Revised: 21 May 2013

Committees

Minutes of the 114th Medicines Adverse Reactions Committee Meeting - 26 June 2003

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

Preface:

In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.

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

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

The recommendations of the committee are in bold typeface.

Minutes:

MARC MEMBERS PRESENT

Associate Professor T.J.B. Maling (Chair)
Professor P. Ellis
Professor D.C.G. Skegg
Dr M. Rademaker
Dr F. McClure
Dr N. Rafter
Dr M. Tatley

marc secretariat present

Dr K. Maclennan (MARC Secretary/Pharmacovigilance Advisor, Medsafe)
Dr S. Jessamine (Principal Technical Specialist, Medsafe)

Invited Experts

Dr R. Savage (NZPhVC)

Visitors

Dr A. Roberts (Ministry of Health) (present for vaccine-related section of CARM Quarterly Report, and the Influenza vaccine and Guillian Barre agenda item).

1. MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed Dr Ruth Savage from the NZPhVC to the meeting. Apologies had been received from Dr H. Kingston and Ms S. Von Afehlt.

1.2 Minutes of the 113^th meeting

Members agreed that the minutes of the 113^th meeting are a true and accurate record of the meeting.

1.3 Date of next meeting

Wednesday 17 September is the confirmed date for the next MARC meeting.

1.4 Conflict of interest

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

1.5 Prescriber Update

Article

.., Insertion studies of the Multiload Cu375 intrauterine device (discussion of comments from peer review of article).

Issue

A key concern arising from peer review of this article was the presentation of data on insertion problems, when comparing doctors with low and moderate insertion rates. One peer reviewer commented that the article is unclear as to whether the difference in the number of insertion problems between these two was statistically significant. It was noted that the large number of insertions required before there is a reduction in insertion problems is impractical and unrealistic with regard to the number of doctors available to provide this service throughout New Zealand.

Discussion

The Committee concurred with the above peer review comments and agreed the article should be re-written to emphasise the low risk of insertion problems in general with this device. The article should clarify the level of statistical significance between all inserting-rate groups, and note the reality about access to IUCD insertion services (e.g., availability in rural areas). In addition, members advised that insertion problems should be reported as annual rates. Members expressed some concern about how meaningful the data in this paper are (given the reporting rates), and did not believe it should be used as a basis for MARC advice about insertion guidelines.

Recommendation

The Committee recommended that .. be asked to re-write the Multiload IUCD article to inform prescribers that this study was carried out, and found a low risk of insertion problems in general with this device. In addition, the article should clarify the level of statistical significance between all inserting-rate groups, and note the reality about access to IUCD insertion services.

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

Reference Material

CARM spontaneous reaction reporting data (as at October 2002): Adverse reactions enquiry for leflunomide.

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.

Issue

Members agreed that Medsafe should collate and evaluate available data in order to decide whether the issue of leflunomide-induced hepatotoxicity or pancytopenia requires regulatory action or comment from the MARC.

Action

Medsafe reported that, in October 1999, the European Agency for the Evaluation of Medicinal Products (EMEA) issued a public safety statement concerning pancytopenia and serious skin reactions with leflunomide. A further EMEA public safety statement was issued in March 2001, this time regarding leflunomide and serious hepatic reactions. It was noted that in many of the ADR case reports, the patients were concomitantly treated with methotrexate. In addition, attention was drawn to the fact that, as the active metabolite of leflunomide is eliminated very slowly, adverse effects may occur even when leflunomide treatment has stopped (similarly, recovery from ADRs may be prolonged).

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.

Discussion

Members noted that leflunomide is not used extensively in New Zealand and is primarily used as a third-line therapy. The product data sheet for Arava states that, "Arava may be used as a first-line treatment in patients who have failed to respond to other treatments." Members noted that this wording is contradictory and recommended that the words "first-line" be removed from this sentence. The Committee also noted that, in some patients, leflunomide can be a life-changing drug and the risk of adverse reactions needs to be weighed carefully against the benefits this treatment can provide. Members agreed that prescribers should be reminded of the profile of serious reactions to leflunomide (including liver dysfunction, haematological disorders, severe skin disorders, and pulmonary dysfunction) by way of a Dear Healthcare Professional letter and a Presciber Update article. The need for linkage between the initial prescribing of leflunomide by rheumatologists, and the subsequent GP review of these patients should be highlighted. It was noted that ADRAC published a Bulletin article entitled 'Leflunomide - serious hepatic, blood, skin and respiratory reactions' in June 2001, and that this may be a useful source of information for a Prescriber Update article. It was also advised that a rheumatologist be closely involved of the writing of this article.

Recommendations

The Committee recommended that Medsafe ask the product sponsor of leflunomide to issue a Dear Healthcare Professional letter to New Zealand prescribers. The letter should convey information about serious reactions to leflunomide, and the importance of patient review and monitoring. In addition, a related article should be published in Prescriber Update.

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

Issue

The Committee recommended that Medsafe act to increase prescriber awareness of the list of adverse reactions of current concern.

Outcome

Adverse Reactions of Current Concern has been listed in the May - November 2003 New Ethicals Catalogue.

Discussion

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

2.1.3 Minute item 2.2.1 Missed-pill advice for Cerazette

Issue

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.

Action

The above request has been made in a letter sent to the product sponsor, Pharmaco. Medsafe is awaiting a response.

Discussion

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

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

Issue

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

Outcome

The Compliance section of Medsafe will test Thyroguard for the presence of thyroxine. Thyroguard is a Nutra-life product and was affected by the Pan Pharmaceuticals product recalls, so there may be some delay before a sample is obtained.

Discussion

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

2.1.5 Minute item 3.1.6.1 Premarin and DVT (53381)

Issue

The Committee recommended that Medsafe request that HRT product information sheets be revised to include an appropriate warning about the risk of thromboembolic disease with these products.

Outcome

A search of the HRT product information available on the Medsafe web site revealed that the risk of thromboembolic disease is covered appropriately in these data sheets. The Premarin data sheet in particular contains a good amount of information about thromboembolic disease in the Contraindications, Precautions, and Adverse Reactions sections. It is likely that the Committee's recommendation was based on an outdated data sheet in the New Ethicals Compendium.

Discussion

Members noted the above and agreed that no further action was necessary.

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

Issue

The Committee recommended that Medsafe liaise with the TGA in Australia with regard to a potential publication warning about the risk of skin reactions with bupropion.

Outcome

The Australian Adverse Drug Reactions Advisory Committee has received 14 reports of bupropion associated with erythema multiforme. The Australian and New Zealand product information for bupropion states that erythema multiforme and Stevens-Johnson syndrome have been reported. In addition, bupropion-related skin reactions were described in a Prescriber Update article in October 2001, and an ADRAC bulletin in June 2001.

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.

Discussion

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

2.1.7 Minute item 3.1.10 Vaccine-related reports

Reference Material

Hayney, M.S. et al. (2002) Effect of influenza immunization on CYP3A4 activity. Vaccine, 20, 858-861.

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.

Issue

At the March 2003 MARC meeting, the Committee noted that the 264^th ADRAC meeting minutes document ADRAC's recommendation that influenza vaccine product information sheets be updated to include the possibility of an interaction with phenytoin, phenobarbitone, carbamazepine, warfarin, and theophylline. ADRAC's advice was prompted by a case report of an interaction between influenza vaccine and carbamazepine, and data published in the literature.

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.

Outcome

Medsafe reported that the influenza vaccine (possibly mediated by interferon production) might decrease hepatic concentrations of CYP450 and the activity of various CYP450-dependent drug metabolising enzymes. Influenza vaccine has been associated with increased serum concentrations of carbamazepine, phenobarbital, phenytoin, warfarin, and theophylline - in some cases up to 28 days post-vaccination. Results are variable however, and effects varied with time. It is possible that sensitivity to changes in CYP450 activity varies between individuals.

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.

Discussion

The Committee noted that the NZPhVC has received no interaction reports for influenza vaccine, and that the New Zealand product data sheets for influenza vaccines are variable with regard to drug interaction statements.

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.

Recommendation

The Committee recommended that a general paragraph about vaccine-drug interactions (alluding to the potential for influenza vaccines to depress CYP450 isoenzymes) be published in Prescriber Update.

2.1.8 Minute item 3.3.5 Presentation on IC-values

Issue

The Committee recommended that Medsafe seek expert comment on the validity of BCPNN and IC-values from an appropriately qualified statistician.

Outcome

Medsafe believes that more value may be gained by inviting a suitably qualified statistician to speak to the MARC on the use of BCPNN methodology in pharmacovigilance. This would allow the practicalities of IC-values to be discussed in person, and make it easier for questions to be asked and answered. Medsafe will arrange for a statistician to speak at an upcoming MARC meeting.

Discussion

Members were concerned that a statistician may not fully understand the context in which the Bayesian methodology is being used. Therefore, it was suggested that .. liaise with an appropriate statistician to present both practical and technical issues around IC-values at a future MARC meeting. It was noted that IC-values are used in pharmacovigilance to obtain a different perspective of the data, rather than as a legitimate statistical tool.

Recommendation

The Committee recommended that .. liaise with an appropriate statistician to present both practical and technical issues around IC-values at a future MARC meeting.

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

Issue

The Committee recommended that, as appropriate, Medsafe ask New Zealand product sponsors for salmeterol and eformoterol to strengthen product datasheet advice emphasising that the use of these medicines as maintenance therapy should be in addition to corticosteroid treatment of asthma.

Outcome

The above request was made in letters sent to GlaxoSmithKline regarding Serevent, and Novartis regarding Foradil. Medsafe is awaiting a response from each company.

Discussion

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

2.2 Report on actions outstanding

2.2.1 Minute item 2.1.4 HRT and cancer/stroke/heart disease

Issue

The Committee recommended that Medsafe request a copy of the minutes of PTAC's osteoporosis and hormone sub-committee meeting. Following this, Medsafe should decide whether it is still necessary to convene an HRT/osteoporosis working party.

Outcome

The minutes of this meeting were viewed by PTAC at its meeting on 22 May 2003. Once the record of that meeting has been formerly endorsed, Pharmac will forward the relevant minutes to Medsafe. Pharmac expects the endorsement process to take two to three weeks.

Discussion

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

2.2.2 Minute item 4.1 High-dose fluticasone and adrenal insufficiency

Issue

The Committee recommended that Medsafe should write to product sponsors requesting that they review their product data sheets in light of the NZGG advice around appropriate daily doses. If appropriate justification for the recommended doses in the data sheets cannot be provided, the data sheets should be suitably updated. Medsafe should determine whether this applies to all inhaled corticosteroids, or to fluticasone alone.

Outcome

A letter was sent to GlaxoSmithKline in March 2003, informing them of the Committee's recommendations and requesting that the dosage advice in the Flixotide product information be updated to reflect that of NZGG. A response from GlaxoSmithKline has been received, and will be reviewed, by Medsafe.

Discussion

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

2.2.3 Sept 2002 minute item 3.3.1 COX-2 inhibitors

Issue

In view of a recent BMJ editorial concerning limitations of the CLASS study, members recommended the sponsor company be asked to revise the Celebrex data sheet. The Committee advised that Medsafe compose appropriate data sheet statements to be presented to the company.

Outcome

In February 2003, Medsafe sent a letter to Pharmacia advising of discrepancies between the New Zealand, and Australia and American product information sheets for Celebrex. If Pharmacia is unable to justify these differences, the New Zealand Celebrex data sheet should be appropriately updated. In addition, Pharmacia has been asked to provide comment on recent findings concerning limitations of the CLASS study.

Medsafe is awaiting a response from Pharmacia.

Discussion

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

Issue

The Committee noted that the American and Canadian data sheets for rofecoxib contain data from the VIGOR study showing an increased risk of myocardial infarction for rofecoxib compared with naproxen. Members advised Medsafe to negotiate with the New Zealand sponsor companies for Celebrex and Vioxx, in order to effect appropriate data sheet updates with regard to cardiovascular effects.

Outcome

In February 2003, Medsafe sent a letter to MSD advising of discrepancies between the New Zealand, and Australia, Canadian, and American product information sheets for Vioxx. Medsafe has accepted the subsequent data sheet revisions proposed by MSD, and an updated version is to be supplied to the Medsafe Evaluation Team for processing.

Discussion

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

2.2.4 June 2002 minute item 2.2.3 SSRIs and GI haemorrhage

Reference Material

van Walraven et al. (2001) Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ, 323, 655-658.

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.

Issue

At the December 2001 MARC meeting, the Committee reviewed three epidemiological studies, which reported an association between SSRIs and GI bleeding. The MARC recommended that: 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 haemorrhage is included as a requirement for SSRI data sheets in the Regulatory Guidelines.
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.

Discussion

The Committee noted that the study by de Abajo et al (1999) is supported by a recent population-based cohort study that reported an increased risk of upper GI bleeding in patients taking SSRIs (observed-expected ratio = 3.6). This effect was potentiated by concurrent use of NSAIDs or low-dose aspirin. Follow-up of patients after cessation of SSRI therapy showed that the risk of GI bleeding dropped during periods of non-use (observed-expected ratio = 1.2). The Committee also noted that there is evidence to suggest that the combination of SSRIs with other medicines (particularly NSAIDs) in elderly patients is a concern. The Committee proposed that a paragraph reviewing the aforementioned population-based studies, and highlighting the association with NSAIDs and the elderly, be published in Prescriber Update.

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.

Recommendations

The Committee recommended that a paragraph, reviewing the published SSRI and GI bleeding population-based studies, and highlighting the association of GI bleeding with SSRIs together with NSAIDs and the elderly, be published in Prescriber Update.

The Committee recommended that Medsafe 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)

Note: In the comment associated with each report, the case has been given a causality designation using terms and definitions developed by the WHO. The precise definitions are available on the website of the WHO Collaborating Centre http://www.who-umc.org. These designations (certain, probable, possible, unlikely, unclassified and unclassifiable) refer to the degree of certainty about the relationship between the medicine and the adverse event. The terms should not be understood literally. For example, "certain" means that the appropriate elements are present to match the international definition. It does not mean there is absolute certainty that the medicine caused the adverse event.
Explanations of the terms used by CARM and MARC can be accessed by hyperlink at each causality designation.

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)

Discussion

Of 58 reports for thioridazine received by CARM, two are associated with QT prolongation, and two with arrhythmia. The Committee noted that the product data sheet for thioridazine refers to the issue of QT prolongation, as well as interaction with fluoxetine. Members also noted that, since this death occurred, an article about thioridazine and arrhythmia (and related prescribing changes) has been published in Prescriber Update. The causal association was deemed "possible" and no further action was recommended.

3.1.1.2 Leflunomide and pulmonary oedema/hypertension aggravated/MI/oedema peripheral/bronchitis (55033)

Discussion

Of eight reports for leflunomide received by CARM, one is associated with aggravated hypertension and one with septicaemia. Members agreed that it is likely this patient had significant ischaemic heart disease and that leflunomide is not directly implicated in his death. However, the persistent chest infection and possibly an effect on blood pressure may have been minor contributory factors. The causal association was deemed to be "possible" for bronchitis, "unlikely" for pulmonary oedema, myocardial infarction, and peripheral oedema, and "unclassifiable" for aggravated hypertension. Members agreed to keep a watching brief for evidence of leflunomide contributing to cardiovascular disorders in susceptible patients.

3.1.1.3 Lamotrigine and pancreatitis haemorrhagic (55349)

Discussion

This report was received from a pharmaceutical company and CARM has requested further information, including an autopsy report. CARM has received no reports of pancreatitis for either of these anti-epileptic medications; however, there is one report of thrombocytopenia and one of disseminated intravascular coagulation with lamotrigine. The Committee agreed that, while there is some evidence to suggest this medication may have played a role in the development of haemorrhagic pancreatitis, further information is required. The causal relationship was deemed to be "possible".

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)

Discussion

Members noted that Herbal X contains several ingredients including muira puama root, tribulus terrestric fruit, ginseng, damiana, and ginkgo biloba. CARM has not received any other reports for Herbal X. The Committee was informed that the Compliance Unit of Medsafe has been asked to investigate this product and will test for the presence of sex steroids.

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)

Discussion

Of ten reports for sodium tetradecyl sulphate received by CARM, there are no reports of venous thromboembolism. Members noted however, that this report is one of a series of six reports from the same doctor (all of asymptomatic DVT found on ultrasound scan following the use of sodium tetradecyl sulphate).

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.

Recommendation

The Committee recommended that the sponsor company for sodium tetradecyl sulphate be asked to update the product information to include current use of HRT as a contraindication. A letter should be sent to the Appearance Medicine Society of Australasia to inform them of this data sheet update, and to suggest that they incorporate this information 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)

Discussion

The CARM database does not hold any other reports of vulvo-vaginal adverse effects associated with isotretinoin. The WHO database holds 25 reports of vulvo-vaginal dryness, 16 reports of vaginitis, five reports of vulva disorder, and two of vulvitis associated with isotretinoin. Members noted that patient pamphlets for isotretinoin describe vaginal and anal drying, however, the data sheets for isotretinoin products do not specify these problems.

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.

Recommendation

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

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

Discussion

This is the first report of this interaction received by CARM. Members noted that there is a case report in the literature of a patient who developed Cushing's syndrome after long-term treatment with itraconazole and budesonide. In addition, there is a recent study showing that itraconazole increased plasma concentrations of budesonide compared with placebo. Members also noted that diltiazem has been reported to inhibit CYP3A and this may have contributed to the inhibition of budesonide metabolism. The Committee agreed that the issue of diltiazem and CYP3A inhibition should be worked into an agenda item for the next MARC meeting.

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.

Recommendations

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

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)

Discussion

Of 231 reports for paroxetine received by CARM, four are associated with anorexia, and one with weight decrease. Of 24242 reports for paroxetine in the WHO database, 446 are associated with weight increase. The causal association was deemed to be "possible" and no further action was recommended.

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)

Discussion

The Committee agreed that this is probably a dose-related effect. The causal association was deemed "possible" for skin atrophy, purpura, and skin fragility. Members recommended that a short comment about this issue be published in Prescriber Update, with particular reference to steroid-accelerated, sun-induced skin atrophy.

Recommendation

The Committee recommended that a short comment about inhaled corticosteroids and skin atrophy be published in Prescriber Update. Particular reference should be made to steroid-accelerated, sun-induced skin atrophy.

3.2.2 Dermatological medication-related reports

3.2.2.1 Pimecrolimus and herpes simplex/erythema multiforme (54279)

Discussion

There are no reports of infection associated with pimecrolimus in either the CARM or WHO databases. Members noted that pimecrolimus is a macrolide that modulates immune cell function by inhibiting the production of pro-inflammatory cytokines. The causal association was deemed to be "possible" for both herpes simplex and erythema multiforme. No further action was recommended.

3.2.3 Psychiatric medicine-related reports

3.2.3.1 Bupropion and paroniria/anxiety/gingival bleeding (54283)

Discussion

Of 272 reports for bupropion received by CARM, one describes epistaxis and one describes increased INR. Evidence from the WHO database suggests that gingival bleeding has a positive IC-value. The causal association was deemed to be "probable" for paroniria, anxiety, and gingival bleeding. The Committee noted that CARM will write this up as a case report for publication in the dental literature. No further action was recommended.

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

Discussion

Members agreed that the patient's reaction is likely to have been due to a large dose in a naïve user, and the interrupted sleep required for her to transit. The Committee did not feel a need to remind prescribers about this problem, and considered this report to be an unintentional minor overdose. The causal association was deemed "probable" for amnesia, ataxia, confusion, hallucination, and manic reaction.

3.3 Spontaneous reporting programme - signals

3.2.1 Influenza vaccine and Guillain Barre Syndrome

Issue

Recently published reports have again focused attention on the link between the influenza virus vaccine and Guillain Barre Syndrome (GBS). A CDC Vaccine Adverse Event Reporting System report, noted an increase in reports of GBS following influenza virus vaccination in the period 1992 to 1994. A study commissioned to investigate this signal documented an adjusted relative risk for GBS of 1.7 (95%CI=1.0-2.8), suggesting slightly more than one additional case of GBS per million vaccinated against influenza. Evidence for causal association has recently been challenged on the grounds of publication bias in reporting, and possible over diagnosis of GBS in the CDC reports. The issue of GBS is currently being considered as part of an Institute of Medicine's Safety Review Committee report on influenza vaccine and possible neurological complications.

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

Discussion

Members noted that, in the period 1997 to 2002, nine reports of GBS following immunisation against influenza were reported to CARM. While it is difficult to establish the accuracy of the diagnosis of GBS from voluntary reports, all reports indicate that diagnosis had been carefully considered through either neurologist opinion or hospitalisation. Seven of the nine reports document duration to onset within the typical six-week period used in case definitions. Antecedent events are reported to be a possible explanation for chance association in some instances.

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.

Recommendation

The Committee recommended that CARM write a letter 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

Issue

Although a number of diverse adverse events are reported in association with statin therapy, tendon disorders have not been recognised. CARM has received five reports of tendon disorders with statin therapy - four of tendonitis (two each with atorvastatin and simvastatin) and one of tendon rupture with simvastatin.

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.

Discussion

Members noted that CARM intends to submit this signal for publication, and no further action was recommended.

3.2.3 Amiodarone and back pain

Issue

Spontaneous reports to CARM (n=15) have drawn attention to severe musculoskeletal pain associated with intravenous infusions of amiodarone. Similar reports have also been received by ADRAC (n=11).

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.

Discussion

Members noted that CARM and ADRAC are preparing an article about intravenous amiodarone and severe back pain. It is hoped that publishing this article will raise awareness of the problem, and elicit information as to why this adverse reaction occurs and how it can be prevented. Members noted the above and no further action was recommended.

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

Note:
Signal is produced by the UMC and presents observations derived from reports submitted to the WHO International Drug Monitoring database by contributing national centres worldwide. This document is published regularly throughout the year, identifying signals of possible causal relationships between adverse events medicines that were previously unknown, or incompletely documented. The topics are researched and authored by the UMC Review Panel comprising international experts.

Signals

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".

Discussion

Members noted the above summary by CARM. It was agreed that the most noteworthy signal is rosiglitazone and pancreatitis. It was proposed that CARM and Medsafe keep a watching brief on this signal.

Recommendation

The Committee recommended that CARM and Medsafe keep a watching brief on the signal of pancreatitis with rosiglitazone.

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

Paracetamol (switch from Panadol to Pacimol): 43 reports, describing choking and vomiting, with difficulty in swallowing the tablets, have been received. It is thought that these reactions are due to the absence of a film coating on the tablets, as well as their relatively sharp edges. It was noted that CARM and Medsafe have liaised on this issue and a letter of concern has been sent to Pharmac. Pharmac has advised that it will be seeking to source a capsule formulation.

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).

Discussion

It was noted that Rivotril and Paxam are not considered by Medsafe to be interchangeable. Members agreed that pharmacists have an obligation not to dispense narrow therapeutic index medications, such as clonazepam, without checking which brand the patient is on. The Committee agreed that CARM should forward their analysis of the clonazepam brand-switch reports to Medsafe, and Medsafe should write to the Pharmacy Guild, reminding pharmacists that they should not be dispensing products with a narrow therapeutic index, without knowing which brand the patient is on.

Recommendations

The Committee recommended that CARM forward their analysis of the clonazepam brand-switch reports to Medsafe.

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

Methylphenidate and reduced therapeutic effect. These reports relate to questions about bioavailability in a specific batch.

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

3.4.1.3 Vaccine-related reports

The pattern of adverse events following immunisation is largely unremarkable and is typical of expected events and previous observations. Vaccines with three or more specific events are MMR, DTaP/HiB, ADT, DTaP/IPV, HepB, Cholera, and HiB/HepB.

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

New listings in this section include the methylphenidate efficacy issue and sodium tetradecyl sulphate and DVT issue mentioned above.

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

Reference Material

Tamam, L. et al. (2002) Oedema associated with risperidone: A case report and literature review. Clinical Drug Investigation, 22(6), 411-414.

Issue

Six case reports of oedema associated with risperidone have been reported to the IMMP, and the WHO database includes 374 such reports. This adverse effect has recently been reviewed in an international journal, which concluded that physicians should be more aware of the possibility of oedema associated with risperidone treatment.

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.

Discussion

Members believed the reported "16% of elderly patients taking risperidone for treatment of dementia reported peripheral oedema in a clinical trial" seemed high, and were unconvinced that this figure accurately reflects the true incidence of risperidone-induced oedema. The Committee agreed that further data regarding this signal are required, and a watching brief was recommended.

3.5.2 Risperidone and epistaxis, bleeding disorders

Issue

The IMMP has received two reports of epistaxis associated with use of risperidone. Both reports came from the sponsor of risperidone, Janssen Cilag Pty Ltd. This adverse reaction has not been reported in association with clozapine, although the association of clozapine with thrombocytopenia is well established. These observations have generated an interest in whether risperidone (and olanzapine and quetiapine) might be associated with 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".

Discussion

The Committee agreed that the second IMMP case report is not a convincing report; therefore, it was considered that there is one well-documented report of risperidone and epistaxis in the IMMP database. Members questioned the quality of the 182 WHO reports of risperidone and thrombocytopenia, especially given the IC-value for this association is negative.

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.

Recommendation

The Committee recommended that Medsafe investigate references to thrombocytopenia in the international product information for risperidone, before deciding whether the current New Zealand data sheet statement ("a mild fall in thrombocyte count has been reported") should be strengthened.

3.5.3 Risperidone and hyperprolactinaemia, male sexual disorder

Reference Material

Hyperprolactinaemia with antipsychotics. Prescriber Update, June 2001.

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

Issue

The IMMP has received several reports of hyperprolactinaemia (and related endocrinological effects) associated with risperidone treatment, both in men and women. There are many published reports mentioning this association, but these papers have largely appeared in journals of psychiatry. The available evidence suggests that risperidone is perhaps more frequently associated with hyperprolactinaemia than other atypical antipsychotics, however, the IMMP is not yet in a position to provide comparative incidence rates.

Discussion

The Committee noted that the NZPhVC intends to write a review article discussing hyperprolactinaemia associated with risperidone.

3.5.4 Risperidone and prolonged QT interval, interaction with paroxetine

Reference Material

Reference list of risk of torsades de pointes -ArizonaCERT

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.

Issue

The IMMP has received two plausible case reports of prolonged QT interval with risperidone. Both cases are associated with the use of paroxetine, and both patients had normal ECGs before commencing risperidone.

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.

Discussion

Members agreed that there is a risk of clinically significant interactions between these medicines. The Committee recommended that a Prescriber Update article be written to remind prescribers about the potential for interaction between SSRIs and atypical antipsychotics. The article should be based on the two IMMP case reports regarding risperidone-paroxetine and QT prolongation, and should include the table produced by .. entitled "Interaction potential of SSRIs and atypical antipsychotics via cytochrome P450 enzyme system".

Recommendation

The Committee recommended that an article, reminding prescribers about the potential for interaction effects when co-prescribing SSRIs and atypical antipsychotics, be written for publication in Prescriber Update. The article should make particular reference to prolonged QT interval with risperidone and paroxetine, and include the IMMP table entitled "Interaction potential of SSRIs and atypical antipsychotics via cytochrome P450 enzyme system".

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

Discussion

Members noted that the status of monitoring of medicines in the IMMP is as follows (n=number of patients):

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

Discussion

Members noted an IMMP analysis of insertion events associated with the IUD, Mirena. Data from an incomplete cohort (covering the period March 1998 to March 2002) indicated that insertion of Mirena was more difficult than the Multiload Cu375, and was associated with more adverse reactions to insertion. The Committee noted that the sponsor company changed the design of the Mirena inserter tube in 2000.

3.5.7 Automated methods of signal detection

Reference Material

Moore N et al (2003) Biases affecting the proportional reporting ratio (PRR) in spontaneous reports pharmacovigilance databases: the example of sertindole. Pharmacoepidemiology and Drug Safety 12, 271-281.

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

Discussion

Members noted the above papers.

4. Pharmacovigilance Issues

4.1 Paroxetine and Risk of Harmful Outcomes in Paediatric Patients

Reference Material

UK Committee on Safety of Medicines - Message from Chairman. Safety of Seroxat (paroxetine) in children and adolescents under 18 years - contraindication in the treatment of depressive illness. June 2003.

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

Issue

On June 10 2003, the UK Committee on Safety of Medicines issued a letter advising against prescribing paroxetine as therapy for children and adolescents with depressive illness. This advice was based on new data from GSK-sponsored clinical trials of Aropax in paediatric patients. These studies failed to demonstrate benefit in the treatment of depressive illness, and indicated an increased risk of suicidal thoughts and behaviour in children and adolescents treated with Aropax.

Discussion

Members noted that paroxetine is not licensed in New Zealand for use in those aged less than 18 years, however, off-label use occurs in this age group. The Committee also noted that CARM has received three reports of suicide, and two of suicide attempt, with paroxetine - all of these reports involved adults.

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.

Recommendations

The Committee agreed that an article about the management of depression in children should be written for publication in Prescriber Update. The article should make particular reference to risk of harmful outcomes with paroxetine, and the fact that in the FDA has approved fluoxetine for the treatment of depressive illness in children.

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

Reference Material

Ministry of Health Media Release (27 May 2003) Women's health initiative memory study.

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

Issue

Recently published findings from the WHI memory study (an ancillary of the WHI study stopped in June 2002), indicate that combination therapy with oestrogen and progestin in women aged 65 years and above is associated with an increased risk of all-cause dementia (HR, 2.05; 95% CI, 1.21-3.48; p = 0.01). The Committee's opinion on whether further regulatory action regarding HRT should be taken in New Zealand as a result of this study was sought.

Discussion

The Committee noted that the WHI memory study is robustly designed and the analysis remains stable when possible pre-disposing factors are controlled. Evidence of increased risk of probable dementia in the combined HRT-treated group appeared at one year after randomisation and persisted over the five years of follow-up. While the risk of probable dementia was twice that of the placebo group, the absolute risk was small (an additional 23 cases of dementia/10,000 women treated with combined HRT/year). Members agreed this was an important issue, which should apply to all combined HRT products. The Committee noted that the oestrogen-only HRT arm of the WHI memory study is on-going and is expected to be completed in 2008.

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.

Recommendations

The Committee recommended that product sponsors for combined HRT be asked to update their data sheets to include a statement about the possible increased risk of dementia.

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

Reference Material

Letter to Medsafe from Janssen-Cilag, April 2003.

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.

Issue

In October 2001, Janssen-Cilag provided Medsafe with an updated Risperdal data sheet, revised to include the statement "Cerebrovascular accidents have been observed in patients taking risperidone". The inclusion of this statement occurred as a result of a risperidone trial in elderly dementia patients, which showed an increased number of cerebrovascular accidents in risperidone-treated patients, relative to those receiving placebo.

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."

Discussion

The Committee was informed that the New Zealand data sheet for Risperdal has now been updated to include the aforementioned warnings issued in Canada and the United States. In addition, Janssen-Cilag will provide Medsafe with copies of the previous two Periodic Safety Update Reports, and all clinical studies investigating haemorrhagic and thrombotic stroke.

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.

Recommendations

The Committee recommended that Medsafe contact the product sponsor for risperidone, requesting that a Dear Healthcare Professional letter be issued to inform prescribers of the risk of cerebrovascular accidents in elderly patients with dementia. 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 recommended that Medsafe seek clarification from the FDA as to why the United States has approved Risperdal only for the treatment of schizophrenia.

Note:
The following material was originally included in Section 5 (Pharmacovigilance Issues for Information only) of the meeting dossier. At the request of the Committee, it was brought forward into Section 4 (Pharmacovigilance Issues) of the dossier, in order for it to be discussed.

4.4 SSRIs and withdrawal reactions

Reference Material

UK newspaper articles regarding paroxetine and withdrawal symptoms (The Guardian, 2002).

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.

Issue

The screening of two Panorama programmes regarding paroxetine and withdrawal reactions stimulated considerable discussion and debate in the UK.

Discussion

Members noted that an article regarding SSRIs and withdrawal reactions was published in a 1997 issue of Prescriber Update. The New Zealand data sheet for Aropax was updated to include information about symptoms seen on discontinuation of paroxetine, and the need to gradually taper the dose when discontinuing treatment.

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

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 Non-antiarrhythmic drugs and prolonged QT interval

Reference

De Ponti et al (2002) Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsades de pointes. Drug Safety, 25(4), 263-286.

5.2 Drug interactions among elderly patients

Reference

Juurlink et al (2003) Drug-drug interactions among elderly patients hospitalised for drug toxicity. JAMA, 289(13), 1652-1658.

5.3 Complementary medicines

References

Baber, N (2003) Complementary medicines, clinical pharmacology and therapeutics. Br J Clin Pharmacol, 55, 225.

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

Reference

Hughes et al. (2002) Review of national spontaneous reporting schemes: Strengths and weaknesses. Adv Drug React Toxicol Rev, 21(4), 231-241.

5.5 Safety of COX-2 inhibitors

References

Gomez Cerezo et al. (2003) Outcome trials of COX-2 selective inhibitors: global safety evaluation does not promise benefits. Eur J Clin Pharmacol, April 16.

Layton et al (2003) Safety profile of rofecoxib as used in general practice in England: results of a prescription-event monitoring study. Br J Clin Pharmacol, 55, 166-174.

5.6 Clozapine and low blood selenium levels

Reference

Vaddadi, K.S. et al (2003) Low blood selenium concentrations in schizophrenic patients on clozapine. Br J Clin Pharmacol, 55, 307-309.

5.7 Hormonal contraceptives and cervical cancer

Reference

Smith, J.S. et al (2003) Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet, 361, 1159-1167.

5.8 CARM case reports

Enzogenol and hypertension aggravated (54849)

Mefloquine and anxiety/character change (55006)

Lopramide and bronchospasm (55026)

Lopramide and sneezing excessive/pruritis/conjunctivitis (55028)

Diane-35 and pulmonary embolism/thrombophlebitis leg deep (54540)

Loette/cyproterone and pulmonary embolism/thrombophlebitis leg deep (54794)

Citalopram and hyperkinesias/paraesthesia (55164)

MMR/DTaP/Hib and erythema multiforme/ecchymosis (54854)

6. New Zealand Activities

6.1 PHARMAC

Consultation on special authority criteria for very high dose inhaled corticosteroids (March 2003)

PreMeC bulletin on appropriate use of inhaled corticosteroids in asthma (March 2003)

6.2 Publications

Parkin et al. (2003) Psychotropic drugs and fatal pulmonary embolism. Pharmacoepidemiology and Drug Safety, (in press).

6.3 New Zealand Food Safety Authority

Pan Pharmaceuticals - Product recalls

7. International Activities

7.1 Australia

Minutes of the December meeting of the Adverse Drug Reactions Advisory Committee

Minutes of the February meeting of the Adverse Drug Reactions Advisory Committee

Minutes of the March meeting of the Adverse Drug Reactions Advisory Committee

Australian Adverse Drug Reactions Bulletin 22(2), April 2003

Australian Adverse Drug Reactions Bulletin 22(3), June 2003

7.2 Canada

Canadian Adverse Reaction Newsletter 13(2), April 2003.

7.3 Ireland

Irish Medicines Board Drug Safety Newsletter 16, December 2002.

7.4 WHO

Advisory Committee of Safety of Medicinal Products - Honorary appointment of David Coulter.

Report by David Coulter on WHO training workshop in pharmacovigilance (Lusaka, Zambia, 24 March - 2 April 2003).

8. Summary of Case Reports Considered by MARC (1997 to 2003)

CARM case reports considered by the MARC

Vaccine adverse reaction reports considered by the MARC

Complementary and alternative medicine case reports considered by the MARC

The meeting ended at 5:00pm