MARC MEMBERS PRESENT

marc secretariat present

invited experts

visitors

1.

MATTERS OF ADMINISTRATION

1.1

Welcome and apologies

Apologies had been received from Dr M. Tatley, Dr M. Rademaker, Dr F. McClure and Dr S. Jessamine.

1.2

Minutes of the 115^th meeting

1.3

Dates of 2004 MARC meetings

1.4

Conflicts of interest

1.5

Prescriber Update

2.

MATTERS ARISING

2.1

Report on actions arising from the 115^th MARC meeting

2.1.1

Minute item 2.2.4 (December 2002 minute item 4.1) High-dose fluticasone and adrenal insufficiency

whereas, the dosage advice for fluticasone in the NZGG Guidelines for the Diagnosis and Treatment of Adult Asthma is:

While it was noted that Guidelines represent a statement of best practice and are not intended to replace the judgement of healthcare professionals in individual cases, the Committee remained dissatisfied with the dosage advice discrepancies between the two documents. The Committee asked that Medsafe prepare a full review of evidence underlying fluticasone dosage advice for discussion at the March 2004 MARC meeting. Members agreed it would be advantageous for a representative of the New Zealand Guidelines Group to be present for this discussion.

2.1.2

Minute item 2.2.5 (September 2002 minute item 3.3.1) COX-2 inhibitors: related discussion around timely response from product sponsors

2.1.3

Minute item 3.1 Hormone replacement therapy, breast cancer and mammography

The Committee recommended that Medsafe write to sponsors of all HRT products, including tibolone, requesting that statements that reflect the risk of breast cancer (and the potential delay in diagnosis through mammography) be included in HRT product data sheets. This request should be separate from the current section 36 notice that has been issued to HRT product sponsors.

Product data sheet update requests will be sent to HRT product sponsors in due course.

2.1.4

Minute Item 4.4.1 Analysis of IMMP events reported for clozapine

2.2

Report on actions outstanding

2.2.1

June 2003 minute item 2.1.2 Leflunomide/methotrexate/ketoprofen/triamcinolone and septic shock/septic arthritis/multiple organ failure/infection streptococcal/vomiting - CARM case report 52507

2.2.2

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

2.2.3

March 2003 minute item 4.1 Safety information from the Salmeterol Multi-centre Asthma Research Trial

2.2.4

Sept 2002 minute item 3.3.1 COX-2 inhibitors

2.2.5

June 2002 minute item 2.2.1 Missed-pill advice for Cerazette

Cerazette is not on the market in New Zealand and is not expected to be so in the foreseeable future. On the condition that Medsafe is advised of any decision to introduce Cerazette to the New Zealand market in the interim, Medsafe has agreed to await the outcome from the European Union evaluation.

3.

Pharmacovigilance issues

3.1

Atypical antipsychotics and lipid abnormalities

Atmaca et al (2003) Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics. Journal of Clinical Psychiatry, May; 64(5):598-604.

Wirshing et al (2002) The effects of novel antipsychotics on glucose and lipid levels. Journal of Clinical Psychiatry, Oct; 63(10);856-65.

Meyer (2002) A retrospective comparison of weight, lipid, and glucose changes between risperidone-and olanzapine-treated inpatients: metabolic outcomes after 1 year. Journal of Clinical Psychiatry, May; 63(5):425-33.

Harrison-Woolrych (2003) Lipid abnormalities with atypical antipsychotics: IMMP update for MARC December 2003.

Gupta (June 2003) Monitoring parameters for atypical antipsychotics - a review of the evidence. Central and North West London Mental Health NHS Trust.

The atypical antipsychotics available in New Zealand are clozapine, olanzapine, quetiapine, and risperidone.

The Committee agreed that the findings of many of the epidemiological studies conducted to date need to be considered with study design limitations in mind. Nevertheless, lipid abnormalities associated with atypical antipsychotic treatment have been observed, and data suggest this association may be stronger for clozapine and olanzapine. It was noted that the New Zealand data sheets for olanzapine and quetiapine make reference to the possibility of lipid abnormalities with treatment. However, the New Zealand data sheets for clozapine and risperidone make no reference to post-marketing reports of lipid abnormalities associated with these products.

The Committee noted that an association between atypical antipsychotics and lipid abnormalities is not obvious from numbers of spontaneous reports to date. However, in general, New Zealand psychiatric pharmacists and consultant psychiatrists appear to be aware of this possible association. Some hospitals throughout New Zealand have already implemented monitoring guidelines in this regard.

The Committee concluded that, while many of the epidemiological studies conducted for atypical antipsychotics to date are not well controlled or are limited by a lack of power, collectively, they suggest that atypical antipsychotic medicines can adversely affect the blood lipid profile. In light of this, members agreed that prescribers should be informed about the potential association between atypical antipsychotics and lipid abnormalities through an article or paragraph in Prescriber Update. Baseline and follow-up lipid monitoring should be encouraged.

The Committee also agreed that product sponsors for clozapine and risperidone should be asked to include data sheet statements to say that reports of a possible association between their product and lipid abnormalities have been made post-marketing. In addition, product sponsors for all four of the atypical antipsychotics available in New Zealand should be asked to comment on the issue of lipid abnormalities.

The Committee also recommended that product sponsors for clozapine and risperidone be asked to include data sheet statements to say that reports of a possible association between their product and lipid abnormalities have been made post-marketing. In addition, product sponsors for all four of the atypical antipsychotics available in New Zealand should be asked to comment on the issue of lipid abnormalities.

4.

matters arising from the New Zealand Pharmacovigilance Centre (NZPHvC)

Spontaneous reporting programme

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

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

4.1

CARM Case Reports

4.1.1

Reports in which death occurred

The product data sheet for cyclophosphamide states that, "The patient's haematologic status must be carefully monitored throughout each cycle of treatment. Cyclophosphamide-induced leukopenia/neutropenia are dose-related and can be used as a guide to adjusting the drug dosage."

The Committee noted the off-label use of cyclophosphamide in this case. The causal association was deemed 'possible' for myelodysplasia and leukaemia, and no further action was recommended.

The causal association was deemed 'probable' for enoxaparin and haemorrhage. The Committee requested that CARM conduct an assessment of the 33 reports of enoxaparin and bleeding/haemorrhage in the CARM database, and report back to the MARC at a future meeting.

The Committee noted that the patient might have been administered amiodarone by paramedics after her collapse. Members agreed that this was an unexplained death, although cannabis and possibly amiodarone may have relevance. The causal association was deemed 'unclassified', and no further action was recommended.

4.1.2

Alternative medicine-related reports

Members agreed that, given the other medicines the patient is taking, it is possible colitis may explain his black stools. The causal association for Jointex, anaemia, and black stools was deemed 'unlikely'.

4.1.3

Musculoskeletal medication-related reports

4.1.4

Vaccine-related reports

Members noted that, although post-immunisation febrile convulsions do occur as a complication of the somatic febrile response, these typically present within 24 to 48 hours following vaccination. The prolonged nature of this convulsion is also an unusual feature. The causal association was deemed 'possible' for fever convulsion, coma, and paralysis, and no further action was recommended.

The causal association was deemed 'possible' for rash maculopapular, and 'unlikely' for urinary frequency, balanitis, candida, and diabetes mellitus. No further action was recommended.

Members agreed that the very short duration to onset may not support a strong association in this case, however an association cannot be excluded. The causal association was deemed 'possible' for thrombocytopenic purpura. No further action was recommended.

4.2

Spontaneous reporting programme - signals

4.2.1

Intramuscular gold, ACE inhibitors, and nitritoid reactions

Members noted that nitritoid reactions appear to occur more commonly with aurothiomalate sodium than with aurothioglucose sodium, which is absorbed less rapidly and achieves lower peak plasma levels. Arthur et al (2001) recommend that patients who experience nitritoid reactions after gold injection be switched to aurothioglucose sodium, with an initial 50% reduction in dose. Such patients should be observed for 20 minutes post-injection. The authors also recommend that patients taking ACE inhibitors be given aurothioglucose, rather than aurothiomalate.

The Committee noted that the product data sheet for aurothiomalate sodium states that, "As with other gold preparations, reactions which resemble anaphylactoid effects have been reported. These effects may occur after any course of therapy, within the first 10 minutes following drug administration. If anaphylactoid effects are observed, treatment with MYOCRISIN should be discontinued". Members agreed that this should be updated to include a more detailed description of nitritoid reaction symptoms, and the potential for interaction with ACE inhibitors.

The Committee suggested that a reminder about the potential for nitritoid reactions with gold injections be written for publication in Prescriber Update. The article should provide advice to prescribers about reintroducing injections at a lower dose, and remind prescribers about the potential interaction with ACE inhibitors.

The Committee also recommended that prescribers be reminded about the potential for nitritoid reactions with gold injections by way of an article in Prescriber Update. The article should provide advice to prescribers about reintroducing gold injections at a lower dose, and a reminder about the potential interaction with ACE inhibitors.

4.2.2

Summary of leflunomide reports to CARM to 30 September 2003 (regardless of causality).

In June 2003, the MARC recommended that an article about serious reactions to leflunomide be written for publication in Prescriber Update. The Committee agreed that pulmonary infiltration should be included in the respiratory disorders section of this article. Members also agreed that they wish to continue receiving CARM reports regarding significant suspected reactions to leflunomide.

4.3

CARM Quarterly report (as at 30 September, 2003)

4.3.1

Multiple occurrence reaction reporting

≥ Three Reports in the Last Quarter

4.3.1.1

Brand-switch related reports

Citalopram (switch from Cipramil to Celapram): 30 reports consistent with a reduced therapeutic effect have been received (as with the 30 reports received in the previous quarter, these describe a return to depressive-like symptoms).

Dipyridamole (switch from Persantin to Pytazen): 12 reports have been received. These reflect a diversity of reactions such as dizziness, headache, blurred vision, dyspepsia and other GI symptoms, and rash.

Gliclazide (switch from Diamicron to Apo-gliclazide): 4 reports consistent with a reduced therapeutic effect have been received.

No further reports of brand-switch reactions were reported with clonazepam, which had previously been reported to result in loss of seizure control in some patients.

4.3.1.2

Other medicine-related reports

4.3.1.3

Vaccine-related reports

≥ Six Reports in the Year-to-Date

Adverse Reactions of Current Concern

It was also suggested that a slide containing MARC medicines safety information or advice should be e-mailed to the weekly Grand Rounds in New Zealand hospitals. The Committee asked that Medsafe explore options regarding how this could be done.

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

4.4

Intensive Medicines Monitoring Programme

4.4.1

Monitoring review of celecoxib and rofecoxib (as at November 2003)

It was also noted that a past or current history of conditions likely to be aggravated by COX-2 inhibitors is common amongst the patient cohort. For example, 60% of patients have had acid-related disorders of the upper GI tract, 20% have a history of hypertension, and 5% have a history of heart failure.

The IMMP adverse event profiles for celecoxib and rofecoxib are similar, with circulatory, alimentary, and death events being the most common. Preliminary data suggest a high death rate, particularly in the elderly. The three most common types of death that are assessed as causally related are circulatory, renal, and alimentary.

The Committee was informed that extensive work is being undertaken on the death events, particularly in relation to cardiovascular disorders, and on possible prothrombotic effects. An initial finding of a shorter time to onset of death with COX-2 inhibitors (compared with all other medicines in the IMMP database) persists, as does the higher proportion of circulatory incidents. Analyses have been undertaken, but not yet reviewed, on risk factors for renal failure, prothrombotic effects, cardiac dysrhythmias, and heart failure.

The phase of monitoring has now switched to completion of the follow-ups (about half have been sent out), and the assessment of the questionnaires and event analyses.

5.

pharmacovigilance ISSUES FOR INFORMATION ONLY

5.1

HRT use in NZ

5.2

Sulfonamide antibiotics

Current Topics from the Drug Information Center - Medication use in sulfa allergy. October 2002.

Current Topics from the Drug Information Center - Medications to avoid in patients with a sulfa allergy. September 2002.

5.3

Vaccine-induced anaphylaxis

5.4

Perioperative COX-2 administration

5.5

St John's wort

5.6

CARM case reports

Ignite and hypertension (57487)

Multivitamins and abdominal pain (57576)

Olive leaf and vomiting (57379)

Olive leaf and abdominal pain (57614)

Estelle 35 and pulmonary embolism (57678)

6.

New Zealand activities

6.1

PHARMAC

Minutes of the Pharmacology and Therapeutics Advisory Committee Meeting, August 2003.

Members agreed it is important for people of all income levels to have equal access to medicines. It was agreed that the MARC should ensure there is an adequate education strategy in place so that all doctors are aware of potential serious adverse reactions to isotretinoin. The Committee asked that Medsafe draft an appropriate letter to PHARMAC for the MARC Chair's comment and signature. Medsafe should also investigate the possibility of monitoring GP prescribing of isotretinoin using the RNZCGP research unit database at Otago University.

The Committee also recommended that Medsafe investigate the possibility of monitoring GP prescribing of isotretinoin using the RNZCGP research unit database at Otago University.

6.2

Publications

Coulter et al (2003) Celecoxib, rofecoxib, and acute temporary visual impairment. BMJ, 327;1214-1215.

7.

international activities

7.1

Australia

Minutes of the August 2003 meeting of the Adverse Drug Reactions Advisory Committee

Minutes of the September 2003 meeting of the Adverse Drug Reactions Advisory Committee

7.2

Canada

7.3

Malaysia

7.3

United Kingdom

7.3

WHO

8.

summary of case reports considered by marc (1997 to 2003)

Vaccine adverse reaction reports considered by the MARC

Complementary and alternative medicine case reports considered by the MARC