Revised: 21 May 2013

Committees

Minutes of the 118th Medicines Adverse Reactions Committee Meeting - 22 June 2004

At the De Havilland 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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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.J.B. Maling (Chair)
Professor P. Ellis
Dr H. Kingston
Dr M. Tatley
Dr F. McClure
Dr J. Moy
Dr M. Rademaker

MARC secretariat present

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

invited experts

Dr S Martindale (Medsafe) - attended the afternoon session only
Dr R. Savage (New Zealand Pharmacovigilance Centre)
Dr M. Harrison-Woolrych (New Zealand Pharmacovigilance Centre)

1. MATTERS OF ADMINISTRATION

1.1 Welcome and apologies

The Chair welcomed Drs Ruth Savage and Mira Harrison-Woolrych from the New Zealand Pharmacovigilance Centre (NZPhvC). Dr Susan Martindale from Medsafe was welcomed to the afternoon session.

Apologies had been received from Professor David Skegg.

1.2 Minutes of the 117^th meeting

Members agreed that the minutes of the 117^th meeting are a true and accurate record of the meeting.

1.2.1 Report to the Minister's delegate

Members noted that the final page of the report to the Minister's delegate contained a typographical error. The statement "Approve and sign-off MARC recommendations 2.1 and 2.16" should read "Approve and sign-off MARC recommendations 2.1 to 2.16".

Recommendation

The Committee recommended that Medsafe rectify this error and represent the report to the Minister's delegate for sign-off.

1.2.2 Medicines Adverse Reaction Committee (MARC) Information for Members

Members expressed their concern over the expertise required for membership of the MARC particularly with regards to "phytotherapy". The Committee discussed this issue and agreed that at present, if "general medicine" were changed to "clinical medicine", the list would be acceptable. It was noted that the terms of reference would need to be rewritten for the joint trans-Tasman adverse reactions committee and thus further discussions could be undertaken at this time.

Recommendation

The Committee recommended that Medsafe replace "general medicine" with "clinical medicine" in this document.

1.3 Dates of 2004 MARC meetings

The Committee noted that the remaining 2004 MARC meetings are to be held on Thursday 23 September, and Wednesday 15 December.

1.4 Conflicts of interest

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

1.5 Prescriber Update

1.5.1 Scheduled Articles

Article

Amiodarone reminder

Issue

At the March 2003 MARC meeting the Committee recommended that an article be written for Prescriber Update that reminded prescribers of the ADR's associated with amiodarone and the need to routinely monitor eye and lung function.

Discussion

Members commented that increasingly, lower doses of amiodarone are being used in hospitals so the incidence of serious side effects is decreasing. However, the Committee felt that it would still be useful to proceed with the article in Prescriber Update.

Recommendation

The Committee recommended that the Prescriber Update article include reference to the pharmacokinetics of amiodarone and in particular its long half-life.

1.5.2 Prescriber Update - May 2004 Issue

Issue

The Committee expressed concern that reference to the IMMP had been removed from the last page of the May issue of Prescriber Update.

Discussion

Medsafe informed the Committee that at the time of going to print there were uncertainties surrounding the IMMP and which medicines would remain on the programme. This followed on, in part, from a review of the IMMP medicines by Medsafe and the IMMP Panel. It was therefore felt that the most appropriate course of action was to remove reference to the IMMP from the May issue of Prescriber Update. Members expressed the opinion that Medsafe had acted prematurely on this issue. Comment was also made that in removing references to the IMMP on the last page of Prescriber Update, the sentence "Please report all suspected reactions to new medicines and all events for IMMP medicines", has been removed. This has important implications for CARM as well as the IMMP, as reporting all reactions to new medicines is of fundamental importance to spontaneous monitoring. Medsafe noted the Committee's concerns and agreed to work with the NZPhvC to resolve this issue.

Recommendation

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

2. MATTERS ARISING

2.1Report on actions arising from the 117^th MARC meeting

2.1.1 Minute item 1.5 Prescriber Update article: Acne, isotretinoin and depression

Issue

Medsafe is seeking permission from the UK Drug and Therapeutics Bulletin (DTB) to reprint their article on acne, isotretinoin, and depression published in October 2003.

Discussion

Members noted the above and agreed that no further action is necessary at this time.

2.1.2 Minute item 2.1.1 (December 2002 minute item 4.1) High dose fluticasone and adrenal insufficiency

Issue

The Committee recommended that a general article about asthma therapy should be written for publication in Prescriber Update. The article should make reference to the New Zealand Guidelines Group Guidelines for the Diagnosis and Treatment of Adult Asthma, and provide dosage advice about starting low and titrating up as necessary. In addition, the article should note the difference in potency between fluticasone and other inhaled corticosteroids.

Outcome

An article for Prescriber Update is in the process of being written.

Discussion

Members noted the above and agreed that no further action is necessary at this time.

2.1.3 Minute item 2.1.5 (December minute item 4.3.1.1) Brand-switch related reports

Issue

The Committee recommended that the CARM citalopram brand-switch report, together with the MARC's concern regarding the need for criteria to determine the clinical significance of brand-switch issues, be brought to the attention of PHARMAC and the Generics Sub-Committee of the Medicines Assessment Advisory Committee (MAAC).

Outcome

Letters were sent to PHARMAC and the Generics Sub-Committee of the Medicines Assessment Advisory Committee advising of MARC's concerns at the lack of standardised criteria available to determine the clinical significance of brand-switch reactions. It was suggested that in view of the increasing use of generic medicines, the development of such criteria would be extremely important. It was recommended that PHARMAC, Medsafe, MARC, and the Generics Sub-Committee each elect a representative to attend a meeting to discuss the development of appropriate criteria.

PHARMAC responded to Medsafe and indicated their willingness to participate in such a meeting. The Generics Sub-Committee of MAAC is yet to respond.

Discussion

The Committee noted the above and agreed that this was still an important issue for the MARC. Members noted that the NZPhvC has produced a report on a possible collaboration between NZPhvC and PHARMAC to study this issue.

Members nominated Michael Tatley as MARC's representative for discussions on this issue.

Recommendation

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 MARC's representative for this meeting.

2.1.4 Minute item 2.1.8 (December minute item 4.1.1.5) Enoxaparin and haemorrhage (57708)

Issue

The Committee recommended that expert advice about the use of enoxaparin in the elderly be sought from a haematologist.

In addition, members recommended that the issue be discussed with the DHBNZ (District Health Board New Zealand) Safe Use of Medicines group to ensure that any potential MARC advice concurs with the recently developed 'tool-kit' for dosage adjustment of medicines in patients with renal impairment.

Outcome

A haematologist and a general physician and member of the Safe Use of Medicines group, were consulted on this issue.

The haematologist did not think that enoxaparin was more risky in the elderly as long as guidelines with respect to renal function and weight were adhered to.

The general physician stated that she is aware of some serious adverse effects with enoxaparin use, but the Safe Use of Medicines group has not produced a protocol for enoxaparin use at this time. It was indicated that the Safe Use of Medicines group would be interested in any advice the MARC might provide.

Discussion

The Committee reiterated the importance of this issue for New Zealand prescribers and stated that he felt that this issue is still not being dealt with well in clinical practice. The Committee was informed that the haematologist had provided references to a review of studies of non-fractionated and low molecular weight heparin in patients with acute coronary syndromes. This review identified age and weight as risk factors for adverse events related to enoxaparin use.

The Committee discussed the role of the DHBNZ Safe Use of Medicines Group and indicated that this group may provide the most appropriate forum for the development of a "tool kit' for enoxaparin use.

Recommendation

The Committee recommended that Medsafe write to the Safe Use of Medicines Group to suggest that they consider developing a protocol for enoxaparin use.

2.1.5 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

The Committee reviewed an analysis of five CARM case reports, from Sept 2002 to Sept 2003, relating to rhabdomyolysis with simvastatin. MARC recommended that simvastatin product sponsors be asked to amend their New Zealand datasheets to state that, "Treatment with simvastatin in a patient taking diltiazem should be started at the lowest possible dose and titrated upwards. For patients already taking simvastatin, the dose should be considerably reduced if calcium channel blockers are prescribed". The Committee also requested that a Prescriber Update article be written on this issue.

Outcome

Merck Sharp & Dohme (MSD) replied to Medsafe on 2^nd April 2004.

MSD stated that they had elected not to update the simvastatin data sheet as requested by the MARC. MSD defend this action by stating that:

"Patients treated with simvastatin 80mg concurrently with diltiazem have a small increase in rate of myopathy/rhabdomyolysis (approximately 1%)…(There have not been)… any reports of myopathy among patients treated with simvastatin 40mg and concomitant diltiazem in clinical trials".

MSD have also supplied a clinical expert report based on the SEARCH trial. This is an ongoing clinical trial of 12 064 patients randomised to simvastatin 80mg or 20mg. The author states that a review of SEARCH data in 2002 identified 32 cases of myopathy. Of those 32 cases, 31 were taking simvastatin 80mg. Eight of the 31 patients were taking diltiazem. The one patient taking simvastatin 20mg who developed myopathy was not taking diltiazem.

In the May 2004 Prescriber Update article, CARM states that they have received eight reports of rhabdomyolysis (two fatal) in patients taking a statin - six were taking simvastatin. Four of those patients were also taking diltiazem. Both fatalities occurred in patients whose dose of simvastatin had recently been increased, one to 40mg and the other to 60mg daily. Ten cases of myopathy have also been reported to CARM up to December 2003.

Discussion

The Committee reviewed the information provided by MSD but did not accept the sponsor's decision not to update the simvastatin data sheet. Members felt that the interaction between simvastatin and diltiazem has been clearly defined and is well recognised. Statin levels have been shown to increase by a factor of 5 when used concurrently with diltiazem. Members reiterated that rhabdomyolysis can occur at the 40mg dose in the elderly, and that the risk of rhabdomyolysis with the 40mg dose used concurrently with diltiazem, is the same as the risk of the 80mg dose used alone.

Members discussed the following excerpt from a report provided by Drug Information in Christchurch in response to a Medsafe query on this issue:

"In cardiovascular disease the combination of verapamil or diltiazem with simvastatin or atorvastatin is often unavoidable. We suggest that the addition of verapamil or diltiazem should be monitored in the same way as would occur with statin dose increases. Particular care is required when adding verapamil or diltiazem to high statin doses with concurrent drugs known to cause increased risk of muscle toxicity and in patients with multi-system disease. As statins cause a dose dependent reduction in serum cholesterol concentration, for patients at high risk, consider a reduction in statin dose and retitrate against serum cholesterol concentrations".

Members agreed that consideration should be given to including this statement in the simvastatin data sheet.

Recommendations

The Committee recommended that Medsafe review the Christchurch Drug Information response for possible inclusion in the simvastatin data sheet. The Committee also recommended that Medsafe review the data sheets for diltiazem and verapamil with regards to potential interactions with statins.

Members recommended that after reviewing the above information, Medsafe write back to MSD to inform them that the MARC disagrees with MSD's decision not to incorporate the MARCs recommendations into the simvastatin data sheet. Medsafe should decide whether to make a further request that the original statement be included in the data sheet or whether to require incorporation of statements from the Christchurch Drug Information response.

2.1.6 Minute item 3.1 SSRIs in child and adolescent Major Depressive Disorder

Issue

The Committee recommended that Medsafe issue a Dear Health Professional letter containing MARC advice about the use of SSRI antidepressants in children and adolescents with depression. The letter should emphasise the need to seek specialist advice before prescribing any antidepressant to children under the age of 18 years, and to monitor all patients with depression for the emergence or worsening of suicidal thoughts and behaviours.

Outcome

A Dear Health Professional letter regarding the above was issued on 22 March 2004. A copy of this is available in the 'for your information' section of the dossier.

Discussion

Members noted the above and agreed that no further action is necessary at this time.

2.1.7 Minute item 4.1.1.1 Risperidone and hypertension worse, stroke, osteoarthritis (57383)

Issue

The Committee recommended that a watching brief should be placed on risperidone and CVA. In addition, Medsafe should review the recent CSM advice on atypical antipsychotic medicines and stroke, and seek further information from the product sponsor, as is deemed necessary.

Outcome

The CSM advice on atypical antipsychotics drugs and stroke (9 March 2004) has been included in this agenda as 'for your interest' material. Medsafe is reviewing the latest Periodic Safety Update Report (PSUR) data from Janssen-Cilag.

Discussion

Members noted the above and suggested that this item be placed on the agenda for discussion at the September MARC meeting.

Recommendation

The Committee recommended that Medsafe review the PSUR on risperidone and report back to the committee at the next MARC meeting.

2.1.8 Minute item 4.1.8.1 Leflunomide and fever, bullous eruption, diarrhoea, MI, PE, UTI, hypothyroidism (58289)

Issue

The Committee recommended that all adverse reactions to leflunomide should be made Adverse Reactions of Current Concern.

The Committee also recommended that Medsafe obtain the most recent Periodic Safety Update Report for leflunomide, along with any relevant communications between Aventis Pharma Head Office and the European Agency for the Evaluation of Medicinal Products (EMEA) regarding leflunomide and interstitial pneumonitis. The Committee requested that Medsafe report back any significant findings at the June 2004 MARC meeting.

Outcome

The Bridging Periodic Safety Update Report (PSUR) for leflunomide has been received. Review of this document covering 1999 to 2004 pertaining to interstitial pneumonitis indicates:

• Interstitial pneumonitis was first reviewed by Aventis in PSUR #4 (March 2000 to Sept 2000). The first mention of Interstitial pneumonitis in the Company Core Data Sheet (CCDS) was after an amendment to the 'adverse reactions' section in June 2002, stating: "very rare: interstitial lung disease. Due to underlying disease and concomitant therapy, a causal relationship could not be established". Aventis indicate that they have received a total of 40 reports of pneumonitis, worldwide, up to March 2004.
• Twenty-nine cases of interstitial pneumonitis were reported in Japan between Sept 2003 and Feb 2004 in patients taking leflunomide; amongst these were 11 fatalities. Aventis classified the association of leflunomide in these deaths as 'possible' (7 case) and 'unlikely/unclassifiable' (4 cases). None of the deaths was considered to have a 'probable' association. However, this has prompted the company to strengthen Japanese datasheets.
• In March 2004, Aventis agreed to Europe's EMEA/CPMP Pharmacovigilance Working Party request that Aventis add a WARNING statement stating: "Interstitial pneumonitis has been reported during treatment with leflunomide. Leflunomide-induced interstitial pneumonitis is a potentially fatal disorder, which may occur acutely during therapy. Pulmonary symptoms, such as cough and dyspnoea, may be a reason for discontinuation of the therapy and a thorough investigation." In addition, it was requested that the datasheet state that frequency of interstitial lung disease is 'rare' (previously 'very rare').
• The latest leflunomide core company data sheet (CCDS) has reference to interstitial lung disease under PRECAUTIONS: "Respiratory: Interstitial lung disease has been reported rarely during treatment with leflunomide (see Section 12). Interstitial lung disease is a potentially fatal disorder, which may occur acutely during therapy. Pulmonary symptoms, such as cough and dyspnoea may be a reason for discontinuation of the therapy and for further investigation as appropriate." and the ADVERSE REACTIONS section: "Rare: Interstitial lung disease (including Interstitial pneumonitis), which may be fatal."
• Aventis has recently submitted to Medsafe an updated leflunomide data sheet that contains similar statements to those in the CCDS re: interstitial pneumonitis.

Discussion

Members noted the changes made to the leflunomide data sheet and agreed that these changes were acceptable.

Members expressed their concern at the increasing number and variety of adverse reactions being reported with leflunomide use. Members felt that it would be useful for the Committee to examine all these issues together instead of individually as they occur. Members asked that the issue of adverse reactions associated with leflunomide use be placed on the agenda for discussion at the next MARC meeting.

Recommendations

The Committee recommended that Medsafe review the latest PSUR for leflunomide.

The Committee also recommended that the NZPhvC prepare a report on all adverse reactions occurring with leflunomide use for discussion at the next MARC meeting.

The Committee also requested that Medsafe determine whether any other regulatory authorities are reviewing the safety of leflunomide.

2.1.9 Minute item 4.2.1 Severe application site reactions with pimecrolimus (Elidel)

Issue

The Committee recommended that the New Zealand sponsor for Elidel should be informed of CARM case reports regarding severe application site reactions with this product. The sponsor should be asked to amend the Elidel data sheet to reflect the potential for severe local reactions.

The Committee also recommended that prescribers be informed about the possibility of severe application site reactions with pimecrolimus by way of an article in Prescriber Update.

Outcome

The above request was made to Novartis in April 2004. The NZPhvC was also informed of the request to facilitate Novartis' access to details of the New Zealand case reports. Medsafe is awaiting a response from Novartis before proceeding with an article for Prescriber Update.

Discussion

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

2.2 Report on actions outstanding

2.2.1 September 2001 minute item 12.1 Progesterone-only contraceptive pills (POP) and current venous thromboembolism (VTE).

Issue

At the September 2001 MARC meeting, the Committee reviewed literature and WHO (World Health Organisation) guidelines about the use of POPs in VTE. The Committee recommended that the following wording be adopted for data sheets:

Contraindications: Current thromboembolic process.

Warnings and precautions: …Progestogen-only contraceptive pills may be considered as an option for contraception in women who have experienced DVT or PE with a combined oral contraceptive, provided the thromboembolic process has resolved. In most cases a progestogen-only contraceptive pill need not be discontinued for major surgery whether it does or does not involve immobilisation.

Outcome

A MARC-requested article "POPs: an option post-VTE" was published in the Prescriber Update July 2002 edition. Medicine datasheets for all POP products have since been updated to reflect the recommendations of the MARC.

Issue

The Clinical Services Group of the Family Planning Association (FPA) wrote to Medsafe about the issue of POPs in current VTE in early 2004. In the Prescriber Update article, they noted the difference between advice given by the WHO guidelines and the Medicines Adverse Reactions Committee (MARC). The FPA debate this point, highlighting the issue that a patient with current VTE should be anti-coagulated, thus acting as prophylaxis against further VTE and presenting a very low risk of further events; therefore, taking a POP should be entirely reasonable in those circumstances. The FPA request that the MARC reconsider their advice that POP's are an absolute contraindication in the presence of a current thromboembolic process, in favour of the WHO's recommendation.

Discussion

Members noted the concerns expressed by the Family Planning Association. The Committee agreed that the WHO recommendations are appropriate and should be adopted by the MARC ie "the use of a POP is not recommended in the presence of current venous thrombo-embolism (VTE) unless other contraceptive methods are not available or are unacceptable".

Recommendation

The Committee recommended that Medsafe write to the Family Planning Association to inform them that the MARC has updated its advice to be in line with the WHO. The Committee also recommended that Medsafe write to the product sponsors of POP's in New Zealand to inform them of the change to the MARC recommendations.

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 product sponsors for clozapine and risperidone be asked to include data sheet statements to say that there are post-marketing reports of a possible association between their product and lipid abnormalities. In addition, 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.

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.

Novartis has forwarded Medsafe a copy of proposed changes to the New Zealand Clozaril data sheet. Hypercholesterolaemia and hypertriglyceridaemia are included as very rare adverse effects. Janssen (Risperdal), Eli Lilly (Zyprexa) and Astra Zeneca (Seroquel) have referred the matter to Head Office.

An article on this issue is in the process of being written for Prescriber Update.

Discussion

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

2.2.3 December 2003 minute item 4.3 Grand Rounds

Issue

The Committee recommended that Medsafe explore options for displaying MARC information or advice at weekly Grand Rounds.

Outcome

Medsafe is in the process of exploring options for displaying MARC advice at weekly Grand Rounds.

Discussion

The Committee noted the above and agreed that this issue did not need to be pursued urgently.

2.2.4 December 2003 minute item 6.1 PHARMAC reference pricing of isotretinoin

Issue

The Committee recommended that Medsafe draft a letter to PHARMAC for the MARC Chair's comment and signature. The letter should seek to ensure there is an adequate isotretinoin education strategy in place for prescribers.

Outcome

Medsafe is in the process of writing a letter to PHARMAC on behalf of the MARC Chair.

Discussion

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

2.2.5 September 2003 minute item 4.4.2 Nocturnal enuresis associated with clozapine.

Issue

The Committee recommended that Medsafe write to product sponsors of clozapine, requesting that nocturnal enuresis be included as an adverse effect in the New Zealand clozapine data sheets.

Outcome

The aforementioned request was made in a letter to clozapine product sponsors in January 2004.

Douglas Pharmaceuticals has responded to say that Clopine is not currently marketed in NZ, however, the requested data sheet change 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.

Novartis has forwarded to Medsafe a copy of proposed changes to the Clozaril data sheet that includes nocturnal enuresis under very rare adverse effects.

Discussion

The Committee noted the above and agreed that no further action is necessary on this issue.

2.2.6 September 2003 minute item 4.4.2 IMMP analysis of adverse events reported for clozapine

Issue

At the September 2003 MARC meeting, the Committee discussed an IMMP analysis of adverse events reported for clozapine. It was noted that some of the adverse events reported more than once to the IMMP are listed in the American clozapine product information, but are not included in the New Zealand data sheet.

Outcome

The Committee recommended that Medsafe write to product sponsors of clozapine, requesting that the following adverse events associated with clozapine, which are present in the American product information, should be included in the New Zealand data sheet: abdominal discomfort, heartburn; dyspnoea, pneumonia, weight loss and increased ESR.

Issue

The aforementioned request was made in a letter to clozapine product sponsors in January 2004.

Douglas Pharmaceuticals has responded to say that Clopine is not currently marketed in NZ, 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.

Novartis has forwarded to Medsafe a copy of proposed changes to the Clozaril data sheet. Abdominal discomfort and heartburn have been included under adverse events. Novartis informed Medsafe that after analysis of their own data it was decided that dyspnoea, pneumonia, weight loss and increased ESR would not be included in the New Zealand data sheet. Novartis stated that there were significant confounding factors and/or lifestyle factors to explain the cases of weight loss, dyspnoea and increased ESR. With regards to pneumonia and aspiration pneumonia, Novartis stated that it is accepted that Clozaril could predispose patients to the development of aspiration pneumonia by way of its anticholinergic effects and excessive salivation. However Novartis did not indicate any plans to change the data sheet in line with this. Novartis stated that the majority of cases of pneumonia without aspiration in their database could be explained by confounding factors and thus Clozaril could not be causally linked with the development of pneumonia.

Discussion

The Committee noted the explanations given by Novartis. Members were prepared to accept Novartis' decision with respect to weight loss, dyspnoea and raised ESR.

Members disagreed with Novartis' decision not to include aspiration pneumonia or pneumonia in the list of adverse effects associated with Clozaril use. Members noted that the New Zealand data sheet includes aspiration of food as an adverse effect but does not include aspiration pneumonia. The IMMP presented members with further reports on deaths of patients taking clozapine and in 3 cases the cause of death was pneumonia - 1 was confirmed aspiration pneumonia. The Committee agreed that Medsafe should contact Novartis again to inform them of the MARC's repeat request that both aspiration pneumonia and pneumonia be included in the adverse events section of the Clozaril data sheet.

Recommendation

The Committee recommended Medsafe write to Novartis to request that both aspiration pneumonia and pneumonia be included in the Clozaril datasheet.

2.2.7 June 2003 minute item 3.1.4.1 Isotretinoin and dry skin/photosensitivity/flushing/vulval vaginitis/vulval discomfort (54986)

Issue

The Committee recommended that the sponsor companies for isotretinoin be asked to specify the possibility of vaginal and anal drying in the product data sheets.

Outcome

A letter requesting that the product data sheets for Roaccutane and Oratane be updated to include drying of the vagina and anus as adverse effects, was sent to Roche Products (NZ) Ltd and Douglas Pharmaceuticals Ltd, respectively.

Douglas Pharmaceuticals Ltd updated the Oratane data sheet as requested in November 2003. Roche has not yet responded to this request; however, it has informed Medsafe that, due to lack of PHARMAC funding, Roaccutane will be discontinued in New Zealand in the very near future. Pacific Pharmaceuticals updated their Isotane data sheet as requested in February 2004.

Discussion

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

2.2.8 June 2003 minute item 3.1.4.2 Itraconazole/budesonide/diltiazem and Cushing's syndrome/drug interaction (54458)

Issue

The Committee recommended that product sponsors for budesonide be asked to include the risk of Cushing's syndrome in the 'Interactions' section of budesonide data sheets.

Outcome

Astra Zeneca Ltd, Pacific Pharmaceuticals, and Douglas Pharmaceuticals were asked to add a statement about the risk of Cushing's syndrome, as a result of CYP3A4 inhibition, to the 'Interactions' section of their budesonide data sheets. In addition, Douglas and Pacific were asked to include the statement "The metabolism of budesonide is primarily mediated by CYP3A4, a subfamily of cytochrome P450. Inhibitors of this enzyme may therefore increase systemic exposure to budesonide."

Douglas and Pacific updated their data sheets as requested in December 2003 and September 2003, respectively. Astra Zeneca Ltd updated their data sheet as requested in April 2004.

Discussion

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

2.2.9 March 2003 minute item 3.1.2.1 Thyroguard and back pain/TSH decreased/fatigue (53598)

Issue

The Committee recommended that the above CARM case report be passed to the Compliance section of Medsafe for investigation and potential testing of Thyroguard.

Outcome

The Compliance section of Medsafe has advised us that they were unable to obtain a sample of Thyroguard in view of the Pan Pharmaceuticals product recalls. However, they will attempt to obtain a sample in the near future, as part of their general testing program.

Discussion

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

2.2.10 September 2002 minute item 3.3.1 COX-2 inhibitors

References

• Silverstein et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS Study, 2000. JAMA; 284:1247-1255.
• Juni P, Rujtes A, Dieppe P. Editorial: Are selective COX-2 inhibitors superior to traditional non-steroidal anti-inflammatory drugs? 2002. BMJ;324:1287-1288.
• Hrachovec J, Mora M. Letters: Reporting of 6-month vs 12-month data in a clinical trial of celecoxib. 2001. JAMA;286:2398-2399.
• Silverstein F, Simon L, Faich G. Letters: In Reply to Reporting of 6-month vs 12-month data in a clinical trial of celecoxib. 2001. JAMA;286:2399-2400.

Issue

In view of a BMJ editorial highlighting limitations of the CLASS study, members recommended that the sponsor company be asked to revise the Celebrex data sheet. The CLASS study claimed that celecoxib was associated with lower incidence rates of upper GI ulcer complications compared to NSAIDS (Ibuprofen or Diclofenac). However, a BMJ editorial pointed out inadequacies of the paper and stated that analysis according to pre-specified protocol indicated no difference in outcome with respect to ulcer-related complications.

The Committee recommended that Medsafe compose appropriate data sheet statements to be presented to the company. This was done on 4/11/03, with a subsequent reminder letter on the 24/02/04.

Outcome

A response letter from Pfizer Australia in March 2004 informed Medsafe that Pfizer is unwilling to remove the following sentence from the 'Special Studies' section of the Celebrex data sheet: "Upper gastrointestinal complications - The incidence of serious upper gastrointestinal complications (bleeding, perforation, gastric outlet obstruction) with CELEBREX is not significantly different from placebo and is approximately 8-fold less than with non-specific COX inhibitors."

Pfizer responded to criticisms raised by the BMJ editorial, and justified the decision to analyse data from the first 6 months only, as follows:

1. Differential loss of patients - a greater proportion of patients in the NSAID-arm were withdrawn from the study in the first 6 months because of development of symptomatic ulcers
2. Excessive withdrawal rates - the withdrawal rate was in excess of the expected 35% rate: 40% by 6 months and 60% by the end of the study. This resulted in an underpowered study.
3. Excessive concurrent aspirin use - when data were adjusted for aspirin use, the complicated ulcer rate was significantly lower in the Celebrex-arm vs the NSAID-arm.

Pfizer state that four large prospective studies (CLASS, SUCCESS, VIGOR, ADVANTAGE), two meta-analyses, and two observational studies indicate that the collected research with celecoxib shows that it "represents an important advance in the GI safety for patients". Pfizer consider the New Zealand datasheet statement about Upper GI complications to be accurate and correct.

Discussion

The Committee noted the information provided by Pfizer. Members were in strong disagreement with Pfizer's decision to retain the sentence highlighted above. The Committee felt that the statement that the risk of upper GI complications with celecoxib was "… approximately 8-fold less than with non-specific COX inhibitors" was not justified by any data presented by Pfizer.

The Committee was presented with information from a Canadian study published in the BMJ in September 2003¹ that found that there was no increased risk of upper GI bleeding complications with celecoxib versus placebo (RR 0.7 - 1.1). This study did not support Pfizer's statement of a "8-fold" reduction in risk. In fact there was only a 4-fold increase in risk of upper GI haemorrhage with standard NSAIDs compared with no NSAID use in this study, in keeping with several other studies.

1. Mamdani et al. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ, Sep 2002; 325:624.

Recommendations

The Committee recommended that Medsafe review the Canadian study referred to in the discussion.

The Committee recommended that Medsafe then write back to the Pfizer asking that the statement be removed and/or modified in line with findings from the Canadian study.

3. Pharmacovigilance issues

3.1 Tricyclic Antidepressants in Children and Adolescents for treating Major depressive Disorder

Discussion

This item was deferred until the September 2004 MARC meeting in order to create more time for the discussion on Pharmacovigilance in New Zealand. (See minute item 5).

3.2 Atypical Antipsychotics and Hyperglycaemia

Reference Material

• Medsafe report: Atypical Antipsychotics and Hyperglycaemia (Jonathan Moy, May 2004)
• Rosack, J (2003). FDA to require Diabetes Warning on Antipsychotics. Psychiatric News, 38 (20):1
• Rosack, J (2003). FDA's Proposed Diabetes Warning. Psychiatric News, 38 (20):26
• American Diabetes Association et al (2004). Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care, 27 (2), 596-601.

Issue

The MARC has considered the issue of atypical antipsychotics and hyperglycaemia on at least 2 previous occasions. In June 1999 a Prescriber Update article was published about hyperglycaemia associated with clozapine. At the December 2001 meeting, the MARC recommended that all product sponsors for the atypical antipsychotics be requested to update their data sheet to 'indicate that there is a causal relationship between diabetes mellitus ad hyperglycaemia and these medicines.' All product sponsors updated their datasheets as requested.

In September 2003, the FDA completed a review of all the available literature on this issue and felt that it justified requesting product sponsors to include the following class warning statements in all atypical antipsychotic product datasheets.

Hyperglycemia and Diabetes Mellitus

"Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including [insert drug name]. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics studied. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. The available data are insufficient to provide reliable estimates of differences in hyperglycemia-related adverse-event risk among the marketed atypical antipsychotics. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at baseline and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug".

Discussion

Members discussed the Medsafe report on this issue. The Committee noted that the atypical antipsychotics, although grouped together, are chemically distinct structures that act on different receptors and have different mechanisms of action. In view of this, it is possible that any effect on glucose metabolism may not be a class effect. The Committee noted that weight gain, which may play a significant part in any effect on glucose metabolism, varied significantly between the different atypical antipsychotics.

Members reviewed the consensus document table on the metabolic abnormalities associated with the atypical antipsychotics. It was felt that there was evidence of an increased risk for the development of diabetes with clozapine, olanzapine, risperidone and quetiapine but not for aripiprazole and ziprasidone. (It was noted that the latter two atypical antipsychotics are very new and are not currently available in New Zealand).

Recommendation

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.

3.3 HRT- PHARMAC proposal to restrict prescribing

Reference material

• Medsafe report on HRT- PHARMAC proposal to restrict prescribing.
• New Zealand Guidelines Group (March 2004). Hormone Replacement Therapy. Evidence Based Best Practice Guideline - Summary Update.
• New Zealand Guidelines Group (April 2004). Hormone Replacement Therapy or HRT. New Information for Women.

Issue

PHARMAC issued a letter on 1 June 2004 requesting submissions on a proposal to restrict the supply of HRT.

Medsafe produced a report for the MARC recommending that the MARC and Medsafe jointly lodge a submission to PHARMAC on this issue. It is Medsafe's view that despite the risks of HRT identified and quantified by recent studies, HRT remains the most effective treatment for the relief of menopausal symptoms that are disruptive to quality of life. Medsafe feels that the prescribing guidelines and consumer information recently produced by the New Zealand Guidelines Group (NZGG) provide prescribers and consumers with adequate, up-to-date information on the risks and benefits of treatment with HRT.

It is Medsafe's view that most women with menopausal symptoms are managed by their GPs and not hospital specialists. Therefore, a special authority arrangement would create an unnecessary barrier to access for this medication.

Discussion

The Committee discussed Medsafe's report on this issue and agreed that a joint submission by Medsafe and MARC would be desirable.

Members agreed with Medsafe's recommendations and commented that menopausal symptoms remain a significant problem for some women and HRT remains the most effective treatment for these symptoms. Members were informed that some women who had discontinued HRT previously were now requesting short courses again. It was reiterated that although menopause is not a disease, its symptoms can cause significant morbidity. Thus it is very important that PHARMAC not create a barrier to provision of an effective treatment for menopausal symptoms.

Recommendation

The Committee recommended that Medsafe draft a submission to PHARMAC and that the submission be peer reviewed by Frances McClure and Tim Maling.

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 Alternative medicine-related reports

4.1.1.1 Multivitamin and mineral supplement, calcium carbonate and hypercalcaemia, renal failure acute and nephrocalcinosis (59078)

Discussion

The Committee noted that the Healtheries multivitamin/mineral tablets each contain 10 micrograms (not 10mg) of Vitamin D. This is well below the recommended maximum tolerable dose of 250 micrograms per day in normal individuals. The Committee also noted that the patient's underlying medical condition was unknown although he was taking both prednisone and azathioprine. The causal association was deemed "possible" for hypercalcaemia, renal failure acute and nephrocalcinosis. No further action was recommended.

4.1.1.2 Methotrexate, fish oil and hepatic enzymes elevated (59699)

Discussion

The Committee noted that there was a reasonably convincing temporal relationship between the administration of Good Health fish oil and abnormal LFTs as the adverse events occurred on 3 separate occasions. The causal association was deemed "probable" for hepatic enzymes elevated.

Recommendation

The Committee recommended that a watching brief be placed on fish oil and hepatic enzymes elevated.

4.1.2 Antidepressants

4.1.2.1 Amitriptyline and suicide attempt, therapeutic response inadequate, overdose (59197)

Discussion

The Committee felt that a 45 mg dose of amitriptyline was inadequate to treat depression. Therefore the Committee felt that this patient's suicide was related to inadequate treatment of his depression. The Committee recommended that the term "therapeutic response decreased" should be changed to "therapeutic response inadequate" The causal association of amitriptyline with suicide attempt, therapeutic response decreased and overdose was deemed "unlikely". No further action was recommended.

4.1.2.2 Citalopram and therapeutic response decreased, suicide attempt, rash (59710)

Discussion

CARM has received 121 adverse reaction reports for citalopram in total including one report of inadequate therapeutic response and 3 of suicidal tendency.

The Committee felt that there was not enough information to determine causality for suicide attempt and therapeutic response inadequate. The causal association with rash was deemed "probable".

Recommendation

The Committee recommended that CARM obtain further information on this case.

4.1.2.3 Venlafaxine and serotonin syndrome (59599)

Discussion

This report was the first report received by CARM of serotonin syndrome with venlafaxine. The literature and WHO data have established the potential for this reaction but usually in association with other medications. The Committee discussed the likelihood of an interaction between venlafaxine and nortriptyline. The causal association between venlafaxine and Serotonin Syndrome was deemed "probable".

Recommendation

The Committee recommended that the venlafaxine data sheet be reviewed with respect to potential interactions with nortriptyline. The Committee also 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.

4.1.3 Anticonvulsant medication-related reports

4.1.3.1 Gabapentin and hearing decreased, cellulitis, suicide, hepatic function abnormal (58777)

Discussion

The CARM database contains 31 reports of adverse reactions to gabapentin including 2 of hepatic function abnormalities, 2 of rash and 1 of urticaria. There have been no reports in New Zealand of previous suicide attempts. The WHO database contains 75 reports of suicide attempts (13 fatal) out of a total of 4973 reports.

The Committee felt that many of the patient symptoms could be explained by his co-morbid conditions. The causal relationship was felt to be "possible" for hearing decreased and "unclassified" for cellulitis, suicide and hepatic function abnormal. No further action was recommended.

4.1.4 Antithrombotic medication-related reports

4.1.4.1 Enoxaparin, heparin fractionated and cerebral haemorrhage, death (59758)

Discussion

The Committee expressed the opinion that factor Xa assays are very unreliable and therefore adjusting enoxaparin doses as per factor Xa levels is not useful. Members commented that the reaction in this case was largely unavoidable. The causal relationship was deemed "probable" for cerebral haemorrhage and death. No further action was recommended.

4.1.5 Endocrine medication-related reports

4.1.5.1 Carbimazole and pancytopaenia, sepsis, cholelithiasis (59111)

Discussion

The causal association was deemed "possible" for pancytopaenia and sepsis and unlikely for cholelithiasis. No further action was recommended.

4.1.5.2 Rosiglitazone and hypercholesterolaemia, hypertriglyceridaemia, high density lipoprotein decreased (59426)

Discussion

CARM has received no previous reports of abnormal lipid profile with rosiglitazone. However the WHO database has 64 reports of hypertriglyceridaemia, and 14 of HDL decreased with rosiglitazone.

The causal association was deemed "possible" for hypercholesterolaemia, hypertriglyceridaemia and high-density lipoprotein decreased.

Recommendation

The Committee recommended that a watching brief be placed on rosiglitazone and lipid abnormalities.

4.1.6 Hormone-related medication reports

4.1.6.1 Leuprorelin and angina aggravated, confusion (59413)

Discussion

CARM has not received any previous reports of angina or confusion with leuprorelin. However, the product datasheet states that angina and cardiac arrhythmia have been observed in <5% of patients in clinical trials. The Committee noted that the patient did have significant co-morbidities that are likely to have contributed to his death.

The causal association was deemed "possible" for angina aggravated and confusion. No further action was recommended.

4.1.7 Musculoskeletal medication-related reports

4.1.7.1 Ibuprofen and necrotising fasciitis, renal function abnormal, varicella (59381)

Discussion

The Committee noted that the possible association between NSAIDs and the development of necrotising fasciitis has been reviewed via a case control study in 2003. This study did not show any increased risk of necrotising fasciitis in patients with varicella infection or in those taking ibuprofen. Ibuprofen and necrotising fasciitis had been an adverse reaction of current concern but no reports were received during that time.

The causal association was deemed "possible" for necrotising fasciitis and renal function abnormal and "unlikely" for varicella infection. No further action was recommended.

4.1.7.2 Leflunomide and pneumonia (59475)

Discussion

The Committee noted that this patient had co-morbid factors that may have predisposed her to the development of pneumonia. The causal association was deemed "possible" for pneumonia.

4.1.7.3 Leflunomide, amiodarone, glipizide, prednisone, triamcinolone and bronchitis, hepatic enzymes elevated, hypoglycaemia, clostridial infection, drug interaction (59189)

Discussion

CARM has not received any previous reports of hypoglycaemia occurring with either leflunomide or amiodarone. However it was noted that in vitro studies suggest that leflunomide inhibits CYP 2C9 of which glipizide is a substrate. The Committee felt that it was possible that the leflunomide may have impaired the metabolism of glipizide thus prolonging its hypoglycaemic effect.

The causal association was deemed "possible" for bronchitis, hepatic enzymes elevated, hypoglycaemia, clostridial infection and drug interaction.

Recommendations

The Committee recommended that a watching brief be placed on hypoglycaemia with leflunomide alone or in combination with oral hypoglycaemic agents.

If further and more definite reports of an interaction occur, the caution in the data sheet re the possibility of interaction with 2C9 substrates (such as glipizide), will need to be re-emphasised to prescribers.

4.1.7.4 Leflunomide, methotrexate and pneumonitis, pulmonary infiltration, respiratory failure (58836)

Discussion

The causal association was deemed "possible" for pneumonitis, pulmonary infiltration and respiratory failure.

4.1.7.5 Leflunomide, methotrexate and pancytopaenia, hepatic enzymes elevated, dehydration, renal failure chronic aggravated, pulmonary infiltration (59203)

Discussion

The Committee noted that the leflunomide datasheet includes the possibility of hepatic reactions and blood dyscrasias with leflunomide use but there is no mention of renal impairment. The committee was informed that although leflunomide is metabolised via hepatic and gut wall mechanisms, in dialysis patients the free-fraction of the main metabolite was doubled. Members agreed that the long half-life of leflunomide supports the possibility of leflunomide being responsible for the pulmonary symptoms, despite being stopped 8 days before. Members were informed that the NZPhvC has planned a publication on this issue.

The causal relationship was deemed "possible" for pancytopaenia, hepatic enzymes elevated, dehydration, renal failure chronic aggravated, and pulmonary infiltration.

Recommendation

The Committee recommended that a watching brief be placed on increased leflunomide toxicity with renal impairment.

4.1.7.6 Methotrexate, leflunomide and pneumonitis, respiratory failure, weight loss, dyspnoea and death. (59496)

Discussion

CARM has received 27 adverse reaction reports for leflunomide including two of pneumonitis and one of leflunomide pneumonia. In Australia, between Feb 2000 and Jan 2002, there were six reports of pneumonitis out of 12708 patients supplied. The Committee noted that the updated leflunomide product data sheet now includes the risk of pulmonary infiltration as occurring rarely (previously very rarely).

Members agreed that adverse reactions associated with leflunomide use appear to be increasing in both scope and severity. The Committee reiterated the need to look into this issue more closely and to place the issue of all adverse effects related to leflunomide use on the agenda for the next MARC meeting. At this time the committee will discuss options on how to proceed on this issue. The suggestion was made of a formal study into a possible synergistic effect between methotrexate and leflunomide in the development of pneumonitis.

The causal relationship was deemed "possible" for pneumonitis, respiratory failure, weight loss, dyspnoea and death.

Recommendation

The Committee recommended that a report on all adverse effects associated with leflunomide use be prepared by NZPhvC and be placed on the agenda for discussion at the next MARC meeting.

4.1.8 Vaccine related medication reports

4.1.8.1 ADT and neuritis, brachial plexus neuropathy (58815)

Discussion

CARM has received seven reports of neuritis/neuropathy with ADT vaccinations since 1994. The literature supports an incidence of 0.5 - 1 per 100 000 Tetanus vaccinations.

The causal relationship was deemed "possible" for neuritis and brachial plexus neuropathy. The Committee recommended that no further action be undertaken.

4.1.9 IMMP review of deaths associated with clozapine and risperidone

IMMP presentation

The committee was presented a summary paper on deaths that have occurred in patients taking clozapine or risperidone. In the IMMP database there are currently 6 reports of death associated with risperidone and 32 reports of death associated with clozapine. A brief review of WHO data and the published literature was also presented.

4.1.9.1 Clozapine and aspiration pneumonia, cardiomegaly (57787)

Report source
Pharmaceutical company and hospital pharmacist

Discussion

The Committee discussed the significance of a high acetone level and discussed the possibility of this being an indication of solvent abuse - a recognised cause of sudden death. The causal relationship was deemed "possible" for aspiration pneumonia and cardiomegaly.

4.1.9.2 Clozapine and gastric ulcer perforated, peritonitis (58517)

Report source
Pharmaceutical company

Discussion

The causal relationship was deemed "unlikely" for gastric ulcer perforated, peritonitis.

4.1.9.3 Clozapine and sudden cardiac death, cardiomegaly (58949)

Report source
Pharmaceutical company

Discussion

The Committee felt that further information including the full autopsy report was required on this case. The causal relationship was deemed "possible" for sudden cardiac death and cardiomegaly.

Recommendation

The committee requested that the NZPhvC obtain more information on this case, including the autopsy report, and report back to the MARC at a later date.

4.1.9.4 Clozapine and pneumonia, respiratory failure (59035)

Report source
General practitioner

Discussion

The causal relationship was deemed "possible" for pneumonia and respiratory failure.

4.1.9.5 Clozapine and cardiomyopathy and CHF (59036)

Report source
General practitioner

Discussion

The Committee agreed that this patient had many co-morbidities that may have contributed to the development of cardiomyopathy and CHF. The causal relationship was deemed "possible" for cardiomyopathy and CHF.

4.1.9.6 Clozapine and bronchopneumonia, diabetes (59299)

Report source
Pharmaceutical company

Discussion

The Committee agreed that further information was required on this case. The causal relationship was deemed "possible" for bronchopneumonia and diabetes.

Recommendation

The committee requested that the NZPhvC obtain more information on this case, and report back to the MARC at a later date.

4.1.9.7 Risperidone and sudden death (58586)

Report source
Pharmaceutical company and hospital doctor

Discussion

The Committee noted that the product data sheet for risperidone does not indicate that sudden deaths have occurred with risperidone use. Members agreed that there was not enough information to assess causality at this point. The causal relationship was deemed "possible" for sudden death.

Recommendation

The Committee recommended that the NZPhvC obtain further information on this case, including the coroner's report, and report back to the committee at a later date. The Committee recommended that Medsafe review the PSUR for risperidone with respect to risperidone and sudden death. The committee also recommended that a watching brief be placed on risperidone and sudden death.

4.2 Brand Switch Reports

4.2.1 Brand-switch reports for Morphine Sulphate

Issue

The NZPhvC presented a report on the brand-switch related reports received by CARM in response to the reference pricing of the MST, Kapanol and LA-Morph brands of long-acting morphine sulphate. The sole-supply of m-Eslon has been widely criticised for both lack of therapeutic effect and increased incidence of adverse effects. PHARMAC is now proposing to fully subsidise LA Morph from 1 July 2004.

CARM has received 27 reports of problems arising from the brand change to the m-Eslon brand of morphine sulphate. Seventeen reports were of therapeutic inefficacy. It was noted by CARM that most patients experienced a loss of therapeutic effect together with other adverse effects. The NZPhvC report stated that this could be due to a number of reasons including:

• Loss of choice -it has been suggested that there may be a psychological response to the brand switch that is somatised. There is no scientific data to confirm this.
• Withdrawal symptoms - it has been suggested that withdrawal could be associated with lack of therapeutic response.
• Higher peak concentrations and shorter half-life - there have been reports of shortened duration of effect. There have been other reports of an increased dose resulting in increased adverse effects in the first few hours and then termination of effectiveness prior to the usual 12 hour dose interval.

CARM reported two cases that illustrated these findings. The CARM report concluded that the m-Eslon reports differ from other brand-switch reports as a large group of patients experienced a decreased therapeutic response together with adverse effects. Dose increases were not always successful. This suggests that m-Eslon in some patients achieves high peak plasma level and has a shorter duration of action than MST. The majority of patients had changed from MST. The majority of reports were for patients with chronic pain rather than cancer. Many had been stable for long periods before being switched over.

Discussion

The Committee reviewed the report on this issue prepared by the NZPhvC. It was noted that Medsafe does not confer Interchangeable Multisource Medicine status to any controlled drug, irrespective of bioequivalence studies.

Members expressed their concern that PHARMAC had elected to fund only one brand in a class of medicines with significant inter-individual variability of effect. Members were able to provide anecdotal reports from their own patients of the extreme distress caused by this brand-switch. The Committee noted that it is well known that the inter-individual variability in effect is increased with the use of slow release formulations. Despite the clear evidence of bioequivalence, members reiterated that this did not confer automatic clinical equivalence - as the CARM reports indicate. Members felt that it was very important for the MARC to express its concerns directly to PHARMAC.

Recommendation

The Committee recommended that the Pharmacovigilance centre draft a letter to PHARMAC on behalf of the MARC, expressing the MARC's concern over this issue. This letter will be peer reviewed by Tim Maling before being forwarded onto PHARMAC.

4.2.2 Proposal to study the effects of Brand Changes using data from CARM and PHARMAC

Discussion

The Committee did not discuss this report. Members recommended that Dr Michael Tatley offer this proposal to PHARMAC when a meeting is arranged with Medsafe, MARC, PHARMAC and the generics sub-committee to discuss this issue further. (See minute item 2.1.2)

4.3 CARM Quarterly report (as at 31 March 2004)

4.3.1 Multiple occurrence reaction reporting

≥ Three Reports in the Last Quarter

4.3.1.1 Brand-switch related reports

• Morphine sulphate (switch from MST to m-Eslon): 24 reports of reduced therapeutic effect. See minute item 4.3.1 for further information on this issue.
• Felodipine (Reintroduction of Felo brand): 44 reports of adverse effects have been received. Only 5 reports of reduced therapeutic effect.
• Citalopram (switch from Cipramil to Celapram): 3 reports of reduced therapeutic effect have been received this quarter (a drop from 8 in the previous quarter).
• Codalgin (switch from panadeine): 4 reports of reduced therapeutic effect.
• Ranitidine (switch from Zantac to Apo-Ranitidine brand): 4 reports of reduced therapeutic effect.

4.3.1.2 Other medicine-related reports

• Three reports of coughing with candesarten have been received this quarter. There have been three reports of pulmonary reactions with methotrexate (see individual case reports). An unusual cluster of hypersensitivity reactions to diclofenac have been received this quarter; 5 of angioedema and 3 of anaphylaxis.
• There were no reports of application site reactions with pimecrolimus this quarter.
• Three or more reports have also been received for simvastatin, flucloxacillin, quinapril and terbinafine, which is not unexpected. A background level of X-ray contrast media hypersensitivity reactions is once again reflected.

4.3.1.3 Vaccine-related reports

• The pattern of adverse events following immunisation is largely unremarkable with typical expected events. Vaccines with three or more specific events are DT, MMR, DTaP/HiB, ADT, DTaP/IPV, HepB, HiB/HepB, and IPV.
• The first few reports of influenza virus vaccine reactions have been received and involve unremarkable and expected events.

≥ Six Reports in the Year-to-Date

• There are four new medicines in this section (morphine, dipyridamole and felodipine brand-switch reports, and amoxycillin/clavulanic acid reports of cholestatic hepatitis).
• The reports reflect reactions that are not unexpected, or those that are reported with low frequency.

Adverse Reactions of Current Concern

Case reports on reactions occurring with leflunomide were reported in section 4.1.

4.4 Intensive Medicines Monitoring Programme

4.4.1 Analysis of IMMP Events Reported for Sibutramine

Issue

IMMP monitoring of sibutramine began in April 2001. To the period ending April 1^st 2004, 256 adverse events (50 incidents and 206 reactions) in 142 reports have been received. The data presented have been obtained from duplicate prescriptions, spontaneous reports, and pharmaceutical company reports and follow-up on 1029 patients from the sibutramine cohort (cohort size is 13,750).

Discussion

The Committee noted that IMMP had identified 5 issues that they felt required further study: cardiac arrhythmias (see minute item 4.4.2), mania and stimulation, migraine, memory impairment and urinary events.

Members noted that further analysis of data would be required before causality could be established.

Recommendation

The Committee recommended that IMMP obtain further data on these issues and report back to MARC at a later date.

4.4.2 Sibutramine and Prolonged QTc

Issue

A case of prolonged QTc with sibutramine was identified from a duplicate prescription report.

The IMMP has received 2 other reports of palpitations with syncope or pre-syncope - neither case had ECG evidence of prolonged QTc interval. IMMP also has received 1 case report of circulatory collapse and 1 of SVT in patients taking sibutramine. The WHO UMC database contains 2 reports of prolonged QTc, 1 report of VF and 1 case of torsades de pointes in patients taking sibutramine.

Discussion

The Committee noted that there has not been any published literature on an association between sibutramine and prolonged QTc interval. Members noted that the licensing for sibutramine was suspended in Italy in the 1990's after two deaths occurred. The details of these cases are not known. The licence has since been reinstated.

The Committee felt that it would be useful for IMMP to obtain further information on this case including review of the initial ECG.

Recommendation

The Committee recommended that a watching brief be placed on sibutramine and prolonged QTc interval. The Committee recommended that IMMP report back to MARC after further analysis had been undertaken.

5 SPECIAL ITEM: Pharmacovigilance in New Zealand

References

The following documents were presented to the Committee to aid discussion:

• Pharmacovigilance in a Trans-Tasman Therapeutic Products Agency - 1 June 2004
• Proposals to Medsafe for Pharmacovigilance Services to be offered by the University of Otago - 5 April 2004
• A review of Pharmacovigilance in New Zealand - August 1999.
• Pharmacovigilance Planning: ICH Harmonised Tripartite Guideline draft - 11 November 2003
• The New Zealand Intensive Medicines Monitoring Programme: A summary

Presentations

There were two presentations to the Committee:

• Update on progress with the Joint Trans-Tasman agency - Medsafe
• Presentation from the NZPhvC. The Committee was presented with a summary of the NZPhvC's proposals for future Pharmacovigilance services. Members were also updated on the Intensive Vaccine-Monitoring Programme with particular emphasis on the new software developments that have enabled reporting to occur on a real-time basis. Members were informed of the potential extrapolation for use in IMMP and the spontaneous reporting programme.

Discussion

The Committee discussed a number of issues regarding Pharmacovigilance in the proposed joint trans-Tasman agency. Members commented that the trans-Tasman agreement should provide the opportunity to enhance the pharmacovigilance services that New Zealand has by sharing expertise and services with Australia.

The Committee was concerned that they had not received the Medsafe discussion document "Pharmacovigilance in a Trans-Tasman Therapeutic Products Agency" early enough to allow them to comment on it fully at this stage. Medsafe informed members that feedback would be welcomed after the meeting.

The following views were expressed by committee members:

• The MARC should be involved in decision-making on Pharmacovigilance as progress is made towards formation of the joint agency.
• It is important to maintain individual pharmacovigilance units in each country with technical assessment of ADR's being undertaken at each site, recognising the need for collaboration.
• It is important to consider both the New Zealand and the Australian viewpoint.
• The MARC is committed to ensuring that the New Zealand voice remains as strong as possible despite the size differences between the two countries.
• It is important to maintain enough expertise in New Zealand to enable post-marketing surveillance to be undertaken as required.
• It is important to ensure that the strengths of the New Zealand system, such as the use of at least two methodologies involving both passive and active surveillance, are not lost.
• It will be vital to maintain the ability to access adverse reaction data on a country-specific basis.
• It is important to ensure that adequate resources are provided for the assessment of post-marketing experience of medicines.
• Members felt that consideration should be given to whether the Quality Use of Medicines concept should be part of the New Zealand pharmacovigilance strategy.
• Members stated that New Zealand health professionals appreciate the personal response they presently receive from CARM, and it would be important that the culture underlying this should be maintained in the new environment.
• Members felt that further discussion needed to be undertaken to explore the ADR triage system currently used by the TGA. Concern was expressed at the potential risks involved if a clinician does not review all ADR reports.

In order to make progress on these issues, the Committee agreed to review the Medsafe/TGA discussion document and to provide feedback to Medsafe.

The Committee also recommended that a working party be set up with representatives from Australia and New Zealand to develop recommendations for a pharmacovigilance strategy in the joint agency. It was suggested membership should be made up of:

• 2 members of MARC
• 2 members of ADRAC
• 1 member of the NZPhvC - Dr Michael Tatley
• 1 member of ADRU
• 1 member of Medsafe
• 1 member of the TGA

Recommendations

Members agreed to review the Medsafe/TGA discussion document and to provide feedback to Medsafe.

The Committee recommended that a working party be set up with members from MARC, ADRAC, Medsafe, TGA, NZPhvC and ADRU to develop recommendations for a pharmacovigilance strategy in the joint agency. Medsafe has agreed to develop a project plan and budget for the working party, and will seek to have it agreed to by the end of July.

6 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.

6.1 Atypical Antipsychotics and Stroke

Reference

• March 2004, Letter from Professor Gordon Duff, Chairman - Committee on Safety of Medicines.

6.2 SSRI's in children

References

• Medsafe/MARC (2004), Dear Health Professional Letter re: The Use of SSRI antidepressants in children and adolescents.
• Jureidini et al (2004) Efficacy and safety of antidepressants for children and adolescents. BMJ, 328, 879 - 883
• Whittington et al (2004). Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. The Lancet, 363, 1341 - 1345.
• FDA Public Health Advisory (March 2004). Worsening Depression and suicidality in patients being treated with antidepressant medications.

6.3 SSRI's and Gastrointestinal haemorrhage

Reference

• The Independent review from Consumers' Association. Do SSRI's cause gastrointestinal bleeding? Drug and Therapeutics Bulletin, 42 (3), 17-18

6.4 Drug induced QT prolongation

Reference

• Roden (2004). Drug-Induced Prolongation of the QT interval. New England Journal of Medicine, 350 (10), 1013 - 1022.

6.5 HRT

References

• New Zealand Guidelines Group (2004). Hormone Replacement Therapy. Evidence Based Best Practice Guideline - Summary Update., March 2004
• New Zealand Guidelines Group (2004). Hormone Replacement Therapy or HRT. New Information for Women. April 2004.
• National Screening Unit Position Statement. (March 2004) Hormone Replacement Therapy
• The Women's Health Initiative Steering Committee (2004). Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy. The Women's Health Initiative Randomised Controlled Trial. JAMA, 291 (14), 1701 -1712
• Hulley et al (2004). The WHI Estrogen-Alone Trial - Do Things Look Any Better? JAMA, 291 (14), 1769 - 1771.
• Warthen et Al (2004). Hormone Replacement Therapy for the primary prevention of chronic diseases: recommendation statement from the Canadian Task Force on Preventive Health Care. CMAJ 170 (10), 1535 - 1539.
• Cheung et Al (2004). Prevention of Osteoporosis and Osteoporotic fractures in post-menopausal women: recommendation statement from the Canadian Task Force on Preventive Heatlh Care. CMAJ 170 (11), 1665 - 1667.

6.6 COX 2 inhibitors and the risk of thromboembolic events

Reference

• Layton et al (2003). Comparison of the incidence rates of thromboembolic events reported for patients prescribed rofecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data. Rheumatology 42, 1342 - 1353

6.7 Sibutramine

Reference

• Arteburn et al (2004). The Efficacy and Safety of Sibutramine for Weight Loss: A Systematic Review. Archives of Internal Medicine 164, 994-1003

6.8 CARM case reports

• TNP detox and rash, eczema, vaginitis (58785)
• Rapture, Charge Jump, ESP pills (58794)
• Nutralife natural vitamin E McCammon Muscle and Joint (58809)
• Glucosamine and chondroitin (58922)
• Cyclopenthiazide, Calcium + Magnesium (58926)
• Blackmores executive B, Stress with herbs (58978)
• Estelle 35 (59048)
• HEBBD (59158)
• Felodipine (59267)
• Felodipine (59316)
• Tub. Bovine (homeopathic remedy) (59653)
• Charge (59779)

7. New Zealand activities

7.1 Minutes of the February 2004 PTAC meeting

8. international activities

8.1 WHO

WHO Pharmaceuticals Newsletter No 2 2004

Signal: Analyses of the Adverse Reaction Reports in the WHO Database, April 2004

8.2 Canada

Canadian Adverse Reaction Newsletter 14(2), April 2004

8.3 Australia

Australian Adverse Drug Reactions Bulletin 23 (2), April 2004

Minutes of the February 2004 meeting of ADRAC

9. Summary of case reports considered by MARC (1997 to 2003)

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 4.45pm