Revised: 21 May 2013

Committees

Minutes of the 112^th Medicines Adverse Reactions Committee Meeting - 4 December 2002

Held by teleconference, commencing at 11:30am

Preface:

In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.

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

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

The recommendations of the committee are in bold typeface.

Minutes:

MARC MEMBERS PRESENT

Associate Professor T.J.B. Maling (Chair)
Professor P. Ellis
Dr J. Goldsmith
Dr H. Kingston
Dr F. McClure (12:10 - 1:00 pm only)
Dr M. Rademaker
Dr N. Rafter
Professor D.C.G. Skegg
Dr M. Tatley

MARC SECRETARIAT PRESENT

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

INVITED EXPERTS

Dr D. Coulter (IMMP Director, CARM)

1. MATTERS OF ADMINISTRATION

1.1 Welcome and apologies 1.2 Minutes of the 111^th meeting

Members agreed that the minutes of the 111^th meeting are a true and accurate record of the meeting.

1.3 Dates of 2003 meetings

12 March, 26 June, 17 September and 4 December were confirmed as the dates of the 2003 meetings.

1.4 Conflict of interest

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

1.5 MARC membership

Medsafe is developing proposals around the membership of MARC (e.g., required skills, committee size, term of membership, frequency of meetings, etc). Input from MARC members and CARM staff is very welcome and will be sought before Medsafe makes a final decision.

Dr John Goldsmith announced his resignation from the MARC after four enjoyable and informative years. Members expressed their disappointment at his leaving, and thanked him for his very important and valuable contribution.

2. MATTERS ARISING

2.1 Report on actions arising from the 111^th MARC meeting

2.1.1 Minute item 2.1.3 Tiaprofenic acid (s.36 notice for Surgam tablets)

Issue

The Committee advised Medsafe to consult the Pharmaceutical Society with regard to an appropriate and practical warning sticker to minimise the risk of tiaprofenic acid-induced cystitis going untreated. Medsafe believes it is more appropriate for the product sponsor to consult with the Pharmaceutical Society. As a result, a letter was sent to Aventis Pharma Ltd asking that they contact the Pharmaceutical Society to discuss the possibility of adding an appropriate warning label to the Society's Cautionary and Advisory Labelling scheme. In addition, Aventis Pharma Ltd was asked to prepare CMI for all Surgam products.

Outcome

The Pharmaceutical Society has advised Aventis Pharma Ltd that it is not feasible for the Society to produce such a label as part of the Cautionary and Advisory Labelling scheme.

The Society indicated that the most appropriate course of action is for Aventis Pharma Ltd to make a submission to the Pharmaceutical Society for inclusion of an appropriate warning statement regarding tiaprofenic acid-induced cystitis in the 2003 edition of the Dispensing Guide. Aventis Pharma Ltd is preparing a submission to be forwarded to the Editorial Committee of the Dispensing Guide.

Medsafe has received CMI from Aventis Pharma Ltd for all Surgam products.

Discussion

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

2.1.2 Minute item 3.3.1 COX-2 inhibitors

Issue

In view of a recent British Medical Journal editorial (Juni et al., 2002, vol. 324, p 1287-1288) concerning limitations of the CLASS study, members recommended the sponsor company be asked to revise the Celebrex data sheet. The Committee advised Medsafe to compose appropriate data sheet statements to be presented to the sponsor company. Members also 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

Medsafe will write a letter to the product sponsor for Celebrex, requesting an explanation for the recent criticism of the CLASS study and any notable discrepancies between the Australian/American/Canadian and New Zealand data sheets. If the sponsor cannot justify these differences, the data sheets should be harmonised. The company's response will be evaluated by Medsafe and, if necessary, taken to the MARC for further clarification. This same action is being taken with regard to inter-country discrepancies in the Vioxx data sheets.

Discussion

Members noted two recent studies published in the British Medical Journal (Mamdani et al, 2002, and Deeks et al, 2002) reporting improved GI safety and tolerability with COX-2 inhibitors compared with non-selective NSAIDs. Given that more than half of the patient data for the Deeks et al, 2002 systematic review came from the CLASS trial, and that the Mamdani et al, 2002 study involved less than six months follow-up of the patients, the Committee did not wish to change its advice regarding the celecoxib data sheet revisions.

On closer examination of the Celebrex data sheet, members agreed that it was not desirable to include a large amount of data from specific studies. D. Coulter informed the Committee that the recently updated format for the European equivalent of the New Zealand product data sheets (Summary of Product Characteristics, SPC) is worth noting.

2.1.3 Minute item 2.2.1 Funding for third generation oral contraceptives

Issue

The Committee recommended that Medsafe, on behalf of the Committee, send a letter to Pharmac that outlines the risk and benefit issues, highlights the need to take action, and requests that, on a safety basis, Pharmac considers funding third generation OCs only when a script is endorsed with 'certified condition'.

Outcome

A letter (signed by MARC Chair) was sent to Pharmac, and copied to Minister of Health, in October 2002.

Discussion

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

2.1.4 Minute item 4.1 HRT and cancer/stroke/heart disease

Issue

Members recommended that Medsafe communicate the Committee's advice about the use of HRT to prescribers in the form of a Prescriber Update article (November 2002 issue) and a Dear Healthcare Professional letter.

Outcome

A Dear Healthcare Professional letter was sent to all doctors and pharmacies on 2^nd October 2002. The letter was accompanied by updated key messages on HRT prescribing from the New Zealand Guidelines Group.

Background information about the advice given in the Dear Healthcare Professional letter, along with the Beral et al (2002) Lancet article, was provided in the November 2002 issue of Prescriber Update.

Issue

Members requested that Medsafe resolve whether the above recommendations should apply to HRT in general (i.e., combined and oestrogen-only), or to specific types of HRT.

Outcome

Much of the evidence on HRT comes from observational studies that did not differentiate among the effects of specific hormone preparations. As a result, Medsafe concluded that, until data indicate that specific HRT regimens have a favourable balance of benefits to risks, the MARC's recommendations should apply to HRT in general.

Issue

Members agreed that Medsafe should negotiate with sponsors of HRT products with regard to the appropriate updating of data sheets.

Outcome

Medsafe is presently working on the appropriate updating of HRT data sheets, with the hope of harmonising with the Australian data sheets.

Issue

Members did not feel they had enough information on the validity of HRT for the prevention/treatment of osteoporosis to make a recommendation on this issue. They therefore proposed that Medsafe convene a working party to examine the risks and benefits of HRT and osteoporosis.

Outcome

An HRT/osteoporosis working party is likely to be convened early 2003.

Discussion

The Committee noted that the Pharmacology and Therapeutics Advisory Committee's osteoporosis and hormone sub-committees have recently convened. Before Medsafe convenes a similar working party it would be sensible to ensure there is no unnecessary duplication of effort.

Action

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 for it to convene an HRT/osteoporosis working party.

2.1.5 Minute item 4.2 Kava and liver toxicity

Issue

The Committee agreed that labels, warning against the possibility of serious liver damage, should be required for kava-containing products. Members recommended that Medsafe write a letter to the New Zealand Food Safety Authority (NZFSA) informing them of this recommendation.

The Committee also advised that Medsafe provide comment in Prescriber Update, reminding prescribers to consider herbal medicines as a possible cause of adverse effects.

Outcome

In early October, a letter was sent to the Principal Advisor at the NZFSA advising the NZFSA of the MARC's recommendation (but informing them that the recommendation had not yet been ratified by the Minister of Health's Delegate). A further letter was sent to the CEO of the NZFSA in November, re-stating the MARC's recommendation and informing them that it has now been approved by the Minister's Delegate.

A reminder regarding herbal medicines and adverse effects will be published in the next issue of Prescriber Update, which is planned for April 2003.

Discussion

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

2.1.6 Minute item 4.3 Propofol and paediatric sedation

Issue

The Committee recommended that Medsafe consult the New Zealand Committee of the Australian and New Zealand College of Anaesthetists (ANZCA), with regard to their opinion on:

• propofol being contraindicated for the sedation of children 18 years or younger receiving intensive care;
• the availability of suitable alternatives for sedation;
• any additional information that should be considered.

Outcome

In October, Medsafe wrote to the New Zealand ANZCA Committee, asking for comment on the proposal that propofol be contraindicated for the sedation of children (18 years or younger) receiving intensive care. A response from ANZCA is yet to be received.

Discussion

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

2.1.7 Minute item 4.4 COX-2 function and bone fracture healing

Issue

The Committee requested that Medsafe seek an expert opinion on the issue of COX-2 function and bone fracture healing. Members also advised Medsafe to conduct a literature search for further information.

Outcome

A literature search revealed a number of papers with differing views regarding the use of NSAIDs for post-operative anaesthesia after fractures or orthopaedic surgery. The results of this search have been sent to .., who has kindly agreed to provide comment to the MARC on this issue.

Discussion

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

2.1.8 Minute item 4.5 High dose fluticasone and adrenal insufficiency

Issue

The Chair requested that .. clarify her issues of concern for possible presentation at the December 2002 meeting.

Outcome

These concerns are included as Section 4.1.1 of the December 2002 MARC meeting agenda.

2.1.9 Minute item 3.1.1.9 Tranexamic acid and deep venous thrombosis/superficial thrombophlebitis/pulmonary embolism - CARM case report (51372)

Issue

Members recommended that CARM write a short Prescriber Update article to remind prescribers about the risk of thromboembolism with tranexamic acid.

Outcome

.. has agreed to author this article for publication in the next issue of Prescriber Update.

Discussion

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

2.1.10 Minute item 3.3.1 COX-2 inhibitors - IMMP adverse event reports

Issue

Members agreed that .. should write a short article regarding COX-2 inhibitors and hepatotoxicity/pancreatitis, to be published in Prescriber Update.

Outcome

.. has prepared a draft of this article, which is to be published in the next issue of Prescriber Update.

Discussion

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

2.2 Report on actions outstanding

2.2.1 June minute item 4.5 Missed-pill advice for Cerazette

Issue

While the New Zealand data sheet for Cerazette gives 12-hour missed-pill advice, it was brought to the attention of the Committee that the UK has 3-hour missed-pill advice for this product. The Committee requested that Medsafe investigate this discrepancy and report back at the September 2002 meeting.

Outcome

The New Zealand data sheet (along with the pharmaceutical company information) gives 12-hour missed-pill advice for this product. .. of Pharmaco is following up this discrepancy with the company's head office in Holland.

Discussion

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

2.2.2 June minute item 4.4 Tamoxifen and uterine sarcoma

Issue

The Committee recommended that Medsafe assess the comments of the two oncologists when they have both been received.

Outcome

Only one response has been received to date. The second oncologist was awaiting the publication of a relevant paper in the Lancet (2002, vol 360 pp 817-824) before officially responding. As he has still not yet replied, Medsafe will assess the response that has been received and consider asking sponsor companies to prepare CMI (and to update data sheets if required) that includes the need for women experiencing abnormal vaginal bleeding to promptly see a doctor.

Discussion

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

3. matters arising from carm

3.1 Spontaneous reporting programme

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.

3.1.1 Reports in which death occurred

3.1.1.1 Atenolol/frusemide/felodipine/cilazapril/flecainide etc and arrhythmia (52604)

Discussion

Members noted a report in the literature describing profound hypotension after atenolol use in severe hypertension. A potential role of flecainide was also discussed. For this case report, the causal association was designated "unclassified" and no further action was recommended.

3.1.1.2 Caesium chloride and torsades de pointes/pneumonia (52069)

Discussion

For this case report, the causal association was deemed to be "probable" for torsades de pointes, and "unlikely" for aspiration pneumonia. No further action was recommended.

3.1.1.3 Cyproterone acetate and hepatic failure (52279)

Discussion

Of 32 reports for cyproterone acetate received by CARM, two are associated with hepatic failure, three with cholestatic hepatitis, two with hepatitis, and two with jaundice. The product data sheet states that hepatotoxicity (including jaundice, hepatitis, and hepatic failure), fatal in some cases, has been reported in patients taking 200 to 300 mg daily. A post-mortem report has been requested by CARM. Members discussed a possible role of allopurinol hypersensitivity syndrome in this case. For this case report, the causal association was designated "possible" and no further action was recommended.

3.1.1.4 Citalopram/clonazepam and cardiac arrest/pulmonary haemorrhage (52465)

Discussion

Of 39 reports for citalopram received by CARM, none are associated with bleeding disorder. Of the CARM reports for fluoxetine (616), paroxetine (246), zimelidine (1), and clonazepam (21), six, 11, one, and one reports, respectively, are associated with bleeding disorders. The WHO database has 17 reports of respiratory tract haemorrhage associated with citalopram. A literature search revealed reports of bleeding with other SSRIs.

Members commented on the large number of medicines this patient was taking (citalopram, quetiapine, metoclopramide, morphine, clonazepam, clarithromycin, cefuroxime, and microlax). In particular, the possibility that clarithromycin could affect the metabolism of other medicines (including citalopram) was noted. Given that quetiapine has been associated with prolonged QT interval, a possible role of this medicine was noted. The Committee recommended that all of the patient's medications be included as suspect medicines. The causal association was designated "possible" and no further action was recommended.

3.1.1.5 Estelle-35 and pulmonary embolism (52233)

Discussion

CARM has received one report of life-threatening pulmonary embolus, and one of iliofemoral vein thrombosis, associated with Estelle-35. Members noted an article produced by the UK Medicines Control Agency (Current Problems in Pharmacovigilance, vol. 28, 2002) reporting that the incidence of VTE in users of cyproterone acetate (Dianette) is higher than that in women using low dose oral contraceptives. For this case report, the causal association was designated "possible" and no further action was recommended.

3.1.1.6 Leflunomide/methotrexate/ketoprofen/triamcinolone and septic shock/septic arthritis/multiple organ failure/infection streptococcal/vomiting (52507)

Discussion

Of 79 reports for methotrexate received by CARM, one is associated with sepsis, and one with septicaemia. CARM has received three reports for leflunomide, none of which are associated with sepsis. Members noted that the patient was receiving a number of medicines likely to modulate immune response to infection. The possibility of a leflunomide and methotrexate interaction resulting in the patient becoming immunocompromised was also discussed. The Committee agreed that hydroxychloroquine should be added to the list of suspect medicines. The causal association was designated "possible" for septic shock, septic arthritis, multiple organ failure, streptococcal infection, and vomiting.

Action

The Committee recommended that Medsafe investigate the extent of leflunomide use in New Zealand.

3.1.1.7 Methotrexate and pneumonitis/cough/dyspnoea/respiratory failure (52541)

Discussion

The causal association for pneumonitis, cough, dyspnoea, and respiratory failure was deemed "probable" and no further action was recommended.

3.1.1.8 Pamidronate and bladder calculus/bladder neck obstruction (52573)

Discussion

Of 33 reports for pamidronate received by CARM, none are similar to the above case. The causal association was deemed to be "unlikely" and no further action was recommended.

3.1.2 Alternative medicine-related reports

3.1.2.1 Jointcare and syncope/incontinence faecal/myocardial infarction (52264)

Discussion

The product data sheet for Jointcare lists a number of ingredients including guggul, boswellia, Indian madder, horseradish, gokshura, musk mallow, guduchi, and liquorice. Members noted that guggul has been reported to cause GI symptoms. The causal association was deemed to be "unlikely" for myocardial infarction, and "certain" for syncope and faecal incontinence. No further action was recommended.

3.1.3 Antifungal-related reports

3.1.3.1 Itraconazole and congestive heart failure (51829)

Discussion

Members noted that CARM received further reports for this patient from a GP, pharmacist, and a pharmaceutical company. These reports reinforced the same symptoms and rechallenge nature of this reaction. The causal association was deemed to be "certain". Of 5571 reports for itraconazole in the WHO database, 40 are associated with congestive heart failure (six fatal). CARM has received one other report of congestive heart failure with itraconazole. The Committee agreed that while congestive heart failure is a recognised adverse effect of itraconazole, it is unlikely to be widely known.

Action

The Committee recommended that an article, reminding prescribers that itraconazole has been associated with reports of congestive heart failure, should be published in Prescriber Update.

3.1.4 Anti-inflammatory-related reports

3.1.4.1 Diclofenac and vision abnormal (51994)

Discussion

Of 577 reports for diclofenac reported to CARM, eight are associated with abnormal vision. There is one report of marked decrease in visual acuity, and one report of a visual field defect with COX-2 inhibitors in the IMMP. Case reports of visual disturbances can be found in the literature. Members noted that .. is writing a paper on the COX-2 inhibitor IMMP cases, in which it is hypothesised that NSAIDs may disturb the regulation of retinal blood flow by, at least in part, inhibiting prostacyclin, thromboxane A2, and prostaglandin H2. The causal association was deemed to be "probable" and no further action was recommended.

3.1.5 Cardiovascular medication-related reports

3.1.5.1 Simvastatin and rhabdomyolysis, myoglobinuria/renal failure acute/somnolence/vision blurred/taste disturbance (52761)

Discussion

Of 343 reports for simvastatin received by CARM, there are none associated with rhabdomyolysis, 70 associated with myalgia (12 report elevated creatine kinase levels), eight with myopathy, 12 with myositis, three with abnormal vision, and one with taste perversion. Members agreed that the causal association for rhabdomyolysis, myoglobinuria, acute renal failure, somnolence, blurred vision, and taste disturbance is "possible".

Action

See below (section 3.1.5.2).

3.1.5.2 Simvastatin and myalgia/nausea/syncope (52835)

Discussion

Of 343 reports for simvastatin received by CARM, there are 70 associated with myalgia (12 report elevated creatine kinase levels), eight with myopathy, and 12 with myositis. Members agreed that the causal association for myalgia, nausea, and syncope is "possible".

Action

The Committee recommended that the above case reports (52761 and 52835) be summarised in a Prescriber Update article. The article should remind prescribers to check creatine kinase levels in patients on statin therapy who develop muscle-related symptoms.

3.1.6 Hormone-related reports

3.1.6.1 Microgynon and cerebrovascular disorder (52266)

Discussion

Of 29 reports for Microgynon received by CARM, one is associated with a cerebrovascular accident. The Committee discussed the use of combined oral contraceptives in women over 50 years of age but could not determine from the case report details whether the oral contraceptive was inappropriately prescribed. Members agreed that the causal association was "possible" and no further action was recommended.

3.1.6.2 Diane-35 and pulmonary embolism (52512)

Discussion

Of 35 reports for Diane-35 received by CARM, 14 are associated with pulmonary embolus, and seven are associated with DVT. As for the above case report (52266), the Committee discussed the use of combined oral contraceptives in women over 50 years of age but again could not determine from the case report details whether the oral contraceptive was inappropriately prescribed. Members agreed that the causal association was "possible" and no further action was recommended.

3.1.7 Muscle relaxant-related reports

3.1.7.1 Suxamethonium and anaphylaxis/cardiac arrest (52912)

Discussion

CARM has requested follow-up information regarding the other agents administered. Of 271 reports for suxamethonium received by CARM, 16 are associated with anaphylaxis, 48 with anaphylactic shock, 50 with anaphylactoid reaction, and 18 with cardiac arrest. The Committee deemed the causal relationship to be "possible" for anaphylaxis and cardiac arrest, and no further action was recommended.

3.1.8 Musculoskeletal-related reports

3.1.8.1 Osteogenic Protein-1 and hyperostosis (52783)

Discussion

CARM has not received any other reports for this product. The product information states that any material dislodged from the non-union site can cause ectopic ossification in the surrounding tissues with potential complications. The Committee deemed the causal association to be "probable" and no further action was recommended.

3.2 Quarterly report (as at 30 September, 2002)

3.2.1 Multiple occurrence reaction reporting

≥ Three Reports in the Last Quarter

3.2.1.1 Brand-switch related reports

• Enalapril (switch from Renitec to Enahexal) was a focus of brand-switch reporting concerns from September 2001 to March 2002. Despite the continued use of Enahexal, reports have all but ceased.
• Felodipine (switch from Plendil to Felo) reports continue to be received. In particular, 'dizziness' reactions have been reported on changing to Felo. Reports of improvement of symptoms on switching from Felo back to Plendil have also been received.
• Simvastatin (switch from Zocor to Lipex) brandswitch reactions resulting in myalgia are a relatively new observation. Interestingly, both products have the same sponsor and the only difference between Zocor and Lipex is a change in brand name.

3.2.1.2 Other medicine-related reports

• Following a drop in the number of reports for bupropion, there has been a small but constant influx of reports, with another three of depression in the last quarter.
• Hypersensitivity reactions with x-ray contrast media continue to be regularly reported.
• A number of reports of moderate to severe diarrhoea with the use of carvedilol have been received.

3.2.1.3 Vaccine-related reports

• Reports to Mencevax have been received as a consequence of an immunisation programme instituted in Balclutha in response to cases of Meningococcal C disease.
• The pattern of adverse events following immunisation is largely unremarkable and typical of expected events and previous observations. Vaccines with three or more specific events are Influenza, DTaP, DTaP/HiB, HiB/HepB, MMR, ADT, and DTaP/IPV.

≥ Six Reports in the Year-to-Date

• Twelve reports of myalgia with simvastatin have been received for the year-to-date. Many of the reports do not provide a creatine kinase level, or indicate that such an estimation was performed.
• Six reports of anaphylaxis with rocuronium have been received for the year-to-date. Reports are all a consequence of skin-testing results following anaphylactic and anaphylactoid reactions during anaesthetic induction. The over-representation of rocuronium in the current reports may simply reflect the current preference for this agent.
• Eleven reports of back pain with iodixanol have been received for the year-to-date. These reactions occurred during, or following, the administration of iodixanol and it is possible they are associated with the rate of infusion.

Action

The Committee recommended that a summary of the quarterly Multiple Occurrence Reaction Reports be published in Prescriber Update. Medsafe and CARM should liaise to ensure this information is reported in a way that is practical and useful to prescribers.

3.2.2 Adverse Reactions of Current Concern

Action

The Committee recommended that the following reactions be removed from the list of Adverse Reactions of Current Concern.

• Celecoxib and warfarin interaction
• Rofecoxib and warfarin interaction
• Nefazodone and hepatic reactions
• NSAIAs and serious soft-tissue infection
• Oral contraceptives and venous thromboembolism (VTE with Estelle-35 and Diane-35 will remain adverse reactions of current concern).

3.2.3 Pharmacovigilance literature of interest

The Committee noted the list of pharmacovigilance-related references.

3.3 IMMP

3.3.1 Atypical antipsychotics

3.3.1.1 Atypical antipsychotics and hypertension

Reference Material

George & Winther (1996) Hypertension after initiation of clozapine. American Journal of Psychiatry, 153(10), 1368-1369.

The Committee noted that the IMMP has received twelve adverse event reports of hypertension with atypical antipsychotics (10 with clozapine and one each with risperidone and quetiapine). Most of the reactions occurred in young patients and the onset of action was rapid. Three of the reports are associated with SSRIs. Members agreed that the association of hypertension with the atypical antipsychotics is not likely to be well known in practice.

Action

The Committee agreed that .. should write a short article for Prescriber Update, warning prescribers of this association. The warning should include the need to monitor blood pressure after each dosage increment, and the interacting potential of SSRIs.

3.3.1.2 Atypical antipsychotics and hyperlipidaemia

Reference Material

• Koro et al. (2002) An assessment of the independent effects of olanzapine and risperidone exposure on the risk of hyperlipidaemia in schizophrenic patients. Arch Gen Psychiatry, 59, 1021-1026.
• McIntyre et al. (2001) Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Canadian Journal of Psychiatry, 46(3), 273-281. (abstract only).

The Committee noted that the IMMP has received seven adverse event reports of hyperlipidaemia with atypical antipsychotics. All of the reactions occurred in young patients and sometimes the lipid abnormalities were severe. Members commented that the Koro et al. (2002) article was not a good study in that no cholesterol levels were given. Rather, the data were taken from the General Practice Research Database and used either diagnosis of hyperlipidaemia or treatment for hyperlipidaemia as an end-point. Members agreed that this is an interesting signal that should be followed up. The Committee also noted that a drug-induced rise in lipids might not necessarily carry the same prognosis as genetic hyperlipidaemia.

Action

The Committee recommended that an IMMP follow-up study be conducted in an attempt to establish whether this is a true signal. Using IMMP cohorts, fasting cholesterol, glucose, and blood pressure levels could be measured in patients in different drug and age groups. Members believed that a well-designed study in this area would be of international significance.

3.3.2 Nefazodone

3.3.2.1 Nefazodone and hepatic reactions

Members noted that the IMMP has received 14 adverse event reports of hepatotoxicity with nefazodone. The low number of reports may reflect low usage of nefazodone in New Zealand. Of these reports, the predominant reaction is hepatocellular liver injury.

4. Pharmacovigilance issues

4.1 High-dose fluticasone and adrenal insufficiency

Reference material

• .. (Sept 2002) Report to MARC members and Medsafe staff: Safety of inhaled steroids in the changing NZ prescribing environment.
• Committee on Safety of Medicines/Medicines Control Agency (2002) Inhaled corticosteroids and adrenal suppression in children. (28), 7.
• PreMeC (2002) Graph showing average daily dose of fluticasone by age group during 2001/2002.
• Pharmac (2002) Asthma Therapy Awareness Strategy: Key messages and analysis of related HealthPAC data.
• Budd, S. (2002) Asthma campaign runs into flak. New Zealand GP, (30 Oct), 1-2.
• New Zealand Guidelines Group (August 2002) Best practice evidence-based guideline summary for the diagnosis and treatment of adult asthma.
• New Zealand data sheet for Flixotide
• New Zealand data sheet for Beclazone
• New Zealand data sheet for Pulmicort Turbuhaler
• Tattersfield, A. et al (2002) Asthma. Lancet, (360), 1313 (extract from article).
• Adams, N. et al. (2002) Fluticasone versus beclomethasone or budesonide for chronic asthma (Cochrane Review abstract). In: The Cochrane Library, Issue 4.
• Pederson & O'Byrne (1997) A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy (52, suppl 39), 1-34.
• Drake et al. (2002) Symptomatic adrenal insufficiency presenting with hypoglycaemia in children with asthma receiving high dose inhaled fluticasone propionate. BMJ, (324), 1081-1083.
• Patel et al. (2002) Symptomatic adrenal insufficiency during inhaled corticosteroid treatment. Arch Dis Child, (85), 330- 334.
• Wong et al. (2002) Growth and adrenal suppression in asthmatic children on moderate to high doses of fluticasone propionate. J Paediatr Child Health, (38), 59-62.
• Todd et al. (2002) Acute adrenal crisis in asthmatics treated with high-dose fluticasone propionate. Eur Respir J, (19), 1207-1209.
• Robinson, J.D. et al. (2002) Inhaled steroids and the risk of adrenal suppression in children. Expert Opinion on Drug Safety, (1), 237-244.
• Letters to the Editor (2002) Adrenal insufficiency after treatment with fluticasone. BMJ, (325), 836-841.

Issue

Following publication of a number of case studies reporting adrenal suppression in children taking high-dose fluticasone, the MARC sought to determine whether there is a need to:

1. alter product data sheets to reflect the 'start low and titrate upwards' advice of the New Zealand Guidelines Group (NZGG) Guidelines for the Diagnosis and Treatment of Adult Asthma (September 2002);
2. remind prescribers about the potency of fluticasone with respect to recommended daily and maximum doses; and
3. provide advice to consumers.

Discussion

Members noted a number of international case reports describing adrenal insufficiency in children taking high-dose fluticasone. While CARM has not received similar reports in New Zealand, the WHO Information Component value (a logarithmic measure of disproportionality) for fluticasone and adrenal suppression is very high (5.91). Members supported the advice regarding inhaled corticosteroid dose regimens in the NZGG Guidelines for the Diagnosis and Treatment of Adult Asthma. These guidelines recommend starting patients on an appropriately low dose, and titrating upwards as required.

The Committee concluded that while fluticasone and beclomethasone/budesonide have different potencies as steroids, at equivalent doses there do not appear to be significant differences between therapeutic effect and frequency/type of adverse effect. It was noted that in general, HealthPAC data indicate New Zealand doctors may be prescribing unnecessarily high doses of fluticasone, and it may be useful to remind prescribers that fluticasone is approximately twice as potent as beclomethasone/budesonide.

The Committee noted that some of the recommended daily and maximum doses in New Zealand product data sheets for inhaled corticosteroids are much higher than those advised in the NZGG Guidelines for the Diagnosis and Treatment of Adult Asthma. It was also noted that as the NZGG Asthma Guidelines refer only to adults, it is pertinent that paediatric asthma treatment guidelines be revised as soon as possible.

Action

The Committee made the following recommendations:

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. Medsafe should approach PreMeC about the potential publication of a PreMeC bulletin reinforcing the inhaled corticosteroid dose recommendations made by the NZGG in their Guidelines for the Diagnosis and Treatment of Adult Asthma.

Medsafe should liaise with Pharmac to ensure there is congruence between the two agencies with regard to Pharmac's Asthma Therapy Awareness Strategy.

Medsafe should write to the Respiratory Medicine sub-committee of the Paediatric Society of New Zealand asking that they consider urgent action to update the Paediatric Asthma Guidelines.

Fluticasone and adrenal insufficiency, hypoglycaemia, and seizure should be made an Adverse Reaction of Current Concern.

5. ISSUES FOR INFORMATION ONLY - full text supplied

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 Safety issues around COX-2 inhibitors

• Howes, L. Krum, H. (2002) Selective cyclo-oxygenase-2 inhibitors and myocardial infarction - How strong is the link? Drug Safety, 25(12), 829-835.
• Ray, W. et al. (2002) Cox-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet, (360), 1071-1073.
• Ahmad, S. et al. (2002) Renal failure associated with the use of celecoxib and rofecoxib. Drug Safety, 27(7), 537-544.

5.2 Seizures in patients taking sildenafil

• Gilad et al (2002) Tonic-clonic seizures in patients taking sildenafil. BMJ, (325), 869.

5.3 Safety of OTC analgesics

• FDA Panel wants stronger acetaminophen warnings. Scrip, Sept, 2002.
• US committee favours more warnings on OTC NSAIs. Scrip, Sept, 2002.
• Medicines Control Agency Statement (Oct 2002) New Advice on Aspirin and Under 16s.
• Moynihan, R. (2002) FDA fails to reduce accessibility of paracetamol despite 450 deaths a year. BMJ, (325), 678.

5.4 CARM case reports

• Arthri-eze Forte/celecoxib and abdominal pain (52646)
• Black cohosh and headache/vomiting/overdose (52593)
• Ginseng/royal jelly and angioedema/bronchospasm/coryza/lacrimation increased (52265)
• St Johns Wort/naproxen/ibuprofen and hepatic enzymes raised/malaise (52277)
• Diclofenac and coagulation factor decreased/ecchymosis (52438)
• Nuvelle and cerebral infarction (52503)
• Bupropion and erythema multiforme/arthralgia (52534)
• Fluoxetine and serum sickness-like reaction (51937)

6. Other New Zealand activities

6.1 Pharmac

• Minutes of the Pharmacology and Therapeutics Advisory Committee Meeting, 22 August 2002.

6.2 Publications

• Coulter, D.M. et al. (submitted) Activation of pain by sumatriptan. Headache.

7. International Activities

7.1 Australia

• Minutes of the 21 June 2002 meeting of the Adverse Drug Reactions Advisory Committee
• Minutes of the 9 August 2002 meeting of the Adverse Drug Reactions Advisory Committee

7.2 Canada

• Canadian Adverse Reaction Newsletter 12(4), October 2002.

7.3 United Kingdom

• Current Problems in Pharmacovigilance 28, October 2002.

7.4 WHO Collaborating Centre for International Drug Monitoring

• Report on activities July 2000 - June 2001.

7.5 Conference Reports

• Working group on pharmacovigilance and safety monitoring of herbal medicines (Amsterdam, 12-13 October 2002).
• 25^th annual meeting of National Centres participating in the WHO programme on international drug monitoring (Amsterdam, 13-16 October 2002).
• Annual conference of the International Society of Pharmacovigilance (ISoP) (Amsterdam, 16-19 October 2002).

8. General Reporting

• 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

9. ISSUES FOR INTEREST ONLY - abstract supplied

The Committee did not discuss this material. It includes updates on issues already known to the Committee, and preliminary information on emerging issues. This material differs from that in section 5 in that it is of more peripheral relevance or importance. The material was provided for the interest of the members, and reading it was optional. Members were able to request that the material be discussed at the present, or at a future, meeting.

9.1 Patients to report adverse drug reactions in the UK

• Sukkar, E. (Sept 2002) UK patients to report ADRs - comment. Scrip, p 5.
• Editorial - Improving ADR reporting. Lancet, (360), 1435.

9.2 Drug safety scares - message management

• McLeay, R. (2002) Drug safety scares: the need for message management. Reactions, (924), 3-4.
• Patel, A et al. (2002) The HRT furore: getting the message right. MJA, (177), 345-346.

9.3 Monitoring of adverse events following immunisation

• Miller, M. & Turner, N. (2002) Suggestions for improving the monitoring of adverse events following immunization in New Zealand. NZMJ, 115(1162), 1-6.
• Tatley, M. (submitted Oct 2002) Letter to the Editor. NZMJ.

9.4 Pharmacovigilance in the future

• WHO identifies challenges for pharmacovigilance. Scrip, Sept 2002.

9.5 HRT and breast cancer patients

• Dixon, J.M. (2002) Hormone replacement therapy: is it safe for breast cancer patients? MJA, (177), 340-341.

9.6 Herbal remedies and liver disease

• Whiting, P.W. et al. (2002) Black cohosh and other herbal remedies associated with acute hepatitis. MJA, (177), 432-435.
• De Smet, P (2002) Safety concerns about kava not unique. Lancet, (360), 1336.

9.7 WISDOM study stopped early

• White (2002) Second long term HRT trial stopped early. BMJ, (325), 987.

9.8 Celecoxib and sulfonamide allergy

• Knowles, S. et al. (2002) Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Drug Safety, 24(4), 239-247.
• Wiholm, B-E. (2002) Correspondence - Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Drug Safety, 25(4), 297-300.

The meeting ended at 5pm.