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Committees

Minutes of the 120th Medicines Adverse Reactions Committee Meeting - 16 December 2004

At the Sunderland Room, Wellington Airport Conference Centre, commencing at 9:00am

Preface:

In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.

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

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

The recommendations of the Committee are in bold typeface.

Minutes:

MARC MEMBERS PRESENT

Associate Professor T Maling (Chair)
Dr F McClure
Dr M Rademaker
Dr H Kingston
Dr M Tatley
Dr J Moy

marc secretariat present

Ms S. Von Afehlt (Senior Pharmacy Advisor/Editor of Prescriber Update, Medsafe)
Dr S Sime (Medical Advisor, Medsafe)
Dr S Jessamine (Principal Technical Specialist, Medsafe)

invited experts

A Consultant Neurologist attended via teleconference for the discussion on pergolide
Dr M Harrison-Woolrych (New Zealand Pharmacovigilance Centre)- attended the afternoon session only

1. MATTERS OF ADMINISTRATION

1.1 Welcome and apologies

The Consultant Neurologist was welcomed via teleconference to the discussion on pergolide. Dr Harrison-Woolrych from the New Zealand Pharmacovigilance Centre (NZPhvC) was welcomed to the afternoon session.

Apologies had been received from Prof D Skegg and Prof P Ellis.

1.2 Minutes of the 119^th MARC meeting

Members agreed that the minutes of the 119^th meeting are a true and accurate record of the meeting.

1.3 Dates of 2005 MARC meetings

The Committee agreed to the following dates for 2005: Tuesday 15 March, Tuesday 14 June and Tuesday 13 September.

1.4 Conflicts of interest

Committee members with undeclared conflicts of interest submitted these to the Secretary.

1.5 Prescriber Update Articles - pre-peer review versions

1.5.1 Medsafe Editorial team: Keep an Eye on Amiodarone Patients

Discussion

Members commented that this article is generally well written. The Committee made the following recommendations for improvement:

• In the abstract, amend wording to strengthen the monitoring recommendations.
• The reference to the long half-life of amiodarone in the first paragraph should indicate that this may "contribute to" (rather than result in) the slow resolution of adverse effects.
• The required baseline assessment and monitoring should be highlighted in bullet points.
• A sentence should be added recommending that the patient's lead carer, i.e. the doctor responsible for amiodarone monitoring, should be clearly identified at the beginning of treatment.

Recommendation

The Committee recommended that Medsafe incorporate the above changes into the article on amiodarone.

1.5.2 COX-2 inhibitor adverse reactions mimic NSAIDs except for myocardial infarction

Discussion

The contents of this article were discussed as part of the general discussion on COX-2 inhibitors. (See minute item 3.5)

2. Recommendation

Members recommended that the section on the cardiovascular adverse effects of the COX-2 inhibitors should be replaced with the key messages of the NICE guidance published in October 2004.

2.1 MATTERS ARISING

Report on actions arising from the 119^th MARC meeting

2.1.1 Minute item 2.1.4 Prescriber Update: November Issue

Issue

The Committee recommended that Medsafe publish an updated list of IMMP medicines in the November Issue of Prescriber Update.

Outcome

An updated list of IMMP medicines was published in the November 2004 Prescriber Update. The following medicines remain on the IMMP: celecoxib* (Celebrex), clozapine (Clozaril, Clopine), etoricoxib* (Arcoxia), levonorgestrel intrauterine system* (Mirena), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), sibutramine* (Reductil) and valdecoxib (Bextra). The cohorts for the asterisked medicines are now closed but follow-up is continuing.

Discussion

Members noted the above and agreed that no further action is required on this issue.

2.1.2 Minute item 2.1.6 March Minute item 2.1.8 (December minute item 4.1.1.5) Enoxaparin and haemorrhage (57708)

Issue

The Committee agreed that Medsafe should write to the product sponsors of the LMWHs requesting that the data sheets be amended to state that LMWHs should not be used in patients with a creatinine clearance <30ml/min unless anti-Xa monitoring is available.

The Committee also recommended that Medsafe should liase with the DHBNZ Safe Use of Medicines Group about developing a protocol for the safe use of LMWHs in patients with severe renal impairment. Medsafe should make the Safe Use of Medicines Group aware of any pertinent information from the recently published article on anti-Xa monitoring of enoxaparin.

Outcome

Medsafe is in the process of reviewing the above article on anti-Xa monitoring of enoxaparin. Medsafe intends to liase with the DHBNZ Safe Use of Medicines Group following this.

Discussion

Members noted the above and agreed that Medsafe should liase with the Safe Use of Medicines Group on this issue.

2.1.3 Minute item 2.1.19 (June minute item 5) Pharmacovigilance in New Zealand

Issue

The Committee was informed that the New Zealand representatives at the meeting of the trans-Tasman working party were Assoc Prof T Maling, Prof P Ellis, Dr M Tatley and Dr S Jessamine.

The MARC was provided with feedback on this meeting. The members who attended the meeting considered that it had been a very positive experience. Both expert advisory committees were in broad agreement as to the future of pharmacovigilance in the joint agency and significant progress was made on amendments to the TGA/Medsafe discussion document. Members felt reassured that the transition from individual expert advisory committees to a joint advisory committee should proceed smoothly.

Medsafe informed the Committee that a report would be prepared that incorporated the recommendations made by the joint trans-Tasman working group. This document will be forwarded to members of the MARC and ADRAC for comment prior to the next MARC meeting in December.

The Committee agreed to review the Medsafe report on the trans-Tasman working party meeting prior to the next MARC meeting.

Outcome

A report on the trans-Tasman working group meeting is being written and will be forwarded to Committee members as soon as possible.

Discussion

Members were informed that although the draft minutes of the working party meeting have been produced, the discussion document on pharmacovigilance in the joint agency is yet to be updated.

The recent Vioxx withdrawal has highlighted the need for changes to be made in the joint agency and it is anticipated that the pharmacovigilance discussion document will therefore need to be extensively rewritten. It is likely that the new requirements will include the ability of the regulator to compel product sponsors to undertake post-marketing studies as a condition of licensing. It will also be necessary to ensure that the medicines evaluation committees will have a greater focus on safety, particularly when safety concerns have been identified in previous members of a class of medicines

Recommendations

The Committee recommended that the working party minutes be made available to all committee members.

2.1.4 Minute item 2.2.2 (December 2003 minute item 3.1) Atypical antipsychotics and lipid abnormalities

Issue

The Committee recommended that prescribers be informed about the potential association between atypical antipsychotics and lipid abnormalities through an article or paragraph in Prescriber Update. Baseline and follow-up lipid monitoring should be encouraged.

The Committee also recommended that the product sponsors for clozapine and risperidone be asked to include data sheet statements that there have been post-marketing reports of a possible association between their product and lipid abnormalities. In addition, the product sponsors for all four of the atypical antipsychotics available in New Zealand should be asked to comment on the issue of lipid abnormalities.

Outcome

The aforementioned requests were made to the respective product sponsors in February 2004.

Novartis (Clozaril) have agreed to update their datasheets as requested. Douglas Pharmaceuticals has responded to say that Clopine is not currently marketed in New Zealand; however, the requested data sheet changes will be incorporated into a clozapine New Medicine Application (presently submitted to Medsafe), or the request for renewal of provisional consent for the 25 mg and 100 mg clozapine tablets. Medsafe is agreeable to this action.

Eli Lilly (Zyprexa) and Astra Zeneca (Seroquel) were asked only to comment on this issue, as their datasheets already adequately refer to this potential association.

Janssen (Risperdal) have recently replied to decline the request to update their datasheet. Janssen supplied Medsafe with a major review (also given to the FDA) with data supporting this refusal. The defence is as follows:

1. Phase 2/3 trials - low incidence of dyslipidemia events in phase 2 and 3 risperidone trials i.e. total of 0.23% (20 lipid-related events in 8784 patients), compared to 0.30% (10 events in 3380 non-risperidone patients (other neuroleptic or placebo)).
2. Lipid lab data in phase 2/4 trials - analysis shows a decrease (improvement) in fasting lipid values from baseline to endpoint for subjects treated with risperidone vs placebo. However, analysis of nonfasting lipids demonstrated some tendency to increased dyslipidemia in patients on risperidone.
3. Phase 4 clinical studies - No lipid-related adverse events were reported in two large phase 4 trials with risperidone; although one small study (n=59) showed non-significant trends towards worsening of lipid profile with risperidone.
4. Investigator-initiated study - An interim analysis of an ongoing RCT of risperidone vs olanzapine (n=147) on measures of metabolic syndrome shows no change in the risperidone group but significant increases in total cholesterol and triglyceride levels in the olanzapine group.
5. Spontaneous reporting - There are 74 case reports with events of dyslipidaemia in the Janssen-Cilag international ADR database up to March 2004. Their analyses of these case reports indicate this is a rarely reported event, and that there is no consistent pattern of acute or sustained increases or decreases in abnormal lipid levels while on risperidone.
6. Literature review - Up to March 2004, a literature search for articles on this topic identified 24 relevant articles (all study designs, but predominantly case reports). The sponsor indicates this literature describes an inconsistent relationship between risperidone and lipid abnormalities. "It is difficult to interpret the literature data…because of the wide variability in reporting of lipid and metabolic data. However, the incidence of abnormal lipids or metabolic syndrome with use of risperidone appeared to be low." Janssen cite a large UK GP database study showing no increased odds ratio compared to no-antipsychotic exposure (Koro et al 2002).

Janssen argue that the sum of the evidence presented above do not establish that there is an association between risperidone and dyslipidaemia.

Reference:

Carol E. Koro; Donald O. Fedder; Gilbert J. L'Italien; Sheila Weiss; Laurence S. Magder; Julie Kreyenbuhl; Dennis Revicki; Robert W. Buchanan. An Assessment of the Independent Effects of Olanzapine and Risperidone Exposure on the Risk of Hyperlipidemia in Schizophrenic Patients. Arch Gen Psychiatry 2002; 59:1021-1026.

Discussion

The Committee did not agree that the evidence presented by Janssen indicates that lipid abnormalities do not occur with risperidone.

Recommendation

The Committee recommended that Medsafe investigate options for requiring Janssen to update the risperidone data sheet.

2.1.5 Minute item 3.1 Tricyclic Antidepressants in Children and Adolescents for treating Major Depressive Disorder

Issue

The Committee recommended that a "Dear Health Professional letter" be written to inform prescribers of the MARC's advice on the use of tricyclic antidepressants (TCAs) to treat child and adolescent depression. The letter should also inform prescribers that the MARC considers the risk/benefit profile of these medicines to be unfavourable in the treatment of nocturnal enuresis.

The Committee recommended that Medsafe write to the product sponsors of all TCAs requesting that the data sheets be amended to state "TCAs are not recommended for use in treating Major Depressive Disorder (MDD) in children and adolescents under 18 years of age".

The Committee also recommended that Medsafe seek permission from the Drug and Therapeutics Bulletin (DTB) to publish their article on the management of bedwetting.

Outcome

A "Dear Health Professional" letter was sent to prescribers on 19 October 2004 entitled "Updated information and advice about the use of antidepressant medicines".

Additionally, the product sponsors for all tricyclic and tetra-cyclic antidepressants were contacted under section 36 of the Medicines Act 1981 requiring that the following data sheet changes be implemented as appropriate:

• Remove the therapeutic indication of both nocturnal enuresis and depression in respect to children and adolescents.
• Remove from the Dosage and Administration section all statements referring to the use of this medicine in children and adolescents for depression and nocturnal enuresis.
• Add to the Dosage and Administration section: Adolescent Depression: Not recommended for use in adolescent patients 13-18 years of age for the treatment of depression, unless under the supervision of a specialist.
• Add to the Contraindications section: (Medicine name) is contraindicated for the treatment of depression in patients 12 years of age and under. ( Medicine name) is contraindicated for the treatment of nocturnal enuresis.

Medsafe has contacted the Drug and Therapeutics Bulletin (DTB) editorial staff and has been advised that there is a £3000 fee for the reprinting of a DTB article. The cost of this is well beyond Medsafe's budgetary constraints and consequently Medsafe will not be reprinting the DTB article on the management of bedwetting. However, this article is cited in the "Dear Health Professional" letter about antidepressants sent to all prescribers on 19 October 2004 and hence full reference details of the DTB article have been provided to prescribers should they wish to obtain a copy.

Discussion

The Committee accepted Medsafe's decision not to reprint the DTB article on bedwetting. However, Members reiterated the need for New Zealand GPs to be aware of the new recommendations for management of this condition. Members recommended that Medsafe liase with New Zealand Doctor magazine to suggest that they consider writing an article on this issue reinforcing the MARC's advice to not use TCAs for this indication.

The Committee reviewed a recently published statement from the NZ branch of the Faculty of Child and Adolescent Psychiatrists¹ regarding the use of SSRIs in children and adolescents.

The MARC considers that the advice disseminated in the "Dear Health Professional" letter in October remains appropriate. The MARC is aware of the difficulty that many GPs may have in accessing specialist child and adolescent psychiatric services. For this reason the "Dear Healthcare Professional" letter recommends seeking advice from a "specialist" which could include consultant paediatricians and consultant adult psychiatrists as well.

The MARC does not consider that any new advice needs to be communicated to prescribers on this issue.

¹ Depression and SSRI antidepressants in Children and Youth. NZMJ 2004:117 (1206). http://www.nzma.org.nz/__data/assets/pdf_file/0003/17949/Vol-117-No-1206-26-November-2004.pdf

Recommendation

The Committee recommended that Medsafe contact New Zealand Doctor magazine to recommend that an article be written on the management of bedwetting.

2.1.6 Minute item 3.2 Antidepressants and Suicide Warnings

Issue

The Committee recommended that Medsafe write to the product sponsors of all antidepressants including SSRIs (selective serotonin reuptake inhibitors), TCAs (tricyclic antidepressants, SNRIs (selective nor-adrenaline reuptake inhibitors) and MAOIs (monoamine oxidase inhibitors), requesting that a generic suicide warning statement be included in their product data sheets.

Outcome

Medsafe has written to the product sponsors of all antidepressants available in New Zealand to request that a generic suicide warning be added to their product data sheets.

Discussion

The Committee noted the above and agreed that no further action is required at this time.

2.1.7 Minute item 3.3 SSRIs in Children and Adolescents with Major Depression

Issue

The Committee recommended that a "Dear Health Professional" letter be written to inform prescribers of the MARC's advice. The Committee recommended that the letter be peer reviewed by MARC members, and a representative from the faculty of Child and Adolescent Psychiatrists.

The Committee also recommended that Medsafe contact the product sponsors for all the SSRIs to request that specific mention of randomised controlled trials in paediatric populations be included in the product data sheets. This is in addition to requests for generic warning statements on the risk of suicidality as outlined in minute item 3.2.

Outcome

A "Dear Health Professional" letter was sent to prescribers on 19 October 2004 entitled "Updated information and advice about the use of antidepressant medicines".

Additionally, the product sponsors for all SSRI antidepressants (except fluoxetine) were asked to include the following information in their product datasheets. Fluoxetine product sponsors were not asked to include sentence 2 of the dosage and administration paragraph.

DOSAGE AND ADMINISTRATION - Use in Children and Adolescents (under 18 years of age): Safety and effectiveness in children have not been established (see Warnings). Consequently, (insert medicine name) should not be used in patients under 18 years of age (See Warnings).

WARNINGS - Children and Adolescents (under 18 years of age): In clinical trials, adverse events related to suicidality (suicidal thoughts and suicidal behaviours) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in children and adolescents treated with SSRIs (and venlafaxine) compared to those treated with placebo.

Discussion

The Committee noted the above and agreed that no further action is required at this time.

2.1.8 Minute item 3.5 Leflunomide and Serious Adverse Effects (Combined Medsafe/CARM report)

Issue

The Committee recommended that leflunomide remain on the list of adverse reactions of current concern.

The Committee recommended that Medsafe continue to monitor the medical literature and review international regulatory activity with respect to leflunomide.

The Committee recommended that Medsafe liase with the product sponsor for leflunomide and inform them of the MARC's recommendations with respect to the proposed "Dear Doctor" letter.

The Committee suggested that the NZPhvC obtain further information on the cases of leflunomide pneumonitis with a view to identifying risk factors for its development.

Outcome

Medsafe informed the product sponsor for leflunomide of the MARC's recommendations with respect to the proposed "Dear Doctor" letter.

The NZPhvC will continue to obtain further information on the New Zealand and Australian cases of leflunomide pneumonitis and will keep the Committee informed of any progress.

Discussion

The Committee noted the above and agreed that no further action is required at this time.

2.2 Report on actions outstanding from previous meetings.

2.2.1 Minute item 2.1.3 (December 2003 minute item 4.3.1.1) Brand-switch related reports

Issue

The Committee recommended that Medsafe organise a meeting with representatives from MARC, Medsafe, the Generics Sub-Committee of MAAC and PHARMAC to discuss the development of standardised criteria for assessing brand-switch reactions.

Dr Michael Tatley has agreed to be the MARC's representative for this meeting.

Outcome

Medsafe has now received responses from both PHARMAC and the generics sub-committee of MAAC indicating their willingness to participate in a meeting on this issue. Medsafe is in the process of arranging such a meeting.

Discussion

The Committee noted the above and agreed that no further action is required at this time.

2.2.2 Minute item 2.1.5, March Minute item 2.2.5 (September 2003 minute item 4.2.1) Simvastatin, diltiazem and rhabdomyolysis - an analysis of reports of rhabdomyolysis with simvastatin in the CARM database

Issue

Members recommended that Medsafe write to MSD (the product sponsor for simvastatin), to indicate the MARC's disagreement with MSD's decision not to incorporate the MARC's recommendations into the simvastatin data sheet. Medsafe should repeat the request for inclusion of information on the simvastatin/diltiazem interaction in the simvastatin data sheet.

Outcome

Another letter has been sent to MSD requesting that the following statement be added to the simvastatin (LIPEX) data sheet under the INTERACTIONS section for diltiazem: "Treatment with simvastatin in a patient taking diltiazem should be started at the lowest possible dose and titrated upwards. If diltiazem treatment is to be added to patients already taking simvastatin, consider a reduction in statin dose and retitrate against serum cholesterol concentrations".

The New Zealand sponsors of diltiazem and verapamil products have all been requested to include a similar statement in their respective data sheets under the INTERACTIONS section for simvastatin.

Discussion

Members were informed that Medsafe is in the process of reviewing correspondence from the product sponsors of diltiazem and verapamil.

The Committee was concerned that this issue has not yet been resolved.

Recommendation

The Committee recommended that Medsafe follow-up this issue and report back to the Committee at the next MARC meeting.

2.2.3 Minute item 2.2.10 September 2002 minute item 3.3.1 COX-2 inhibitors

Issue

The Committee recommended that Pfizer amend or supply information supporting a statement that the risk of upper GI complications with celecoxib was "…approximately 8-fold less than with non-specific COX inhibitors". Pfizer declined this request to update the datasheet without adequate justification. A second letter was sent to Pfizer in July 2004 repeating this request.

Outcome

Pfizer have responded again declining any changes to the datasheet, but this time have provided a published article that supports the above datasheet statement. The results of this study indicated an annual incidence of upper GI ulcer complications 8-fold lower for celecoxib than for non-specific NSAIDs (0.20% vs 1.68%; p=0.002).

See ANNEX 1 "Goldstein et al. Reduced Risk of Upper Gastrointestinal Ulcer Complications With Celecoxib, A Novel COX-2 Inhibitor. The American Journal of Gastroenterology 2000; 95:1681-1690."

Discussion

The Committee reviewed the information provided by Pfizer on this issue. Members are now prepared to accept Pfizer's reference to a 8-fold reduction in risk of upper GI complications. However, members would prefer the sentence to state that patients taking celecoxib have 1/8th the risk of upper GI complications than non-specific NSAIDs.

Recommendation

The Committee recommended that Medsafe write back to Pfizer to indicate that the MARC is prepared to accept the current Celebrex data sheet statements.

2.2.4 Minute item 2.1.13 (June 2004 minute item 3.2) Atypical antipsychotics and hyperglycaemia

Issue

The Committee recommended that Medsafe write to the product sponsors of clozapine, olanzapine, risperidone and quetiapine requesting that the FDA warning statement be included in the warnings section of the product data sheets.

Letters have been sent to all product sponsors of atypical antipsychotics requesting that the recent FDA statement relating to atypical antipsychotics and hyperglycemia be added to the New Zealand datasheets. Novartis (product: Clozaril) has submitted an update to their datasheet that fully complies with the MARC request.

Outcome

Medsafe is currently awaiting replies from Janssen (Risperdal), Eli Lilly (Zyprexa), AstraZeneca (Seroquel), and Douglas (Clopine).

Discussion

The Committee noted the above and agreed that no further action is required at this time.

3. Pharmacovigilance issues

3.1 Atenolol in the treatment of hypertension (Review of the literature)

Reference Material

• Carlberg et al (2004). Atenolol in hypertension - is it a wise choice? Lancet 364(6): 1684-1689
• Centre for Reviews and Dissemination (2004). Blood pressure drug "not effective"? National Electronic Library for Health. Accessed 8/11/04
• Freemantle et al (1999). Beta blockade after myocardial infarction: systemic review and meta regression analysis. BMJ 318: 1730-1737. June 1999.
• Soriano et al (1997). Increased Survival with Beta-blockers: Importance of Ancillary Properties. Progress in Cardiovascular Diseases, Vol XXXIX, No 5: 445-456.
• Wikstrand et al (1991). Beta-Blockade in the Primary Prevention of Coronary Heart Disease in Hypertensive Patients. Review of the Evidence. Circulation 84 (suppl VI): VI-93 - VI-100.
• Dahlof et al (2002). Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against Atenolol. Lancet 359: 995-1003.

Issue

The purpose of this agenda item was to draw the Committee's attention to a recently published systematic review of the efficacy of atenolol in the primary prevention of myocardial infarction and cardiovascular mortality.

In November 2004, the Lancet published a systematic review by Carlberg et al (2004), of 9 clinical trials of atenolol versus either placebo or other anti-hypertensive medicines (although no other beta blockers were included). The authors found that atenolol was no better than placebo in preventing all-cause mortality, cardiovascular mortality and myocardial infarction, although atenolol use was associated with a lower risk of stroke. The study also found that atenolol was associated with a higher mortality when compared to other active treatments.

The authors of the review concluded that their results "cast doubt on atenolol as a suitable drug for hypertensive patients".

The Centre for Reviews and Dissemination, which is based at the University of York, published an evaluation of the findings of the Carlberg et al (2004) meta-analysis. They concluded, "This research demonstrated that when atenolol was used as a single drug for the treatment of hypertension the long-term goals of treatment were not achieved. Other treatments may be better, but this was not demonstrated clearly. Many factors such as type of patient, level of blood pressure and dose of treatment need to be taken into account in order to fully interpret these findings".

Medsafe is in agreement with this interpretation and does not consider that any regulatory action is required at this time.

Discussion

The Committee noted that in New Zealand, atenolol is not indicated for the primary prevention of cardiovascular events. It is indicated for the control of hypertension, long-term management of angina pectoris, control of cardiac dysrhythmias and; the early intervention in the acute phase and long-term prophylaxis after recovery from myocardial infarction.

Members noted that as the Carlberg et al (2004) meta-analysis did not compare atenolol to any other beta-blockers, it could not be determined from this study whether atenolol differs from other member of the class. Members noted that studies in other beta-blockers, such as metoprolol, have demonstrated a clear reduction in cardiovascular morbidity and mortality. The Committee considered that it is unclear why atenolol should be different from metoprolol in this respect. Members also commented that as atenolol is one of the oldest beta-blockers available there are very few recent efficacy studies, which may have biased the results.

The Committee concluded that the Carlberg et al (2004) meta-analysis has identified a potential new signal with atenolol that requires further evaluation. However, members consider that at present the data are insufficient to enable the Committee to offer definitive advice to prescribers on this issue. The MARC commented that the review of the Carlberg et al (2004) meta-analysis by the Centre for Reviews and Dissemination (2004) would provide a good overview of the evidence for GPs.

The Committee recommended that Medsafe contact the New Zealand Guidelines Group (NZGG), who are likely to have reviewed many of the studies included in the Carlberg et al (2004) meta-analysis when developing their guidelines on the "Assessment and Management of Cardiovascular Risk". The MARC would be interested to know if the NZGG intends to change their advice regarding the medical treatment of hypertension in light of this new information.

Recommendation

The Committee recommended that Medsafe liaise with other international regulators on this issue. Members also recommended that an opinion be sought from the New Zealand Guidelines Group regarding advice to prescribers on the use of atenolol in blood pressure management.

3.2 Thioridazine - Market withdrawal due to unfavourable risk-benefit profile

Reference Material

• Letter of discontinuation notification from Novartis (dated 28 Oct 2004)
• Risk-benefit re-assessment conducted by the Swedish Medical Products Agency (dated 15 July 2004)
• Reilly J et al (2002). Thioridazine and sudden unexplained death in psychiatric in-patients. Brit J Psychiatry 180:515-522
• Menkes D, Knight J (2002). Cardiotoxicity and prescription of thioridazine in New Zealand. Aust NZ J Psychiatry 36:492-498
• Glassman A, Bigger J (2001). Antipsychotic drugs: prolonged QTc interval, torsade de points and sudden death. Am J Psychiatry 158:1774-1782
• Hennessy S et al (2002). Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using administrative data. BMJ 325:1070-1072
• Ellis P (2004). Comments on MARC agenda item on thioridazine. Personal correspondence

Issue

The purpose of this agenda item was to bring to the MARC's attention Novartis' decision to withdraw the Melleril brand of thioridazine from the worldwide market by 30 June 2005. This decision was based on an unfavourable risk-benefit reassessment undertaken by Swedish Health Authorities.

The MARC previously reviewed the risk-benefit profile of thioridazine in 2001. At that time the MARC review focused on data regarding the risk of QT-prolongation with thioridazine. In June 2001, the following advice was issued to prescribers:

"Thioridazine (Melleril™, Aldazine™) increases the risk of arrhythmia from QT-prolongation. Consequently, the Medicines Adverse Reactions Committee has recommended the following changes to how thioridazine is prescribed in New Zealand.

• Thioridazine is now contraindicated in the following circumstances, all of which are risk factors for arrhythmia:
  • Use with medicines which inhibit the metabolism of thioridazine (cimetidine, most antidepressants, pindolol, propranolol)
  • Use with medicines which prolong the QT-interval (some antiarrhythmics, most antipsychotics, cisapride)
  • Use in patients with predisposing factors for arrhythmia or pre-existing QT-prolongation (QTc > 500ms).
• Thioridazine should be initiated only by a specialist and only as third-line therapy. In addition, the following precautions should be observed for new patients:
  • Assess for risk factors for arrhythmia
  • Check the QTc-interval and serum potassium
  • Use the minimum effective dose
  • Observe a maximum of 200mg daily ordinarily
  • Use dosages above 200mg daily up to a maximum of 600mg daily only under specialist supervision and only with QTc-interval monitoring following each increase.
• For all patients currently taking thioridazine:
  • Assess for risk factors for arrhythmia
  • Check the QTc-interval and serum potassium
  • Specialist review is required for all children taking thioridazine and for adults taking doses above 200mg daily
  • Reduce the dose if QTc-interval is >500ms and withdraw thioridazine if the QTc interval is persistently >500ms
  • If thioridazine discontinuation is necessary, gradually reduce the dose over a period of one month and concurrently introduce alternative medication. Specialist supervision may be advisable for the withdrawal process."

PHARMAC prescription data for September 2004 indicates that approximately 3000 patients per quarter are receiving thioridazine in New Zealand.

After review of the Swedish risk-benefit analysis and published literature, Medsafe considers that there is sufficient evidence to support a decision to remove all brands of thioridazine from the market. Currently Melleril SR and all strengths of Aldazine (Pacific Pharmaceuticals generic brand) are supplied to the New Zealand market.

Discussion

Members reviewed comments tabled by Prof Ellis, Consultant Psychiatrist, who was unable to attend the meeting.

It was noted that after consultation with colleagues, Prof Ellis estimates that approximately 300 patients in New Zealand are receiving thioridazine appropriately, in line with MARC recommendations made in 2001. It is likely that the other 90% of patients are receiving thioridazine for the treatment of conditions such as acute mania, agitated dementia and psychotic depression for which there are a number of alternative treatments available. PHARMAC prescription data supports this estimate.

The Committee agreed that the absolute risk of QT prolongation with thioridazine use is very low and for the approx 300 patients with genuine clinical need, the risk-benefit profile remains favourable. Therefore, members agreed that thioridazine should continue to be available in New Zealand but its use must be restricted to the approved indications only. Members were informed that this could be achieved by making thioridazine a specialist-only medicine via Section 23 of the Medicines Act. It was noted that it might also be possible for PHARMAC to restrict thioridazine funding to Special Authority.

Members noted that Novartis will continue to supply Melleril to certain patients on compassionate grounds after the worldwide withdrawal is complete. It was also noted that most strengths of the Melleril brand have already been withdrawn from the Australian market.

The MARC recommended that a Prescriber Update article be written to remind prescribers of the MARC's earlier advice (June 2001) regarding the safe use of thioridazine.

Recommendations

The Committee recommended that Medsafe explore the regulatory options for limiting the use of Thioridazine to the approved indications only.

The Committee recommended that Medsafe reiterate the MARC's June 2001 advice in the next issue of Prescriber Update.

The Committee recommended that Medsafe write to PHARMAC to request that the funding of thioridazine be restricted to Special Authority.

3.3 Pergolide and Cardiac Valvulopathy

Reference material

• Eli Lilly. "Dear Doctor" letter re: cardiac valvulopathy with pergolide. April 2003
• Baseman DG et al. Pergolide use in Parkinson disease is associated with cardiac valve regurgitation. Neurology 2004 Jul 27; 63:301-304.
• Bonuccelli U. Comparing dopamine agonists in Parkinson's disease. Curr Opin Neurol 2003; 16(suppl 1): S13-S19.
• (August 2004). Personal correspondence.
• Rascol et al (2004). New Concerns About Old Drugs: Valvular Heart Diseae on Ergot Derivative Dopamine Agonists as an Exemplary Situation of Pharmacovigilance. Movement Disorders 2004; 19:611-613.
• Samii A, Nutt J and Ransom B. Parkinson's disease. Lancet 2004; 363:1783-1793
• (September 2004). Personal correspondence.
• Van Camp G et al. Heart valvular disease in patients with Parkinson's disease treated with high-dose pergolide. Neurology 2003; 61:859-861.
• Van Camp G et al. Treatment of Parkinson's disease with pergolide and relation to restrictive valvular heart disease. Lancet 2004 Apr 10; 363(9416): 1179-83.

Issue

The purpose of this agenda item was to update the Committee on new information regarding the risk of cardiac valvulopathy with pergolide use.

Pergolide is an ergot-derivative dopamine agonist (DA) that is indicated in New Zealand for the treatment of Parkinson's Disease (PD).

In New Zealand, there are two classes of DAs available for the treatment of PD: ergot derivatives such as pergolide, bromocriptine, lisuride, and apomorphine; and non-ergot derivatives such as ropinirole and pramipexole. All the ergot-derivative DAs are funded by PHARMAC. However, no non-ergot derivative DAs is funded.

The potential for ergot-derivatives to cause cardiac valvulopathy was first identified with dexfenfluramine and fenfluramine in 1997. However, despite 15 years of international post-marketing experience, an association between pergolide use and the development of cardiac valvulopathy has only recently been identified. Concrete epidemiological data on this risk is lacking, with rate estimates of 1 in 20 000 (Eli-Lilly's own data) to a more recent case-control study by Van Camp et al (2004) that reported an estimated incidence of 1 in 3.

In April 2003, Eli Lilly updated the New Zealand pergolide datasheet and issued a "Dear Doctor" letter to warn of case reports of cardiac valvulopathy related to pergolide use. In this letter, Eli Lilly claimed that their data suggested a rate of pergolide-associated valvulopathy of 1 in 20 000 (0.005% - very rare) since first marketed in 1989.

In September 2004, Eli Lilly again updated the pergolide data sheet to provide more detailed descriptions of the risk of cardiac valvulopathy as well as the risk of pleuritis, pleural effusion, pleural fibrosis, pericarditis and pericardial effusion. Prescribers are advised to undertake a careful risk benefit analysis before prescribing pergolide to their patients. It is recommended that all patients should have a baseline echocardiogram performed before initiating treatment with pergolide. All patients should then undergo regular clinical monitoring as appropriate. Specific advice is given to discontinue pergolide if a patient develops a fibrotic condition or cardiac valvulopathy.

Eli Lilly intends to distribute another "Dear Doctor" letter in New Zealand to inform prescribers of these changes.

In response to the emerging information on the risk of cardiac valvulopathy with pergolide the following international regulatory action has been undertaken:

• Australia - An ADRAC Bulletin article "Cardiac valvulopathy with pergolide" was distributed to prescribers in August 2004. ADRAC have not received any reports of this ADR as of yet.
• USA - Product datasheets were updated in 2003 similar to the changes made internationally (including NZ). A "Dear Doctor" letter was distributed to US prescribers soon after these updates were finalised.
• Canada - Product datasheets were updated in 2003 similar to the changes made internationally. A Canadian "Dear Doctor" letter was sent out soon after these updates. In October 2004, further updates and a "Dear Doctor" letter were sent relating to information in the recent published studies.
• United Kingdom - Following product datasheet updates, the Committee on Safety of Medicines (CSM) included an article, "Pergolide and cardiac valvulopathy" in the September 2003 edition of Current Problems in Pharmacovigilance.

After reviewing the recent literature on this issue, Medsafe considers that the true incidence of cardiac valvulopathy associated with pergolide use is unknown. Well-controlled prospective comparative studies are needed to clarify these issues. In light of the known association of the ergot derivatives dexfenfluramine and fenfluramine with cardiac valvulopathy, and increasing evidence of this association with pergolide, it is likely that this is a class effect. The literature suggests that ergot and non-ergot DA's have similar efficacy in the treatment of PD, although levodopa (L-Dopa) remains at the core of PD treatment. There is no current evidence of an association between the non-ergot DAs and cardiac valvulopathy, although it is acknowledged that post-marketing experience with these agents is limited.

Due to funding restrictions, most New Zealand patients with PD will require treatment with an ergot derivative DA such as pergolide. It is extremely important that doctors undertake full risk-benefit discussions with their patients before initiating treatment. The new monitoring guidelines specified in the data sheet will also need to be strictly followed.

Medsafe recommends that the following action be undertaken:

• Eli Lilly should be asked to distribute the "Dear Doctor" letter informing prescribers of the new monitoring requirements for pergolide use.
• A Prescriber Update article should be written on this issue
• A watching brief should be maintained.

Discussion

The MARC invited a consultant neurologist to attend the discussion on pergolide via teleconference.

Members were informed that pergolide has been one of the most commonly prescribed anti-Parkinson's medicines in New Zealand. It has been used predominantly in younger patients to smooth out motor fluctuations that may occur with L-Dopa therapy. In the US particularly, it has been used first-line in patients under 50 to delay the need for L-Dopa therapy. As with all DAs, pergolide can cause confusion in older patients, hence it is less commonly used in this age group.

In the neurologist's clinical experience, the addition of pergolide to the treatment of patients experiencing severe motor fluctuations with L-Dopa therapy can often result in dramatic improvements. Members were informed that although there are other ergot-derivative DAs available in New Zealand, pergolide seems to last longer and be better tolerated than other treatments such as bromocriptine.

The Committee was informed that New Zealand neurologists have been concerned about literature reports of the risk of cardiac valvulopathy with pergolide for some time, although the neurologist stated that he has never personally seen a case of cardiac valvulopathy with pergolide use. He informed members that his concern has increased since the Lancet published a case control study by Van Camp et al (April 2004) that reported that the incidence of cardiac valvulopathy with pergolide use could be as high as 1 in 3 patients. In response to this study, some neurologists are now choosing not to prescribe pergolide to new patients.

The neurologist informed members that he has a limited number of patients paying for ropinirole, a non-ergot DA. Although it is difficult to determine from the literature whether one DA is better than another (due to the extremely variable nature of the disease in each individual patient), in his clinical experience ropinirole is often superior to pergolide in the treatment of PD. He notes that the literature suggests an increased risk of side effects such as somnolence and sleep attacks with non-ergot DAs but he has seen these side effects with all DAs. Members were informed that it is important to have a range of treatment options available, as some patients will respond well to one treatment but not to another.

Members were informed that most neurologists in New Zealand agree that cardiac valvulopathy is likely to be a class effect. However, in the absence of funded non-ergot DAs, pergolide should remain available as a treatment option as long as extensive cardiac monitoring is instigated. The following monitoring guidelines are recommended:

1. Best practice: All patients presently taking pergolide or about to initiate treatment with pergolide should have a baseline echocardiogram with a follow-up clinical cardiac examination every 6 months.
2. Minimum: All patients taking pergolide should have a clinical cardiac examination including auscultation every 6 months. An echocardiogram should be performed if any abnormalities are detected.

Committee members expressed their appreciation for the neurologist's participation in the discussion on this issue.

The MARC agreed that it is not possible to determine the true incidence of cardiac valvulopathy with pergolide at this stage. Members agreed that the fibrotic adverse effects seen with pergolide are likely to be a class effect. Members also noted that there is no present evidence to suggest that the non-ergot derivative DAs are associated with this potentially life-threatening adverse reaction.

The Committee reviewed the pergolide data sheet changes and monitoring recommendations made by Eli-Lilly. Members agreed that a baseline echo should be performed in all patients before initiating treatment with pergolide. Members also supported the recommendation that all patients should undergo a clinical cardiac review every 6 - 12 months after initiating treatment.

Members were concerned that in some parts of New Zealand, it may be difficult to access echocardiograms for baseline screening purposes. It was noted that this might result in long treatment delays for patients and may also significantly add to the cost of pergolide treatment.

The Committee noted that pergolide is being used off-label to treat restless legs syndrome. The MARC considers that the risk-benefit profile in this case is unfavourable.

Recommendations

The Committee recommended that the product sponsor be required to distribute the "Dear Doctor" letter as soon as possible, with particular emphasis on the new monitoring requirements.

Members recommended that a Prescriber Update article should be written on pergolide and cardiac valvulopathy. The article should indicate that pergolide should not be used for the treatment of restless leg syndrome.

Medsafe should continue to monitor the literature on this issue and report back to the Committee if there are any new developments.

3.4 Domperidone and the risk of QT prolongation

Reference material

• FDA Warns Against Women Using Unapproved Drug, Domperidone, to Increase Milk Production http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm173886.htm
• Da Silva O and Knoppert D (2004). Domperidone for lactating women. CMAJ 171(7): 725.
• Gabay M (2002). Galactagogues: Medications That Induce Lactation. Journal of Human Lactation 18(3): 274-279
• Da Silva, O et al (2001). Effect of domperidone on milk production in mothers of premature newborns: a randomised, double-blind, placebo-controlled trial. CMAJ 164 (1): 17-21.
• Domperidone handout #19a and #19b January 2003. http://www.breastfeedingonline.com/domperidone.shtml, http://www.kellymom.com/utilities (page no longer available)

Issue

The purpose of this agenda item was to review the cardiovascular safety of oral domperidone in light of the release of an FDA talk paper on June 7 2004. In this paper, the FDA warned women against using domperidone to increase milk production because of published reports and case studies of cardiac arrhythmias, cardiac arrest and sudden death in patients using the intravenous form of domperidone. (The intravenous form of domperidone was withdrawn worldwide in the mid 1980s)

In New Zealand domperidone is indicated for the treatment of dyspeptic symptoms associated with delayed gastric emptying or gastro-oesophageal reflux and; for the treatment of nausea and vomiting of varying cause. Domperidone is not indicated for use as a galactagogue in any country.

Although domperidone is primarily used for its anti-emetic and pro-kinetic effects in New Zealand, it is also being used off label as a galactagogue. From discussion with the New Zealand College of Midwives, it appears that this use is primarily being initiated in specialist neonatal units upon the advice of paediatricians and/or lactation consultants. However, some junior doctors working in O&G have also been asked to prescribe domperidone. It appears that advice on domperidone's use as a galactagogue is being obtained from websites associated with Dr Jack Newman, MD in the US. This advice recommends the use of domperidone at standard anti-emetic doses.

After reviewing the product sponsor's report on this issue, it is evident that intravenous domperidone has the potential to cause QT prolongation at high doses resulting in high peak plasma concentrations. Both preclinical and clinical data support an association between the rate of rise of plasma domperidone levels and the occurrence of this pro-arrhythmic effect. It is important to note that the recommended oral dosing regimens result in peak plasma concentrations well below that determined from electrophysiological and clinical studies to be associated with prolonged QTc.

Since intravenous domperidone was withdrawn from the market in the mid 1980s there have been no published case reports of QTc prolongation with oral domperidone use. International post-marketing reports of QT prolongation and arrhythmia have occurred very rarely with oral domperidone. Over a period of 24 years, only 26 spontaneous reports of QT prolongation, arrhythmia or torsades de pointes (TdP) have been reported. In the majority of these cases, causality was questionable. (NB There has been no New Zealand case reports). Reassuringly, two large retrospective population based cohort studies of oral domperidone use showed that there was no evidence of an increased risk of arrhythmia or sudden death in patients taking oral domperidone. (NB. These studies were not published).

There is clear evidence that concomitant administration of domperidone and ketoconazole can cause a significant increase in the QTc interval. The product sponsor suggests that as well as a pharmacokinetic interaction via CYP3A4; a pharmacodynamic interaction between domperidone and ketoconazole is also possible. However, it is very likely that a similar effect on QTc prolongation will occur with other potent CYP3A4 inhibitors such as erythromycin.

Although there has been very little literature published on the use of oral domperidone as a galactagogue, there is no current evidence that the off-label use of domperidone for this purpose would confer any additional risk of QT prolongation. Domperidone does not cross the blood-brain barrier and there is anecdotal evidence that domperidone is less likely to cause extra-pyramidal side effects (in mother and baby) than the other medicines used off label as galactagogues (e.g. metoclopramide and chlorpromazine).

It is Medsafe's view that the risk of QTc prolongation, TdP or sudden death with oral domperidone at standard doses is very small. However, this risk is likely to be increased by other factors that predispose to QTc prolongation such as hypokalaemia, the use of other QT prolonging medicines or an underlying genetic predisposition. It is also likely to be increased by the use of other medicines that inhibit CYP3A4 activity. It is Medsafe's view that the off-label use of domperidone as a galactagogue is unlikely to confer any additional risk.

Medsafe recommends that the product sponsor for domperidone should be asked to update the domperidone data sheet to include the following information:

In the warnings section: A statement should be included that indicates that cases of QT prolongation and sudden death have occurred in patients taking high-dose intravenous domperidone. Domperidone should be used with caution in patients with risk factors for QT prolongation and arrhythmia. A recommendation should be made not to use domperidone in association with other CYP3A4 inhibitors with specific mention of erythromycin.

A watching brief should be maintained on oral domperidone and QT prolongation, arrhythmia and sudden death.

Discussion

Members provided anecdotal evidence of increasing requests for the prescription of domperidone as a galactagogue. However, it was noted that in New Zealand domperidone is primarily used on-label as an anti-emetic and prokinetic agent.

The Committee agreed that although the absolute risk of QT prolongation with oral domperidone is small, this risk would be increased by other risk factors for QT prolongation.

Members expressed concern that the domperidone data sheet contraindicates the concomitant use of ketoconazole and domperidone, but no advice is given regarding the potential for domperidone to interact with other CYP3A4 inhibitors such as erythromycin. Members commented that as breast-feeding women are at risk of the development of mastitis, the concomitant use of domperidone and erythromycin is likely to occur.

Members agreed that the MARC is unable to comment on the efficacy of domperidone as a galactagogue. However, members agreed that off-label use is unlikely to confer an additional risk of QT prolongation, unless the medicine is given to patients with other risk factors for QT prolongation. Members were reassured that as only very small amounts of domperidone pass into breast milk there would be very little potential risk to the baby.

Members agreed that prescribers should be informed of the potential risk of QT prolongation and arrhythmia with domperidone use by way of data sheet changes. Members also agreed that the product sponsor be asked to provide evidence of its safety when co-administered with other CYP3A4 inhibitors such as erythromycin.

Recommendations

The Committee recommended that Medsafe write to the product sponsor of domperidone to request that the data sheet be updated to include the following statement:
"Cases of QT prolongation, arrhythmia and sudden death have occurred with the intravenous form of domperidone. In most cases the serum domperidone concentration was well in excess of that achieved from maximal recommended oral dosing regimens. Domperidone should be used with caution in patients with risk factors for QT prolongation."

Members also recommended that the product sponsor be asked to supply Medsafe with evidence of the cardiovascular safety of domperidone when it is administered with other CYP3A4 inhibitors such as erythromycin. Alternatively the product sponsor should be asked to include the following statement included in the domperidone data sheet:
"Domperidone should not be prescribed in combination with CYP3A4 inhibitors such as erythromycin" Members also recommended that Medsafe write to the NZ College of Midwives to inform them of the MARC's recommendations.
The Committee recommended that a watching brief be maintained on domperidone and QT prolongation, arrhythmia or sudden death.

3.5 Review of the Cardiovascular safety of the COX-2 inhibitors

Reference material

• Medsafe overview
• NZPhvC report: The Pharmacology of cyclo-oxygenase inhibition
• NZPhvC review of published literature on cardiovascular adverse events associated with the COX-2 inhibitors.
• IMMP Monitoring of COX-2 inhibitors: Summary for MARC December 2004
• ADRU spontaneous reporting data on the COX-2 inhibitors
• Merck, Sharp and Dohme. APPROVe Study Update.
• Medsafe Editorial Team (2004). COX-2 Inhibitors - where to from here? Prescriber Update 2004; 25 (2) November.
• Press release: EMEA to review COX-2 inhibitors. London, 22 October 2004
• Annex 6: Other references provided for review
• Juni et al (2004). Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet published online November 5, 2004
• Day, R et al (2004). The vascular effects of COX-2 selective inhibitors. Australian Prescriber (in press).
• FDA Memorandum: Risk of Acute Myocardial Infarction and Sudden cardiac Death in Patients Treated with COX-2 Selective and Non-Selective NSAIDs. September 30 2004.
• Ray W et al (2002). COX-2 selective non-steroidal anti-inflammatory drugs and the risk of serious coronary heart disease. Lancet 360:1071-1073.
• Mamdani et al (2004). Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet 363: 1751-1756
• Solomon D et al (2004). Relationship between Selective Cyclooxygenase-2 Inhibitors and Acute Myocardial Infarction in Older Adults. Circulation 109:2068-2073
• White et al (2002). Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 2002 Feb 15; 89(4): 425-30.
• White W et al (2004). Effects of the Cyclooxygenase-2 specific inhibitor Valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. American Journal of Therapeutics 11.244-250.
• Farkouh M et al (2004). Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 364:675-684
• Howes L and Krum H (2002). Selective cyclo-oxygenase-2 inhibitors and myocardial infarction. How strong is the link? Drug Safety 25(12): 829-835.
• Ott et al (2003). Efficacy and safety of the cyclo-oxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. Journal Thorac Cardiovasc Surg; 125(6): 1481-92.
• Howard P and Delafontaine P (2004). Non-steroidal anti-inflammatory drugs and cardiovascular risk. J Am Coll Cardiol 43(4): 519-525.
• Clark D et al (2004). Do Some Inhibitors of COX-2 increase the risk of Thromboembolic Events? Linking Pharmacology with Pharmacoepidemiology. Drug Safety 27(7): 427-456.
• BPAC NZ (2004). COX-2 inhibitors: NICE guidance
• Wallace, I. (2004). Co-prescription of Proton Pump Inhibitors with NSAIDs in at risk patients.

Issue

The purpose of this agenda item was to provide the MARC with a preliminary review of the literature and IMMP data regarding the cardiovascular safety of the COX-2 inhibitors (celecoxib, etoricoxib, parecoxib, valdecoxib, lumiracoxib and meloxicam) in light of the worldwide withdrawal of rofecoxib (Vioxx).

Medsafe, along with other international regulators, was notified on 1 October 2004 that Merck Sharp and Dohme (MSD) had decided to withdraw Vioxx (rofecoxib) worldwide due to concerns regarding its cardiovascular safety. This decision was based on the findings of the APPROVe study, a 3-year study designed to compare the effectiveness of Vioxx 25mg/day with placebo in the prevention of adenomatous polyps. The APPROVe study was also planned to serve as a component of a placebo controlled cardiovascular outcomes study for Vioxx.

The APPROVE study was stopped by an independent External Safety Monitoring Board who noted that after 18 months, a deviation in the rate of cardiovascular adverse events had occurred in the Vioxx group compared to the placebo group. The relative risk of a cardiovascular adverse event in the Vioxx group was calculated to be 1.96 (95% CI 1.20,3.19 p =0.0071).

It has been hypothesised that the excess of cardiovascular thromboembolic adverse effects in the Vioxx group can be explained by the physiology of COX-2 inhibition. Unopposed COX-1 activity has the theoretical potential to increase the risk of thromboembolism through a COX-1-mediated increase in platelet aggregation, and a consequent increase in the risk of emboli occluding the myocardial and cerebral arterioles.

At this stage it is unclear whether all COX-2 inhibitors confer the same increased risk of thromboembolic cardiovascular events i.e. is this a class effect? It has been suggested that the risk may be related to the specificity of COX-2 inhibition. In an attempt to answer this question, Medsafe, along with other international regulators, requested that the product sponsors for all COX-2 inhibitors provide us with all available cardiovascular safety data on their products. Medsafe has now received this data and it is hoped that analysis of this data will be complete in early 2005.

MARC members were provided with an overview of the APPROVe trial and the international regulatory activity that occurred in response to the Vioxx withdrawal. Members were also provided with both the original articles and a summary of published clinical studies looking at the cardiovascular safety of the COX-2 inhibitors.

An outline of the data collected by the IMMP on the cardiovascular safety of the COX-2 inhibitors was provided to members with options for further analysis of this data.

Committee members were asked whether they felt that it would be possible to issue specific advice to prescribers ahead of completion of the review of COX-2 inhibitor cardiovascular safety data.

Discussion

The MARC reviewed the literature provided by Medsafe on this issue.

Members commented that the increased risk of cardiovascular events found for rofecoxib (Vioxx) might also occur to some degree for all other COX-2 inhibitors. It was considered that there is less published evidence of cardiovascular risk associated with celecoxib, although it is important to note that there have not been any published long-term studies of celecoxib that were powered to detect an increased risk of cardiovascular adverse events.

The MARC considers that until the review of cardiovascular safety is complete it is not possible to offer definitive advice to prescribers. However, in the interim the Committee indicated that it broadly supports the guidance issued by the United Kingdom "National Institute of Clinical Excellence" (NICE), which was distributed to all GPs by the New Zealand Best Practice Advocacy Centre in October 2004.

The MARC's key messages are:

• COX-2 agents are not recommended for routine use in patients with rheumatoid arthritis (RA) or osteoarthritis (OA) except in circumstances where the patient is at "high risk " of developing a serious gastrointestinal adverse effect from other standard non-steroidal anti-inflammatory agents;
• COX-2 agents should not be routinely prescribed to patients at high risk of cardiovascular events (absolute risk of event >15-20% over 5 years) as there remains uncertainty about the safety of these agents when used in this group of patients;
• Prescribing COX-2 agents to patients already taking aspirin cannot be justified on current evidence.
• The increased benefit associated with use of COX-2 agents in patients at high risk of serious gastrointestinal adverse effects (estimated as between a 4 and 8 times reduction in serious events), may outweigh the increased risk of cardiovascular events in patients at low risk of myocardial infarction.

After reviewing the NZPhvC report on the IMMP monitoring of the COX-2 inhibitors the Committee agreed that an interim analysis of the data should be prepared for the next MARC meeting in March. It was also agreed that no further follow-up data should be collected on the COX-2 inhibitor cohorts.

Recommendations

The Committee recommended that MARC advice and NICE guidance be disseminated to prescribers in the Prescriber Update article currently in progress. (See minute item 1.5.2) Members recommended that Medsafe should continue with the analysis of data submitted by the product sponsors of the COX-2 inhibitors available in New Zealand, and report back to the MARC when this is complete.

The MARC agreed that the NZPhvC should complete a preliminary analysis of the COX-2 inhibitor IMMP data (with an explanation of potential confounders). It was also agreed that no further follow-up data should be collected.

4. matters arising from the New Zealand Pharmacovigilance Centre (NZPHvC)

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 CARM Case Reports

4.1.1 Deaths

4.1.1.1 Atorvastatin, simvastatin and cerebrovascular disorder (62102)

Discussion

Members commented that it is likely that the patient had a number of risk factors for stroke and it is possible that the change from atorvastatin to simvastatin occurred because of poorly controlled hypercholesterolaemia.

The causality assessment was deemed "unlikely" and no further action was recommended.

4.1.1.2 Diltiazem and cardiac failure left, cardiomyopathy, drug level increased, coronary artery disorder (62132)

Discussion

The Committee noted that it is not known what effect post-mortem decomposition may have had on the diltiazem level, thus the blood levels may be unreliable. Causality was deemed "possible" for diltiazem and left cardiac failure, "unlikely" for cardiomyopathy and coronary artery disorder and "certain" for drug level increased. No further action was recommended.

The Committee commented that it is important that pathologists and/or coroners are reminded that prescription medicines may contribute to a patient's death.

Recommendation

The MARC chair agreed to write a letter to the New Zealand College of Pathologists requesting that their members are reminded of the need to consider that prescription medicines may have a contributory role in sudden death.

4.1.1.3 Thalidomide and agranulocytosis (62222)

Discussion

The Committee noted that thalidomide treatment is contraindicated in patients with an absolute neutrophil count less than 0.75 x 10^9/L. However, in this case the patient's neutrophil count was adequate prior to initiating treatment.

The causality assessment for thalidomide and agranulocytosis was deemed "possible". No further action was recommended.

4.1.1.4 Fluoxetine and convulsions, hypokalaemia, overdose (61643)

Discussion

The Committee noted that citalopram was not listed as one of the patient's medicines. Members considered that the details of this case were not clear from the report. It was considered that more information was required on this case including exactly what medicines the patient had been prescribed before causality could be determined.

It was noted that all antidepressant product sponsors in New Zealand have been asked to update their data sheets to include the potential risk of suicidality and/or suicide.

Recommendation

The Committee recommended that the NZPhvC obtain further information on this case and report back to the Committee at a later date.

4.1.1.5 Paroxetine and suicide, agitation, insomnia, psychosis (62128)

Discussion

Members considered that it is possible that the patient was poorly compliant with paroxetine therapy and thus inadequately treated depression was the major cause of her suicide. However, an effect of the SSRI could not be ruled out.

The causality assessment was deemed "possible" for suicide, agitation, insomnia and psychosis. No further action was recommended.

4.1.1.6 Streptokinase, aspirin, blinded study medication and cerebral haemorrhage (61313)

Discussion

The Committee noted that the study medication was still blinded in this case. It was noted that both streptokinase and aspirin might have contributed to this patient's intracerebral haemorrhage. It could not be determined whether the study medication had played a role also. It was noted that the CT scan findings were consistent with a cerebral tumour, which may have predisposed this patient to intracerebral bleeding with streptokinase, aspirin and/or heparin.

The causality assessment was deemed "possible" for streptokinase, aspirin, blinded study medication and intracerebral haemorrhage. No further action was recommended.

4.1.1.7 Tiotropium and sudden death (61512)

Discussion

The Committee noted that CARM has received 11 reports of adverse reactions to tiotropium including one report of sudden death. Members considered it very unlikely that tiotropium was responsible for this patient's death.

Causality was assessed as "unlikely" for tiotropium and sudden death. No further action was recommended.

4.1.2 Alternative Medicine related reports

4.1.2.1 Estrosoy Plus and post-menopausal bleeding(61635)

Discussion

The Committee noted that Estrosoy Plus contains black cohosh, red clover and soy, all of which have been shown to have oestrogen or oestrogen-like effects. It was noted that black cohosh has also been implicated in the development of metastatic cancer in animals with existing cancer, so it should not have been used in this woman.

The Committee noted that the use of these types of products might be increasing in light of recent recommendations regarding the use of HRT in menopausal women.

The causality assessment was deemed "probable" for Estrosoy Plus and post-menopausal bleeding. The Committee recommended that information on the use of products such as Estrosoy Plus should be disseminated to GPs and prescribers.

Recommendation

The Committee recommended that Dr Harrison-Woolrych investigate how best to disseminate this information.

4.1.2.2 Joint-X and hyperkalaemia (61714)

Discussion

The Committee noted that Joint-X contains glucosamine, chondroitin and boron. CARM has not received any other reports of hyperkalaemia with either Joint-X or glucosamine. The WHO has received two reports of hyperkalaemia with glucosamine.

The causality assessment was deemed "probable" for Joint-X and hyperkalaemia.

Recommendation

The Committee recommended that a watching brief be placed on Joint-X, glucosamine and hyperkalaemia.

4.1.3 Anticonvulsant medication-related reports

4.1.3.1 Sodium valproate and developmental delay, foetal valproate syndrome, otitis media (62131)

Discussion

It was noted that previous reports of foetal valproate syndrome have occurred in children of mothers who were taking valproate for the treatment of epilepsy. In these cases, it was argued that the foetal abnormalities might have been caused by epileptic seizures rather than the medicine itself.

The causality assessment was deemed "possible" for developmental delay, foetal valproate syndrome and otitis media.

Recommendation

The Committee recommended that a watching brief be maintained on maternal valproate use and foetal abnormalities.

4.1.4 Anti-infective medication-related reports

4.1.4.1 Cephazolin and amylase increased, abdominal pain (61742)

Discussion

The Committee noted the above case report. Causality was deemed "probable" for cephazolin and amylase increase and abdominal pain.

Recommendation

The Committee recommended that a watching brief be maintained on cephazolin and pancreatitis.

4.1.5 Cardiovascular medication-related reports

4.1.5.1 Flecainide and malformation hand, foetal disorders (62343)

Discussion

The causality assessment was deemed "possible" for flecainide and malformation hand, foetal disorders. No further action was recommended.

4.1.5.2 Simvastatin and aggressive reaction, confusion(62274) (62274)

Discussion

The Committee noted that CARM has received 118 reports of psychiatric reactions with simvastatin.

The causality assessment was deemed "probable" for simvastatin and aggressive reaction and confusion.

Recommendation

The Committee recommended that the NZPhvC obtain further information on psychiatric reactions with simvastatin and report back to the Committee at a later date.

4.1.6 Immunosuppressive medication-related reports

4.1.6.1 Leflunomide, methotrexate and pneumonitis, hypoxia, dyspnoea, cough, pulmonary infiltration (62152)

Discussion

The Committee noted that this case was similar to other cases of leflunomide/methotrexate pneumonitis presented to the Committee at recent meetings. A member raised the possibility of an interaction between leflunomide and piroxicam.

Causality was assessed as "possible" for leflunomide, methotrexate and pneumonitis, hypoxia, dyspnoea, cough and pulmonary infiltration.

Recommendation

The Committee recommended that the NZPhvC investigate a potential interaction between piroxicam and leflunomide. The Committee also recommended that a watching brief be maintained on leflunomide and pneumonitis.

4.1.7 Musculoskeletal medication-related reports

4.1.7.1 Alendronate and synovitis (61720)

Discussion

Members noted that as a result of funding changes, the use of alendronate is increasing.

Causality was assessed as "possible" for alendronate and synovitis.

4.1.7.2 Alendronate and synovitis, carpal tunnel syndrome, ankle oedema and arthralgia (62186)

Discussion

The Committee noted that there is clear dechallenge and rechallenge data on this case. It was noted that although this phenomenon had been documented previously, the mechanism was unclear.

Causality was assessed as "possible" for alendronate and synovitis and carpal tunnel syndrome, and "certain" for ankle oedema and arthralgia.

Recommendation

The Committee recommended that Medsafe review the literature to see if there is sufficient data to support publishing a Prescriber Update article on the pro-inflammatory adverse effects associated with alendronate use.

4.1.7.3 Ibuprofen and oedema generalised, hyponatraemia, rash, pruritus (61493)

Discussion

Members noted that the patient had inadvertently consumed double doses of ibuprofen. It was felt that this highlighted the need for doctors to inform their patients not to take OTC NSAIDs when prescribed a prescription NSAID.

Causality was assessed as "probable" for ibuprofen and oedema, hyponatraemia, rash and pruritis.

Recommendation

The Committee recommended that a watching brief be maintained for errors associated with the use of OTC medicines.

4.1.7.4 Ibuprofen (Panafen), warfarin and drug interaction, GI haemorrhage, medication error (62200)

Discussion

Members agreed that the brand name of the ibuprofen was confusing for patients.

Causality was assessed as "probable" for ibuprofen/warfarin interaction and GI haemorrhage, medication error, drug interaction.

Recommendation

The Committee recommended that a watching brief be maintained on the Panafen brand name confusion.

4.1.8 Vaccine-related reports

4.1.8.1 MMR and irritability, fever, rash, arthritis (61286) (61286)

Discussion

Members considered that there was inadequate information to determine if the child had a septic or non-septic arthritis. The Committee felt that further information should be obtained before a causality assessment could be made with respect to the arthritis.

Causality was assessed as "probable" for MMR and irritability, fever and rash.

Recommendation

The Committee recommended that the NZPhvC obtain further information on the nature of the child's arthritis. The Committee also recommended that a watching brief be maintained on this issue.

4.1.9 IMMP medicine related reports

4.1.9.1 Rofecoxib and renal failure acute, hyperkalaemia (62318)

Discussion

Members were concerned that the patient had not had any pre-operative blood tests done, and hence her pre-operative renal function and electrolyte status is unknown.

It was noted that the patient might have had pre-existing renal impairment in view of her underlying amyloid disease. The patient was taking multiple diuretics including frusemide that may have caused dehydration (particularly likely in the post-op period) and have precipitated renal failure. The patient was taking potassium supplements as well as spirinolactone and amizide, which in combination with renal failure may have precipitated life-threatening hyperkalaemia and cardiac arrest. Members noted that the patient had received four doses of rofecoxib post-operatively, which has been known to cause renal failure in situations where maintenance of glomerular pressure is dependent on renal prostaglandins. However, members considered it unlikely that rofecoxib could be solely implicated in the development of ARF, hyperkalaemia and death in this patient.

The causality assessment was deemed "possible" for rofecoxib and acute renal failure and hyperkalaemia. No further action was recommended.

4.1.9.2 Rofecoxib and renal function abnormal, GI haemorrhage (62320) (62320)

Discussion

The Committee commented that it was generally inappropriate to use any NSAID, including a COX-2 inhibitor, in a man of 80 in the peri-operative setting.

Causality was assessed as "probable" for aspirin and rofecoxib, and renal function abnormal and GI haemorrhage.

Recommendation

The Committee recommended that the NZPhvC review any other reports of renal failure with COX-2 inhibitors in the post-operative setting.

4.2 CARM Quarterly report (as at 31 March 2004)

4.2.1 Multiple occurrence reaction reporting

≥ Three Reports in the Last Quarter

4.2.1.1 Brand-switch related reports

• Felodipine: 12 reports in total
• Morphine (M-Eslon): 3 reports in total
• Allopurinol: 4 reports in total; 2 of reduced effect, 1 of a dry throat with coughing and 1 with hypersensitivity.

4.2.1.2 Other medicine-related reports

• Leflunomide and methotrexate: 3 reports of pneumonitis and 3 reports of pulmonary infiltration.
• Simvastatin: 19 reports of myalgia, 6 reports of headache, 5 of arthralgia, 4 of paraesthesias and 3 of hepatic enzyme abnormalities
• Botulinum toxin: 3 reports of dysphagia in children with cerebral palsy.
• X-ray contrast media: a background level of hypersensitivity reactions.

4.2.1.3 Vaccine-related reports

• Meningococcal vaccine: The MeNZ-B vaccine was introduced into New Zealand on 19 July 2004. Most reports have been of injection site reactions and systemic reactions such as fever and vomiting. There were 4 reports of vaso-vagal reactions arising from school-based campaigns.
• Otherwise the pattern of Adverse Events Following Immunisation is unremarkable.

≥ Six Reports in the Year-to-Date

• Patterns of reporting are in-line with that for the previous quarter.

Adverse Reactions of Current Concern

• All reports with a Reaction of Current Concern received in the last quarter were tabled for discussion in the MARC agenda.

4.3 Adverse reactions to blood components 2003

Issue

The Committee was provided with a report from the New Zealand Blood Service on adverse reactions to blood and blood products in 2003.

Discussion

The Committee noted that there were four reports of acute transfusion reactions and one report each of a delayed transfusion reaction and possible bacterial contamination.

Recommendation

The Committee recommended that Medsafe write to the New Zealand Blood Service on the MARC's behalf to thank them for their report.

5 pharmacovigilance ISSUES FOR INFORMATION ONLY

The Committee did not discuss this material. It includes 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.

5.1 COX-2 Inhibitors

References

• Topol E (2004). Perspective: Failing the Public Health - Rofecoxib, Merck, and the FDA. New England Journal of Medicine 351(17): 1707-1709.
• FitzGerald G (2004). Coxibs and Cardiovascular Disease. New England Journal of Medicine 351(17): 1709-1711.
• Horton R (2004). Vioxx, the implosion of Merck, and aftershocks at the FDA. Lancet. Published online November 5 2004.
• Sibbald B (2004). Drug Regulation. Rofecoxib (Vioxx) voluntarily withdrawn from the market. CMAJ 171(9): 1027-1028.
• Dieppe P (2004). Lessons from the withdrawal of rofecoxib. Patients would be safer if drug companies disclosed adverse events before licensing. BMJ 329: 867-868.
• Langton P et al (2004). Editorial: Cardiovascular safety of rofecoxib (Vioxx): lessons learned and unanswered questions. MJA 181(10): 524-525.
• Topol E, Falk G (2004). A coxib a day won't keep the doctor away. Lancet 364: 639-640.
• Lenzer J (2004). News: FDA is incapable of protecting "against another Vioxx". BMJ online accessed 26 November 2004.
• Lenzer J (2004). News: Public interest group accuses FDA of trying to discredit whistleblower. BMJ online accessed 26 November 2004.

5.2 Post-marketing surveillance

References

• Fontanarosa P (2004). Postmarketing Surveillance - Lack of Vigilance, Lack of Trust. (Editorial). JAMA 292(21): 2647-2650.

5.3 Intravenous corticosteroids

References

• CRASH trial collaborators (2004). Effect of corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet 364: 1321-1328.

5.4 Antipsychotic therapy

References

• Lambert T and Chapman, L (2004). Diabetes, psychotic disorders and antipsychotic therapy: a consensus statement. MJA 181 (10): 544-548

5.5 St John's Wort

References

• Tzhou, S et al (2004). Pharmacokinetic interactions of drugs with St John's Wort. Journal of Psychopharmacology 18 (2): 262-276

5.6 HMG-CoA reductase inhibitors

References

• Chang J et al (2004). Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiology and Drug Safety 13:417-426
• Lilja, J et al (2004). Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. British Journal of Clinical Pharmacology 58(1): 56-60.
• Graham D et al (2004). Incidence of Hospitalised Rhabdomyolysis in Patients Treated With Lipid-Lowering Drugs. JAMA 292(21): 2585-2590.
• Psaty B et al (2004). Potential for Conflict of Interest in the Evaluation of Suspected Adverse Drug Reactions: Use of Cerivastatin and Risk of Rhabdomyolysis. JAMA 292(21): 2622-2631.
• Piorkowski J (2004). Bayer's Response to "Potential for Conflict of Interest in the Evaluation of Suspected Adverse Drug Reactions: Use of Cerivastatin and Risk of Rhabdomyolysis". JAMA 292(21): 2655-2657.
• Psaty B et al (2004). Authors' Reply to Bayer's Response to "Potential for Conflict of Interest in the Evaluation of Suspected Adverse Drug Reactions: Use of Cerivastatin and Risk of Rhabdomyolysis". JAMA 292 (21): 2658-2659.
• Strom B (2004). Potential for Conflict of Interest in the Evaluation of Suspected Adverse Drug Reactions: A Counterpoint. JAMA 292(21): 2643-2646

5.7 Erythromycin

References

• Ray W et al (2004). Oral erythromycin and the Risk of Sudden Death from Cardiac Causes. New England Journal of Medicine 351(11): 1089-1096

5.8 IMMP

References

• Coulter D (2004). Focused Surveillance. Presentation to WHO National Centres meeting in Dublin.

5.9 CARM case reports

• Listerine pocket packs (61243)
• Lifestream Bioactive Ginger capsules (61304)
• Mela-Cal (61724)
• Femulen (61776)
• Thermotrim (61810)
• Blackmores Chondrosamine (61870)
• Simvastatin, cyclosporine (61248)
• Methotrexate, leflunomide (62184)
• Methotrexate, leflunomide (62185)
• Influenza vaccine (61393)

6. New Zealand activities

6.1

Clark, D and Harrison-Woolrych M (2004). Sibutramine may be associated with memory impairment. Drug Points

7. international activities

7.1 WHO

WHO Pharmaceuticals Newsletter No 5 2004

MUR 27: Uppsala Reports October 2004

7.2 Canada

Canadian Adverse Reaction Newsletter 14(4), October 2004

7.3 Australia

Australian Adverse Drug Reactions Bulletin 23 (5), October 2004
Australian Prescriber 27 (4), August 2004
Minutes of the July 2004 meeting of the Adverse Drug Reactions Advisory Committee
Minutes of the September 2004 meeting of the Adverse Drug Reactions Advisory Committee

7.4 United Kingdom

Current Problems in Pharmacovigilance. Volume 30, October 2004

8 summary of case reports considered by marc (1997 to 2004)

CARM case reports considered by the MARC
Vaccine adverse reaction reports considered by the MARC
Complementary and alternative medicine case reports considered by the MARC

The meeting ended at 4:00pm