Revised: 21 May 2013

Committees

Minutes of the 113th Medicines Adverse Reactions Committee Meeting - 12 March 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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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

Professor P. Ellis
Dr H. Kingston
Dr F. McClure (Acting Chair)
Dr N. Rafter
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, NZPhVC)

Visitors

Dr J. McEwen (Principal Medical Advisor, Adverse Drug Reactions Unit, TGA)
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 John McEwen from the Adverse Drug Reactions Unit in Australia. Apologies had been received from Professor D.C.G. Skegg, Dr M. Rademaker, and Associate Professor T.J.B. Maling.

1.2 Minutes of the 112^th meeting

Members agreed that the minutes of the 112^th meeting are a true and accurate record of the meeting.

1.3 Date of next meeting

Thursday June 26 is the confirmed date for the next MARC meeting.

1.4 Conflict of interest

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

1.5 Prescriber Update

Upcoming articles

.., COX-2 inhibitors and hepatotoxicity (final version of article - MARC to approve for publication).

Discussion

Members approved the above article for publication. Any comments from members were communicated to the Editor outside of the meeting.

2. MATTERS ARISING

2.1 Report on actions arising from the 112^th MARC meeting

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

Issue

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

Action

Medsafe has requested a copy of sub-committee minutes. PHARMAC expects these minutes to be signed-off within the next week, and will forward a copy to Medsafe when this process is complete.

Discussion

Members noted the above and agreed that the Committee should be informed when Medsafe makes a decision about whether the working party will be convened.

2.1.2 Minute item 3.1.1.6 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 investigate the extent of leflunomide use in New Zealand.

Outcome

Sales data from Aventis Pharma for 2002 indicate that approximately 500 patients used Arava that year.

Discussion

Dr McEwen informed the Committee that 11 reports of pancytopenia with leflunomide have been received in Australia. In many of these reports, low-dose methotrexate was a concomitant medication. Unfortunately, there are no good data on pancytopenia with methotrexate, so it is difficult to establish a base-line incidence of pancytopenia in patients also taking leflunomide. Members noted that Canada and the FDA have received reports of hepatotoxicity with leflunomide, and that these issues are being discussed at the videoconferences between Medsafe, Health Canada, the FDA, and the TGA.

Recommendation

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

2.1.3 Minute item 3.1.3.1 Itraconazole and congestive heart failure - CARM case report 51829

Issue

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.

Action

.. has agreed to author this article for publication in an upcoming issue of Prescriber Update.

Discussion

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

2.1.4 Minute item 3.2.1 Multiple Occurrence Reaction Reporting

Issue

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.

Outcome

.. will liaise to ensure that points of significance to prescribers are communicated in upcoming issues of Prescriber Update.

Discussion

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

2.1.5 Minute item 3.2.2 Adverse Reactions of Current Concern

Issue

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).

Outcome

The updated list of Adverse Reactions of Current Concern will be included in the next issue of Prescriber Update.

Discussion

Members questioned how well the list of adverse reactions of current concern is communicated to prescribers. The Committee suggested that it might be useful to have the list published in the New Ethicals catalogue, or to pursue its inclusion in GP prescribing software.

Recommendation

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

2.1.6 Minute item 4.1 High-dose fluticasone and adrenal insufficiency

Issue

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

Outcome

Medsafe decided to seek update only for fluticasone datasheets. A letter has been sent to GlaxoSmithKline informing them of the Committee's recommendations, and requesting that the dosage advice in the Flixotide product information be updated to reflect that of the NZGG.

Discussion

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

Issue

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.

Outcome

As PHARMAC is to discontinue PreMeC funding, the Committee was asked if it wished to reconsider the above recommendation.

Discussion

Members noted than an asthma treatment information kit has been sent by PHARMAC to GPs throughout New Zealand. In addition, members were informed that PreMeC intends to publish asthma-related vignettes in its final bulletin. Given this, members did not feel it was necessary to explore other potential publication options regarding the NZGG dosage recommendations at this time. The Committee agreed however, that it will be important to evaluate whether the actions taken by Pharmac and others have a positive influence on the safe prescribing of fluticasone.

Recommendation

Members recommended that Medsafe request an analysis of fluticasone prescribing from Pharmac in six-months time.

Issue

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.

Outcome

In December 2002, .. received an e-mail from the Paediatric Society, informing him that the Society is proceeding with a National Asthma Guideline of the Paediatric Society of NZ, and asking for input into their Asthma Guidelines Committee.

In .. response, .. informed the Paediatric Society of the MARC discussion regarding fluticasone and adrenal suppression, and enclosed copies of relevant articles for incorporation into the Guideline review.

Discussion

Members noted two articles recently published in the Medical Journal of Australia. One paper presents an analysis of a Cochrane database systematic review on the use of inhaled corticosteroids (Powell & Gibson, vol 178). The other presents a case series of adrenal crises in children taking inhaled corticosteroids (Macdessi, vol 178).

Recommendation

Members recommended that the Macdessi (2003) article be brought to the attention of the Paediatric Society.

Issue

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

Outcome

The updated list of Adverse Reactions of Current Concern will be included in the next issue of Prescriber Update.

Discussion

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

2.1.7 Minute item 3.3.1.1 Atypical antipsychotics and hypertension - IMMP adverse event reports

Issue

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.

Outcome

.. has agreed to author this article for publication in an upcoming issue of Prescriber Update.

Discussion

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

2.1.8 Minute item 3.1.5.1 & 3.1.5.2 Simvastatin and rhabdomyolysis, myoglobinuria/renal failure acute/somnolence/vision blurred/taste disturbance - CARM case report 52761 & Simvastatin and myalgia/nausea/syncope - CARM case report 52835

Issue

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.

Outcome

An article will be drafted by .. for publication in an upcoming issue of Prescriber Update.

Discussion

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

2.2 Report on actions outstanding

2.2.1 June 2002 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.

Outcome

.. of Pharmaco advised Medsafe that during the mutual recognition procedure in EU countries in 1998, the UK opposed the 12-hour missed-tablet advice for Cerazette. The clinical assessor in the reference state, Sweden, advised against the adaptation of missed-tablet advice from 12 to 3 hours in the SmPC. However, for marketing reasons, Organon decided to accept the 3-hour rule in the EU labelling text, and this was automatically imposed on the other EU countries under the provision of the Mutual Recognition procedure.

Other non-EU regions have the 12-hour rule (Asia, Sth America, Switzerland etc), and Organon intends to have the 12-hour rule accepted in the UK (and therefore the EU). The UK has suggested that an additional pharmacodynamic trial be performed. Preparations for this trial are ongoing and the current planning is that the trial should start in February 2003.

Discussion

Members agreed it would be prudent for Medsafe to evaluate the available data regarding missed-pill advice for Cerazette. Unless there are data to support the 12-hour rule in the New Zealand product information, Pharmaco should be asked to change this advice from 12 to 3 hours in the Cerazette datasheet.

Recommendation

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.

2.2.2 Sept 2002 minute item 3.3.1 COX-2 inhibitors

Issue

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

Outcome

In February 2003, Medsafe sent a letter to Pharmacia advising of discrepancies between the New Zealand, and Australian and American product information sheets for Celebrex. If Pharmacia is unable to justify these differences, the New Zealand Celebrex data sheet should be appropriately updated (requested changes are with regard to GI effects, anaphylactoid reactions, and serious adverse reactions which occur rarely (<0.1%)).

In addition, Pharmacia has been asked to provide comment on recent findings concerning limitations of the CLASS study.

Issue

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

Outcome

In February 2003, Medsafe sent a letter to MSD advising of discrepancies between the New Zealand, and Australian, Canadian, and American product information sheets for Vioxx. If MSD is unable to justify these differences, the New Zealand Vioxx data sheet should be appropriately updated (requested changes are with regard to dosage and administration, contraindications, cardiovascular adverse events, and renal insufficiency).

Discussion

Members agreed that, when possible, it would be useful for the Medicines Assessment Advisory Committee (MAAC) to be aware of information provided in international data sheets when evaluating draft data sheets for approval in New Zealand.

Recommendation

The Committee recommended that the MAAC be asked to consider information provided in international product datasheets when evaluating draft data sheets for approval in New Zealand. Members requested that Medsafe communicate this view to the MAAC.

2.2.3 Sept 2002 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'. This letter should also state that the MARC does not advocate Special Authority restrictions on third generation contraceptives.

Outcome

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

Pharmac responded that previous experience with "certified condition" endorsements shows that doctors often forget to write the endorsement and the pharmacist is left to sort the issue out. Also, with computerised prescribing, it is possible for the doctor to set the endorsement as a default on the system, so defeating the purpose of the requirement. Pharmac appreciates there is a small but significant risk associated with third generation OCs, and feels that an informed public is what drove the recent change from third to second generation OCs. In light of this, Pharmac suggests that pharmacists be encouraged to apply a cautionary label to each packet dispensed.

The Minister of Health has responded acknowledging the MARC's concerns that funding third generation contraceptives would encourage their use. However, she is concerned about the high abortion rate in NZ and supports any mechanisms that enable women to have access to as wide a range of OCs as possible. The Minister has seen a copy of Pharmac's reply to MARC and believes the cautionary label suggestion is a better solution.

Discussion

Members did not believe that Pharmac's cautionary label suggestion was practical. There were questions around exactly what such a label would say, the length of development/implementation time, and who would accept the financial cost. The Committee agreed that it would be useful to assess the impact Pharmac's funding of the third generation pill has on prescriber behaviour, and to re-evaluate this issue at a later time.

Recommendation

The Committee recommended that Medsafe request third generation oral contraceptive prescribing data from Pharmac now, in six-months, and in 12-months time.

2.2.4 Sept 2002 minute item 4.1 HRT and cancer/stroke/heart disease

Issue

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

Outcome

In February 2003, a letter was sent from Medsafe to all New Zealand sponsors of HRT products. The letter contains a number of statements that must be inserted into the data sheets for all HRT products, including topical preparations, by 30 June 2003.

Discussion

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

2.2.5 Sept 2002 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 2002, 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.

The ANZCA had provided comment regarding propofol and paediatric sedation to Medsafe/MARC in May 2001. The ANZCA does not support the proposed change, and states there is no evidence supporting propofol-infusion syndrome when the use is restricted to less than 24 hours (a recent abstract from the proceedings of the Society of Critical Care Medicine Congress in January 2003 was included with their letter). It is the view of ANZCA that if propofol-infusion syndrome does occur, it occurs after 48 hours, in doses greater than 5 mg/kg/hr. Propofol is extremely useful in a subset of patients who would otherwise be very difficult to manage. Alternative sedative agents, such as barbiturates and narcotics, have also been associated with adverse outcomes.

Discussion

Members discussed the comment provided by the ANZCA and agreed that there does not appear to be any evidence of propofol-infusion syndrome occurring within 24 hours of sedation in paediatric intensive care patients.

Recommendation

The Committee agreed that the current 24-hour restriction on the use of propofol for sedation of paediatric intensive care patients is appropriate. Members recommended that propofol should not be contraindicated for the sedation of children receiving intensive care.

2.2.6 Sept 2002 minute item 4.4 COX-2 function and bone fracture healing

Issue

The Committee requested that Medsafe seek an expert opinion on this issue. 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 were sent to .., who kindly agreed to provide comment to the MARC on this issue.

.. noted that, while there is a consistent body of in vitro evidence for prostaglandin effects on bone, clinical studies of bone density, fracture incidence, or fracture healing have not produced consistent evidence for an effect of NSAIDs. As a result, .. advised that it would be premature to issue a general warning counselling against the use of these medicines, however, it would be prudent to keep a watching brief in this area.

Discussion

The Committee agreed with .. that the clinical relevance of NSAID/COX-2-induced prostaglandin effects on bone remains unclear.

Recommendation

The Committee recommended that Medsafe keep a watching brief on the effect of NSAIDs/COX-2 inhibitors and bone fracture healing.

3. Matters Arising from the New Zealand Pharmacovigilance Centre (NZPHVC)

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

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

3.1.1 Reports in which death occurred

3.1.1.1 Actifed/cetirizine/fluticasone/livostin and weight loss/somnolence/conjunctivitis/arrhythmia/death (53830)

Discussion

CARM has received no reports for Actifed (pseudoephedrine hydrochloride/ triprolidine hydrochloride). Of 15 reports received for cetirizine, two are associated with palpitations, two with dizziness, and one with arrhythmia. Of 45 reports for fluticasone, two are associated with chest pain, two with dizziness, and one with myocardial infarction. CARM has received three reports for livostatin - two associated with tachycardia, and one with palpitation. Members noted the possibility of a cardiac sarcoid and questioned whether the heart had been sectioned on autopsy. The Committee also questioned what the patient had been doing at the time of death. The causal association was designated "unclassified" and no further action was recommended.

3.1.1.2 Docetaxel/trastuzumab and agranulocytosis/rash/skin exfoliation/death (53534)

Discussion

CARM has received two reports for docetaxel, one of which is associated with agranulocytosis. CARM has requested a copy of the post-mortem report. It was noted that the skin rash might have been due to sudden cessation of epidermal turnover in association with the medications. This would have been a direct toxic effect rather than an immunological reaction. The causal association was designated "certain" and no further action was recommended.

3.1.1.3 Donepezil/alendronate/acetylsalicylic acid/hydroxycarbamide/simvastatin and gastric ulcer/gastrointestinal haemorrhage/muscle cramps/pneumonia (53215)

Discussion

Of 48 reports for alendronate received by CARM, one is associated with gastric ulcer and two are associated with gastrointestinal haemorrhage. CARM has received 238 reports for acetylsalicylic acid, two associated with gastric ulcer and 13 with gastrointestinal haemorrhage. Members noted that the patient's muscle cramps might have been associated with simvastatin. The Committee agreed that the causal association for acetylsalicylic acid and alendronate, and gastric ulcer and gastrointestinal haemorrhage is "possible". The causal association for donepezil; alendronate; acetylsalicylic acid; and hydroxycarbamide, and pneumonia was deemed to be "unclassified". No further action was recommended.

3.1.1.4 Infliximab and death (54091)

Discussion

No reports of hepatic neoplasm with infliximab have been received by CARM. The WHO database holds three reports of hepatic neoplasm, and three reports of hepatic neoplasm malignant, associated with infliximab. The Committee noted that there is no evidence in the literature to support this association; however, it is plausible that as an immunosuppressant, infliximab might have facilitated the rapid growth of the tumor. The causal association was designated "unclassified" and no further action was recommended.

3.1.2 Alternative medicine-related reports

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

Discussion

This is the first report for Thyroguard received by CARM. Members agreed that it is important to determine exactly what this product contains, and noted the possibility that it might contain bovine thyroid extracts. The Committee noted that in testing for thyroid extracts, it is important to include an enzymatic digestion step in the assay. The causal association was designated "probable" for back pain, TSH decreased, and fatigue.

Recommendation

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

3.1.2.2 Voluptua and erythema nodosum/fever/polyarthralgia/headache/orbital oedema (53352)

Discussion

Members noted that Internet information suggests that Voluptua may contain: black cohosh, dong quai, calendula, damiana, saw palmetto, wild yam, and fenugreek. Damiana and fenugreek have been reported in the literature to cause hypersensitivity reactions. Given that the patient improved on dechallenge, the causal association for erythema nodosum, fever, polyarthralgia, headache, and orbital oedema was deemed "probable". No further action was recommended.

3.1.3 Antibacterial-related reports

3.1.3.1 Flucloxacillin/paracetamol and anion gap abnormal/acidosis/delirium/hyperventilation (53710)

Discussion

Of 233 reports for flucloxacillin received by CARM, none are associated with the above reactions. The causal association was deemed "probable" and no further action was recommended.

3.1.4 Anti-inflammatory-related reports

3.1.4.1 Diclofenac and cellulitis (53967)

Discussion

Of 550 reports for diclofenac received by CARM, one is associated with streptococcal septicaemia, and one with necrotising fasciitis. The causal association was deemed "possible" and no further action was recommended.

3.1.4.2 Naproxen and cellulitis (53202)

Discussion

CARM has received 333 reports for naproxen, however, this is the first report associated with soft tissue infection. The causal association was deemed "possible" and no further action was recommended.

3.1.5 Cardiovascular medication-related reports

3.1.5.1 Amiodarone and optic neuritis (53531)

Discussion

Of 312 reports for amiodarone received by CARM, 65 are associated with the eyes (one with retinal disorder, one with scotoma, one with chromotopsia, 10 with abnormal vision, and many with corneal and conjunctival events). The WHO database holds 11065 reports for amiodarone, 134 of which are associated with optic neuritis (IC=3.95). Members noted that, according to reports in the literature, amiodarone-induced optic neuropathy has been reported to occur at an incidence of approximately 1.8%. These reports indicate that following discontinuation of amiodarone, visual acuity and visual field deficits tend to stabilise but optic nerve swelling may persist for several months. The causal association for the current report was designated "possible".

Members also discussed other adverse effects of amiodarone, including pulmonary toxicity, QT prolongation, and hepatotoxicity. It was noted that the data sheets for amiodarone advise regular chest x-rays, and ECG, liver function, and ophthalmological monitoring.

Recommendation

The Committee recommended that an article reminding prescribers about the adverse effects of amiodarone, and the need for regular monitoring, be published in Prescriber Update

3.1.6 Hormone-related reports

3.1.6.1 Premarin and DVT (53381)

Discussion

CARM has received 22 reports for Premarin - eight associated with pulmonary embolism and four with deep vein thrombosis. The causal relationship for deep vein thrombosis was deemed to be "possible". Members noted that the risk of thrombosis with HRT is established; yet not all of the New Zealand product information sheets reflect this risk.

Recommendation

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

3.1.7 Musculoskeletal-related reports

3.1.7.1 Pamidronate and otosclerosis/deafness nerve (53392)

Discussion

Of 33 reports for pamidronate received by CARM, none are associated with hearing disorders. Members noted that there is one report in the literature describing otosclerosis with pamidronate (but not in patients with osteogenesis imperfecta). The causal association was deemed to be "possible" and no further action was recommended.

3.1.8 Psychiatric medicine-related reports

3.1.8.1 Bupropion and erythema multiforme/arthralgia (52534)

Discussion

CARM has received four reports of bupropion associated with erythema multiforme. Members noted that there are two case reports in the literature - one of which has been disputed as a possible Sweet-syndrome. The product information for bupropion lists both arthralgia and erythema multiforme as potential adverse reactions. The causal association for the current report was designated "possible".

Dr McEwen offered to investigate whether similar reports have been received in Australia. It may be possible to publish a joint Australia/New Zealand warning about bupropion-related skin reactions.

Recommendation

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

3.1.9 Urological medicine-related reports

3.1.9.1 Sildenafil and convulsions (53700)

Discussion

Of 10419 reports for sildenafil held in the WHO database, 49 are associated with seizure (IC=-2.06). CARM has received 14 reports for sildenafil, four of which are associated with the nervous system. Members questioned exactly what the reporter might have meant by "seizure" (e.g., convulsions, fainting etc). The causal association was deemed "certain".

Recommendation

The Committee recommended that CARM request further information from the patient's general practitioner with regard to the type of seizure that was experienced.

3.1.10 Vaccine-related reports

3.1.10.1 Hep A/Hep B and jaundice (53443)

Discussion

Members noted that CARM has requested further information about this case, including the outcome of any liver function tests. CARM has received reports of elevated serum transaminases in some patients with the recombinant HBsAg vaccine. Of 2935 reports for Hep A vaccine in the WHO database, six are associated with decreased hepatic enzymes (IC=-1.23). Of 40525 reports for Hep B vaccine in the WHO database, nine are associated with cholestatic hepatitis (IC=-3.06). The Committee questioned whether there are any reports of haemolysis with these vaccines (given that the reported jaundice continued for two-three days following vaccination it is likely to be haemolytic). The causal association was deemed to be "unclassified".

Recommendation

The Committee recommended that CARM investigate whether there are any reports of haemolysis with Hep A and Hep B vaccines.

3.2 Quarterly report (as at 31 December, 2002)

3.2.1 Multiple occurrence reaction reporting

≤ Three Reports in the Last Quarter

3.2.1.1 Brand-switch related reports

Paracetamol (switch from Panadol to Pacimol): 41 reports, describing choking and vomiting, with difficulty in swallowing the tablets, have been received. It is thought that these reactions are due to the absence of a film coating on the tablets, as well as their relatively sharp edges. It was noted that CARM and Medsafe have liaised on this issue and a letter of concern has been sent to Pharmac.

Felodipine (switch from Plendil to Felo): reports indicating decreased efficacy continue to be received. Reports of improvement of symptoms on switching from Felo back to Plendil have also been received.

Glyceryl trinitrate (switch to Glytrin): reports have been received reflecting application site events (burning) when Glytrin is sprayed into the oral cavity.

3.2.1.2 Other medicine-related reports

Application site reactions have been reported with pimecrolimus.

Myalgia has been reported with alendronate.

Three reports of VTE with Estelle-35 have been received - reinforcing the thrombotic potential of this type of therapy.

3.2.1.3 Vaccine-related reports

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

Members noted that the minutes of the 264^th meeting of the Australian Adverse Drug Reactions Committee (ADRAC) document ADRAC's recommendation that influenza vaccine product information sheets be updated to mention the possibility of interaction with phenytoin, phenobarbitone, carbamazepine, warfarin, and theophylline. The Committee questioned whether New Zealand should also be investigating this issue.

Recommendation

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

Members welcomed Dr Alison Roberts who was representing the Ministry of Health's Immunisation Programme Committee (IPC). The Committee agreed that it would be valuable for CARM, MARC, and the IPC to liaise with regard to adverse events following immunisation. It was noted that it might be advantageous for .. to attend IPC meetings, and for a representative of the IPC to attend MARC meetings, when appropriate.

Recommendation

The Committee recommended that Medsafe write to the IPC to explore options of collaboration between MARC and the IPC.

≤ Six Reports in the Year-to-Date

New listings in this section include the paracetamol brandswitch issues mentioned above, cilazapril angiodema (n=6), alendronate myalgia (n=6), terbinafine urticaria (n=6), and antibiotic hypersensitivity reactions.

Members noted the large number of reports (142) of massive, but painless, injection site reactions with DTaP/HiB.

3.3 Intensive Medicines Monitoring Programme

3.3.1 Nefazodone and hepatotoxicity

Reference Material

Nefazodone. WHO Pharmaceuticals Newsletter No.1, 2003.

Discussion

Since IMMP monitoring of nefazodone began in December 1998, 14 adverse event reports associated with hepatotoxicity have been received. On comparing these data with the number of hepatic reaction reports for fluoxetine and moclobemide, the rate for nefazodone is only slightly higher. The IMMP intends to conduct one more follow-up of nefazodone before the monitoring is complete. The Committee agreed that no unexpected information has come to light in New Zealand or overseas, and that no further action is necessary at this time.

3.3.2 IMMP findings in relation to the SMART interim study results on salmeterol

Discussion

The Committee noted that interim results from the Salmeterol Multi-centre Asthma Research Trial (SMART) study showed a higher, though not statistically significant, number of asthma-related life-threatening experiences in patients receiving salmeterol treatment compared with placebo. The IMMP holds event data for both salmeterol and eformoterol. These data include deaths from all causes, and information on severity of asthma at baseline - however, more work is required before rates can be stratified by severity of disease.

Preliminary analysis of IMMP data in 1999 suggested a signal of tachyphylaxis - causing blunting of effect of the short-acting beta agonist relievers as a result of chronic salmeterol or eformoterol use. There is some evidence in the literature to suggest that this may occur on a genetic basis. Failure of beta agonist relievers in an acute situation could result in serious relapse or death, and is a possible mechanism for an increased rate of intubations or death on salmeterol.

.. informed the Committee that the possible increased death rate due to treatment with salmeterol and eformoterol will be further investigated. .. has written a research proposal regarding the frequency and distribution of variants of genes coding for beta-receptors in patients experiencing specific adverse events after treatment with long-acting beta-agonists. In addition, publication of the IMMP case reports of decreased therapeutic response, and relapses of asthma resistant to treatment, is now an urgent priority for the NZPhVC.

Note: Further MARC discussion regarding the SMART study is documented in Section 4.1.

3.3.3 Update on celecoxib and rofecoxib

Discussion

The Committee noted IMMP monitoring summaries for both celecoxib and rofecoxib. From prescription data analysed to date, it was noted that, on average, patients taking rofecoxib are younger than those taking celecoxib, and that celecoxib is used for long-term therapy more than rofecoxib. 'Indications for use' data indicate that celecoxib is used more for the treatment of osteoarthritis, whereas rofecoxib is used more in the treatment of pain disorders.

Baseline questionnaires requesting information about acid-related disorders (ARD), cardiovascular disease, and exposure to conventional NSAIDs are being sent out for each patient. Preliminary analysis of returned questionnaires indicates that results for the two medicines are similar (approximately 30% of patients were currently on treatment for ARD when a COX-2 inhibitor was commenced; upper gastrointestinal problems with past use of conventional NSAIDs had occurred in 64 and 58% of patients on celecoxib and rofecoxib, respectively; approximately one-third of patients on celecoxib and rofecoxib have a history of cardiovascular disease).

Members noted that, to date, death has been the most commonly reported event for celecoxib and rofecoxib (34 of these have been assessed as being causally related to the COX-2 inhibitor). The data suggest that the elderly may be more susceptible to serious adverse reactions to the COX-2 inhibitors; however, further analysis is required to investigate this thoroughly as a number of potentially confounding variables exist.

.. reported that the following new signals for celecoxib and rofecoxib have been identified through IMMP: coughing, visual field defect, acute psychiatric events, pancreatitis, hepatotoxicity, psoriasis, and acute urinary retention. In addition, arrythmias due to COX-2 inhibitor/tricyclic antidepressant interaction, and increased INR and bleeding due to rofecoxib/warfarin interaction, have been identified.

Recommendation

The Committee recommended that a general paragraph about COX-2 inhibitors be published in Presciber Update. The paragraph should remind prescribers that many of the adverse effects that can occur with conventional NSAIDs (e.g., renal failure, exacerbation of heart disease and hypertension) have been associated with COX-2 inhibitors.

3.3.4 Update on tolcapone

Discussion

An interim report regarding the IMMP monitoring of tolcapone was provided to the Committee. IMMP monitoring of tolcapone commenced in 1999 and, in the cohort of 448 patients, there have been no reports of serious hepatotoxicity. The most commonly reported event was death, however this is consistent with the age structure of the cohort, and none of the deaths were considered to be related to the use of tolcapone. The Committee noted the above and agreed that no further action is necessary at this time.

3.3.5 Presentation on IC-values

Discussion

D.Coulter delivered a presentation on the Bayesian Confidence Propagation Neural Network (BCPNN) methodology, which uses neural network architecture to measure dependencies between medicines and adverse reactions within a database. The BCPNN can be used to compare what is expected with what is actually observed (i.e., prior versus posterior probability), and uses a measure of disproportionality called the Information Component (IC).

The IC-value equals log₂(posterior probability/prior probability) and can provide a measure of the strength of the dependency between a medicine and an adverse reaction. A positive IC-value indicates that the association between a medicine and an adverse reaction has been reported more often than would be expected.

The addition of data to a database may cause the IC-value to fluctuate. The standard deviation for each IC provides a measure of the robustness of the value. The IC minus two standard deviations (IC-2std) is the same as 95% confidence, or p<0.05, for the IC.

The usefulness of IC-values is limited by the quality of the data being used. In addition, as the IC does not give any information about the causality of an association, clinical analyses of case series remains essential.

The Committee did not feel sufficiently skilled to comment on the validity of the BCPNN methodology. Members expressed concern about the potential for false-positive results, and the use of IC-values in pharmacovigilance decision-making.

Recommendation

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

4. Pharmacovigilance issues

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

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

Reference Material

MedWatch Safety Alert, GlaxoSmithKline Dear Healthcare Professional letter (January 2003).

FDA Talk Paper (January 2003) Study of asthma-drug halted.

Discussion

The Committee noted that interim analysis of the Salmeterol Multi-centre Asthma Research Trial (SMART) showed a higher, although not statistically significant, number of life-threatening experiences in salmeterol-treated patients. A statistically significant greater number of primary events and asthma-related events (including deaths) were observed in African American patients receiving salmeterol, compared to those receiving placebo. Members noted however, that the SMART study was not powered to investigate differences between sub-populations of patients, and differences between African American and Caucasian patients recruited into the study (e.g., baseline severity of asthma) may have contributed to the higher rate of asthma-related events seen in African American patients.

The SMART study findings also showed that in the total population of patients not receiving inhaled corticosteroids at baseline, there was a statistically significant greater number of asthma-related deaths in those taking salmeterol, compared to those taking placebo.

Recommendations

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

The Committee also recommended that a general article about asthma therapy be published in Prescriber Update. The article should reinforce the current NZGG Guidelines for the Diagnosis and Treatment of Adult Asthma, provide information about tachyphylaxis, and remind prescribers about appropriate fluticasone dosage and the need to continue corticosteroids when taking beta agonists.

4.2 Clozapine and Cardiac Safety

Reference Material

MCA (2002) Clozapine and cardiac safety: updated advice for prescribers. Current Problems in Pharmacovigilance, vol 28, 8.

New Zealand product information sheet for Clozaril

Discussion

Members noted that the UK Committee on the Safety of Medicines (CSM) has recently published updated advice for prescribers regarding clozapine and cardiac safety (Current Problems in Pharmacovigilance, vol 28). This article advised UK prescribers that:

A patient history and physical examination must be undertaken prior to starting therapy. The treating physician should consider performing a pre-treatment ECG;

Patients who have persistent tachycardia at rest, especially during the first two months of treatment, should be closely observed for other signs or symptoms of myocarditis or cardiomyopathy. These include palpitation, arrythmias, symptoms mimicking myocardial infarction, chest pain and other unexplained symptoms of heart failure;

Patients in whom myocarditis or cardiomyopathy is suspected should stop clozapine and undergo urgent diagnostic evaluation by a cardiologist;

Patients with clozapine-induced myocarditis or cardiomyopathy must not be re-exposed to clozapine.

The MARC supported the advice provided by the CSM and agreed that similar information should be communicated to New Zealand prescribers.

Recommendation

The Committee recommended that Medsafe contact the Medicines and Healthcare products Regulatory Agency in the UK (formally known as the Medicines Control Agency), to request permission to reprint the aforementioned Current Problems in Pharmacovigilance article in an upcoming issue of Prescriber Update, and in a New Zealand College of Psychiatrists Newsletter.

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 CARM case reports

• Lean system 7 and agitation/irritability (53124)
• Folic acid/Womens' Multi and rash maculopapular (53600)
• Estelle-35 and embolism pulmonary (53214)
• Estelle-35 and thrombosis venous deep (53396)
• Estelle-35 and thrombosis venous deep (53711)
• Estelle-35 and thrombosis venous deep (53824)
• Mercilon and thrombosis venous deep/pulmonary embolism/pain back/rash (53839)
  

6. Other New Zealand Activities

6.1 PHARMAC

Minutes of the Pharmacology and Therapeutics Advisory Committee Meeting, November 2002.

6.2 Publications

Harrison-Woolrych, M. et al. (2002) Insertion of the Multiload Cu375 intrauterine device; experience in over 16,000 New Zealand women. Contraception, 66, 387-391.

Harrison-Woolrych, M. et al. (2003) Uterine perforation on intrauterine device insertion: is the incidence higher than previously reported? Contraception, 67, 53-56.

Harrison-Woolrych, M. (2003) Progestogen-only contraception and ectopic pregnancy. Journal of Family Planning and Reproductive Health Care, 29(1), 5-6.

Coulter, D. et al. (submitted) COX-2 inhibitors may cause acute temporary visual disturbance. Clinical Review: Drug Points.

Zhou, L. et al. (submitted) Use of the New Zealand IMMP to study the levonorgestrel-releasing device (Mirena).

Clark, D, & Coulter, D. (submitted letter to the Editor) Psoriasis associated with rofecoxib.

7. international activities

7.1 Australia

Minutes of the September 2002 meeting of the Adverse Drug Reactions Advisory Committee

Minutes of the November 2002 meeting of the Adverse Drug Reactions Advisory Committee

Australian Adverse Drug Reactions Bulletin 21(4), December 2002

Australian Adverse Drug Reactions Bulletin 22(1), February 2003

7.2 Canada

Canadian Adverse Reaction Newsletter 13(1), January 2003.

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 Traditional Chinese Medicines

Ministry of Health media release (January and February 2003)

Medsafe Dear Doctor letter (January 2003)

9.2 COX-2 inhibitors

Chan et al. (2002) Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. New Engl J Med, 347(26), 2104-2110.

Warner et al. (2002) Cyclo-oxygenase-2 inhibitors and cardiovascular events. Lancet, 360, 1700-1701.

Meyer & Gahler (2002) Central retinal vein occlusion in a patient with rheumatoid arthritis taking rofecoxib. Lancet, 360, 1100.

9.3 SSRIs and GI bleeding

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

9.4 HRT

Grodstein et al. (2003) Understanding the divergent data on postmenopausal hormone therapy. NEJM, 348(7), 645-650.

Solomon et al. (2003) Rethinking postmenopausal hormone therapy. NEJM, 348(7), 579-580.

Rymer et al. (2003) Making decisions about hormone replacement therapy. BMJ, 326, 322-326.

9.5 Safety of fluoroquinolones in paediatrics

Cuzzolin & Fanos (2002) Safety of fluoroquinolones in paediatrics. Expert Opinion in Drug Safety, 1(4), 319-324.

9.6 Adverse events associated with complementary and alternative medicines

TGA correspondence regarding NZ participation in a Kava Evaluation Group Rasmussen, P. (2002)

Alleged hepatotoxicity for Black Cohosh: response to article published in the Medical Journal of Australia. Phytomed, 14, 3-4. Rasmussen, P. (2002)

Kava withdrawn in Australia. Phytomed, 14, 1-2. McElroy (2003)

Liver-related risks cast shadow over kava. NZ Pharmacy, January, 16. Palmer et al. (2003)

Adverse events associated with dietary supplements: an observational study. Lancet, 361, 101-106.

9.7 New legislation in Saskatchewan

Ehman (2003) Saskatchewan first with mandatory reporting of medical errors. Canadian Medical Association Journal, 168(4), 471.

The meeting ended at 4pm.