor of Fosamax; alendronate) suggested that the mean time to onset of ONJ was four years. The experts advised that, as the evidence suggested a lag of several months between initiation of treatment and increased risk of ONJ, any prophylactic dental treatment should be completed within 4-6 months of initiation of treatment with a nitrogen-containing oral bisphosphonate, such as alendronate. This dental treatment could be carried out by any dentist and would not require referral to a specialist. They advised annual review by a dentist thereafter, as per standard dental care for individuals not taking bisphosphonates, for treatment of dental infection or pathology. General practitioners should question their alendronate patients about oral symptoms, but dentists were best placed to fully assess the oral health of the patient. Members asked the invited experts whether the advice should be revised should the funding criteria for alendronate be broadened to include the prevention of osteoporosis. They responded that the evidence should be reviewed under those circumstances. However, as the current evidence suggested the risk of ONJ with alendronate was very low, the current advice was likely to remain appropriate.

The Committee discussed the use of non-nitrogen-containing oral bisphosphonates, such as etidronate, in the prevention and treatment of osteoporosis and Paget's disease. Members noted that etidronate was less potent than the nitrogen-containing alendronate. The invited experts informed the Committee that the evidence base for efficacy with etidronate was weaker than that for alendronate. Members noted etidronate was most efficacious in spinal osteoporosis and for prevention of steroid-induced osteoporosis. The experts advised that patients should only be prescribed etidronate if they were not eligible for alendronate funding and that patients should not be changed from alendronate to etidronate without clear clinical grounds. Members noted that there had been no international cases of ONJ reported in association with etidronate, to date.

Members asked the invited experts about the most appropriate management should a patient develop ONJ. They advised that patients should be referred to a specialist oral and maxillofacial surgery unit at a tertiary centre. Dentists wanting further information should contact their regional specialist oral medicine unit. NZPhvC advised that any suspected cases of ONJ should be reported to CARM.

The experts advised the Committee that endocrinologists and dentists in New Zealand were collaborating on drafting an article on this issue for publication in the New Zealand Medical Journal, focusing on the risk with the intravenous bisphosphonates. Medsafe requested a pre-publication copy of this article, when available. Medsafe also advised that consideration would be given to reprinting the article in Prescriber Update, with the authors' permission.

The Committee noted they had previously recommended that a Prescriber Update article be published on this issue, and agreed that this remained appropriate. The MARC agreed that Medsafe should write to the New Zealand Guidelines Group asking them to give consideration to revising their guideline on The Prevention of Hip Fracture Amongst People Aged 65-Years and Over to reflect the current evidence on the risks of ONJ associated with the use of nitrogen-containing oral bisphosphonates.

Recommendations

The Committee recommended that Medsafe should write to the New Zealand Guidelines Group asking them to give consideration to revising their guideline on The Prevention of Hip Fracture Amongst People Aged 65-Years and Over to reflect the current evidence on the risks of osteonecrosis of the jaw associated with the use of nitrogen-containing oral bisphosphonates.

The Committee recommended that Medsafe should liaise with the experts regarding their planned New Zealand Medical Journal article.

The Committee recommended that the issue of bisphosphonates and osteonecrosis of the jaw should remain on the active monitoring list, for review in June 2007. Data provided should include usage data for the nitrogen-containing oral bisphosphonates, such as alendronate.

3.3 Tramadol and Hepatic Reactions: Watching Brief Review

References

R. Savage. Report for the MARC. June 2006.

Issue

The report on hepatic reactions with tramadol was provided as a review of the watching brief held since March 2004. This issue was also reviewed at the June 2005 MARC meeting (June 2005 minute item 4.3.1). Tramadol was first approved in New Zealand in September 1997.

At the time of this report there were a total of 113 reports for tramadol in the CARM database, including five reports of hepatic disorders. Three of the reports of hepatic disorders had been received since June 2005, all in patients taking co-suspect medicines. Prior to June 2005 there was one report of a positive rechallenge.

Since June 2005, there had been a further 53 reports to the WHO Vigibase of serious hepatic reactions with tramadol, including 29 of hepatitis. The information component (IC) values were negative for hepatitis and hepatitis cholestatic. There was still only one report where tramadol was the sole suspect medicine in a case of fulminant hepatitis (as reported in June 2005). There were five case reports of hepatitis with documented improvement or recovery on dechallenge and with tramadol as the sole suspect medicine. However, there were also a small number of reports where hepatitis occurred following use for one day or less so that tramadol was discontinued before the hepatic reaction became evident. There were a large number of reports of hepatitis and a small number of life-threatening hepatic reactions where tramadol was a co-suspect medicine.

The Australian Adverse Drug Reactions Unit had received two reports of hepatic failure with tramadol, both in patients taking co-suspect medicines; and three reports of hepatic disorders where tramadol was the sole suspect medicine. New Zealand and Australian case reports supported a causal relationship between tramadol and elevated hepatic enzymes.

A search of the literature found no relevant publications.

Discussion

The Committee noted the NZPhvC report, as summarised above. Members agreed that there was evidence for mild hepatic aberrations with tramadol, and that there was empirical evidence that serious hepatic adverse reactions were rare.

Members noted that the Zytram data sheet was inconsistent with the other tramadol brands with respect to hepatic enzyme elevation as a rare adverse effect, and asked that Medsafe request a data sheet update.

Members agreed that this issue should be removed from the watching brief list.

Recommendations

The Committee recommended that Medsafe should ask the Zytram sponsor to update the data sheet, in line with the other tramadol brands, with respect to hepatic enzyme elevation.

The Committee recommended that the issue of tramadol and hepatic reactions should be removed from the watching brief list.

4. matters arising from the new zealand pharmacovigilance centre

Spontaneous reporting programme

All spontaneous reports presented at the MARC meeting have been assessed by the Centre for Adverse Reactions Monitoring (CARM) and replies have been sent to the reporters. The purpose of these responses is to assist the practitioner to discharge his/her responsibility to patients. These individual replies include as appropriate:
  • comment about causality;
  • information about similar suspected adverse reactions reported with the same or related medicines;
  • prescribing advice;
  • advice related to the care of the patient, including information that may assist the practitioner to make a risk:benefit assessment for future treatment; and
  • any specific action being taken by the Centre, including: entry of the reaction into the National Health Index against the patient's name, presenting the case report to the MARC, etc.


Note: In the comment associated with each report, the case has been given a causality designation using terms and definitions developed by the WHO. The precise definitions are available on the website of the WHO Collaborating Centre 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 Centre for Adverse Reactions Monitoring (CARM) Spontaneous Case Reports

4.1.1 Deaths

4.1.1.1 Enoxaparin and spinal haematoma, quadriplegia, decubitus ulcer and sepsis [death] (70025)

Reference

Heppner PA et al. Spontaneous spinal haematomas and low molecular weight heparin. J Neurosurg (Spine 1) 2004; 2: 232-236

Discussion

This case report was sourced from the New Zealand literature (see reference) and reported by a pharmaceutical company along with three other cases listed as minute items 4.1.10.1, 2 and 3.

The Committee noted that since this event had occurred (in 2004) the MARC had discussed the safety of enoxaparin on several occasions. Furthermore, this issue had been reviewed by the New Zealand Guidelines Group, and was currently being reviewed by the Quality Safe Use of Medicines Group.

The causal association with enoxaparin was deemed to be 'probable' for spinal haematoma, quadriplegia, decubitus ulcer and sepsis. The Committee agreed that no further regulatory action was required at that time.

4.1.1.2 Baclofen and cardio-respiratory arrest, abdominal pain, hypertension, vomiting and coughing [death] (70111)

Discussion

An attendee at the MARC meeting was familiar with this case and provided further background information. At post-mortem, it was not clear whether the baclofen pump had been delivering the medicine to the intrathecal space. Although the pump had been returned to the supplier it remained unclear whether the pump was faulty. The Committee asked that NZPhvC seek further information from the reporter in this case.

The Committee noted that if the baclofen pump had been faulty, this would be a medical device issue. If further information proved this to be the case, it should be reported to Medsafe's Medical Device team.

Members noted that intrathecal baclofen had been discontinued in New Zealand by the sponsor, but was available under Section 29 of the Medicines Act 1981. Members noted that the United States Food and Drug Administration (FDA) disseminated a Dear Healthcare Professional letter in 2002 highlighting a black box warning "Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in sequelae that include high fever, altered mental status, exaggerated rebound spasticity and muscle rigidity that, in rare cases, has advanced to rhabdomyolysis, multiple organ-system failure and death." Members considered that this case might have been a withdrawal reaction and agreed that 'withdrawal syndrome' should be added to the adverse reaction terms in this case.

The causal association with baclofen was deemed to be 'unclassified' for withdrawal syndrome, cardio-respiratory arrest, abdominal pain, hypertension, vomiting and coughing.

Recommendations

The Committee recommended that NZPhvC should seek further information from the reporter in this case (70111).

The Committee recommended that NZPhvC should add 'withdrawal syndrome' to the adverse reaction terms in this case (70111) if the baclofen pump was found to have been faulty.

4.1.1.3 Diclofenac and gastrointestinal haemorrhage [death] (70131)

Discussion

The Committee noted that this patient was being treated with a high dose of diclofenac as part of her palliative care.

The causal association with diclofenac was deemed to be 'probable' for gastrointestinal haemorrhage. The Committee agreed that no further regulatory action was required at that time.

4.1.1.4 Alteplase and oedema [death] (70710)

Discussion

The Committee noted that this report and the following two (minute items 4.1.1.5 and 4.1.1.6) were received together from the product sponsor with very few details provided. NZPhvC informed the Committee that further information had been sought from the sponsor and a response was awaited. Members noted that there was some inconsistency in the dates on the three reports and asked that NZPhvC investigate further.

NZPhvC informed the Committee that no other reports of any type had been received by CARM for alteplase and no references were found to oedema with alteplase in the literature (other than reports of anaphylactoid and angioedema). In the WHO database, from a total of 3,227 reports for alteplase there were 24 reports of pulmonary oedema (IC-2sd = +1.62, 9 fatal), 4 reports of periorbital oedema (IC-2sd = +0.46, 2 fatal) and 40 reports of angioedema (IC-2sd = -1.4, 1 fatal).

The causal association with alteplase was deemed to be 'unclassified' for oedema.

Recommendation

The Committee recommended that NZPhvC should report back to the MARC once further information had been received from the sponsor on these three cases (70710, 70711 and 70712) and the report dates had been checked.

4.1.1.5 Alteplase and oedema [death] (70711)

Discussion

See minute item 4.1.1.4 for discussion and a recommendation on this issue.

The causal association with alteplase was deemed to be 'unclassified' for oedema.

4.1.1.6 Alteplase and sudden death (70712)

Discussion

See minute item 4.1.1.4 for discussion and a recommendation on this issue.

The causal association with alteplase was deemed to be 'unclassified' for sudden death.

4.1.1.7 Carvedilol and sudden death (71152)

Discussion

NZPhvC informed the Committee that from a total of 15 reports for carvedilol in the CARM database there were two others of sudden death (previously considered by the MARC). In the WHO database there were 18 reports of sudden death with carvedilol.

The Committee considered that it was not possible to determine if this was an adverse reaction.

The causal association with carvedilol was deemed to be 'unclassified' for sudden death. The Committee agreed that no further regulatory action was required at that time.

4.1.2 Alternative Medicines

4.1.2.1 Nutralife Cold and Flu Fighter and paraesthesia, dyspnoea and flushing (70119)

Discussion

Members noted that all adverse reactions to complementary and alternative medicines were Adverse Reactions of Current Concern, scheduled to be reviewed by the MARC in March 2007.

NZPhvC informed the Committee that Nutralife Cold and Flu Fighter contained andrographis panniculata, andrographolide, echinacea, calcium ascorbate and ascorbic acid.

The Committee considered that the signs and symptoms in this case suggested that it was a hypersensitivity reaction.

The causal association with Nutralife Cold and Flu Fighter was deemed to be 'probable' for paraesthesia, dyspnoea and flushing. The Committee agreed that no further regulatory action was required at that time.

4.1.3 Anti-Malarial Medicines

4.1.3.1 Quinine and purpura and thrombocytopenia (70373)

Discussion

NZPhvC informed the Committee that it was unclear from the report whether the patient had been taking quinine regularly or intermittently. Members considered it unlikely that this adverse reaction could have occurred following administration of only one tablet.

NZPhvC informed the Committee that in the CARM database there were 43 reports of thrombocytopenia from a total of 125 reports for quinine. Twelve of the thrombocytopenia reports had been received in the past five years. Three patients had life-threatening reactions.

Medsafe informed the Committee that, at the time of this meeting, quinine was indicated:

Members noted that thrombocytopenia in association with quinine was well documented in the literature. The Apo-Quinine data sheet listed thrombocytopenia under 'Adverse Effects' and advised under 'Dosage and Administration' that "in the treatment of nocturnal recumbency leg cramps quinine should be discontinued if leg cramps do not occur after several consecutive nights of therapy to determine if continued therapy is needed."

The Committee noted that the United States Food and Drug Administration (FDA) withdrew the indication of nocturnal cramps from all quinine products in 1995 as the risk associated with use, in the absence of evidence of its effectiveness, outweighed any potential benefit in treating and/or preventing this benign, self-limiting condition.

Members noted that, in Australia, approval for quinine in the treatment of nocturnal cramps was rescinded in 2004 as a consequence of the risk of thrombocytopenia. In the Australia New Zealand Therapeutic Products Authority (ANZTPA) the indications for all products would be harmonised and, therefore, this issue would be reviewed. In New Zealand, in March 2006, quinine was reclassified to be a prescription medicine except in medicines containing 50 mg or less per recommended daily dose. The change was made to harmonise with Australia where quinine was rescheduled in 2004 because of the risk of thrombocytopenia.

Members queried whether quinine was being used appropriately in New Zealand and asked that NZPhvC review the 12 cases of thrombocytopenia received in the last five years and discuss this issue with Medsafe, then bring it back to the MARC if warranted.

The causal association with quinine was deemed to be 'probable' for purpura and thrombocytopenia.

Recommendation

The Committee recommended that NZPhvC should review the 12 cases of thrombocytopenia with quinine received in the last five years and discuss this issue with Medsafe, then bring it back to the MARC if warranted.

4.1.4 Cardiovascular Medicines

4.1.4.1 Propranolol and placental disorder and intra-uterine death (71094)

Discussion

Members noted that propranolol was Australian Drug Evaluation Committee (ADEC) pregnancy category C (Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible), with the warning that beta-adrenergic blocking agents "may cause pharmacological effects such as bradycardia in the foetus and newborn infant."

NZPhvC informed the Committee that the data sheet for Cardinol (propranolol) stated, "As with all other medicines, propranolol should not be given in pregnancy unless its use is essential. There was no evidence of teratogenicity with propranolol. However, beta-adrenoreceptor blocking medicines reduce placental perfusion, which may result in intra-uterine foetal death, immature and premature deliveries."

The causal association with propranolol was deemed to be 'possible' for placental disorder and intra-uterine death. The Committee agreed that no further regulatory action was required at that time.

4.1.5 Endocrine Medicines

4.1.5.1 Rosiglitazone and sialoadenitis and salivary gland enlargement (70125)

Discussion

Members noted that all adverse reactions to rosiglitazone and pioglitazone were Adverse Reactions of Current Concern, scheduled to be reviewed by the MARC in March 2007.

NZPhvC informed the Committee that, from a total of 20 reports for rosiglitazone in the CARM database there were no others for sialoadenitis or salivary gland enlargement. In the WHO database there were a total of 7,417 reports for rosiglitazone, of which 23 were for salivary gland enlargement and seven for sialoadenitis. The only other literature reference was from Heath Canada (Canadian Adverse Reaction Newsletter 2006; 16(1):3). NZPhvC had published an article in the Signal document (see minute item 7.4) on this issue.

Members noted that diabetes itself is known to cause salivary gland enlargement. They noted that this case was consistent with those in the WHO database, with regard to a long duration of the condition.

The causal association with rosiglitazone was deemed to be 'possible' for sialoadenitis and salivary gland enlargement. The Committee agreed that no further regulatory action was required at that time.

4.1.6 Hormones

4.1.6.1 Femodene and myocardial infarction (70790)

Discussion

NZPhvC informed the Committee that in the CARM database there were no reports of myocardial infarction or myocardial ischaemia with gestodene/ethinylestradiol products, from a total of 43 reports. The Femodene data sheet described the risks of arterial thrombosis and myocardial infarction in the 'Warnings and Precautions' section.

The Committee commented that Femodene was a third generation oral contraceptive, and that issues related to thombosis had been considered by the MARC in the past.

The causal association with Femodene was deemed to be 'possible' for myocardial infarction. The Committee agreed that no further regulatory action was required at that time.

4.1.7 Immunosuppressive Medicines

4.1.7.1 Leflunomide / hydroxychloroquine and deep venous thrombosis, aggravated hepatitis, arthritis, myalgia and leg cramps (70028)

Discussion

Members noted that all adverse reactions to leflunomide were Adverse Reactions of Current Concern (ARCC), scheduled to be reviewed by the MARC in March 2007.

NZPhvC informed the Committee that in the CARM database, from a total of 55 reports for leflunomide, there was one of deep vein thrombosis, one of mesenteric vessel thrombosis and none of chronic active hepatitis aggravated. For hydroxychloroquine there were no relevant reports from a total of 18.

In the WHO database for leflunomide, from a total of 4,285 reports, there were 13 for deep vein thrombosis and one for mesenteric vessel thrombosis (IC values not available). The following reports were also found in the WHO database for leflunomide: 12 hepatitis viral, 5 hepatitis C, 4 hepatitis B, 1 hepatitis A, 2 hepatitis viral unspecified, 5 hepatitis chronic active (IC 2.82, IC 025 1.34). One patient with hepatitis C was also taking penicillamine. Several patients with hepatitis B or unspecified viral hepatitis were taking other disease modifying anti-rheumatic drugs (DMARDs), usually methotrexate. It was not clear if the chronic active hepatitis was due to viral infection or hepatitis caused by leflunomide. In the WHO database for hydroxychloroquine there was one report of hepatitis C in a patient also taking leflunomide, and no other relevant reports.

In the literature, NZPhvC could find no mention of venous thrombosis or reactivation of viral hepatitis with leflunomide or hydroxychloroquine.

NZPhvC commented that there was some evidence linking vasculitis and lupus erythematosus with leflunomide, which might predispose to deep vein thrombosis. Members commented that this situation would be unusual.

The Committee asked that NZPhvC analyse the cases of hepatitis in the WHO database more fully and bring the results back at the next ARCC review (March 2007).

The causal association with leflunomide and hydroxychloroquine was deemed to be 'possible' for deep venous thrombosis, aggravated hepatitis, arthritis, myalgia and leg cramps.

Recommendation

The Committee recommended that NZPhvC should analyse the cases of hepatitis with leflunomide in the WHO database more fully and bring the results back at the next Adverse Reactions of Current Concern (ARCC) review in March 2007.

4.1.8 Musculoskeletal Medicines

4.1.8.1 Simvastatin / cyclosporin / diltiazem / alendronate and rhabdomyolysis, acute renal failure and increased creatine phosphokinase (70412)

Discussion

NZPhvC informed the Committee that the reporter considered that this was an interaction between several of the medications used post-cardiac transplant. The interactions between simvastatin and cyclosporin or diltiazem were well documented in the literature and in the simvastatin data sheets.

NZPhvC informed the Committee that in the CARM database there were 873 reports for simvastatin, including nine of rhabdomyolysis. Since May 2004 (when a Prescriber Update article was published) there had been nine reports of interactions with simvastatin (2 cyclosporin, 2 diltiazem, 2 bezafibrate, 1 erythromycin, 1 fluconazole, 1 isoniazid). Most of these reports were for myalgia, with two for myopathy or myositis. One interaction with cyclosporin was for rhabdomyolysis. For alendronate there were a total of 222 reports with no others of renal failure.

In the WHO database for alendronate there were 21 reports of acute renal failure (IC value not available).

Members noted that a Prescriber Update article was published in May 2004 entitled 'Myopathy with Statins: Check CK Levels and Interactions'. The article included warnings that concomitant medicines (including diltiazem and cyclosporin) may increase the risk of myopathy.

Members considered that there was limited evidence in this case to implicate alendronate.

The causal association with simvastatin, cyclosporin, diltiazem and alendronate was deemed to be 'probable' for rhabdomyolysis, acute renal failure and increased creatine phosphokinase. The Committee agreed that no further regulatory action was required at that time.

4.1.9 Psychiatric Medicines

4.1.9.1 Fluoxetine / topiramate / carbamazepine and congenital anomaly (70638)

Reference

Medicines in Pregnancy Working Party of the Australian Drug Evaluation Committee. Prescribing Medicines in Pregnancy – An Australian categorisation of risk of drug use in pregnancy. 4th edition. Commonwealth of Australia, 1999.

Discussion

Members noted that the issue of selective serotonin reuptake inhibitor (SSRI) antidepressants and teratogenicity was on the watching brief list, scheduled to be reviewed by the MARC in September 2006. Fluoxetine was Australian Drug Evaluation Committee (ADEC) pregnancy category C, topiramate was category B3 and carbamazepine category D (refer to reference for details).

NZPhvC informed the Committee that there was evidence from spontaneous reports and the data sheets implicating all three medicines. The indications for therapy were unclear, but presumed to be for epilepsy, which in its own right is considered to attribute a higher risk of foetal anomaly.

Members considered that topiramate and carbamazepine were more strongly implicated in this case.

The causal association with fluoxetine, topiramate and carbamazepine was deemed to be 'possible' for congenital anomaly. The Committee agreed that no further regulatory action was required at that time.

4.1.10 Other Reports

4.1.10.1 Enoxaparin and acetylsalicyclic acid (70022)
4.1.10.2 Enoxaparin and acetylsalicyclic acid (70023)
4.1.10.3 Enoxaparin and acetylsalicyclic acid (70024)
4.1.10.4 Omeprazole (70031)
4.1.10.5 Omeprazole (70044)
4.1.10.6 Omeprazole (70148)
4.1.10.7 Omeprazole (70368)
4.1.10.8 Omeprazole (70379)
4.1.10.9 Cholesterol-lo (70426)
4.1.10.10 Slimfast (70436)
4.1.10.11 Nioxin, Finasteride (70651)
4.1.10.12 Whizzer Party Pill (70722)
4.1.10.13 Bupropion (70733)
4.1.10.14 Leflunomide (70787)
4.1.10.15 Meno-mize (70836)
4.1.10.16 Comvita Fortacold (70940)
4.1.10.17 DHEA (Redwood Brand) (70941)

4.2 Pharmacovigilance Issues Arising from Reports to CARM

4.2.1 Proton Pump Inhibitors and Interstitial Nephritis

Reference

CARM. A report on action taken regarding omeprazole and other proton pump inhibitors and the development of interstitial nephritis. Report for the MARC June 2006.

Issue

This report was provided to the MARC largely for members' information.

As at June 2006, there were 32 reports of interstitial nephritis attributed to omeprazole in the CARM database (18 confirmed by renal biopsy) and three similar reports for pantoprazole (one confirmed by renal biopsy). Proton pump inhibitors were the most commonly implicated class of medicines in interstitial nephritis reports. Because of the increasing number of reports, Medsafe and NZPhvC prepared a reminder paragraph for publication in the June 2006 edition of Prescriber Update.

NZPhvC was contacted by a renal specialist who was writing a paper on this issue. He informed NZPhvC that proton pump inhibitors were thought to be the most common cause of interstitial nephritis in the Auckland region, probably because of their widespread use. He estimated that the incidence was about 1 in 12,000 patients.

NZPhvC examined the proton pump inhibitor data sheets, which all contained information on the risk of interstitial nephritis.

Discussion

Members noted the report provided by NZPhvC. NZPhvC informed the Committee that this issue was being considered as a topic for an adverse reaction slide for presentation during hospital Grand Rounds.

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

4.3 Quarterly Reports from CARM as at 31 March 2006

Reference

CARM. Reports of Headache relating to Apo-Zopiclone. Report for the MARC June 2006.

Discussion

The Committee noted the quarterly reports from CARM as at 31 March 2006, and the reports of headache related to Apo-Zopiclone.

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.

6. new zealand pharmacovigilance-related activities

7. international pharmacovigilance-related Activities

7.1 Australia

7.2 Canada

7.3 Singapore

7.4 WHO

8. Summary LISTINGS of case reports considered by MARC (1997-2006)

9. Other business

9.1 Future Arrangements for Pharmacovigilance in New Zealand

References
  1. Australia New Zealand Therapeutic Products Regulatory Scheme (Administration and Interpretation) Draft Rule 2006.
  2. Fees and Charges under the Australia New Zealand Therapeutic Products Regulatory Scheme. Consultation Document. May 2006.
  3. Australia New Zealand Therapeutic Products Regulatory Scheme (Medicines) Draft Rule 2006.
  4. Guidelines for Transition to the Joint Regulatory Scheme for Class 1 Medicines, Class 2 Medicines and Medical Devices. Consultation Draft. May 2006
  5. Australia New Zealand Therapeutic Products Regulatory Scheme. Plain English Guide to the Draft Medicines Rule, Draft Medical Devices Rule, and key components of the Draft Administration and Interpretation Rules. May 2006.
  6. Extracts from Papers [Draft ANZTPA Rules] Relating to Adverse Reactions. June 2006.
  7. Volume 9A of the Rules Governing Medicinal Products in the European Union Guidelines on Pharmacovigilance for Medicinal Products for Human Use. Draft. 16 December 2005.
  8. United States Government Accountability Office. Improvement Needed in FDA's Postmarket Decision-making and Oversight Process. March 2006.
  9. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline Clinical Safety Data Management: Definitions and Standards for Expedited Reporting E2a. October 2004.
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Discussion

Dr S. Martindale, Team Leader (Business Development and Support), Medsafe attended the meeting to update the Committee on the arrangements for pharmacovigilance in the Australia New Zealand Therapeutic Products Authority (ANZTPA).

Medsafe provided the Committee with an update on the proposed timeline and key milestones in the transition to the Australia New Zealand Therapeutic Products Authority (ANZTPA). Medsafe explained that the details of the proposed arrangements for pharmacovigilance had yet to be finalised and reassured the Committee that pharmacovigilance was a key activity of the ANZTPA. Members were advised that consultation documents regarding the arrangements for pharmacovigilance were currently being drafted and were expected to be available for formal consultation in September 2006, as part of phase two of the consultation process. The MARC would continue to function under the Medicines Act 1981 until the commencement of the ANZTPA.

Members expressed their desire to have input into the development of the pharmacovigilance consultation documents. They expressed concern regarding potential flaws in some international pharmacovigilance systems and commented that it would be important to avoid these in the ANZTPA. Medsafe reassured the Committee that previous submissions made by the MARC and NZPhvC, as well as critiques of international pharmacovigilance systems, were being used to inform the development and planning for pharmacovigilance in the ANZTPA. The MARC would have the opportunity to make submissions on the pharmacovigilance plans during the formal consultation period in September 2006.

Members had some questions regarding the proposed terms of reference and skill set for the ANZTPA Expert Advisory Committee on Adverse Reactions to Medicines. Medsafe explained that it was deemed important for the ANZTPA committee to represent a wide range of skills. However, the committee should not be larger than needed. ANZTPA committee members would be appointed by the Ministers on the Ministerial Council. The ANZTPA committee would provide recommendations to the Managing Director of ANZTPA, who would also receive technical advice from ANZTPA staff. Medsafe explained that the draft Rules provided to the MARC were proposals released as part of the phase one consultation and were subject to change following consideration of input from the consultation process.

Members asked about the penalties for those situations where sponsors did not respond to ANZTPA on a safety-related issue by the proposed 20-day deadline. Medsafe explained that the Bill, rather than the Medicines Rules, would deal with the penalties. Medsafe reassured that Committee that there would be a detailed framework for penalties. Medsafe explained that there would be an opportunity to make submissions on the proposed penalties during the passage of the Bill.

Members queried how intravenous fluids and total parenteral nutrition products were to be regulated under the ANZTPA. Medsafe advised the Committee that these products would be regulated as medicines.

The MARC Chair suggested that a joint discussion between the MARC and the Australian Adverse Drug Reactions Advisory Committee (ADRAC) would be of value to develop proposals in relation to the joint scheme. Medsafe undertook to explore this suggestion with the Australian Therapeutic Goods Administration (TGA).

Members were advised that the MARC Chair had written to the Manager of Medsafe in May 2006, inviting him to attend the June 2006 MARC meeting. Unfortunately, Medsafe's Manager was not able to attend the meeting due to prior commitments. However, in May 2006, Medsafe's Manager wrote to the MARC Chair inviting him to meet to discuss the Committee's concerns regarding the future arrangements for pharmacovigilance. This meeting was not able to be scheduled prior to the June 2006 MARC meeting, but was still seen as important by Medsafe. The MARC members commented that it would be valuable for such a meeting to go ahead as soon as possible and agreed that the Chair should communicate with members regarding their specific concerns before the meeting with Medsafe's Manager, and feed-back to members after the meeting.

9.2 Oral Terbinafine Serious Adverse Reactions

Reference

Minutes of the 290th meeting of the Adverse Drug Reactions Advisory Committee (ADRAC) held on 10 February 2006.

Discussion

Members noted item 7.3.1 in the minutes of the 290th ADRAC meeting, regarding oral terbinafine and agranulocytosis. They noted that, from 1 September 2005, access to funded oral terbinafine had been widened by PHARMAC. At the time of this meeting oral terbinafine was fully funded, including when prescribed by general practitioners.

The Committee queried whether the Lamisil data sheet contained adequate warnings regarding the recognised adverse reactions to oral terbinafine, including blood dyscrasias, hepatic dysfunction, gastrointestinal effects (particularly taste disturbance), skin disorders and Stevens-Johnson syndrome; and whether these reactions were well-known among prescribers. Members asked that Medsafe and NZPhvC review this issue, including the usage of oral terbinafine in New Zealand, and bring it back to the MARC if warranted. Recommendation The Committee recommended that Medsafe and NZPhvC should review the issue of serious adverse reactions to oral terbinafine and bring it back to the MARC if warranted.

Recommendation

The Committee recommended that Medsafe and NZPhvC should review the issue of serious adverse reactions to oral terbinafine and bring it back to the MARC if warranted.

There being no further business, the Acting Chair thanked members, guests and the secretariat for their attendance and closed the meeting at 2:45pm.

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