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 OF THE 142^nd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING,
10 June 2010

The one hundred and forty-second meeting of the Medicines Adverse Reactions Committee (MARC) was held on 10 June 2010 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9.30 am and closed at 2 pm.

MARC Members Present

Associate Professor M Rademaker (Chair)
Dr L Bryant
Associate Professor C Frampton
Dr F McClure
Associate Professor D Reith
Dr S Sime
Dr M Tatley

marc secretariat present

J McNee (MARC Secretary)

MEDSAFE STAFF IN ATTENDANCE FOR PARTS OF THE MEETING

A Cutfield (Advisor, Pharmacovigilance)
J Hart (Manager, Clinical Risk Management)
C James (Senior Advisor, Pharmacy)
S Kenyon (Senior Advisor, Pharmacovigilance)
E Yousuf (Principal Clinical Advisor)

1 Matters of Administration

1.1 Welcome and Apologies

The Acting Chair welcomed the attendees to the meeting. Apologies were received from Prof Ellis and Dr Savage.

[..] attended the meeting to present a CME topic on the monitoring of medical devices in New Zealand.

1.2 Minutes of the 141^st MARC Meeting

The minutes of the 141^st meeting of the Committee were accepted as a true and accurate record of the meeting.

1.3 Dates of Future MARC Meetings

The dates for the MARC meetings for 2010 were 23 September and 2 December.

1.4 Potential Conflicts of Interest

Committee members submitted their Conflict of Interest Declaration forms to the Secretary. The Chair reminded the MARC members that, in addition to conflicts disclosed in the declaration forms, members should declare conflicts of interest at the commencement of discussion of any relevant agenda item.

1.5 Prescriber Update

1.5.1 Schedule of Planned Prescriber Update Articles

Discussion

The Committee noted the schedule of planned Prescriber Update articles.

1.5.2 Prescriber Update. Volume 31, Number 2. June 2010

Discussion

The Committee noted the latest edition of Prescriber Update.

2 STANDING AGENDA ITEMS

The Committee considered the list of issues monitored by MARC, Medsafe and NZPhvC.

2.1 Report on Standing Agenda Items from previous meetings of the MARC

Background information on these issues is available on the Medsafe web site at www.medsafe.govt.nz/profs/MARC/Minutes.asp.

2.1.1 Methotrexate, hydroxychloroquine, venlafaxine, and myocarditis, cardiac arrest [death] (84033)
March 2010 minute item 2.1.16, September 2009 minute item 4.1.1.2

MARC Recommendation

The Committee recommended that the sponsor be required to update the Warnings section as well as the Overdose section of the Plaquenil (hydroxychloroquine) data sheet to include information on risk of QT prolongation and/or torsades de pointes. The Committee also recommended that the chloroquine data sheet be similarly updated.

The Committee recommended that a Prescriber Update article be published on medicines which can cause QT prolongation, including reference to the Arizona CERT website.

Outcome

Medsafe advised that the New Zealand sponsor for Plaquenil has agreed to the requested Warning statement regarding QT prolongation, torsades de pointes and sudden death.

A Prescriber Update article will be published on medicines which can cause QT prolongation, including reference to the Arizona CERT website.

Discussion

The Committee noted the above.

2.1.2 Removal of specialist prescribing restriction from retinoids
March 2010 minute item 2.1.24, June 2009 minute item 2.1.21, March 2009 minute item 2.1.13, December 2008 minute item 9.4

MARC Recommendation

The Committee recommended that Medsafe request the sponsor to provide an updated CMI for isotretinoin, further highlighting the need to avoid pregnancy while taking this medicine.

Outcome

The product sponsor has been requested to provide an updated CMI for isotretinoin.

Discussion

The Committee considered that there was a lack of awareness amongst prescribers about the various isotretinoin resources and suggested Medsafe investigate options of raising awareness of resources available to prescribers and patients.

2.1.3 Medsafe Signal Detection and Evaluation summary
March 2010 minute item 2.2

MARC Recommendation

The Committee recommended that a Prescriber Update article be considered around the topic of hypersensitivity syndrome in association with anticonvulsants.

Outcome

Medsafe will consider publishing an article if a safety signal is detected in the spontaneous reports for NZ.

Discussion

The Committee noted the above.

2.1.4 In utero exposure to serotonin reuptake inhibitors and risk of congenital abnormalities
March 2010 minute item 3.1

MARC Recommendation

The Committee recommended that sponsors for fluoxetine medicines be requested to update their data sheets regarding the risk of congenital anomalies when used in pregnancy. The Committee recommended that sponsors for relevant medicines other than fluoxetine and paroxetine be requested to add a general warning to the data sheets stating that there may be an increased risk of congenital abnormalities associated with SSRI (SNRI) treatment in pregnancy. The Committee recommended that a Prescriber Update article be written on this issue.

Outcome

Medsafe is investigating the safety of tricyclic antidepressants in pregnancy and the risk of other adverse outcomes regarding the use of SSRIs in pregnancy and will write to all relevant companies once this review is complete. A Prescriber Update article will be written thereafter.

Discussion

The Committee noted the above.

2.1.5 Adverse reactions to pioglitazone and rosiglitazone
March 2010 minute item 3.2

MARC Recommendation

The Committee recommended that Medsafe report back to the MARC with the outcome of the FDA review, and include New Zealand usage data.

The Committee recommended that pioglitazone and rosiglitazone remain on the Scheduled Review list and the list of adverse reactions of current concern.

Outcome

Usage data is contained in the paper reviewing Adverse Reactions of Current Concern.

Pioglitazone and rosiglitazone will remain on the Scheduled Review list and the list of Adverse Reactions of Current Concern.

Discussion

The Committee noted the above.

2.1.6 Oral terbinafine and serious adverse reactions (blood dyscrasias, hepatotoxicity, and dermatological reactions)
March 2010 minute item 3.3

MARC Recommendation

The Committee agreed that Medsafe request the following updates to the New Zealand data sheets for oral terbinafine:

Rhabdomyloysis and creatine phosphokinase (CPK) increase
Permanent anosmia and other effects on the sense of smell
Anaphylaxis, serum sickness-like reaction, vasculitis, influenza-like illness, pyrexia
Pancreatitis
Anaemia.

The Committee recommended that the issue of oral terbinafine and serious adverse reactions be removed from the Scheduled Review list.

Outcome

Medsafe has contacted the innovator to confirm these events will be included in their products data sheets. Medsafe will request updates to the generic data sheets as required to ensure consistency.

The issue of oral terbinafine and serious adverse reactions has been removed from the Scheduled Review list.

Discussion

The Committee noted the above.

2.1.7 Statins, neuromuscular degenerative disease and amotrophic lateral sclerosis-like syndrome
March 2010 minute item 3.4

MARC Recommendation

The Committee recommended that the issue of statins and neuromuscular degenerative disease and an ALS-like syndrome be removed from the Scheduled Review list.

Outcome

The issue of statins and neuromuscular degenerative disease and an ALS-like syndrome has been removed from the Scheduled Review list.

2.1.8 HPV, medroxyprogesterone and parathesia, cognition abnormal, muscle weakness, night sweats, sudden death [death] (87237)
March 2010 minute item 4.1.1.5

MARC Recommendation

The Committee recommended that NZPhvC report back to the MARC when the autopsy and Coronial findings are available.

Outcome

CARM has requested the findings from the Coroner and will provide follow-up information to the MARC when available.

Discussion

The Committee noted the above.

2.1.9 Omeprazole and hypomagesaemia, hypocalcaemia (86867)
March 2010 minute item 4.1.1.7

MARC Recommendation

The Committee recommended that a Prescriber Update article be published advising prescribers of the recent data sheet changes for omeprazole.

Outcome

An article was published in the June 2010 edition of Prescriber Update.

Discussion

The Committee noted the above.

2.1.10 Acitretin and medication error (87470)
March 2010 minute item 4.1.1.9

MARC Recommendation

The Committee recommended that an article be published in Prescriber Update on the indications and use of acitretin.

Outcome

An article was published in the June 2010 edition of Prescriber Update.

Discussion

The Committee noted the above.

2.1.11 Methylphenidate SR (Rubifen SR) brand switch-aggressive and defiant behavioural reactions- Scheduled Review
March 2010 minute item 2.1.2, December 2009 minute item 2.1.14, September 2009 minute item 2.1.3, June 2009 minute item 2.1.5, March 2009 minute item 3.4

MARC Recommendation

In December 2010, the Committee discussed the proposed amendments to the European methylphenidate product information and recommended this information be included in the New Zealand methylphenidate data sheets.

Outcome

Product data sheets are in the process of being updated.

An article entitled 'Methylphenidate- updated guidance when treating children' was published in the June 2010 edition of Prescriber Update.

Discussion

The Committee noted the above.

2.1.12 Sodium valproate and foetal valproate syndrome, drug exposure during pregnancy (82615)
December 2009 minute item 2.1.25, September 2009 minute item 2.1.20, June 2009 minute item 4.1.6.1

MARC Recommendation

In December 2009, the Committee recommended that the Precautions section of the Epilim data sheet be revised to ensure that the risk-benefit statement is clear at the beginning of the section. The Committee also recommended that the sponsor be requested to include information in the data sheet from the Meador et al paper.

Outcome

The data sheets are in the process of being updated and published with improved presentation of information regarding the use of sodium valproate in pregnancy.

Discussion

The Committee noted the above.

2.1.13 Consideration of dextropropoxyphene-containing medicines under Section 36 of the Medicines Act 1981
March 2010 minute item 2.1.4, December 2009 minute item 3.1, September 2009 minute item 2.1.16, June 2009 minute item 3.2

MARC Recommendation

In December 2009, the Committee recommended that consent to distribute dextropropoxyphene-containing medicines in New Zealand be revoked.

In March 2010, Medsafe advised the Committee of the Dear Healthcare Professional letter advising of the withdrawal of dextropropoxyphene-containing medicines, and accompanying media release, Question and Answer information, and the Medsafe risk-benefit review of dextropropoxyphene recently published.

Outcome

The date for the revocation of consents for dextropropoxyphene-containing medicines in New Zealand has been confirmed as 1 August 2010.

The Committee was advised that BPAC have agreed to publish further information in the Best Practice Journal.

Discussion

The Committee noted that Medsafe had published a Prescriber Update article entitled "Dextropropoxyphene withdrawal on 1 August 2010 - a reminder" , which included BPAC advice..

2.1.14 Drospirenone/ethinyloestradiol: risk of venous thromboembolism compared to other combined oral contraceptives
December 2009 minute item 3.2

MARC Recommendation

In December 2009, the Committee recommended that Medsafe write to the sponsor of drospirenone-containing medicines requesting that they review the risk of venous thromboembolism in association with their products (including preclinical, clinical, post-market and observational studies) and report back to the MARC.

Outcome

The New Zealand sponsor of Yasmin and Yaz has been contacted and requested to undertake a review of the risk of VTE associated with these medicines based on data from pre-clinical studies, clinical trials, spontaneous reports and epidemiological studies. Medsafe expects to present the results of this review to the MARC at the September meeting.

Discussion

The Committee noted the above.

2.1.15 Gabapentin and renal failure acute, hyperkalaemia, cardiac arrest (85589)
December 2009 minute item 4.1.1.2

MARC Recommendation

In December 2009, the Committee recommended that a Prescriber Update article be published to alert healthcare professionals of the risk of renal failure in association with gabapentin.

Outcome

Further information from CARM on this case report is required before a decision can be made on the content and format of an article.

Discussion

The Committee noted the above.

2.1.16 Sibutramine and cardiac arrhythmia [death] (85606)
December 2009 minute item 4.1.1.3

MARC Recommendation

In December 2009, the Committee recommended that Medsafe review the SCOUT study and the New Zealand Reductil data sheet and report back to the MARC.

Outcome

Refer to agenda item 3.1 for this review.

2.1.17 Quarterly Reports from CARM as at 30 June 2009
December 2009 minute item 4.1.2

MARC Recommendation

In December 2009, the Committee recommended that NZPhvC and Medsafe review the format of the quarterly report.

Outcome

The NZPhvC and Medsafe have begun to review the format of the quarterly report.

Discussion

The Committee noted the above.

2.1.18 Abuse of ibuprofen/codeine combination products
March 2010 minute item 2.1.19, December 2009 minute item 2.1.13, September 2009 minute item 8.1

MARC Recommendation

Medsafe agreed to provide clarification of the reclassification of codeine.

Outcome

In June 2010, Medsafe published an article in Prescriber Update describing the classification and labelling changes. This is attached to this report as Annex 2.

Discussion

The Committee noted the above.

2.1.19 Infanrix-hexa, Prevenar and sudden death [death] (82290)
September 2009 minute item 2.1.5, June 2009 minute item 2.1.9, March 2009 minute item 4.1.1.9

MARC Recommendation

In March 2009 the Committee recommended that NZPhvC bring further information to the MARC when the Coroner's report has been received.

Outcome

The NZPhvC will bring back any further information to the MARC when received.

Discussion

The Committee noted the above.

2.1.20 Ropivacaine and convulsion grand mal, cardiac arrest, drug overdose [death] (80093)
September 2009 minute item 2.1.11, June 2009 minute item 2.1.18, March 2009 minute item 2.1.7, December 2008 minute item 4.1.1.1

MARC Recommendation

In December 2008 the Committee recommended that NZPhvC provide a follow-up report to the MARC when the Coroner's report has been received.

Outcome

CARM has requested the findings from the Coroner and will provide follow-up information to the MARC when available.

Discussion

The Committee noted the above.

3 Pharmacovigilance Issues

3.1 CONSIDERATION OF SIBUTRAMINE-CONTAINING MEDICINES UNDER SECTION 36 OF THE MEDICINES ACT 1981

Background

Sibutramine (Reductil®) is the only product containing sibutramine approved for use in New Zealand. It was approved in 2000 and there are currently about 5000-6000 patients taking sibutramine in New Zealand.

In March 2002, the European Medicines Agency (EMEA) began a review of sibutramine due to safety concerns based on fatal adverse reactions. This review was triggered by the suspension of the Reductil product licence in Italy due to reports of fatalities following sibutramine use. After reviewing these cases, the Committee for Medicinal Products for Human Use (CHMP) considered the sibutramine risk-benefit balance to be favourable. However the sponsor of Reductil was required to conduct a large cardiovascular outcome study to compare sibutramine to placebo in overweight or obese subjects aged 55 years or older, who were at risk of cardiovascular events. As a result the sibutramine cardiovascular outcomes trial (SCOUT) was initiated by the sponsor.

A further review was triggered by the EMEA in 2009 following the release of preliminary results from the SCOUT study, which showed a 16% increased risk of cardiovascular events in subjects taking sibutramine versus placebo. The CHMP concluded that the benefit:risk ratio for sibutramine was unfavourable and recommended the suspension of the marketing authorisation for these medicines.

Medsafe issued the sponsor of Reductil, Abbott Laboratories, with a notice under Section 36 of the Medicines Act 1981. This decision was made following a review of the preliminary results of the SCOUT study and in response to the EMEA's decision to suspend the product licence for all sibutramine containing medicines.

The Section 36 notice requested that the sponsor provide data in support of the safety and efficacy of their medicine in order to allow a full risk-benefit review to be conducted. Medsafe considered the response and, acting under the powers delegated by the Director General of Health, referred the issue to the appropriate committee (the MARC).

Regulatory action has also been taken by other agencies in response to the European decision to suspend sibutramine marketing authorisations.

The FDA requested changes to the product label, including additional contraindications such as history of coronary artery disease, uncontrolled hypertension and use in patients over 65 years of age. The FDA has also required additional warnings relating to increases in blood pressure following treatment with sibutramine. All changes to sibutramine product information in the US are already included in the New Zealand Reductil data sheet.

The TGA has undertaken a review of the preliminary results of the SCOUT study, and requested label changes, local risk minimisation activities, Dear Health Care Provider Letter(s).

Registrations have now been suspended in 42 countries. In addition to the EU countries this includes 13 countries reliant on EU approvals such as Croatia, Montenegro, Turkey, Jordan, Serbia, Bahrain, Qatar, Oman, Curacao, Belarus, Moldova, Switzerland and the Ukraine.

Four countries have withdrawn licences: Armenia, Aruba, Bosnia and Saudi Arabia.

Medsafe review

The Committee was presented with data on the efficacy and safety of sibutramine, including:

Pre-registration randomised controlled studies to support the efficacy and safety of sibutramine.
Independent published systematic reviews of sibutramine.
Reductil Periodic Safety Update Reports and current Reductil Risk Management Plan.
Copies of all patient and prescriber education and promotion resources.
Analysis of Intensive Medicines Monitoring Programme data for sibutramine use in New Zealand.
Sibutramine Cardiovascular Outcome trial (SCOUT) study report

The SCOUT study was designed and conducted by the sponsor of Reductil as a post-approval commitment to the European Committee for Proprietary Medicinal Products (now the CHMP).

The SCOUT study was a randomised, double-blind, placebo controlled, parallel group study with a six week single blind lead-in period during which all subjects were treated with sibutramine 15 mg daily (titrated from 10 mg daily). The objective of the SCOUT study was to compare the effect of sibutramine with placebo on the incidence of a composite cardiovascular outcome in overweight or obese subjects at cardiovascular risk. Over 90% of the subjects involved in the SCOUT study would be considered to be contraindicated for treatment in New Zealand.

The primary endpoint for SCOUT was the time-to-event analysis of the first occurrence of an event included in the composite of primary outcome events (POE). POEs included: nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest (RCA) and cardiovascular death (including fatal MI and fatal stroke).

Discussion

The Committee had a preliminary discussion on the data provided to support the safety and efficacy of sibutramine. The Committee considered further data was required before a final recommendation could be made on the safety and efficacy of sibutramine in the indicated population. The Committee recommended that Medsafe present this data to the Committee at its next meeting on 23 September 2010.

Recommendation

The Committee recommended that a decision on the risk-benefit balance for sibutramine containing medicines be deferred until its next meeting on 23 September 2010 so additional data could be obtained.

3.2 PARACETAMOL ASSOCIATED WITH CHILDHOOD ASTHMA

References

Interview questions on paracetamol exposure and asthma outcomes included in the Kang et al (2009) study.
Summary of data from recent cohort studies investigating an association between prenatal paracetamol exposure and development of asthma at age 5-7.
Etminan et al (2009). Acetaminophen Use and the Risk of Asthma in children and Adults: A Systematic Review and Metaanalysis. Chest 136: 1316-1323 doi 10.1378/chest.09-0865.
Kang et al (2009). Prenatal Exposure to Acetaminophen and Asthma in Children. Obstetrics and Gynecology 114(6): 1295-1306.
Perzanowski et al (2010). Prenatal acetaminophen exposure and risk of wheeze at age 5 years in an urban low-income cohort. Thorax 65: 118-123. doi:10.1136/thx.2009.121459.
Rebordosa et al (2008). Pre-natal exposure to paracetamol and risk of wheezing and asthma in children: A birth cohort study. International Journal of Epidemiology 37:583-590.
Persky V et al (2008). Prenatal exposure to acetaminophen and respiratory symptoms in the first year of life. Ann Allergy Asthma Immunol 101(3): 271-278
Farquahar et al (2010). Review. The role of paracetamol in the pathogenesis of asthma. Clinical and Experimental Allergy 40: 32-41.
Persky V (2010). Acetaminophen and Asthma. Thorax 65(2): 99-100.

Issue

In September 2008, Beasley et al published an analysis of data from Phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). The study reported that paracetamol, given in the first year of life, is associated with an increased risk of asthma symptoms developing by the age of 6 - 7 years (Odds Ratio 1.46 [95% CI 1.36 - 1.56]), and the use of paracetamol within the last twelve months is associated with an increased risk of having current asthma symptoms.

In response to the publication of this study, Medsafe sought input out of session from three MARC members prior to distributing a fax (in September 2008) to prescribers and pharmacists outlining the findings of the Beasley et al (2008) study. The following advice was offered:

Paracetamol is effective for the symptomatic treatment of fever and mild to moderate pain.
Paracetamol has a generally benign side effect profile when used appropriately.
As with any medication, paracetamol should be used only as indicated.
Alternatives to paracetamol include ibuprofen and diclofenac. Prescribers should however, consider the risks associated with these alternatives such as causing renal damage in dehydrated children as well as gastro-intestinal irritation, ulceration and bleeding.
Aspirin should not be used in children under 12 years of age.

The MARC reviewed the potential for paracetamol use to increase the risk of developing asthma at their meeting in December 2008. At that time, the MARC considered that although there was evidence for an association between paracetamol use and asthma, further evidence was required before any firm recommendations could be made. The Committee noted that limited alternatives were available to treat pain or fever in children and during pregnancy. The MARC considered that as the association appeared to be stronger with increased frequency of paracetamol use, paracetamol should be used sparingly for the treatment of fever and significant pain in all age groups. The MARC recommended that an article be published in Prescriber Update and the sponsors for all prescription paracetamol products be required to include a warning about the possible risk of asthma associated with paracetamol use during pregnancy.

A Prescriber Update article was published in February 2009 which advised that clinical intervention should be aimed at reducing excessive use of paracetamol. To date none of the New Zealand sponsors of prescription paracetamol-containing medicines have agreed to include information in their data sheets on a potential increased risk of asthma.

The purpose of this report was to update the MARC on international regulatory action and published literature that have arisen since September 2008. The report focused on the risk of asthma in association with prenatal exposure to paracetamol in light of the paucity of new data published on paracetamol exposure in children or adults.

Discussion

The Committee noted the 2010 Medsafe report.

The Committee reviewed the recent studies and noted the limitations of each.

They noted the Kang et al (2009) study of 1871 predominantly white women in New England, which found no association between prenatal paracetamol use and the development of current wheeze at age 6. The authors also found that women with asthma or allergy symptoms and those exposed to second-hand tobacco smoke were more likely to take paracetamol during pregnancy; thus highlighting the importance of careful adjustment for these factors in any analyses. Kang et al undertook the most comprehensive assessment of dose and frequency of paracetamol use of any of the cohort studies reviewed and found higher doses and dosage frequencies of paracetamol use than other studies. They did not find any dose-response relationship. This study was powered to detect a 52% increase in risk thus was probably underpowered to detect a smaller increase in risk.

Perzanowski et al (2010) studied 725 African-American and Dominican Republic women in New York. They found a much lower prevalence of paracetamol use than other studies (34%) and found an overall increased risk of current wheeze at 5 years of 1.71 (1.20-2.42) with the greatest risk in the second (1.54, 1.06-2.25) and third trimester (1.55, 1.03-2.34). However, this study experienced more than 50% loss to follow-up by age 5. Paracetamol use was only ascertained once during the pregnancy which is likely to have affected the accuracy of usage estimates. The authors also found a dose-response association with paracetamol use, although the majority (75%) of patients reported usage of paracetamol of 1-4 days only throughout the entire pregnancy. Due to the low prevalence of paracetamol use and the wide confidence intervals around the point estimates, the Committee considered that this study may have been underpowered. The authors also found that the risk of asthma was increased by the presence of a genetic polymorphism of the GST gene (GSTP1). The authors suggest that a gene-environment interaction may influence individual susceptibility to asthma in association with paracetamol use, and may explain differences in risk observed in different populations.

Rebordosa et al (2008) conducted the largest cohort study of the studies reviewed using the Danish National Birth Cohort, although only 25% of the original cohort completed a questionnaire at age 7. Paracetamol exposure was obtained on three occasions during the pregnancy. The authors found an overall increased risk of asthma at age 7 associated with any prenatal paracetamol exposure (RR 1.15, 1.01-1.29) and the highest risk was found for usage in the first trimester. Rebordosa et al did not find any evidence of a dose-response effect. The Committee noted that the authors did not appear to have adjusted for exposure to second-hand tobacco smoke, suggesting that residual confounding could explain their positive findings.

Persky et al (2008) conducted the smallest cohort study of 345 predominantly Hispanic women in Chicago. The Committee noted that data is only available for the first year post delivery, limiting its comparability with the other studies reviewed here.

The Committee agreed that although all four studies included in this report were well designed prospective cohort studies, they were still subject to potential limitations that affect the ability to infer a causal association between prenatal paracetamol exposure and the development of asthma in children. The three positive cohort studies were inconsistent in their timing of risk which may have an impact on the biological plausibility of their findings. In addition, only one study found a dose-response relationship. The single study published that found no association between prenatal paracetamol exposure and childhood asthma was also the one that made the best assessment of both paracetamol exposure (including dose and frequency), and potential confounding variables. However, the Committee noted that this study was probably underpowered to detect a very small increase in risk. The Perzanowsky et al (2010) study raised the possibility that specific genetic polymorphisms may be responsible for any observed increase in risk associated with paracetamol exposure. The Committee agreed that asthma is a highly complex condition that is likely to be caused by a complex interplay between genetic and environmental factors, and that the benefit-risk balance for the use of paracetamol in pregnancy remained positive.

Due to the paucity of published literature since September 2008 assessing paracetamol exposure in adults and children and the development of asthma, the Committee considered that the benefit-risk balance for use in adults and children was unchanged since the MARC's previous review. The Committee agreed that it's previous advice issued in 2008 and 2009 to only use paracetamol to treat symptomatic fever and mild to moderate pain, and to reduce any excessive use of paracetamol remained appropriate.

The MARC considered that there was insufficient data to warrant making changes to either the data sheets or product labelling for paracetamol containing medicines in New Zealand at this time. They noted it is unclear when further data will become available, and so recommended that paracetamol and asthma be removed from the scheduled review list. They noted that Medsafe will continue to monitor the safety of paracetamol containing medicines and if further information emerges that could significantly alter the benefit-risk balance this information will be presented to the Committee.

Recommendation

The Committee recommended that the issue of paracetamol and asthma be removed from the Scheduled Review list.

3.3 ADVERSE REACTIONS OF CURRENT CONCERN REVIEW

Issue

Medsafe provided a review for the MARC on the Adverse Reactions of Current Concern (ARCC) scheme. The MARC first initiated the ARCC scheme in December 1994. The aim was to bring particular medicine adverse reactions to the attention of prescribers, to evoke reports so more information could be gathered, and further action taken if necessary. Each Prescriber Update edition contains a listing of the ARCC, along with information on what and how to report. The Medsafe website also contains this information, as well as historical information about additions to, and removals from the listing.

The last item to be removed from the list was at the March 2006 MARC meeting, while the last item to be added was in June 2006. The scheme was last reviewed in 2005, when the Committee noted that:

There was a low level of awareness of the ARCC system among prescribers in NZ.
It was difficult to assess whether the current ARCC system was achieving its purpose of encouraging prescribers to report the adverse reactions of interest to CARM.
Anecdotal evidence suggested that reporting of adverse reactions did not increase in response to being listed on ARCC.

The current ARCC list has remained unchanged for four years, and contains:

Complementary and alternative medicines
Leflunomide
Pioglitazone and Rosiglitazone

The Committee was asked to advise whether:

The current ARCC system achieves its purpose of encouraging reports to CARM.
ARCC should continue.
Investigation into an alternative system should be initiated.

Discussion

The Committee noted the 2010 Medsafe report. They agreed that the conclusions from the 2005 MARC review remained valid. They noted the schemes in place of other international regulators and discussed various options which may be feasible in this country.

The Committee made the following observations:

The scheme had been useful for some issues, but not others
Some issues had been added late in the lifecycle of the particular safety signal and this may have explained why additional reports had not been received.
There was still potential in using such a scheme
That a more informal, ad hoc system may be preferable to the current scheme.

The Committee recommended that the current list be suspended as an interim measure, and that Medsafe investigate and propose a feasible alternative to the ARCC.

Recommendation

The Committee recommended that the current list be suspended as an interim measure, and that Medsafe investigate and propose a feasible alternative to the ARCC.

4 Matters arising from the New Zealand Pharmacovigilance Centre

4.1 Centre for Adverse Reactions Monitoring (CARM) Spontaneous Case Reports

Spontaneous reporting programme

All spontaneous reports presented at the MARC meeting have been assessed by the Centre for Adverse Reactions Monitoring (CARM) and responses have been sent to the reporters. The purpose of these responses is to assist the practitioner to discharge his/her responsibility to patients. These individual replies include as appropriate:

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

Note: In the discussion notes for each report, the case has been given a causality designation using terms and definitions developed by the World Health Organisation. The precise definitions are available on the website of the The Uppsala Monitoring Centre, which is the WHO Collaborating Centre for International Drug Monitoring - 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 these terms can be found on the Medsafe website via the hyperlink at each causality designation.

The Committee was advised that the way in which the spontaneous case reports were presented to the MARC had been refined, with the focus of cases presented to the Committee being on advice and signal detection. The remainder of case reports are included as list reports, with an expanded section for relevant comments.

4.1.1 Case reports

4.1.1.1 Clopidogrel, heparin, abciximab,aspirin and haemoptysis [death] (88344)

Discussion

CARM advised that it has received four reports of major haemorrhagic events leading to the deaths of patients taking multiple anticoagulant medicines in the last quarter. The deaths occurred in 2007 and 2008.

The Committee noted that these cases were complex and that there were a number of factors which may have increased the risk of bleeding. The Committee considered that there was unclear prescribing guidance in some areas. They recommended that groups such as the New Zealand Guidelines Group and the Safe and Quality Use of Medicines be advised of the recurring cases of haemorrhage in conjunction with multiple anticoagulant therapy, with a suggestion that they consider disseminating advice to prescribers.

The causal association with clopidogrel, heparin, abciximab, aspirin was considered to be 'probable' for haemoptysis.

Recommendation

The Committee recommended that groups such as the New Zealand Guidelines Group and the Safe and Quality Use of Medicines be advised of the recurring cases of haemorrhage in conjunction with multiple anticoagulant therapy, with a suggestion that they consider disseminating advice to prescribers.

4.1.1.2 Enoxaparin, aspirin and haematoma retroperritoneal [death] (88356)

Discussion

See minute item 4.1.1.1,

The causal association with enoxaparin, aspirin was considered to be 'probable' for haematoma retoperitoneal.

4.1.1.3 Enoxaparin, warfarin and haemorrhage, medication error [death] (88357)

Discussion

See minute item 4.1.1.1,

The causal association with enoxaparin, warfarin was considered to be 'probable' for haemorrhage, medication error.

4.1.1.4 Enoxaparin, clopidogrel, acetylsalicyclic acid, dipyridamole and haemorrhage intra-abdominal [death] (88881)

Discussion

See minute item 4.1.1.1,

The Committee considered the causal association with enoxaparin, clopidogrel, acetylsalicyclic acid, dipyridamole to be 'probable' for haemorrhage intra-abdominal.

4.1.1.5 Etoricoxib and convulsions, bronchospasm (86768)

Discussion

NZPhvC advised that it has received 84 reports for etoricoxib. Of these, 50 have been received since Medsafe issued prescriber advice concerning cardiovascular adverse effects in 2005. As well as this advice, other NZ advice has come from BPAC and the NZ Guidelines Group.

An analysis of the 50 reports showed that 20 patients (40%) were taking maximum recommended daily doses, and 15 (30%) were taking cardiovascular medicines, the largest group being ACE inhibitors and angiotensin 2 receptor blockers (A2RBs).

Eleven of the 50 reports were of complicated serious gastrointestinal reactions, renal failure, cardiac failure and/or thrombotic adverse effects. Assessment of these 11 reports indicated that lack of gastroprophylaxis according to NZ guidelines, co-prescription of other NSAIDs, established cardiovascular disease, co-prescription of medicines that might contribute to impaired renal function and use of high doses especially in the elderly, or combinations of these, were apparently modifiable contributing factors. In some cases prescribing advice was not adhered to, in others advice was followed but a combination of risk factors for adverse reactions were present.

The Committee agreed that this issue should be highlighted to prescribers, and recommended that a Prescriber Update article be published reminding prescribers that etoricoxib is associated with gastro-intestinal bleeding. They recommended that BPAC be contacted with the suggestion of an article in their publication.

The Committee recommended that the New Zealand Guidelines Group be advised of the recent case reports and asked if the NZ guidelines for the management of dyspepsia and heartburn will be reviewed in light of the recent NICE guidelines.

The Committee considered the causal association with etoricoxib to be 'probable' for convulsions, bronchospasm.

Recommendations

The Committee recommended that a Prescriber Update article be published reminding prescribers that etoricoxib is associated with gastro-intestinal bleeding.

4.1.1.6 Etoricoxib, acetylsalicylic acid and duodenal ulcer haemorrhagic (88769)

Discussion

See minute item 4.1.1.5,

The Committee considered the causal association with etoricoxib, acetylsalicylic acid to be 'probable' for duodenal ulcer haemorrhagic.

4.1.2 Fatalities Listing

Members were given a brief description of these reports, with the option of requesting that any particular report/s can be discussed at the current, or a subsequent meeting, if they considered that there was a safety issue that prescribers should be informed about or regulatory action was required.

The Committee noted the following case reports:

4.1.2.1 Allopurinol (88246)
4.1.2.2 Capecitabine (88127)
4.1.2.3 Cilazapril (88107)
4.1.2.4 Clozapine (88227)
4.1.2.5 Clozapine (88228)
4.1.2.6 Clozapine (88450)
4.1.2.7 Cotrimoxazole (88352)
4.1.2.8 Dianeal, icodextrin (88129)
4.1.2.9 Fentanyl (88753)
4.1.2.10 Flucloxacillin, amoxicillin/clavulanic acid, cefuroxime, simvastatin, metronidazole (88188)
4.1.2.11 Oseltamivir (88137)
4.1.2.12 Physioneal (87956)
4.1.2.13 Rituximab, cyclophosphamide, vincristine, prednisone, doxorubicin hydrochloride (88128)
4.1.2.14 Simvastatin, erythromycin (88561)
4.1.2.15 Tenecteplase, acetylsalicylic acid, clopidogrel (88389)
4.1.2.16 Terlipressin (88387)
4.1.2.17 Terlipressin (88388)
4.1.2.18 Thalidomide (88308)
4.1.2.19 Warfarin (88530)
4.1.2.20 Warfarin, ibuprofen, amoxicillin/clavulanic acid, ciprofloxacin (88543)
4.1.2.21 Warfarin (88601)

4.1.3 List reports

These reports are typically due to disease progression, or contain insufficient data for an assessment to be made. They also include non-serious or well known reactions to medicines on the Adverse Reactions of Current Concern (ARCC) list. Members were asked to note these reports, with the option of requesting that any particular report/s be discussed at the current, or a subsequent meeting.

The Committee noted the following case reports:

4.1.3.1 Adalimumab (88634)
4.1.3.2 Adalimumab (88635)
4.1.3.3 Bevicizumab (88296)
4.1.3.4 Leflunomide, methotrexate (87974)
4.1.3.5 Leflunomide (88122)
4.1.3.6 Pioglitazone (88944)
4.1.3.7 Pioglitazone (88977)
4.1.3.8 Triamcinolone (88834)
4.1.3.9 Venlafaxine (87999)

4.2 Quarterly Reports from CARM as at 31 December 2009

Discussion

The Committee noted the quarterly reports from CARM as at 31 March 2010.

4.3 Human Papillomavirus Vaccine (HPV) reports

Discussion

The Committee noted the CARM reports of reactions to the HPV vaccine up to 30 April 2010.

The Committee noted that reports were similar to the pattern of adverse reaction reports received previously.

4.4 Seasonal Flu Vaccine reports

Discussion

The Committee noted the CARM report of reactions to the seasonal flu vaccine up to 7 May 2010.

5 New Zealand pharmacovigilance-related activities - for information

DHBNZ Safe and Quality Use of Medicines Group. 2010. Newsletter. Volume 6, Number 2

6 International pharmacovigilance-related Activities - for information

6.1 Australia

Advisory Committee on the Safety of Medicines (ACSOM). 2010. Medicines Safety Update. Issue 2

6.2 Canada

Canadian Adverse Reaction Newsletter. 2010. Volume 20, Issue 2

6.3 Singapore

Health Sciences Authority (HSA). 2009. Adverse Drug Reaction. Volume 12, Number 1

6.4 United Kingdom

Medicines and Healthcare products Regulatory Agency (MHRA). 2010. Drug Safety Update. Volume 3, Issue 8
Medicines and Healthcare products Regulatory Agency (MHRA). 2010. Drug Safety Update. Volume 3, Issue 9
Medicines and Healthcare products Regulatory Agency (MHRA). 2010. Drug Safety Update. Volume 3, Issue 10

7 OTHER BUSINESS

7.1 ACC reports

Recommendation

The Committee recommended that an annual report of cases received by ACC be generated, in order to identify possible areas of concern.

7.2 Statins and dose response

The Committee noted the MHRA advice issued in May 2010 regarding the increased risk of myopathy with high dose statins and noted that this was in line with the information previously presented to the Committee. They recommended that the Chair write to PHARMAC advising of this information.

Recommendation

The Committee recommended that the Chair write to PHARMAC advising of the recent information around statin use and dose response data

Secretary's note: On 17 June 2010, PHARMAC announced the removal of the Special Authority for atorvastatin effective 1 September 2010, resulting in atorvastatin being fully subsidised without the previous requirement of a trial of simvastatin 80mg.

7.3 Continuing Medical Education

[..] gave a presentation on the monitoring of medical devices in New Zealand.

The Acting Chair thanked members and the secretariat for their attendance and closed the meeting at 2 pm.

Associate Professor M. Rademaker
Acting Chair
Medicines Adverse Reactions Committee

Committees