Revised: 21 May 2013

Committees

Minutes of the 119th Medicines Adverse Reactions Committee Meeting - 22 September 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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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)
Professor P Ellis
Dr H Kingston
Dr M Tatley
Dr J Moy
Professor D Skegg - attended morning session via teleconference

marc secretariat present

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

invited experts

Dr R. Savage (New Zealand Pharmacovigilance Centre)
Dr A Harrison (Rheumatologist) - attended for the discussion on leflunomide
Dr A Roberts (Ministry of Health) - attended for the discussion on vaccine-related adverse reactions

1. MATTERS OF ADMINISTRATION

1.1 Welcome and apologies

The Chair welcomed Dr R Savage from the New Zealand Pharmacovigilance Centre (NZPhvC). Dr A Harrison was welcomed to the discussion on leflunomide. Dr A Roberts was welcomed to the afternoon discussion on vaccine adverse reactions.

Apologies had been received from Dr F McClure and Dr M Rademaker.

1.2 Minutes of the 118^th meeting

Members agreed that the minutes of the 118^th meeting are a true and accurate record of the meeting.

1.3 Dates of 2004 MARC meetings

The Committee noted that the next MARC meeting would be held on Wednesday 15 December 2004.

1.4 Conflicts of interest

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

1.5 Prescriber Update

Discussion

The Committee noted the schedule of proposed articles for Prescriber Update.

2. MATTERS ARISING

2.1 Report on actions arising from the 118^th MARC meeting

2.1.1 Minute item 1.2.1 Report to the Minister's delegate

Issue

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

Outcome

The above typographical error was rectified in the electronic copy of the report to the Minister's delegate.

Discussion

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

2.1.2 Minute item 1.2.2 Medicines Adverse Reaction Committee (MARC) Information for Members

Issue

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

Outcome

The above changes were made to the "MARC information for members" document.

Discussion

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

2.1.3 Minute item 1.5.1 Prescriber Update: Amiodarone reminder

Issue

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

Outcome

Medsafe will modify the Prescriber Update article on amiodarone to incorporate the committee's recommendations.

Discussion

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

2.1.4

Minute item 1.5.2 Prescriber Update: May issue

Issue

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

Outcome

An updated list of IMMP medicines will be published in the next Prescriber Update.

Discussion

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

2.1.5 Minute item 2.1.3 (December 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.

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

Issue

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

Outcome

In New Zealand, enoxaparin (Clexane) and dalteparin (Fragmin) are the most commonly used low molecular weight heparins (LMWHs). The NZPhvC has received 18 reports of haematoma and 5 of haemorrhage with enoxaparin use but only 3 reports of major bleeding with dalteparin - none of the dalteparin case reports provided evidence of renal impairment. However, as all the LMWHs are renally cleared, patients with renal impairment who are prescribed any of the LMWHs are likely to accumulate anti-factor Xa and be at an increased risk of bleeding. Thus any tool kit for dose adjustment in patients with renal impairment will need to be applicable to all LMWHs.

Before writing to the Safe Use of Medicines Group, Medsafe conducted a literature search to determine whether or not a tool kit for LMWH dose adjustment in renal impairment had already been developed.

Medsafe reviewed a recent review article entitled "Low Molecular Weight Heparin Use in Special Patient Populations" that was published in CE Forum in 2004¹. This article reviewed the use of LMWH in patients with renal impairment. It was noted that very few clinical studies have been undertaken in patients with renal impairment and in fact many studies of the LMWHs have specifically excluded patients with renal impairment. Pharmacokinetic data obtained from studies of enoxaparin and tinzaparin have demonstrated a prolonged half-life of anti-Xa activity, impaired clearance and thus accumulation, in patients with renal impairment. This effect appears to be proportional to the reduction in renal function. The author notes that there is evidence from clinical trials of an increased bleeding rate in patients with renal impairment receiving LMWHs.

The review article in CE Forum¹ identified three possible strategies for dosage adjustment based on measurement of anti-factor Xa levels. This advice is based on:

1. Recommendations from the University of Washington.
2. A nomogram developed for paediatric patients by the American College of Chest Physicians (from the 2001 Consensus Conference on Antithrombotic Therapy).
3. Recommendations from the College of American Pathologists.

The author made the following recommendations:

• Dose adjustment and monitoring of anti-Xa activity in patients with renal impairment may help to prevent adverse events associated with LMWH use.
• An adult nomogram for dose adjustment in renal impairment needs to be developed. It may be possible to base this on the paediatric nomogram that is already available. Measurement of anti-Xa trough levels will be important to detect accumulation and thus allow adjustment of dose frequency.

Haematological opinion

Expert haematological opinion was sought on this issue from a haematologist at Wellington Hospital. The haematologist agreed that dosage adjustment is extremely important in patients with renal impairment and she noted that measurement of anti-Xa levels is the only way to safely monitor patients with renal impairment. The haematologist was not aware of any nomograms available for this purpose and was interested to know that one had been developed for use in children.

Discussion

There is good evidence of a need for dose adjustment of the LMWHs in patients with renal impairment. However, there are no clear clinical guidelines on how this should be undertaken. The anti-Xa assay is the best available marker of the biological activity of the LMWHs. The New Zealand data sheets for the LMWHs are inconsistent in their advice. The enoxaparin data sheet provides guidelines for both prophylactic and treatment dose adjustment in renal impairment. However, it does not recommend anti-Xa monitoring. The data sheet for dalteparin recommends twice daily rather than once daily dosing in patients with severe renal impairment but does not recommend a reduced total dose. However, the data sheet for Fragmin does provide some advice on anti-Xa monitoring.

¹ Wittowsky A (2004). Low Molecular Weight Heparin Use in Special Populations. CE Forum 1 (1): 3-10

Discussion

Medsafe informed Members that an article entitled "Anti-Xa Monitoring of Enoxaparin for Acute Coronary Syndromes in Patients with Renal Disease"² has been published this week. Medsafe intends to review this article to determine whether it may assist the development of a protocol for dose adjustment in New Zealand.

Members were concerned to note the paucity of literature available to assist clinicians and pharmacists in determining the required dosage adjustment for patients with severe renal impairment. It was also noted that the New Zealand data sheets were variable in their advice. The data sheets do not indicate that there is a risk of accumulation of anti-Xa activity and hence an increased bleeding risk in patients with renal impairment taking LMWHs for extended periods of time.

The Committee agreed that any protocol/nomogram for dose adjustment should be applicable to all LMWHs and not just to enoxaparin. It was noted that consideration needed to be given to the increasing use of LMWHs by GPs in the community setting, where access to anti-Xa monitoring may not be readily available.

Members agreed with Medsafe's proposal to write to the Safe Use of Medicines Group recommending that they consider the University of Washington advice¹, when developing a protocol for the safe use of LMWHs in patients with renal impairment. It was noted that Medsafe would also provide them with the information on the paediatric nomogram for dose adjustment as per anti-Xa levels¹. Medsafe will suggest to the Safe Use of Medicines group that it may be possible to conduct a study to test the nomogram's validity for use in adults.

The Committee also agreed with Medsafe's proposal to contact the product sponsors of the LMWHs available in New Zealand. Medsafe will request that unless the product sponsors can provide Medsafe with evidence to the contrary, the data sheets of all LMWHs should be amended to indicate that LMWHs should not be used in patients with a creatinine clearance <30ml/min unless anti-Xa monitoring is available.

² Ma J (2004). Anti-Xa monitoring of Enoxaparin for Acute Coronary Syndromes in patients with renal disease. The Annals of Pharmacotherapy 38(10): 1576-1581.

Recommendations

The Committee agreed that Medsafe should write to the product sponsor's of the LMWHs requesting that the data sheets be amended to state that LMWHs should not be used in patients with 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.

2.1.7 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

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 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

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

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

Issue

The Committee recommended that Medsafe review the risperidone PSUR with respect of Cerebrovascular Adverse Events (CVAEs) and report back to the Committee at the next MARC meeting.

Outcome

This item is incorporated into this meeting's pharmacovigilance item on 'risperidone and cerebrovascular accidents'.

Discussion

See Minute item 3.3 for discussion on this issue.

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

Issue

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.

Outcome

The latest PSUR for leflunomide has been reviewed. A combined Medsafe/NZPhvC report on this issue has been provided for discussion.

Discussion

See minute item 3.5 for discussion on this issue.

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

Issue

The Committee recommended that Medsafe write to the Family Planning Association (FPA) 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.

Outcome

Letters have been distributed to the FPA and POP product sponsors informing them that the MARC has amended its advice regarding the use of POPs in patients with current VTE.

Discussion

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

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

Issue

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

Outcome

After reviewing the data submitted by Novartis, Medsafe considered that there was strong evidence for causality with respect to clozapine and aspiration pneumonia. However, the evidence for pneumonia without aspiration is less clear.

Medsafe informed Novartis of the MARC's discussions on this issue and requested that aspiration pneumonia be added to the adverse events section of the Clozaril data sheet. Novartis notified Medsafe in August 2004 of its decision to include "aspiration pneumonia" in the adverse effects section of the Clozaril data sheet.

Discussion

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

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

Issue

The Committee recommended that Medsafe review the Mamdami et al study referred to during the meeting. Members recommended that Medsafe then write back to Pfizer asking that the statement that the risk of upper GI complications with celecoxib was "…approximately 8-fold less than with non-specific COX inhibitors", be removed and/or modified in line with findings from this study.

Outcome

The Mamdani et al. study was reviewed, and although it supported the statement that the incidence of upper GI complications with Celebrex was not significantly different from placebo, this study found that non-selective NSAID's were associated with a relative risk of 4.4 (CI 2.3 to 8.5) for upper GI complications compared to celecoxib (not supporting the "8-fold" reduction claimed in the datasheet).

A second request has been made to Pfizer informing them that the MARC considers their response to be inadequate, and again asks the company to adequately justify the above statement or remove/amend it from the Celebrex datasheet.

Discussion

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

2.1.13 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.

Outcome

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. Medsafe is 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.

2.1.14 Minute item 3.3 HRT- PHARMAC proposal to restrict prescribing

Issue

The Committee recommended that Medsafe draft a joint Medsafe/MARC submission to PHARMAC.

Outcome

The above submission was presented to the PHARMAC board in July 2004. After consideration of all the submissions received, PHARMAC's board informed Medsafe that it had elected to add the following prescribing guideline to all HRT medicines listed in the pharmaceutical schedule:

• HRT should be taken at the lowest dose for the shortest period of time necessary to control symptoms. Patients should be reviewed 6 monthly in line with the updated NZGG Evidence-based Best Practice Guidelines on Hormone Replacement Therapy.

A media release indicates that PHARMAC will also be distributing the NZGG guidelines and patient leaflet to GPs and interest groups.

N.B. The findings of the oestrogen-only arm of the WHI study (FYI paper included in the June 2004 dossier) will be incorporated into the HRT medicine datasheets along with other outstanding requests.

Discussion

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

2.1.15 Minute item 4.1.2.3 Venlafaxine and serotonin syndrome (59599)

Issue

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.

Outcome

The venlafaxine data sheet was reviewed with respect to interactions with tricyclic antidepressants. In the interactions section, under CNS active drugs, the following information is stated: "Based on the known mechanism of action of venlafaxine and the potential for serotonin syndrome, caution is advised when Efexor (venlafaxine) is co-administered with other drugs that may affect the serotonergic neurotransmitter systems (such as triptans, SSRIs or lithium)".

A Prescriber Update article will be written on this issue at a later date.

Discussion

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

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

Issue

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.

Outcome

See agenda item 3.4 for a combined Medsafe/NZPhvC report on this issue.

Discussion

See Minute item 3.5 for discussion on this issue.

2.1.17 Minute item 4.1.9.7 Risperidone and sudden death (58586)

Issue

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.

Outcome

The latest PSUR for risperidone covering the period 1 June 2003 to 30 November 2003 was reviewed. Over this time period there were 5 reports of sudden death in patients taking risperidone.

There was one report of sudden death in a patient in his 20's. The patient was a male with schizophrenia who was prescribed risperidone 6mg daily from July 2003 until he died suddenly in November 2003. He was also taking citalopram. No other details were available on this case.

The other four cases of sudden death with risperidone consisted of a 70-year-old man who had taken risperidone 3mg/day for 3 years; a 61-year-old woman who had taken risperidone 12mg/day for 2.5 years; a 63-year-old man who had received IM risperidone 50mg per fortnight for 1 year; and a 59-year-old woman who received IM risperidone of unknown dose and 6mg oral risperidone daily. No further details were available on these cases.

Discussion

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

2.1.18 Minute item 4.2.1 Brand-switch reports for Morphine Sulphate

Issue

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.

Outcome

The NZPhvC has drafted a letter on this issue that is awaiting peer review.

Discussion

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

2.1.19 Minute item 5 SPECIAL ITEM: Pharmacovigilance in New Zealand

Issue

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

The Committee recommended that a working group 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.

Outcome

Members provided Medsafe with feedback on the Medsafe/TGA discussion document for inclusion in the next draft of this document.

A working group has been set up with representatives from the MARC, ADRAC, Medsafe, TGA, NZPhvC and ADRU. A meeting of this group has been arranged for 16^th September 2004.

Discussion

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.

Recommendation

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

2.2 Report on actions outstanding

2.2.1 March 2004 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 the 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.

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.

Outcome

Novartis has now obtained data on these cases from the NZPhvC. The Elidel (pimecrolimus) data sheet was updated in September 2004 to include the risk of severe application site reactions.

Discussion

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

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 request was 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, in which, hypercholesterolaemia and hypertriglyceridaemia are included as very rare adverse effects. The Seroquel data sheet already incorporates a statement on hyperlipidemia, so AstraZeneca was merely asked to comment on the issue.

Janssen (Risperdal) and Eli Lilly (Zyprexa) have referred the matter to Head Office, and both indicate that response will be forwarded in the second half of the year.

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

Discussion

Members noted that Medsafe has now received replies from all the above product sponsors. All except Janssen (Risperdal) have agreed to update their data sheets as requested. Medsafe is in the process of reviewing the response from Janssen and will report back to the Committee at the December MARC meeting.

Recommendation

The Committee recommended that Medsafe review the response from Janssen and report back to the Committee at the December 2004 MARC meeting.

2.2.3 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

The above letter was forwarded to PHARMAC in July 2004. PHARMAC issued a response to the MARC's letter stating that prior to Isotane being approved as the sole subsidised supply of isotretinoin, the product sponsor was required to provide satisfactory patient and clinician material and was also required to provide a free phone number for prescribers and patients to obtain further advice. It is PHARMAC's view that the MARC should address any safety concerns to Medsafe.

Discussion

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

2.2.4 June 2002 minute item 2.2.1 Missed-pill advice for Cerazette

Issue

A discrepancy in the product information for Cerazette, between the UK and New Zealand, was brought to the Committee's attention. The Committee recommended that Medsafe ask the product sponsor for Cerazette to change the missed-pill advice from 12 to 3 hours in the New Zealand datasheet, unless the company is able to provide evidence supporting the 12-hour rule.

Outcome

Organon advised Medsafe in June 2004 that the 12-hour rule has now been accepted in all MRP (Mutual Recognition Procedure) countries - including the UK.

As supporting evidence for this, Organon provided a report on a pharmacodynamic study involving 103 women. The study involved the study participants missing 1 Cerazette tablet by 12 hours, on three specified days, during the course of one cycle. Progesterone levels were measured to determine if ovulation had occurred. Ovulation was defined as a progesterone level greater that 16nmol/L for 5 consecutive days. In this study only one woman ovulated after missing a pill for more than 12 hours. (NB: The data itself was not presented.) This study supports previous findings that the primary contraceptive action of Cerazette is inhibition of ovulation, with lesser effects on viscosity of cervical mucus.

In view of the above findings the 12-hour rule will remain in the New Zealand Cerazette data sheet. As at June 2004, Cerazette is still not marketed in New Zealand.

Discussion

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

3. Pharmacovigilance Issues

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

Reference Material

• Medsafe Report (2004). Tricyclic Antidepressants in Children and Adolescents for treating Major depressive Disorder.
• Hazel et al (2003). Tricyclic drugs for depression in children and adolescents (Review). The Cochrane Database of Systematic Reviews. Volume (3) 2003.
• Ray et al (2004). Pharmacoepidemiology and Drug Utilization. Cyclic antidepressants and the risk of sudden cardiac death. Clinical Pharmacology and Therapeutics 2004, 75: 234-241.
• Wilens et al (1996). Cardiovascular effects of Therapeutic Doses of Tricyclic Antidepressants in Children and Adolescents. Journal of The American Academy of Child and Adolescent Psychology. 35 (11): 1491-1501.
• Varley, C (2000). Case Study: Sudden death of a child treated with Imipramine. Journal of Child and Adolescent Psychopharmacology 10 (4), 321-325.
• Shah R et al (2001). Deaths from antidepressants in England and Wales 1993-1997: analysis of a new national database. Psychological Medicine 31:1203-1210.
• Drug and Therapeutics Bulletin (2004). Management of bedwetting in children. DTB 42(5): 3-37.
• Faculty of Child and Adolescent Psychiatry-New Zealand Branch (2004). Tricyclic Antidepressants for treating Major Depressive Disorder in Children and Adolescents. Personal Correspondence.

Issue

The purpose of this agenda item was to review the use of the Tricyclic Antidepressants (TCAs) in treating child and adolescent major depressive disorder (MDD). The Committee reviewed the use of SSRI antidepressants in children and adolescents at the March 2004 MARC meeting. Following on from this review, it was considered necessary that the efficacy and safety of TCAs should also be reviewed in detail.

A Medsafe report on TCA use in child and adolescent depression, indicated that current guidelines, reviews, case reports and meta-analyses of published trials, collectively suggest that it is no longer appropriate to use TCA medicines to treat depression in children. The evidence indicates that TCAs are no more efficacious than placebo in treating childhood depression although there is evidence for modest efficacy in treating adolescent depression. In adults there is clear evidence of dose- dependent cardiovascular toxicity associated with TCA use. There is also clear evidence of an effect on heart rate, blood pressure and ECG parameters in children and adolescents. There have been case reports of sudden cardiac death in children taking TCAs at standard doses. It is unclear whether this is an idiosyncratic reaction or is dose dependent as it is for adults. In addition, there is clear evidence that TCAs are more dangerous in overdose than the SSRIs, making the TCAs less preferred in patients at a greater risk of accidental or intentional overdose.

The New Zealand data sheets for amitriptyline, nortriptyline, doxepin, dothiepin, desipramine and trimipramine specifically state that their products are not recommended for use in children. The data sheets for clomipramine, imipramine, maprotriline and mianserin provide specific dosage instructions for children. None of the New Zealand TCA data sheets recommend the use of their product in children aged less than 5 years.

A submission from the New Zealand Branch of the Faculty of Child and Adolescent Psychiatry states that TCAs have no place in the treatment of depression in pre-pubertal children. However, it considers that that the "TCAs have a limited place in the treatment of MDD in older adolescents where their clinical presentation has significant features of psychomotor retardation and/or psychosis".

Discussion

The Committee reviewed the reports and literature provided on this issue. Members noted that there is inadequate evidence of efficacy for the use of TCAs to treat MDD in children and in view of the clear evidence of potential harm, the risk/benefit ratio is unfavourable for children with depression. Members noted that there is some evidence of efficacy in the treatment of adolescent MDD, and agreed that it may be appropriate to prescribe a TCA in this age group but only if the adolescent is under the care of a specialist.

Members commented that although there are no clinical trial data to suggest an increased risk of suicidality with the TCAs, there is also no adequate data to exclude this possible risk. It is unlikely that future studies will be undertaken to address this issue in view of the demonstrated superiority of fluoxetine over the TCAs in the treatment of adolescent depression.

Members also reviewed the DTB article on the management of bedwetting in children. Members noted that it was concluded that the risk/benefit ratio for imipramine in the treatment of enuresis is also generally unfavourable.

The Committee concluded that the TCAs have an unfavourable risk/benefit profile and thus should not be used to treat children with MDD or enuresis. TCAs should only be prescribed to adolescents with MDD if under the care of a specialist.

Recommendations

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 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.

3.2 Antidepressants and Suicide Warnings

Reference Material

• Medsafe Report (2004). Antidepressants and Suicide Warnings
• FDA Public Health Advisory (March 22^nd 2004). Worsening depression and suicidality in patients being treated with antidepressant medication.
• PAXIL Dear Health Professional Letter (May 2004).
• Jick H et al (2004). Antidepressants and the risk of suicidal behaviours. JAMA 292:338-343
• Wessley S and Kerwin R (2004). Editorial: Suicide Risk and the SSRIs. JAMA 292:379-381.

Issue

The purpose of this agenda item was to review the content of all New Zealand antidepressant data sheets (including SSRIs, TCAs, SNRIs and MAOIs) with respect to suicide warnings.

This item was brought to the Committee's attention for the following reasons:

1. US and Canadian regulators have recently required that a generic suicide warning statement be placed in the product information of all SSRI antidepressants.
2. Recent literature has supported the premise that depressed patients are at the greatest risk of suicide in the early stages of treatment regardless of which antidepressant is prescribed.

The MARC has considered the issue of increased risk of suicidality with the SSRI antidepressants on a number of occasions. A Prescriber Update article was published in 2002 indicating that reports of increased suicidal preoccupation had occurred in adults taking SSRI antidepressants. The MARC has also specifically reviewed the issue of suicidality with SSRIs in child and adolescent major depression. (See Minute item 3.3 for discussion on this issue).

A recent case-control study by Jick, Kaye & Jick (2004), published in JAMA used the UKGPRD database to assess the risk of suicidal behaviours in patients prescribed 2 types of SSRI antidepressants and 2 types of TCAs. The results indicated that there was no significant difference in the risk of suicidal events amongst the users of the four different study antidepressants. The study also documented that suicidal events were more likely to occur within the first month after receiving a first prescription, and especially, within the first 1-9 days. The authors suggest that this probably reflects the fact that antidepressant treatment is not immediately effective, and hence there is a higher risk of suicidal behaviour in newly diagnosed and treated patients compared to those who have been treated for a longer period of time.

A JAMA editorial discussing the Jick et al (2004) study notes that of the 15 adolescent suicides recorded from 1993-1999, in the UKGPRD, none of these adolescents were prescribed an antidepressant. It is relevant that no adolescent prescribed an antidepressant in the study completed suicide.

Medsafe recommends that product sponsors of all antidepressants be requested to update their respective datasheets to include a generic warning statement similar to that required by the FDA. This statement warns about the possibility of worsening depressive symptoms early in treatment (which may or may not be related to the medicine), and the need to monitor patients carefully.

Discussion

The Committee noted that the New Zealand antidepressant datasheets contain highly variable information on the need to monitor patients for worsening depression and/or emerging suicidality in the early stages of treatment.

Members noted the findings of the Jick et al (2004) study and agreed that depressed patients are likely to remain at risk of suicide until their depression is adequately treated. There may be a significant delay in clinical response from the date of initiating antidepressant treatment and it is crucial that all patients, regardless of which antidepressant they are prescribed, are monitored carefully during this time period.

The Committee agreed that the product sponsors for all antidepressants in New Zealand should be required to include a warning statement in their datasheets in line with the Medsafe recommendation above.

Recommendation

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.

3.3 SSRIs in Children and Adolescents with Major Depression

Reference material

• March J et al (2004). Fluoxetine, Cognitive-Behavioral Therapy, and Their Combination for Adolescents With Depression. Treatment for Adolescents With Depression Study (TADS). Randomized Controlled Trial. JAMA 292(7): 807-820.
• Glass R (2004). Treatment of Adolescents With Major Depression. Contributions of a Major Trial (Editorial). JAMA 292(7): 861-863.
• Mackay K (2004). Notes from joint meeting of the FDA Psychopharmacologic Drugs Advisory Committee and the Paediatric Advisory Committee 13 and 14 September 2004.
• FDA Statement on Recommendations of the Psychopharmacologic Drugs and Pediatric Advisory Committees. September 16, 2004

Issue

The purpose of this agenda item was to update the Committee on recent international regulatory activity and recent international literature on this issue. The Committee was asked to comment on what regulatory action, if any, should be undertaken in New Zealand.

In March 2004, the Medicines Adverse Reactions Committee (MARC) reviewed the safety of SSRIs in the treatment of child and adolescent depression. The Committee concentrated on a potential increased risk of suicidality with these medicines. At that time the MARC examined reports from the UK CSM, the American College of Neuropsychopharmacology, US Food and Drug Administration (FDA) advisory committees, and the Royal Australian and New Zealand College of Psychiatrists. Although the Committee considered that the available evidence was inconclusive, they recommended that a Dear Health Professional letter be distributed to all prescribers emphasising the need to seek specialist advice before prescribing any antidepressant to children under the age of 18 years. It also reinforced the need to monitor all patients with depression for the emergence or worsening of suicidal thoughts and behaviours.

At the conclusion of the March meeting, members agreed to review this issue again after the results of the FDA commissioned re-analysis of the raw data from paediatric clinical trials was completed. The FDA published the results of the Columbia University reanalysis of paediatric clinical trial data in August 2004. The re-analysis showed that when combining the results from all trials, patients taking an SSRI or an SNRI were 1.78 (CI 95%, 1.14-2.77) times more likely to experience serious suicide-related events than patients taking placebo. There was no significant increased risk of these events from analysis of the SSRI-only trials in MDD. Only fluoxetine was shown to have efficacy. It was noted that no patients had committed suicide in any of the clinical trials.

A joint meeting of the FDA Psychopharmacologic Drugs Advisory Committee and the Paediatric Advisory Committee was held on 16-17 September 2004. The Advisory Committees concluded the following:

• The finding of an increased risk of suicidality in paediatric patients applied to all the drugs studied (Prozac, Zoloft, Remeron, Paxil, Effexor, Celexa Wellbutrin, Luvox and Serzone) in controlled clinical trials;
• Any warning related to an increased risk of suicidality in paediatric patients should be applied to all antidepressant drugs, including those that have not been studied in controlled clinical trials in paediatric patients, since the available data are not adequate to exclude any single medication from an increased risk;
• Endorsed a patient information sheet ("Medication Guide") to be provided to the patient or their caregiver with every prescription;
• Recommended that the products not be contraindicated in the US because the Committees thought access to these therapies was important for those who could benefit; and
• Recommended that the results of controlled paediatric trials of depression be included in the labelling for antidepressant drugs.

Discussion

Members were reminded that in New Zealand, none of the SSRIs have ever been approved for use in treating MDD in children and adolescents.

The Committee noted that the reanalysis of paediatric clinical trial data undertaken by Columbia University was in broad agreement with the previous conclusions drawn by the FDA Office of Drug Safety. Members discussed the recommendations of the joint FDA advisory committee and noted that there was a recommendation not to contraindicate the use of SSRIs in children and adolescents.

The Committee also discussed the significance of the March J et al (2004) TADS study recently published in JAMA. Members agreed that this study provides good evidence of efficacy for fluoxetine in treating child and adolescent depression and also supported the appropriateness of using fluoxetine as first-line treatment. The synergistic effect of fluoxetine plus Cognitive Behavioural Therapy (CBT) in combination was noted. However members stated that in view of the limited availability of CBT in New Zealand, this combination is unlikely to be used extensively in clinical practice.

Members expressed concern that any advice on the risk of suicidality in children and adolescents taking SSRIs may inadvertently support the prescription of TCAs in this age group. It was agreed that the MARC advice must include risk/benefit statements with respect to both the SSRIs and the TCAs.

After review of the literature provided on this issue as well as that provided in agenda items 3.1 and 3.2 the MARC concluded the following:

• There is some evidence of an increased risk of suicidality with the use of all SSRI's in children and adolescents.
• It is unknown if the TCAs confer a similar risk of suicidality as studies have not been undertaken to address this issue.
• There is no evidence of efficacy for the TCAs in the treatment of depression in children.
• Fluoxetine is the only SSRI for which there is evidence of efficacy in the treatment of child and adolescent depression. There is no evidence of efficacy for the other SSRIs from meta-analyses of randomised controlled trials.
• The risk/benefit analysis for the use of SSRIs in adults remains positive.
• The MARC accepts that it may still be appropriate to use these agents in individual cases (such as treatment resistant depression) when under the care of relevant specialists.
• SSRIs are less dangerous in overdose than other classes of antidepressants.
• The MARC aims to support the safe use of these medicines by way of improved warnings in the product data sheets and consumer medicine information, and by asking Medsafe to issue a "Dear Health Professional" letter to all prescribers.

The MARC still considers that the data on SSRIs and suicidality are inconclusive in establishing the strength of this association. The MARC maintains a high priority on reviewing the safety of all antidepressant medicines as more data becomes available.

Recommendations

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.

3.4 Risperidone and Cerebrovascular Adverse Events (CVAEs) in elderly patients with dementia

Reference material

• Medsafe Report (2004). Risperidone and Cerebrovascular Adverse Events (CVAE) in elderly patients with dementia.
• Duff G (2004) UK Committee on Safety of Medicines. Dear Colleague letter: Atypical Antipsychotic drugs and stroke. Australian Drug Evaluation Committee (ADEC) Minutes of the Meeting. October 2003.
• Herrmann N, Mamdani M, Lanctot K. Atypical antipsychotics and risk of cerebrovascular accidents. American Journal of Psychiatry 2004; 161:1113-1115
• Lee P, Gill S, Freedman M, Bronskill S, Hillmer M, Rochon P. Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review. BMJ 2004; 329:75-80

Issue

The purpose of this agenda item was to re-consider the risk of CVAEs in patients taking risperidone for dementia, in light of recent advice released by the UK Committee on Safety of Medicines (CSM).

In March 2004, after review of four placebo-controlled trials, the CSM concluded that there was an increased risk of CVAEs with risperidone and olanzapine use. The CSM advised its prescribers that risperidone should not be used to treat the behavioural symptoms of dementia, should only be prescribed under specialist advice of the management of acute psychotic conditions in elderly patients with dementia and should only be prescribed with caution to any patient with a previous history of stroke or TIA. This action was in line with that undertaken by Canadian and US regulators in 2003.

In New Zealand, risperidone is indicated for the treatment of behavioural and psychological symptoms of dementia such as aggressiveness (verbal outburst, physical violence), activity disturbance (agitation, wandering) or psychotic symptoms (in addition to its other indications). Australian and Canadian regulators have also approved this indication, although the US and the UK have not.

In 2001, the New Zealand data sheet for risperidone was updated to state in the PRECAUTIONS section: "Cerebrovascular accidents have been observed in patients taking risperidone".

The MARC first reviewed this issue in June 2003, after the US and Canadian regulators required data sheet updates and the distribution of "Dear Doctor" letters to inform prescribers of the risk of CVAEs in elderly, demented patients taking risperidone. The MARC reviewed the four trials reviewed by other regulators and required similar changes be made to the New Zealand datasheet. A "Dear Doctor" letter was sent to New Zealand prescribers in late June 2003.

The Australian ADEC thoroughly reviewed this issue in October 2003 (including review of the same placebo-controlled trials reviewed by the CSM), and concluded that they still supported the use of risperidone in elderly patients with dementia.

Discussion

The Committee was informed that the product sponsor for risperidone has now updated the New Zealand data sheet to be in line with the Australian product information. The Precautions section now states:

"In placebo controlled trials, there was a significantly higher incidence of cerebrovascular adverse events, including cerebrovascular accidents and TIAs, in patients treated with risperidone compared to patients treated with placebo (mean age 85 years, range 73-97)."

The Committee reviewed the Medsafe report on this issue and noted that the NZPhvC has received four reports of CVA in patients taking risperidone; three in patients treated for schizophrenia (aged 55, 66, and 69 years old), and one in a patient with multi-infarct dementia (aged 82 years old).

Members commented that anecdotally, the use of risperidone for this indication has been reducing in the hospital setting. This seems to have been in response to the "Dear Doctor" letter distributed to prescribers in June 2003.

The Committee noted that medical literature supports the statement that risperidone has similar efficacy to the typical antipsychotics in treating the behavioural and psychological symptoms of dementia. It was also noted that the Herman et al (2004) study showed that the risk of CVA with risperidone was not significantly different from that for the typical antipsychotics.

The Committee concluded that the CSM advice was based on the same information previously reviewed by MARC, ADRAC and other international regulators in 2003. Members considered that the information in the precautions section of the risperidone data sheet is now adequate and that no further regulatory action is required at this time. Members recommended that a watching brief be placed on risperidone and CVAEs.

Recommendation

The Committee recommended that a watching brief be placed on risperidone and CVAEs.

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

Reference material

• Medsafe report (2004). Leflunomide: Post-marketing Safety Concerns (Medsafe Report)
• NZPhvC report (2004). Leflunomide: Adverse reaction Reports to CARM March 2000 to July 2004.
• Suissa et al (2004). Newer Disease-Modifying Antirheumatic Drugs and the Risk of Serious Hepatic Adverse Events in Patients with Rheumatoid Arthritis. Am J Med 117: 87-92
• O'Dell J (2004). Therapeutic Strategies for Rheumatoid Arthritis. New England Journal of Medicine 350 (25) 2591-2602.
• Olsen N, Stein M (2004). New Drugs for Rheumatoid Arthritis. New England Journal of Medicine 350 (21) 2167-2179.
• Bonnel et al (2004). Pharmacoepidemiology and Drug utilisation: Peripheral neuropathy in patients treated with leflunomide. Clinical Pharmacology and Therapeutics 75:580-585.
• Carulli M, Davies U (2002). Peripheral neuropathy: an unwanted effect of leflunomide. Rheumatology 41:952-953.
• Aventis Pharma (August 2004). Proposed Dear Doctor letter for Arava (leflunomide).
• Kremer et al (2004). Combination Leflunomide and Methotrexate (MTX) Therapy for Patients with Active Rheumatoid Arthritis Failing MTX Monotherapy: Open-Label Extension of a Randomized, Double Blind, Placebo Controlled Trial. Journal of Rheumatology 31:1521-1531.

Issue

The Committee was provided with an overview of the international regulatory action that has been undertaken in response to emerging safety concerns with leflunomide use. An overview was also provided of the safety issues previously considered by the MARC and the action undertaken by the MARC and Medsafe in response to these concerns. The NZPhvC provided members with a report on the adverse effects of leflunomide in New Zealand.

Medsafe's report on this issue indicated that a number of serious safety concerns have been identified since leflunomide was licensed in 1998. International regulators have required changes to the data sheet warning statements with respect to serious hepatic, skin, haematological and respiratory adverse effects. The monitoring requirements for leflunomide have been increased and the product sponsor has been required to issue "Dear Health Professional" letters warning prescribers of emerging safety concerns.

Medsafe cautioned that when considering the risk/benefit profile of leflunomide, it is important to take into account the following issues:

• Rheumatoid arthritis is an incurable systemic disease associated with significant morbidity and mortality. The aim of rheumatoid arthritis treatment in all patients must be early and complete control of inflammation in order to minimise morbidity and mortality. This requires early and intensive introduction of DMARD therapy. Combination DMARD therapy may be required, particularly in patients with an inadequate response to methotrexate.
• In New Zealand, leflunomide is funded under special authority and therefore its use is restricted to patients who have failed or are intolerant to other DMARD's - thus this is a group of patients with limited other treatment options.
• All the DMARD's available are associated with potentially serious and/or life threatening adverse effects. Individual patients may be able to tolerate the adverse effects of some DMARD's better than others.
• It is very important that a range of treatment options is available to allow individual tailoring of therapy to achieve maximum control of symptoms with a minimum of side effects.

Discussion

Members reviewed the combined Medsafe/NZPhvC report on this issue. A Wellington Rheumatologist attended the meeting to offer his expert opinion on the New Zealand experience with leflunomide (Arava^®) in the treatment of rheumatoid arthritis.

The rheumatologist explained that in New Zealand, leflunomide is a third-line agent that can only be used if patients have not responded to or have had an inadequate response to methotrexate and sulfasalazine. In Wellington, the loading dose of leflunomide is not given, in order to minimise the risk of adverse effects such as diarrhoea. Any delay in therapeutic response caused by the absence of a loading dose can be managed by a short course of prednisone therapy. In most cases, a patient who has had an inadequate response to methotrexate or sulfasalazine will have those medicines stopped before commencing leflunomide. If response is incomplete, low dose methotrexate (e.g. 7.5mg weekly) may be added.

The Committee was informed that many patients respond extremely well to leflunomide with great improvement in quality of life. If leflunomide were not available in New Zealand, it would severely restrict treatment options, particularly for patients with severe disease unresponsive to other treatments. If PHARMAC elected to fund one of the biologic DMARDs such as etanercept this would provide additional treatment options but would not replace leflunomide as a treatment. However it was considered that if a fourth-line agent was available then it might be possible to stop leflunomide therapy earlier if serious adverse effects occurred. The Committee were informed that the use of etanercept as a first-line agent is losing favour in the international literature.

The rheumatologist indicated that the risk of leflunomide pneumonitis has only recently been brought to the attention of New Zealand Rheumatologists. He noted that the cases of pneumonitis in New Zealand and Australia were frequently in patients taking methotrexate as well as leflunomide. It was questioned whether or not these patients were being given doses of methotrexate that were too high.

The Committee was informed that New Zealand rheumatologists are familiar with the risk of methotrexate-induced interstitial lung disease (ILD). He noted that risk factors for methotrexate pneumonitis such as increasing age and renal impairment have been identified. Methotrexate is now avoided in this population of patients and the incidence of methotrexate pneumonitis has fallen as a result. It was recommended that the NZPhvC obtain further information on the New Zealand/Australian patients with pneumonitis with a view to identifying the risk factors for the development of leflunomide pneumonitis.

It was noted that because of the way leflunomide is funded in New Zealand, it is likely that more patients are on leflunomide in combination with methotrexate than in other countries. In New Zealand, Arava is indicated for the treatment of rheumatoid arthritis, to improve signs and symptoms, to retard joint destruction and to improve functional ability and quality of life. Arava may be used in patients who have failed to respond to other treatments or as a first line of treatment in patients who have a contraindication to other treatments.

Members reviewed the content of Aventis' proposed "Dear Doctor" letter on leflunomide (Arava). Members were unhappy with the fourth to last paragraph. Members felt that the paragraph should be reworded to remove reference to epidemiological studies suggesting that ILD does not occur more frequently in patients treated with leflunomide. The Committee also asked that the company reference the statement that 40-50% of RA patients will eventually develop ILD. The Committee recommended that a bolded statement be added stating that prescribers should inform their patients of the need to seek medical attention if they develop signs and symptoms of pulmonary disease. Dr agreed that it would be helpful if the "Dear Doctor" letter stated that Medsafe recommends that the leflunomide loading dose be omitted if leflunomide is added to existing methotrexate therapy.

The Committee commented that although there have been significant safety concerns identified with leflunomide, leflunomide remains an important treatment option for rheumatoid arthritis patients with limited other options. Members commented that the issue of interstitial pneumonitis associated with leflunomide use has arisen subsequent to the June 2004 Prescriber Update article on safety concerns associated with leflunomide use. The Committee agreed that the Aventis "Dear Doctor" letter will serve to inform prescribers of this new safety concern as well as reminding them of the monitoring requirements and the warning signs that patients need to be aware of.

The Committee agreed that Medsafe, NZPhvC and the MARC should continue to monitor the safety profile of leflunomide. However, no further regulatory action is required at this time.

Recommendations

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, in line with the recommendation made by the expert rheumatologist, suggested that the NZPhvC obtain further information on the cases of leflunomide pneumonitis with a view to identifying risk factors for its development.

4. Matters Arising From the New Zealand Pharmacovigilance Centre (NZPHvC)

4.1 CARM Case Reports

4.1.1 Alternative medicine-related reports

4.1.1.1 Chlorella, Norimin and therapeutic effect reduced, drug interaction, pregnancy (60360)

Discussion

The Committee noted that the contraceptive failure in this case might have been caused by either a drug interaction resulting in increased metabolism of Norimin, or by malabsorption of Norimin secondary to diarrhoea.

The causality assessment was deemed "possible" for Chlorella, Norimin and therapeutic effect reduced, drug interaction and pregnancy. No further action was recommended.

4.1.1.2 HSII and retinal haemorrhage, blindness (60308)

Discussion

It was noted that HSII contains a combination of hawthorn, capsicum and garlic. Hawthorn berries have been associated with nosebleeds. Capsicum has been associated with reports of impaired blood coagulation. Garlic is known to have an effect on platelet function and to increase the risk of bleeding. It was noted that this effect has also been observed in patients taking dietary garlic only. The Committee considered that it is possible that all three ingredients acted synergistically to increase the risk of bleeding in this case.

The causality assessment was deemed "possible" for HSII and retinal haemorrhage and blindness. No further action was recommended.

4.1.1.3 System Slim Vitamin B Complex and anaphylactic reaction, angioedema (60361)

Discussion

The Committee noted the presence of passion fruit flower differentiated this product from other Vitamin B complexes. Members noted that the patient's severe allergic reaction could have been caused by the passion fruit flower or by an excipient of the vitamin complex. The Committee also discussed the possibility that the patient had ingested a new food as part of her weight loss diet and that this may have caused the allergic reaction.

The causality assessment was deemed "probable" for System Slim Vitamin B complex and anaphylactic reaction and angioedema.

Recommendation

The Committee recommended that the NZPhvC obtain further information on the nature of the other allergic reactions experienced with this product. The Committee also recommended that the NZPhvC obtain a copy of the package insert/label of this product to enable Medsafe to review the composition of this product.

4.1.2 Analgesic medicine-related reports

4.1.2.1 Tramadol and hepatic enzymes increased (61185)

Discussion

Members noted that the NZPhvC has received two reports of increased hepatic enzymes and one of jaundice with tramadol use. It was noted that there is one case report in the literature of fatal hepatic failure secondary to an overdose of tramadol.

The causality assessment was deemed to be "certain" for tramadol and hepatic enzymes increased.

Recommendation

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

4.1.3 Anticonvulsant medication-related reports

4.1.3.1 Gabapentin, prednisone, methotrexate, diclofenac, amitriptyline and tremor, depression, anxiety, speech disorder, duodenal ulcer perforated, myocardial infarction, stroke (60590)

Discussion

Members noted that it was not possible to obtain information on exactly which medicines the patient had been taking in the period leading up to her death. It was noted that reactions such as tremor, anxiety and depression are identified in the gabapentin data sheet as potential adverse effects. It was noted that there is a potential interaction between methotrexate and NSAID's although it is not considered to be of any clinical significance. The patient had at some time been prescribed prednisone and diclofenac and although it was not clear whether she had been taking these in the time leading up to her death, it was noted that these medicines may have contributed to the development of the patient's duodenal ulcer.

The causality assessment was deemed to be "unclassified" for gabapentin, prednisone, methotrexate, diclofenac, amitriptyline, and tremor, depression, anxiety, speech disorder, duodenal ulcer perforated, myocardial infarction and stroke.

No further action was recommended.

4.1.4 Antithrombotic medication-related reports

4.1.4.1 Enoxaparin and haemorrhage retro-peritoneal (61062)

Discussion

The Committee reviewed the case report on this patient. It was noted that no information was available on whether or not the patient suffered from renal impairment.

The causality assessment was deemed to be "probable" for enoxaparin and retro-peritoneal haemorrhage. No further action was recommended. See Minute item 2.1.6 for discussion on dosage adjustment of LMWHs in renal impairment.

4.1.5 Cardiovascular medication-related reports

4.1.5.1 Carvedilol and cardiomyopathy (59973)

Discussion

The Committee noted that carvedilol is indicated for the treatment of dilated cardiomyopathy and CHF. However, it was also noted that if dose titration occurs too quickly then carvedilol could actually precipitate CHF. Members discussed the possibility of a fluoxetine/carvedilol interaction via CYP2D6 that may have caused increased levels of carvedilol. However it was felt that this was unlikely as the fluoxetine was not a new addition to his treatment regimen.

The causality assessment was deemed "unlikely". No further action was recommended.

4.1.6 Musculoskeletal medication-related reports

4.1.6.1 Leflunomide and tendonitis (60619)

Discussion

It was noted that CARM has received 2 reports of tendonitis and one report of tendon rupture with leflunomide use. The WHO database has 2 reports of tendonitis and 3 of tendon rupture.

The causality assessment was deemed "probable" for leflunomide and tendonitis. No further action was recommended.

4.1.6.2 Leflunomide and headache, cystitis, Haematuria (60932)

Discussion

The Committee noted that there have been no previous reports to CARM or the WHO of headache, cystitis or haematuria with leflunomide use.

The causality assessment was deemed "possible" for leflunomide and headache, cystitis and haematuria.

Recommendation

The Committee recommended that a watching brief be placed on leflunomide and headache, cystitis and haematuria.

4.1.7 Psychiatric medication-related reports

4.1.7.1 Chlorpromazine and arrhythmia, cardiac failure, drug level increased (59947)

Discussion

The Committee noted the description of this case and the coroner's verdict. Members considered that in view of the patient's risk factors for IHD, it was possible that the patient had suffered an MI. It was noted that the coroner's report did not comment on the state of the patient's coronary arteries. Members noted that the NZPhvC has received one other report of CHF with chlorpromazine.

The causality assessment was deemed "probable" for arrhythmia, cardiac failure and death, and definite for drug level increased.

Recommendation

The Committee recommended that the NZPhvC review the post-mortem report on this patient with respect to the possibility of myocardial infarction as a cause of the patient's death.

4.1.7.2 Fluoxetine and therapeutic response inadequate (60457)

Discussion

The Committee agreed that this report highlighted the need for close monitoring of patients in the initial weeks after commencing anti-depressant treatment. See minute item 3.2 for further discussion on this issue.

The causality assessment was deemed "possible" for fluoxetine and therapeutic response inadequate. No further action was recommended.

4.1.8 Vaccine related medication reports

4.1.8.1 Hib/HepB, DtaP/IPV and sudden death (60045)

Discussion

The members discussed the above case report. The causality assessment was deemed "unclassified" for Hib/HepB, DtaP/IPV and sudden death.

Recommendation

The Committee recommended that a watching brief be placed on Hib/HepB, DtaP/IPV and sudden death.

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

• Moclobemide: 5 reports of reduced therapeutic effect.
• Morphine sulphate (switch from MST to M-Eslon): 25 reports of reduced therapeutic effect.
• Felodipine (reintroduction of Felo brand): 16 reports in total with only 1 for reduced therapeutic effect. Other reports include palpitations, chest pain, dizziness, nausea, diarrhoea, rash, headache, tremor, paraesthesia, visual disturbances and fatigue.
• Enalapril: 5 reports of which 3 were for reduced therapeutic effect.

4.2.1.2 Other medicine-related reports

• Simvastatin: reports of biochemical hepatitis
• Alendronate: reports of abdominal pain
• Quinine sulphate: reports of thrombocytopaenia
• Xray contrast media: reports of hypersensitivity reactions.

4.2.1.3 Vaccine-related reports

• The pattern of adverse events following immunisation is largely unremarkable with typically expected events. The reports for Influenza Virus vaccine reactions have increased in synchrony with the vaccination season. As in previous years they have been largely unremarkable with many expected events.
• Other vaccines reporting 3 or more specific events are IPV, MMR, DtaP/IPV, Hep B, HIB/HepB and Pneumococcal vaccines.

≥ Six Reports in the Year-to-Date

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

Adverse Reactions of Current Concern

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

4.3 Intensive Medicines Monitoring Programme

Issue

The NZPhvC provided the Committee with a report on the medicines that remain on the IMMP, along with an outline of the work the IMMP is to undertake in 2004-2005.

Discussion

Members reviewed the NZPhvC report on this issue. The Director of NZPhvC advised that the cohorts for sibutramine and Mirena will shortly be closed, therefore only the four atypical antipsychotics (i.e. clozapine, risperidone, olanzapine and quetiapine) will be monitored on the IMMP. The Committee was in agreement with the decision as to which medicines should remain on the IMMP.

5 PHARMACOVIGILNCE 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 HRT

References

• Naftolin et al (2004). The Women's Health Initiative could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition. Fertility and Sterility 81(6). 1498-1501.
• PHARMAC. Notification of the decision made by PHARMAC's Board regarding the subsidised prescribing of Hormone Replacement Therapy (HRT).
• PHARMAC. Media release: PHARMAC to fund information to doctors, patients on HRT. August 2004.

5.2 Pharmacovigilance language/methodology

References

• Tsintis P and La Mache E (2004). CIOMS and ICH initiatives in Pharmacovigilance and Risk Management: Overview and Implications. Drug Safety 2004; 27(8): 509-517.
• Nebeker R (2004). Clarifying Adverse Drug Events: A Clinician's Guide to Terminology, Documentation, and Reporting. Annals of Internal Medicine 2004; 140:795-801.
• Griffin M et al (2004). Postmarketing surveillance for drug safety: Surely we can do better. Clinical Pharmacology and Therapeutics 2004; 75(6): 491-494.
• Brown E (2004). Using MEDRA: Implications for Risk Management. Drug Safety 2004; 27(8): 591-602.
• McEwen J (2004). Risk Management from an Asian/Pacific Rim Regulatory Perspective. Drug Safety 2004; 27(8): 491-497 (Abstract only).

5.3 Cox 2 inhibitors

References

• Schnitzer T et al (2004) Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 364: 665-674.
• 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.
• Clark et al (2004). Do some inhibitors of COX-2 Increase the Risk of Thromboembolic Events? Linking Pharmacology with Pharmacoepidemiology. Drug Safety 2004; 27(7): 427-456. (Abstract only).

5.4 CARM case reports

• 30 Plus (59880)
• Percutane (60006)
• Rapture, Charge (60226)
• Bio-Oil (60707)
• Evening Primrose Oil (60737)
• Imaglow (60868)
• ALJ Capsules (60872)
• Blis Bio Restore (61141)
• Influenza vaccine (60356)
• Influenza vaccine (61181)

6. New Zealand activities

6.1 Minutes of the May 2004 PTAC meeting

7. international activities

7.1 WHO

WHO Pharmaceuticals Newsletter No 3 2004
Signal: Analyses of the Adverse Reaction Reports in the WHO Database, June 2004
MUR 26: Uppsala Reports July 2004

7.2 Canada

Canadian Adverse Reaction Newsletter 14(3), July 2004

7.3 Australia

Australian Adverse Drug Reactions Bulletin 23 (3), June 2004
Australian Adverse Drug Reactions Bulletin 23 (4), August 2004
Australia Prescriber 27 (4), August 2004
Minutes of the May 2004 meeting of the Adverse Drug Reactions Advisory Committee
Minutes of the June 2004 meeting of the Adverse Drug Reactions Advisory Committee

7.4 Singapore

Adverse Drug Reaction News 6 (2), July 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 2:30pm

Excerpt from draft minutes