MARC MEMBERS PRESENT

marc secretariat present

invited experts

visitors

1.

MATTERS OF ADMINISTRATION

1.1

Welcome and apologies

1.2

Minutes of the 113^th meeting

1.3

Date of next meeting

1.4

Conflict of interest

1.5

Prescriber Update

2.

MATTERS ARISING

2.1

Report on actions arising from the 113^th MARC meeting

2.1.1

Minute item 2.1.2 Leflunomide/methotrexate/ketoprofen/triamcinolone and septic shock/septic arthritis/multiple organ failure/infection streptococcal/vomiting - CARM case report 52507

Advisory for Health Professionals. Important safety information on Arava: severe and serious hepatic reactions. Aventis Pharma Inc (via Health Canada website), May 2001.

Bonnel et al. (2002) Office of Drug Safety Review: Leflunomide: Severe hepatotoxicity and liver failure. Food and Drug Administration.

Raczkowski, V. (2003) Post-marketing safety memo: Leflunomide: Hepatotoxicity. Food and Drug Administration.

New Zealand data sheet for ARAVA. August 2002.

The above safety information led to rapid modifications to the prescribing and patient information for Arava. Included among these changes were extensive monitoring and washout recommendations.

In May 2001, Aventis Pharma Inc. issued a Dear Healthcare Professional letter in Canada conveying important safety information about severe and serious hepatic reactions with Arava. A related article published in the Canadian Adverse Reaction Newsletter (October 2002) stated that, of 99 ADR reports for leflunomide received by Health Canada from April 2000 to June 2002, 20 involved hematologic reactions and 11 involved hepatic reactions. The article reminded prescribers that leflunomide may have serious hepatic, hematologic, and respiratory effects, and that these risks may be increased by concomitant methotrexate use. Strict vigilance in monitoring the liver function of all patients prescribed leflunomide was recommended.

In November 2002, the FDA's Office of Drug Safety produced a report examining the issue of leflunomide and severe hepatotoxicity and liver failure. From September 1998 to September 2002, the FDA received 54 case reports of serious hepatic injury that were temporally associated with the use of leflunomide. The authors examined the risks and benefits of leflunomide and found an absence of documented long-term benefit (based on objective indices of functional ability or delayed mortality). It was concluded that the risks of leflunomide greatly exceed its benefits, and leflunomide should be withdrawn from the market.

In January 2003, the above recommendation was directly contradicted in a memorandum written by senior FDA officials. In this memorandum it was noted that, although many of the ADR reports of leflunomide hepatotoxicity are confounded, inconclusive, or incomplete, the data provide credible evidence that leflunomide may cause serious hepatic events. However, the Office of Drug Safety report did not adequately consider the substantial medical burden imposed on patients by rheumatoid arthritis; the considerable toxicities of other treatments; or that management of rheumatoid arthritis often requires that a range of treatment options be available. An external advisory panel to the FDA concurred with this view.

The Committee recommended that the product sponsor for Arava be asked to remove the words "first-line" from the data sheet statement, "Arava may be used as a first-line treatment in patients who have failed to respond to other treatments".

2.1.2

Minute item 2.1.5 Adverse Reactions of Current Concern

2.1.3

Minute item 2.2.1 Missed-pill advice for Cerazette

2.1.4

Minute item 3.1.2.1 Thyroguard and back pain/TSH decreased/fatigue (53598)

2.1.5

Minute item 3.1.6.1 Premarin and DVT (53381)

2.1.6

Minute item 3.1.8.1 Bupropion and erythema multiforme/arthralgia (52534)

After further discussion between Medsafe and ADRU, it was decided that there is insufficient merit in re-publicising the well-known skin reactions with bupropion.

2.1.7

Minute item 3.1.10 Vaccine-related reports

Robertson W.C. (2002) Carbamazepine toxicity after influenza vaccination. Pediatr Neurol, 26, 61-63.

Grabenstein, J.D. (1990) Drug interactions involving immunologic agents. Part I. Vaccine-vaccine, vaccine-immunoglobulin, and vaccine-drug interactions. Drug Intelligence and Clinical Pharmacy, Annals of Pharmacotherapy, 24, 67-81.

Jann & Fidone (1986) Effect of influenza vaccine on serum anticonvulsant concentrations. Clinical Pharmacy, 5, 817-820.

Meredith, C.G. et al. (1985) Effects of influenza virus vaccine on hepatic drug metabolism. Clin Pharmacol Ther, 37, 396-401.

The Committee recommended that Medsafe consider the issue of influenza vaccine interactions and decide whether it is necessary for it to be included in the June 2003 MARC meeting agenda.

Given that many patients receiving the influenza vaccine are likely to be on multiple medications (the influenza vaccine is especially indicated for the elderly, and most patients with chronic diseases), the theory that the influenza vaccine can cause depression of CYP450 isoenzymes responsible for the oxidation of many medicines has important clinical implications.

The Committee agreed that there is not enough firm evidence to justify a data sheet change at this time. It was proposed that a general paragraph regarding vaccine-drug interactions (alluding to the potential around influenza vaccines) be published in Prescriber Update.

2.1.8

Minute item 3.3.5 Presentation on IC-values

2.1.9

Minute item 4.1 Safety information from the Salmeterol Multi-centre Asthma Research Trial

2.2

Report on actions outstanding

2.2.1

Minute item 2.1.4 HRT and cancer/stroke/heart disease

2.2.2

Minute item 4.1 High-dose fluticasone and adrenal insufficiency

2.2.3

Sept 2002 minute item 3.3.1 COX-2 inhibitors

Medsafe is awaiting a response from Pharmacia.

2.2.4

June 2002 minute item 2.2.3 SSRIs and GI haemorrhage

Layton et al. (2001) Is there an association between selective serotonin reuptake inhibitors and risk of abnormal bleeding? Results from a cohort study based on prescription event monitoring in England. Eur J Clin Pharmacol, 57, 167-176.

De Abajo, et al. (1999) Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ, 319, 1106-1109.

Letter and Health Authority Response (re Anafranil and GI bleeding) from Novartis to Medsafe. June 2002.

Letter and report (re Prozac and GI bleeding) from Eli Lilly to Medsafe. August 2002.

Williams, D et al (2000) Association between SSRIs and upper gastrointestinal bleeding (letter). BMJ, 320, 1405.

Dunn, N.R. et al (2000) SSRIs are no more likely than other drugs to cause such bleeding (letter). BMJ, 320, 1406.

Dalton et al. (2003) Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding - a population-based cohort study. Archives of Internal Medicine, 163, 59-64.

A Prescriber Update article on SSRIs and gastrointestinal bleeding, with mention of age and NSAID/aspirin use as risk factors, is written for publication. The central message should be that if a patient has a gastrointestinal bleed, SSRI use should be considered as a potential causative factor.

Gastrointestinal bleeding is included as a potential adverse reaction in SSRI data sheets.

As serotonin potentiates platelet aggregation, there is a plausible pharmacological mechanism in support of the aforementioned studies. The MARC recommendations extended to tricyclic antidepressants that are also potent inhibitors of serotonin reuptake (e.g., clomipramine).

At the June 2002 MARC meeting, the Committee was informed that some companies had updated the data sheets as requested, others had requested permission to use alternative statements (e.g., abnormal bleeding, ecchymosis), and others had not yet replied.

Subsequently, Medsafe received a report from Novartis that disagreed with the MARC's recommendation to include GI bleeding in the Anafranil data sheet. Similarly, in August 2002, Medsafe received a report from Eli Lilly that disagreed with the MARC's recommendation to include GI bleeding in the Prozac data sheet. In October 2002, the Committee advised against publishing a Prescriber Update article on this topic as, in comparison to other safety issues present at the time, it was a relatively minor issue.

Members suggested that Medsafe investigate whether the issue of SSRIs and GI bleeding is mentioned in international data sheets for Anafranil and Prozac. If so, the sponsor companies should be asked to also include this information in the New Zealand product data sheets. The Committee agreed that Medsafe should thank Novartis and Eli Lilly for their reports, and inform them that the MARC is keeping a watching brief on the issue of SSRIs and GI bleeding.

The Committee recommended that Medsafe investigate whether the issue of SSRIs and GI bleeding is mentioned in international data sheets for Anafranil and Prozac. If so, the sponsor companies should be asked to also include this information in the New Zealand product data sheets.

3.

matters arising from the New Zealand Pharmacovigilance Centre (NZPHVC)

Spontaneous reporting programme

• comment about causality;
• information about similar suspected adverse reactions reported with the same or related medicines;
• prescribing advice;
• advice related to the care of the patient, including information that may assist the practitioner to make a risk/benefit assessment for future treatment; and
• any specific action being taken by the Centre, including entry of the reaction into the National Health Index against the patient's name, presenting the reaction to the MARC, including it in an article to be published, etc.

Explanations of the terms used by CARM and MARC can be accessed by hyperlink at each causality designation.

3.1

High Priority Case Reports

3.1.1

Reports in which death occurred

3.1.1.1

Thioridazine/fluoxetine and sudden death/arrhythmia/drug interaction (55013)

3.1.1.2

3.1.1.3

Lamotrigine and pancreatitis haemorrhagic (55349)

3.1.2

Alternative medicine-related reports

3.1.2.1

Herbal X and ovarian disorder/menopausal symptoms/oestrogens decreased/LH decreased/FSH decrease (54950)

The Committee agreed that caution should be exercised in ascribing causality to this report. Temporary menopause or transient changes in FSH and LH levels is not abnormal, and it may even be a somewhat common event as women approach menopause. The Committee was not aware of any longitudinal studies investigating this issue. Members also questioned whether the intensity of the exercise the woman had been doing remained the same throughout the time-period of the report.

The causality was deemed to be "possible" and no further action was recommended.

3.1.3

Cardiovascular medication-related reports

3.1.3.1

Sodium tetradecyl sulphate/Premia 5 and DVT, drug interaction (54298)

The product data sheet for sodium tetradecyl sulphate lists concomitant administration of oral contraceptives as a contraindication. The Committee agreed that HRT should also be included in this list. In addition, members agreed that a letter should be sent to the Appearance Medicine Society of Australasia to inform them of the data sheet update and suggest that it be incorporated into their Guidelines.

3.1.4

Dermatological medication-related reports

3.1.4.1

Isotretinoin and dry skin/photosensitivity/flushing/vulval vaginitis/vulval discomfort (54986)

The Committee noted that drying of the vagina and anus is uncommon with isotretinoin, and is becoming even less common with decreasing doses being prescribed. Members agreed that, while the vaginal dryness during treatment was probably related to the isotretinoin, most of the patient's symptoms were related to underlying vulvar vestibulitis, and this was not related to the medication.

The Committee agreed that, for completeness, the product data sheets should be updated to include drying of the vagina and anus as adverse effects, and no further action was recommended.

3.1.4.2

Itraconazole/budesonide/diltiazem and Cushing's syndrome/drug interaction (54458)

The product data sheets for Sporonox and budesonide refer to inhibition of medicines metabolised by the CYP3A family. The data sheet for diltiazem makes no mention of CYP3A inhibition. Members agreed that the risk of Cushing's syndrome (as a result of drug interaction) should be stated on the budesonide data sheets. The causal association was deemed to be "possible" for both Cushing's syndrome and drug interaction.

The Committee also recommended that the issue of diltiazem interactions due to CYP3A inhibition be placed on the September 2003 MARC meeting agenda.

3.1.5

Psychiatric medicine-related reports

3.1.5.1

Paroxetine and weight increase (54907)

3.2

Medium Priority Case Reports

3.2.1

Corticosteroid-related reports

3.2.1.1

Inhaled steroids (multiple) and skin atrophy/purpura/skin fragility (55075)

3.2.2

Dermatological medication-related reports

3.2.2.1

Pimecrolimus and herpes simplex/erythema multiforme (54279)

3.2.3

Psychiatric medicine-related reports

3.2.3.1

Bupropion and paroniria/anxiety/gingival bleeding (54283)

3.2.3.2

Zopiclone and amnesia/ataxia/confusion/hallucination/manic reaction (54567)

3.3

Spontaneous reporting programme - signals

3.2.1

Influenza vaccine and Guillain Barre Syndrome

The following is a review of cases of GBS following immunisation reported to CARM.

The Committee was not aware of any epidemiological study in which antecedent events in GBS patients were investigated. Members agreed that there is insufficient evidence to suggest an increased risk of GBS following influenza virus vaccination in New Zealand. There are uncertainties with regard to the degree of under-reporting to CARM, and the number of actual related cases (i.e., some cases of GBS following influenza immunisation will occur by chance). The Committee suggested that CARM write to the Neurological Association of New Zealand to seek their views on the issue of influenza vaccine and GBS, and the need for epidemiological research in this area.

3.2.2

Statins and tendonopathy

The five CARM case reports (affecting four men and one woman) reflect a consistent pattern of tendonopathy occurring within six-months of initiation of statin therapy. Two of the reports provide rechallenge evidence of tendonopathy with atorvastatin.

A search of the WHO database revealed 205 reports of tendonitis, tendon disorder or tendon rupture associated with statins. These occurred predominantly with simvastatin (n=71) and atorvastatin (n=58), although this may reflect the wider use of these agents.

A search of the literature revealed four cases of tendonopathy in patients on statin therapy (both atorvastatin and simvastatin). The events occurred within two-months of treatment initiation and resolved within a similar period.

3.2.3

Amiodarone and back pain

There is evidence from the case reports that amiodarone is being administered incorrectly (i.e., the volume of diluent is less than that recommended by the manufacturer). An excessively concentrated solution may be one explanation for the pain occurring in some patients.

It has been noted that some other parenteral medicines, including iodinated contrast media and protamine sulphate, can cause severe musculoskeletal pain. Both of these, like amiodarone, are used for cardiological conditions often in anticoagulated patients.

3.2.4

NZPhVC review of March 2003 issue of 'Signal - Analyses of adverse reaction reports in the WHO database.'

Rosiglitazone and pancreatitis

This medicine is now available, but not funded, in New Zealand. The UMC reviewer has concluded that there is a strong signal, despite the fact that many of the patients would have received other medicines or had other disorders that could cause pancreatitis. Rosiglitazone improves insulin sensitivity at sites where resistance occurs most often, and is therefore used as an adjunctive treatment in type-2 diabetes.

Alendronate and synovitis

The sponsor company for alendronate does not believe this is a signal, however, there is one positive rechallenge and CARM holds a further report (not yet in the WHO ADR database, Vigibase), which described synovitis, an elevated C-reactive protein, and a positive rechallenge. Alendronate is widely used in New Zealand for severe osteoporosis with fractures.

Sirolimus and GI haemorrhage

There is one further report in the CARM database of diarrhoea and haematemesis (Mallory-Weiss tear found on endoscopy).

Moxifloxacin and respiratory insufficiency

This may be part of an anaphylactic reaction. The data sheet for moxifloxacin states that severe hypersensitivity reactions can occur, although it does not specifically mention respiratory effects.

Gatifloxacin and rhabdomyolysis

There is one report for gatifloxicin in the CARM database (fasciitis). The UMC reviewer commented, "Myalgia and rhabdomyolysis can occur with fluoroquinolones but are not well documented".

3.4

CARM Quarterly report (as at 31 March, 2003)

3.4.1

Multiple occurrence reaction reporting

≥ Three Reports in the Last Quarter

3.4.1.1

Brand-switch related reports

Clonazepam (switch from Rivotril to Paxam): reports of reduced therapeutic effect have been received. This raises concern around the strategy of allowing brand substitution in patients with serious conditions, such as epilepsy, that are well controlled on a particular brand.

Citalopram (switch from Cipramil to Celapram): 25 reports of reduced therapeutic effect have been received (three of these have involved suicidal ideation).

The Committee recommended that Medsafe write to the Pharmacy Guild, reminding pharmacists that they have an obligation not dispense narrow therapeutic index medications, such as clonazepam, without checking which brand the patient is on.

3.4.1.2

Other medicine-related reports

Sodium tetradecyl sulphate and DVT (these are a cluster of reports from a single reporter).

3.4.1.3

Vaccine-related reports

The Committee queried the number of hypotonic-hyporesponsive episode (HHE) reports (n=6) for both HiB/HepB and DTaP/HiB. It was noted that these episodes are not classic, severe HHE (e.g., collapsed child), but are short-lived and mild (child is slightly floppy). These HHE reports can be separated by their grading on the CARM database (i.e., severe or not severe).

≥ Six Reports in the Year-to-Date

3.5

Intensive Medicines Monitoring Programme

Note:

Members noted that reports 3.5.1 to 3.5.4 are not founded on complete IMMP cohorts. The observations described are preliminary and are based on reports to the IMMP and WHO databases, along with published literature.

3.5.1

Risperidone and oedema

The data sheet for Risperdal lists oedema as a 'less common' adverse effect, although a clinical trial (in elderly people) reported that about 16% of patients taking risperidone experienced oedema.

Risperidone, particularly in high doses, may lead to sodium and fluid retention and thus peripheral oedema, through its pharmacological mechanism in blocking dopamine receptors. Other mechanisms may also contribute. For example, there is evidence that prolactin (the levels of which are increased by risperidone) plays a role in increasing the production of several mediators of the inflammatory response, including prostaglandins such as PGE2, which promote vasodilation and increase capillary permeability to fluid and electrolytes. It is possible that if risperidone induces fluid retention in some patients, this may result in heart failure in those at risk. No cases of heart failure associated with risperidone have been reported to the IMMP, but the WHO database includes 51 cases. Further review of these cases would be required to determine if risperidone-induced fluid retention was part of the aetiology in these patients.

3.5.2

Risperidone and epistaxis, bleeding disorders

The WHO database holds 56 reports of epistaxis associated with risperidone. A literature search did not identify any publications citing risperidone and epistaxis. The WHO database also holds 260 reports of platelet and bleeding disorders with risperidone, including 182 for thrombocytopenia. If risperidone is associated with an increased bleeding tendency in some individuals, it may also lead to an increased risk of haemorrhagic stroke.

It was noted that the New Zealand data sheet for risperidone states that, "a mild fall in thrombocyte count has been reported".

It was suggested that Medsafe investigate references to thrombocytopenia in the international product information for risperidone, before deciding whether the current New Zealand data sheet statement should be strengthened.

3.5.3

Risperidone and hyperprolactinaemia, male sexual disorder

Dickson, R.A. (1999) Hyperprolactinaemia and male sexual dysfunction. Journal of Clinical Psychiatry, 60 (2), 125.

3.5.4

Risperidone and prolonged QT interval, interaction with paroxetine

Al-Khatib S.M, et al (2003) What clinicians should know about the QT interval. JAMA, 289, 2120-2127.

Moss A.J. (2003) Long QT syndrome. JAMA, 289, 2041-2044.

Evidence from the IMMP reports, WHO database, ArizonaCERT database, and recent articles in the literature indicate that risperidone may cause QT prolongation. This in turn may lead to an increased risk of torsades de pointes, which may be a cause of sudden unexplained death.

3.5.5

Status of monitoring of IMMP medicines (as at May 2003)

Celecoxib (n=33034) and Rofecoxib (n=26741) cohorts are closed. Prescription data entry is complete. Twenty percent of follow-ups have been processed. Quality checks on the data are almost complete for all regions except Auckland. Follow-up questionnaires are ready to be sent out by region in succession.

Etoricoxib (n=501) cohort is open and prescription data entry commenced.

Parecoxib (n=0) cohort is open. The method of data collection is being negotiated with hospitals and the sponsor company.

Sibutramine (n=5453) cohort is open. Prescription data entry is underway for next follow-up. A sufficient cohort size may be achieved with this year's data, and the study should be complete by the end of 2004.

Tolcapone (n=546) and Entacapone (n=51) cohorts are open. Follow-ups are currently being processed.

Montelukast (n=1424) cohort is open. Follow-ups are currently being processed.

Zarfirlukast (n=0) cohort is open. No action is being taken.

Nefazodone (n=4005) cohort is open. Final prescription data entry is in progress and the final follow-up will follow. The study should be complete by early 2004.

Clozapine (n=232), Olanzapine (n=2762), Quetiapine (n=104), and Risperidone (n=313) cohorts are open. Prescription data entry is on hold while the IMMP processes the COX-2 data. When the current scripts are entered, the cohorts may be adequate. A restricted follow-up planned, with an expected completion early 2005. A special study is to be undertaken on metabolic disorders.

Mirena (n=7602) cohort is closed. Elements of data entry are still to be completed and the next follow-up will be sent.

Multiload (n=16159) cohort is closed. Data are undergoing final quality control. This will be followed by final analysis and papers.

Salmeterol (n=9975) and Eformoterol (n=2170) cohorts are closed. Data entry and quality checks are to be undertaken prior to final follow-up enquiries. A particular emphasis on deaths will be made.

3.5.6

Mirena and insertion difficulties

3.5.7

Automated methods of signal detection

Waller P. (2003) Dealing with uncertainty in drug safety: lessons for the future from sertindole. Pharmacoepidemiology and Drug Safety, 12, 283-287.

4.

Pharmacovigilance issues

4.1

Paroxetine and Risk of Harmful Outcomes in Paediatric Patients

GlaxoSmithKline - Dear Healthcare Professional letter to New Zealand prescribers. Changes to the Aropax data sheet regarding use of Aropax in children. June 2003.

GlaxoSmithKline - Technical Document Summaries for Paroxetine: Summary of Clinical Safety. 2003

The New Zealand data sheet for Aropax has been updated to advise that clinical trials do not support the use of paroxetine in the treatment of children with major depressive disorder (MDD). In addition, GSK issued a related Dear Healthcare Professional letter to New Zealand prescribers on June 12 2003, and a follow-up letter on June 26 2003.

On review of the Summary of Clinical Safety data provided to Medsafe by GSK, members agreed that the data indicate an increased risk of behavioural-related adverse experiences in paediatric patients using paroxetine. The Committee noted that reports of serious emotional lability (e.g., suicide attempt, suicidal thinking) occurred predominantly in paroxetine-treated adolescents with MDD. Members agreed that this is a significant signal, however, they did not believe the data justifies that paroxetine be contraindicated for the treatment of depressive illness in paediatric patients at this time.

The Committee noted that in the United States, fluoxetine is approved for the treatment of depressive illness in children. Members suggested that Medsafe investigate evidence that fluoxetine is effective, and no more dangerous than paroxetine, in the treatment of depression in children.

The Committee agreed that an article regarding the management of depression in children should be written for publication in Prescriber Update. The article should be written by a child psychiatrist and should make particular reference to risk of harmful outcomes with paroxetine, and the fact that fluoxetine is licensed for the treatment of childhood depression in the United States.

Members recommended that Medsafe investigate evidence that fluoxetine is effective, and no more dangerous than paroxetine, in the treatment of childhood depression.

4.2

Combined Hormone Replacement Therapy and Dementia

Yaffe, K. (2003) Hormone therapy and the brain. Déjà vu all over again? JAMA, 289(20), 2717-2719

Shumaker et al. (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. JAMA, 289(20), 2651-2662

Rapp et al (2003) Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the WHIMS: a randomised controlled trial. JAMA, 289(20), 2663-2672

Wassertheil-Smoller et al. (2003) Effect of estrogen plus progestin on stroke in postmenopausal women. JAMA, 289(20), 2673-2684

Grady, D. (2003) Postmenopausal hormones - therapy for symptoms only. NEJM, 348(19) 1835-1837

Hays et al (2003) Effects of estrogen plus progestin on health-related quality of life. NEJM, 348(19), 1839-1854

Humphries & Gill (2003) Risks and benefits of HRT: the evidence speaks. CMAJ, 168(8), 1001-1010

Members agreed that the MARC advice issued in September 2002 has not changed as a result of the WHI memory study. MARC continues to advise that:

Combined HRT should normally be used only where menopausal symptoms are disruptive to the quality of life of the woman;

In most circumstances, the risks of long-term treatment outweigh the benefits; and combined HRT should not be used for longer than 3-4 years;

All prospective and current users of HRT should be advised of the risks and benefits of oestrogen and progestogens;

The need for continued treatment with HRT should be reviewed at the woman's next visit to her General Practitioner and thereafter on a yearly basis.

The Committee was informed that the New Zealand Guidelines Group has updated its HRT guidelines to include information about dementia risk. The Guidelines Group's HRT consumer leaflet will be similarly updated.

Members agreed that combined HRT product data sheets should be updated to include a statement about the possible risk of dementia. In addition, the Committee proposed that an article describing the findings of the WHI memory study be written for publication in Prescriber Update. The article should state that the study findings reinforce the MARC advice regarding HRT issued in September 2002.

The Committee recommended that a related article be published in Prescriber Update. The article should describe the findings of the WHI memory study, and emphasise the fact that the MARC advice regarding HRT has not changed from that issued in September 2002.

4.3

Risperidone and Cerebrovascular Accidents in Elderly Patients with Dementia

Advisory for the Public. Updated safety information for Risperdal in elderly dementia patients. Health Canada, October 2002.

Advisory for Health Professionals. Risperdal and cerebrovascular adverse events in placebo-controlled dementia trials. Health Canada, November 2002.

FDA MedWatch Safety Alert - Risperdal Dear Healthcare Provider letter. April 2003.

New Zealand data sheet for Risperdal. April 2002.

Following consultation with Health Canada in October-November 2002, Janssen-Ortho Inc advised healthcare professionals and consumers that data from four clinical studies showed an increased incidence of stroke or related events in patients taking Risperdal, compared with placebo-treated dementia patients. Amongst other advice, the Dear Healthcare Professional letter advised physicians to reassess the risks and benefits of Risperdal use in elderly patients with dementia, taking into account risk factors for stroke in individual patients.

More recently, Janssen Pharmaceutica Inc. agreed to revise the United States prescribing information for Risperdal. The following paragraph has been added to the 'Warnings' section of the Risperdal product information, and a related Dear Healthcare Professional letter was issued in April 2003.

"Cerebrovascular adverse events (e.g., stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. Risperdal has not been shown to be safe or effective in the treatment of patients with dementia-related psychosis."

Members agreed that the product sponsor for Risperdal should be asked to issue a Dear Healthcare Professional letter, informing New Zealand prescribers of this issue. The letter should advise prescribers to reassess the use of Risperdal in elderly dementia patients, and inform patients/caregivers of the signs and symptoms of potential cerebrovascular adverse events.

The Committee questioned why the United States has approved Risperdal only for the treatment of schizophrenia, whereas in New Zealand it is indicated for the treatment of schizophrenia and other psychotic disorders, and the treatment of behavioural and psychological symptoms of dementia. Members advised that Medsafe seek clarification on this issue from the FDA.

The Committee recommended that Medsafe seek clarification from the FDA as to why the United States has approved Risperdal only for the treatment of schizophrenia.

4.4

SSRIs and withdrawal reactions

MacGillivray et al. (2003) Efficacy and tolerability of SSRIs compared with TCAs in depression treated in primary care: systematic review and meta-analysis. BMJ, 326, 1014-1019

Hall et al. (2003) Association between antidepressant prescribing and suicide in Australia, 1991-2000: trend analysis. BMJ, 326, 1008-1013

New Zealand data sheet for AROPAX. May 2003.

The Committee was informed that of the total number of adverse reactions associated with paroxetine reported to CARM, approximately 10% are related to withdrawal reactions. According to the Panorama documentary in the UK, this may reflect only a small proportion of those patients who actually experience withdrawal reactions.

Members agreed that withdrawal events might be more likely to occur with shorter-acting SSRIs such as paroxetine. The Committee suggested a watching brief be kept on this issue, and no further action was recommended at this time.

5.

pharmacovigilance ISSUES FOR INFORMATION ONLY

5.1

5.2

Drug interactions among elderly patients

5.3

Complementary medicines

Barnes, J. (2003) Quality, efficacy and safety of complementary medicines: fashions, facts and the future. Part I. Regulation and quality. Br J Clin Pharmacol, 55, 226-233.

Barnes, J. (2003) Quality, efficacy and safety of complementary medicines: fashions, facts and the future. Part II. Efficacy and safety. Br J Clin Pharmacol, 55, 331-340.

Currie & Clough (2003) Kava hepatotoxicity with Western herbal products: does it occur with traditional kava use? MJA, 178, 421-422

Moulds & Malani (2003) Kava: herbal panacea or liver poison? MJA, 178, 451-453.

Gow et al. (2003) Fatal fulminant hepatic failure induced by a natural therapy containing kava. MJA, 178, 442-443.

5.4

Spontaneous reporting schemes

5.5

Safety of COX-2 inhibitors