Revised: 21 May 2013

Committees

Minutes of the 116th Medicines Adverse Reactions Committee Meeting - 10 December 2003

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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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

MARC Secretariat Present

Dr K. Maclennan (Pharmacovigilance Advisor/MARC Secretary, Medsafe)
Ms S. Von Afehlt (Senior Pharmacy Advisor/Editor of Prescriber Update, Medsafe)
Dr J. Moy (Medical Advisor, Medsafe)

Invited Experts

Dr R. Savage (New Zealand Pharmacovigilance Centre)
Dr R. Hill (Acting Director, Adverse Drug Reactions Unit, Therapeutic Goods Administration, Australia)

Visitors

Dr A. Roberts (Ministry of Health) (present for vaccine-related section of CARM Quarterly Report)

1. MATTERS OF ADMINISTRATION

1.1 Welcome and apologies

The Chair welcomed Dr Richard Hill from the TGA in Australia, Dr Ruth Savage from the NZPhvC, and Dr Jonathan Moy from Medsafe to the meeting. Dr Moy has recently joined the Medsafe pharmacovigilance team as a Medical Advisor, and will be appointed to the MARC as a Ministry of Health ex officio member.

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

Members agreed that the minutes of the 115^th meeting are a true and accurate record of the meeting.

1.3 Dates of 2004 MARC meetings

The Committee agreed that the 2004 MARC meetings should be held on Wednesday 10 March, Wednesday 23 June, Thursday 23 September, and Wednesday 1 December.

1.4 Conflicts of interest

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

1.5 Prescriber Update

Article

.., Skin atrophy with inhaled corticosteroids (pre-peer review version).

Discussion

Members agreed that it should be made clear that skin atrophy can occur with all forms of corticosteroids, not just inhaled corticosteroids. Prescribers should be aware of all dose forms of corticosteroid being taken by an individual.

Recommendation

The Committee recommended that the article should be amended so that it is clear that skin atrophy can occur with all forms of corticosteroids.

Article

.., Visual disturbances with COX-2 inhibitors (pre-peer review version).

Discussion

Members agreed that the article should not draw attention to potential mechanisms for COX-2-induced visual disturbances. It was agreed the article should state that COX-2 inhibitors have been associated with a variety of ocular adverse effects, and that these are not all suggestive of a visual field defect. As there is no evidence to suggest that COX-2 inhibitors are more likely to induce these disturbances than NSAIDs, the article should be titled 'Visual Disturbances with COX-2 Inhibitors and Other NSAIDs'.

Recommendation

The Committee recommended that the article should be amended so that it does not focus on potential mechanisms for COX-2-induced visual disturbances. In addition, the article should state that the adverse effects include a variety of ocular reactions, which are not all suggestive of a visual field defect. The title of the article should be 'Visual Disturbances with COX-2 Inhibitors and Other NSAIDs'

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

Issue

Members recommended that a paragraph, indicating to prescribers that the MARC supports the NZGG Guidelines for the Diagnosis and Treatment of Adult Asthma dosage advice, and that this advice is different to that in the Flixotide data sheet, be written for publication in Prescriber Update. This information should be published as MARC advice, and should accompany the general article about asthma therapy currently being prepared for Prescriber Update.

Outcome

The posology section in the Flixotide data sheet is based on a body of evidence that was accepted by the Medicines Assessment Advisory Committee at the time of licensing of this product. In addition, it is in line with the Australian product information, the British National Formulary (September 2003), the British Thoracic Society Guidelines (2003), and the Global Initiative for Asthma Control Guidelines (2002). Alerting prescribers to the fact that there is a discrepancy between the dosing advice in the Flixotide data sheet and that in the NZGG Guidelines (which the MARC supports) implies that the dosage information in the data sheet is inappropriate. Given the MARC has not reviewed the body of evidence underlying the data sheet dosage advice, Medsafe does not support the MARC recommendation that, "a paragraph, indicating to prescribers that the MARC supports the NZGG Guidelines for the Diagnosis and Treatment of Adult Asthma dosage advice, and that this advice is different from that in the Flixotide data sheet, be written for publication in Prescriber Update".

Discussion

The Committee again noted that the dosage advice for adults and children over 16 years of age in the Flixotide data sheet is:

Mild asthma	100 to 250 mcg twice daily
Moderate asthma	250 to 500 mcg twice daily
Severe asthma	500 to 1000 mcg twice daily

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

Mild to Moderate asthma	100 to 200 mcg twice daily
Severe asthma	Up to 400 mcg twice daily

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.

Recommendation

The Committee recommended that a review of evidence underlying fluticasone dosage advice be prepared for discussion at the March 2004 MARC meeting. A representative from the New Zealand Guidelines Group should be invited to attend this part of the MARC meeting.

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

Issue

The Committee recommended that Medsafe develop a process to ensure responses from product sponsors are timely. The drafted process should be brought to the December 2003 MARC meeting for discussion.

Outcome

Medsafe notes and appreciates the MARC's concern around timely responses from industry, in particular regarding pharmacovigilance issues. However, Medsafe does not believe it is the Committee's role to direct Medsafe operational processes. In light of this, Medsafe will review and develop processes around industry response, and will present these to the MARC for the Committee's information.

Discussion

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

2.1.3 Minute item 3.1 Hormone replacement therapy, breast cancer and mammography

Issue

The Committee recommended that the key findings of the recent HRT and breast cancer studies be communicated to prescribers by way of a Prescriber Update article. In particular, this article should provide an indication of the absolute risk of breast cancer with HRT, and note that the risk is greatest with combined HRT preparations. The article should also inform prescribers that the MARC has altered its advice that, "in most circumstances…combined HRT should not be used for longer than 3-4 years", and now simply states that the risk of adverse effects increases with duration of HRT use, and should be used for as short a time as possible. In addition, the MARC now advises that the need for continued treatment with HRT should be reviewed on a six-monthly, rather than a yearly, basis.

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.

Outcome

An article entitled 'HRT - New advice from the Medicines Adverse Reactions Committee' was published in the November 2003 issue of Prescriber Update.

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

Discussion

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

2.1.4 Minute Item 4.4.1 Analysis of IMMP events reported for clozapine

Issue

The Committee recommended that the issue of hyperlipidemia with atypical antipsychotics be placed on the agenda for the December 2003 MARC meeting.

Outcome

See Section 3.1 of these minutes.

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

Issue

The Committee recommended that Medsafe ask the product sponsor for 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.

Outcome

Aventis has submitted a changed medicine notification for Arava in order to make the New Zealand data sheet consistent with the Australian product information. Subsequent to Medsafe approval of these changes, Aventis will provide a Dear Healthcare Professional letter to Medsafe for review.

Discussion

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

2.2.2 March 2003 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 is necessary at this time.

2.2.3 March 2003 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 to strengthen product data sheet advice, emphasising that the use of this medicine as maintenance therapy should be in addition to corticosteroid treatment of asthma.

Outcome

The salmeterol data sheet advice has been strengthened, as requested. GSK has advised Medsafe that further analyses from the Salmeterol Multi-centre Asthma Research Trial have been conducted. A final expert report is being sent to GSK New Zealand from the UK, and a copy will be forwarded to Medsafe. Medsafe will review these new data before deciding on an appropriate course of action.

Discussion

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

2.2.4 Sept 2002 minute item 3.3.1 COX-2 inhibitors

Issue

In view of a 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

The Celebrex data sheet update request was not actioned by the Pfizer office in New Zealand. The New Zealand office has since merged with the Pfizer office in Sydney, where the Celebrex data sheet update request is under urgent review.

Discussion

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

2.2.5 June 2002 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.

Outcome

Organon has advised Medsafe that a Cerazette pharmacodynamic trial has now been completed. A European Variation Expert Report is being written and a submission to change the missed-pill advice to a 12-hour statement will be made in January 2004.

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.

Discussion

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

3. Pharmacovigilance Issues

3.1 Atypical antipsychotics and lipid abnormalities

Reference Material

Atypical antipsychotics and lipid abnormalities (Medsafe report, November 2003)

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.

Issue

At the September 2003 MARC meeting, it was noted that the NZPhvC had received ten reports of lipid abnormalities with clozapine. The Committee asked that the issue of hyperlipidemia with atypical antipsychotics be further discussed at the December 2003 MARC meeting.

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

Discussion

Members discussed a Medsafe summary of several recent studies and reviews regarding atypical antipsychotics and lipid abnormalities.

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.

Recommendations

The Committee recommended that prescribers be informed about the potential association between atypical antipsychotics and lipid abnormalities through an article or paragraph in Prescriber Update. Baseline and follow-up lipid monitoring should be encouraged.

The Committee also recommended that product sponsors for clozapine and risperidone be asked to include data sheet statements to say that 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)

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.

4.1 CARM Case Reports

4.1.1 Reports in which death occurred

4.1.1.1 DTaP/IPV, Hib/HepB and sudden death (57028)

Discussion

There are no reports of death or Sudden Infant Death Syndrome (SIDS) in the CARM database for the aforementioned vaccines. The Committee agreed that, although the temporal association raises concerns regarding the immunisation in this case, this infant was also in the age group at risk for SIDS. In the absence of further information regarding post-mortem findings or other potential causes, the report was deemed 'unclassified'.

4.1.1.2 Colchicine and metabolic acidosis, renal failure, hepatic failure, overdose, death (57524)

Discussion

There are three reports of death associated with intentional overdose of colchicine in the CARM database. The product data sheet for colchicine states that fatalities have been reported following ingestion of 6 to 7 mg in 24 hours. The causal association was deemed 'probable' for metabolic acidosis, renal failure, hepatic failure, overdose, and death. No further action was recommended.

4.1.1.3 Cyclophosphamide and myelodysplasia, leukaemia (57557)

Discussion

The CARM database holds 35 reports for cyclophosphamide, 12 of which are haematological events (one report each of leucopenia and a myeloproliferative disorder). The WHO database holds 34 reports of myelodysplasia, and 26 reports of leukaemia, in association with cyclophosphamide.

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.

4.1.1.4 Docetaxel, trastuzumab and hepatic necrosis, hepatic failure (57640)

Discussion

There are no reports of liver failure associated with docetaxel or trastuzumab in the CARM database. The WHO database holds 13 reports of hepatic failure associated with docetaxel, and two associated with trastuzumab. The product data sheet for docetaxel advocates caution in patients with hepatic impairment, while the trastuzumab data sheet refers to the possibility of hepatic toxicity with this product. The causal association for both docetaxel and trastuzumab was deemed 'probable' for hepatic necrosis and hepatic failure. No further action was recommended.

4.1.1.5 Enoxaparin and haemorrhage (57708)

Discussion

The CARM database holds 33 reports of enoxaparin associated with various forms of bleeding and haemorrhage. The product data sheet for enoxaparin states that, "Elderly patients (especially patients eighty years of age and older) may be at an increased risk for bleeding complications with the therapeutic dosage ranges. Careful clinical monitoring is advised."

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.

Recommendation

The Committee recommended that CARM conduct an assessment of the 33 reports of enoxaparin and bleeding/haemorrhage in the CARM database. The findings of this analysis should be reported to the MARC at a future meeting.

4.1.1.6 Flupenthixol and sudden death, convulsion (57280)

Discussion

Of seven reports for flupenthixol held in the CARM database, two are associated with neuroleptic malignant syndrome, and there are no reports of death.

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

4.1.2.1 Comvita Fortacold, Echinacea and stridor (57683)

Discussion

The Committee noted that Comvita products are typically bee product-based formulations and, therefore, could cause stridor as an allergic reaction. In addition, Echinacea has been implicated in reports of hypersensitivity reactions. The causal association for Comvita Fortacold, Echinacea, and stridor was deemed 'probable'.

4.1.2.2 Jointex and anaemia, stool black (57419)

Discussion

The Committee noted that the Australian Complementary Medicines Evaluation Committee is reviewing 143 adverse reaction reports for glucosamine. Of these reports, four are associated with bleeding, and one with anaemia.

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'.

4.1.2.3 Thompson's Ginkgo biloba complex and epistaxis (57685)

Discussion

Of two reports for Ginkgo biloba in the CARM database, one is associated with cerebral haemorrhage. The Natural Medicine Database reports that spontaneous bleeding is one of the most concerning potential side effects of Ginkgo biloba. The causal association was deemed 'probable', and no further action was recommended.

4.1.3 Musculoskeletal medication-related reports

4.1.3.1 Aurothiomalate, cilazapril and hypotension, sweating increased, taste perversion, palpitations, drug interaction (57153)

Discussion

The causal association was deemed 'certain' for hypotension, sweating increased, taste perversion, palpitations, and drug interaction. For further discussion, see section 4.2.1.

4.1.3.2 Aurothiomalate and hypotension, hemiplegia, aphasia (57394)

Discussion

The causal association was deemed 'certain' for hypotension, and 'possible' for hemiplegia and aphasia. For further discussion, see section 4.2.1.

4.1.3.3 Leflunomide and hepatic enzymes elevated, neutropenia (56813)

Discussion

The causal association was deemed 'probable' for hepatic enzymes elevated, and 'possible' for neutropenia. For further discussion, see section 4.2.2.

4.1.3.4 Leflunomide and atrial fibrillation, chest pain, DVT, diarrhoea (56816)

Discussion

The causal association was deemed 'unlikely' for atrial fibrillation and chest pain, 'unclassifiable' for thrombosis venous deep, and 'possible' for diarrhoea. For further discussion, see section 4.2.2.

4.1.3.5 Leflunomide, azathioprine and infection, tooth disorder, ascites, oedema peripheral, portal hypertension, hepatic disorder, thrombocytosis, splenomegaly, hypoproteinaemia (57045/57354)

Discussion

The Committee agreed that the hepatic disorder was most likely attributable to azathioprine. The causal association was deemed 'possible' for infection, tooth disorder, ascites, oedema peripheral, portal hypertension, hepatic disorder, thrombocytosis, splenomegaly, and hypoproteinaemia. For further discussion, see section 4.2.2.

4.1.3.6 Leflunomide and pulmonary infiltration, respiratory depression, pneumonia (57491)

Discussion

It was noted that CARM has received one other report of pulmonary infiltration with leflunomide, and that the leflunomide product data sheet states that interstitial lung disease is a very rare adverse reaction. The causal association was deemed 'probable' for pulmonary infiltration, respiratory depression, and pneumonia. For further discussion, see section 4.2.2.

4.1.3.7 Leflunomide, methotrexate and pulmonary infiltration, diverticulitis, intestinal fistula, breast neoplasm benign, pneumonia, neutropenia (57615)

Discussion

Members noted that the inflammation of the diverticulae and subsequent fistula formation could be attributable to infection. The causal association was deemed 'unlikely' for pulmonary nodules, 'possible' for diverticulitis, intestinal fistula, pneumonia, and neutropenia, and 'unclassified' for benign breast neoplasm. For further discussion, see section 4.2.2.

4.1.4 Vaccine-related reports

4.1.4.1 DTaP/IPV and rash erythematous, skin exfoliation (57150)

Discussion

CARM has no other reports of 'scalded skin' type reactions with DTaP/IPV, although there are 53 reports describing rash. The causal association was deemed 'possible' for rash erythematous and skin exfoliation. No further action was recommended.

4.1.4.2 MMR and fever convulsion, coma, paralysis (57222)

Discussion

Of 964 reports for MMR held in the CARM database, 25 are associated with febrile convulsions, and 11 are associated with convulsions. It was noted that the DTaP was not in typical use at the time this reaction was experienced, and it is more likely the vaccine was DTwP.

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.

4.1.4.3 MMR, DTaP/Hib and rash maculopapular, urinary incontinence, balanitis, candida, diabetes mellitus (57477)

Discussion

Of 964 reports for MMR held in the CARM database, 38 are associated with rash, three with measles-like symptoms, and one with thirst. It was noted that the onset of rash, occurring at approximately 11 days following MMR vaccination, is in keeping with post-MMR vaccine-associated measles disease. However, the polyuria and thrush balanitis is an unusual association with immunisation. The absence of supporting reports and publications suggests the diabetic-related events may well represent a coincidental occurrence.

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

4.1.4.4 Influenza vaccine and thrombocytopenic purpura (57262)

Discussion

Of 744 reports for influenza virus vaccine held in the CARM database, 11 are associated with haematological reactions, and three with INR changes. It was noted that there are occasional reports in the literature of thrombocytopenic purpura after influenza vaccination.

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

Reference

Arthur et al (2001) Nitritoid reactions: case reports, review and recommendations for management. Journal of Rheumatology, 28;2209-2212.

Issue

Nitritoid reactions to gold are vasomotor reactions characterised by weakness, hypotension, flushing, tachycardia, palpitations, sweating, and sometimes syncope. Most reactions are mild but the hypotension can be severe and has been reported to cause stroke, myocardial infarction and transient ischaemic attacks. In the last quarter, CARM has received two reports of nitritoid reactions to intramuscular gold (see sections 4.1.3.1 and 4.1.3.2).

Discussion

The Committee noted that several published case reports have referred to patients experiencing nitritoid reactions to intramuscular gold while taking ACE inhibitors. It was noted that, of the seven reports of hypotension with aurothiomalate sodium in the CARM database, three involved concomitant administration of an ACE inhibitor.

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.

Recommendations

The Committee recommended that the New Zealand sponsor for aurothiomalate sodium be asked to update the product data sheet to include a more detailed description of nitritoid reaction symptoms, and the potential for 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).

Issue

As at 30 September 2003, CARM has received 22 reports for leflunomide (regardless of causality). The reports include five reactions each for the gastrointestinal, hepatic, cardiovascular, and respiratory body systems, and six haematological, three musculoskeletal, one skin, one endocrine and five infection-related reactions.

Discussion

The Committee noted that a number of patients had multiple disorders, which made causality difficult to assess. In addition, all patients with infection-related reactions were taking more than one immunosuppressive agent. It was also noted that, apart from thrombotic disorders, the serious suspected reactions are labelled in the New Zealand data sheet, although interstitial lung disease is stated to occur very rarely without any further detail.

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.

Recommendation

The Committee recommended that pulmonary infiltration be included in the respiratory disorders section of the leflunomide article planned for publication in Prescriber Update. Members also recommended that CARM continue to inform the MARC about significant adverse reaction reports 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

Triazolam (switch from Halcion to Hypam): 3 reports consistent with a reduced therapeutic effect have been received.

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.

Discussion

Members noted that brand-switch reaction reports were still being received for citalopram. The Committee agreed that CARM and Medsafe should work together to investigate this issue.

Recommendation

The Committee recommended that Medsafe and CARM further investigate the brand-switch issues with citalopram.

4.3.1.2 Other medicine-related reports

Three or more reports have been received for amoxycillin, X-ray contrast media, and enoxaparin. In addition, there are four reports of application site reactions with pimecrolimus in this quarter, with eight in the year to date.

4.3.1.3 Vaccine-related reports

The pattern of adverse events following immunisation is largely unremarkable with typical expected events. However, there are three reports of apnoea following the DTaP/IPV vaccine. These events have largely occurred following the first (six-week) immunisation, typically in infants with a history of prematurity. There have been case series and reports published implicating the pertussis component in this reaction, suggesting that the degree of prematurity is a risk factor. Vaccines with three or more specific events are MMR, DTaP/HiB, ADT, DTaP/IPV, HepB, HiB/HepB, and IPV.

≥ Six Reports in the Year-to-Date

There are no new medicines in this section, and the reports reflect reactions that are not unexpected or those that are reported with low frequency.

Adverse Reactions of Current Concern

Members agreed that the Adverse Reactions of Current Concern list should be reviewed at the March 2004 MARC meeting.

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.

Recommendations

The Committee recommended that the list of Adverse Reactions of Current Concern be reviewed at the March 2004 MARC meeting.

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)

Issue

IMMP monitoring of celecoxib and rofecoxib began in December 2000. The cohorts are now closed, with the celecoxib and rofecoxib cohorts containing 32,630 and 26,666 patients, respectively. Follow-up is complete for 6,200 celecoxib patients, and 4,536 rofecoxib patients.

Discussion

The Committee noted that rofecoxib 50 mg/day is prescribed in 9% (3000) of prescriptions. Sixty-three percent of these were for greater than five days - this is of some concern given that chronic use at this dose is not recommended in the product data sheet. Both medicines are also being prescribed relatively frequently in the elderly; approximately 10% of the patient cohort is over 80 years of age. Members agreed that these medicines are likely to be used often in palliative care.

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

The Committee did not discuss this material. It includes updates on issues already known to the Committee, commentaries, review articles, and preliminary information on emerging issues. Members were asked to read this material, with the option of requesting that it be discussed.

5.1 HRT use in NZ

Reference

Lawton et al (2003) Changes in use of hormone replacement therapy after the report from the Women's Health Initiative: cross sectional survey of users. BMJ, 327, 845-846.

5.2 Sulfonamide antibiotics

References

Strom et al (2003) Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med, 349(17), 1628-1635.

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

Reference

Bohlke et al (2003) Risk of anaphylaxis after vaccination of children and adolescents. Pediatrics, 112(4), 815-820.

5.4 Perioperative COX-2 administration

Reference

Buvanendran et al (2003) Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement. JAMA, 290(18), 2411-2418.

5.5 St John's wort

References

Markowitz et al (2003) Effect of St John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA, 290(11), 1500-1504.

5.6 CARM case reports

• Centrum tiredandness, diarrhoea, dizziness (57281)
• 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

Reference pricing of isotretinoin

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

Discussion

The Committee noted that the generic brand of isotretinoin, Isotane, will become sole supply in May 2004, and will be available at a lower price to consumers than it is currently. The requirement that the prescription be written by a dermatologist (in order for the medicine to be fully-funded by PHARMAC) will be retained; however, members expressed concern that the reduced price of this brand might lead to a greater number of General Practitioners and appearance medicine practitioners prescribing isotretinoin. A consequence of this could be an increased incidence of potentially severe adverse reactions (e.g., teratogenic effects).

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.

Recommendations

The Committee recommended that Medsafe draft a letter to PHARMAC for the MARC Chair's comment and signature. The letter should seek to ensure there is an adequate isotretinoin education strategy in place for prescribers.

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

Clark et al (to be submitted) Do some inhibitors of cyclooxygenase-2 (COX-2) increase the risk of thromboembolic events? Linking pharmacology with pharmacoepidemiology.

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

7. international activities

7.1 Australia

Australian Adverse Drug Reactions Bulletin 22(5), October 2003

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

Canadian Adverse Reaction Newsletter 13(4), October 2003.

7.3 Malaysia

Malaysian Adverse Drug Reaction Newsletter 2003

7.3 United Kingdom

Current Problems in Pharmacovigilance September 2003

7.3 WHO

WHO Pharmaceuticals Newsletter No. 5, 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 3pm.