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:

The one hundred and forty-eighth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 8 December 2011 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9.30 am and closed at 1.55 pm.

marc members present

Associate Professor M Rademaker (Acting Chair)
Dr L Bryant
Dr N Cole
Professor P Ellis
Associate Professor C Frampton
Dr S Jayathissa
Associate Professor D Menkes
Dr M Tatley
Dr K Wallis

marc secretariat present

J McNee (MARC Secretary, Medsafe)

MEDSAFE STAFF IN ATTENDANCE

A Cutfield (Advisor, Pharmacovigilance)
R Jaine (Senior Medical Advisor)
C James (Manager, Clinical Risk Management)
S Kenyon (Senior Advisor, Pharmacovigilance)
E Yousuf (Principal Clinical Advisor)

Invited guests and experts IN ATTENDANCE

Sarah Reader, Manager Product Regulation (Medsafe) attended the meeting.

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Assoc Prof Peter Jones, Dr Sime, and Assoc Prof David Reith.

1.2 Minutes of the 147^th MARC Meeting

The minutes of the 147^th 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 2012 MARC meetings were scheduled for 8 March, 7 June, 13 September, and 6 December.

1.4 Potential Conflicts of Interest

Committee members submitted their Conflicts of Interest Declaration forms to the Secretary. The Acting 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.

There were no potential conflicts of interest which were considered likely to influence the discussions or decisions of the MARC at this meeting.

1.5 Prescriber Update

1.5.1 Prescriber Update. Volume 32, Number 4. December 2011

Discussion

The Committee noted the latest edition of Prescriber Update.

2. STANDING AGENDA ITEMS

2.1 Report on Standing Agenda Items from Previous Meetings of the MARC

The Committee reviewed the list of outstanding recommendations made by the MARC at previous meetings. Background information on these issues can be found in the minutes of previous MARC meetings from the Medsafe website at www.medsafe.govt.nz/profs/marc/minutes

There were no standing agenda items for which the MARC made further recommendations.

3. pharmacovigilance issues

3.1 Matters Referred to the MARC under Section 36 of the Medicines Act 1981

No items.

3.2 Matters Referred to the MARC by Medsafe

3.2.1 Update on the safety profile of dabigatran (Praxada)

Background.

At the September 2011 meeting the MARC were provided with a summary of the known information on the risks and benefits of dabigatran (Pradaxa). The Committee concluded that Risk Management Plan was satisfactory. However, the Committee had a number of requests for further information.

The December report was produced to provide the Committee with information on events since the last meeting, including:

The spontaneous reports of suspected adverse reactions to dabigatran.
The information provided by the company in response to MARC requests.
Activities undertaken by Medsafe in relation to dabigatran (Pradaxa) since the last MARC meeting.

At the previous meeting, the MARC agreed that a number of changes should be made to the data sheet. In addition the company proposed a number of additions based on changes to the core data sheet. These changes included the need to monitor renal function. A Dear Healthcare Professional letter was distributed in New Zealand by the company on 17 November 2011, advising of the updates.

PHARMAC data suggested that most patients taking dabigatran had previously been on warfarin. A further breakdown of these data indicated that the majority of patients were receiving the correct dose.

An analysis of the Centre for Adverse Reactions Monitoring (CARM) data indicated that the rate of reporting of adverse drug reactions in the very elderly was twice that of other age groups. However, CARM concluded that this reflects the frailty of this population in general rather than a specific concern with the medicine.

Of interest is how the safety of medicines used in the same indication compares. It is very difficult to compare the spontaneous reporting profile of dabigatran with warfarin. Due to the age of warfarin, current knowledge and acceptance of adverse reactions very few adverse reactions are reported. In addition changes in the reporting system and improvements in standards of patient care mean that reports of suspected adverse reactions to warfarin when it was first introduced cannot be compared with present day reports. It should also be noted that the media interest associated with dabigatran has probably stimulated reporting.

The Committee were provided with an overview of spontaneous reports received by CARM for warfarin over the previous five years. The proportion of serious reports received for warfarin was higher than for dabigatran, including a number of reports where the patients were judged to have died due to the effect of warfarin. This higher percentage of serious reports for warfarin reflects the length of time that warfarin has been in use and the stimulated reporting of dabigatran. The lack of fatal reports considered related to dabigatran treatment is likely due to the short time this medicine has been used compared to warfarin.

CARM have identified a potential signal of cardiac failure with dabigatran. At the end of September CARM had received four reports of cardiac failure (including cardiac failure aggravated and congestive cardiac failure), and a number of reports detailing possible symptoms. The number of subjects in the RE-LY study experiencing cardiac failure was noted by the FDA to be similar across the treatment arms and so was not identified as a potential risk. Medsafe has requested a review of this issue from the sponsor.

At the last meeting, the Committee requested further information on the renal clearance of dabigatran; specifically whether there was any active excretion. The information provided by the company is consistent with clearance by renal filtration only.

The Committee also requested information on how major bleeds were treated in patients taking dabigatran in clinical trials. The company has provided the recommendations for treatment given to the investigators in the RELY study. The company have stated that they are not yet able to describe the success of such treatments in the market as not enough information is generally contained in the spontaneous reports they have received.

One of the findings of RE-LY was a numerically, but not statistically significantly greater occurrence rate of myocardial infarction in both dabigatran etexilate treatment groups compared to the warfarin treatment group. The company have provided the results of an internal review following this imbalance between patients pre-treated with warfarin and those not previously exposed. The reasons for the imbalance remain unclear. The company concludes that in the RE-LY study the modest imbalance in MI is more than counterbalanced by dabigatran's substantial and larger beneficial effects on stroke and lower observed rates of cardiovascular mortality and total mortality.

The Committee was asked to advise whether any safety issues warranting further action have been identified as a result of this review

Discussion

The Committee noted the 2011 Medsafe report.

The Committee noted that since the last MARC meeting, alerts regarding the risk of bleeding have been issued internationally by Japan, Europe, Canada, and the FDA.

The Committee discussed the imbalance of MI noted in the RE-LY study and concluded that overall it is not possible to determine if the MI imbalance was due to chance or a protective effect of warfarin. They noted further studies are ongoing.*

The Committee discussed the adverse reaction reports with event terms that may be suggestive of cardiac failure and noted that the New Zealand Pharmacovigilance Centre will be investigating this possible signal.

The Committee noted the majority of the adverse reaction reports of medication error were reported in the first few weeks of funding; only two reports were received in October. The Committee was satisfied that the number of medication errors is decreasing.

The Committee noted the increased rate of adverse reaction reports in the elderly. They considered that this reflects frailty in that population rather than a specific concern about dabigatran.

The Committee agreed that the balance of benefits and risks for dabigatran remains positive and that no further action is required at present. They noted that CARM and Medsafe will continue to closely monitor adverse reaction reports to dabigatran, particularly those relating to cardiac failure and myocardial infarction.

*Secretary's note: since the time of the meeting, further information has been published online in Circulation, and another paper in the Archives of Internal Medicine.

3.2.2 Benefit risk review of Nicobrevin

Background

In April 2011, the Medicines and Healthcare products Regulatory Agency (MHRA) announced that Nicobrevin had been withdrawn from the UK market as the risks outweigh the benefits. Subsequently Medsafe requested a review of the benefits and risks of this medicine from the sponsor. The 2011 Medsafe report included information provided by the product sponsor, the MHRA, and information about the individual ingredients from Martindale The Extra Pharmacopoeia, 31st Edition and the scientific literature.

Nicobrevin is a smoking cessation product in capsule form. Each capsule, in the 48 capsule treatment course, contains:

Menthyl valerate 100mg.
Camphor 10mg.
Quinine 15mg.
Eucalyptus oil 10mg.

Information provided by the company included the rationale for inclusion of the various ingredients; however, no data was provided in support of this rationale. No studies were provided by the company on the pharmacokinetics of Nicobrevin to support the dosages of active ingredients.

The company states that the efficacy of Nicobrevin was demonstrated in a randomised double blind placebo controlled trial (Dankwa 1988). This was a small study including a total of 92 smokers. The outcome was based on the number of subjects not smoking on the last day of treatment. The authors concluded that Nicobrevin was significantly more effective than placebo in aiding smoking cessation.

The MHRA also included information from a study by Schmidt 1974. The MHRA concluded that given the limitations of the study and the results, this study did not provide any evidence of the effectiveness of Nicobrevin as an anti-smoking preparation.

Neither of these studies met the Cochrane review criteria of randomised trials comparing Nicobrevin to placebo or an alternative therapeutic control which reported smoking cessation with at least six months follow up.

Medsafe undertook a search of the scientific literature and Martindale to obtain additional information regarding the rationale for inclusion of each of the individual components in a smoking cessation product.

Valerian has been granted well established use and traditional use indications, in Europe, for the relief of mild nervous tension and sleep disorders. Whilst efficacy does not have to be shown for this type of registration there is at least a history of use for the indication and this is consistent with the rationale for inclusion in Nicobrevin. A monograph for valerian is published on the European Medicines Agency website. Similarly both camphor and eucalyptus oil are included in medicines intended for the treatment of coughs and colds; therefore they are expected to have expectorant properties. No information was found to substantiate the stated rationale for inclusion of quinine in Nicobrevin. The quantity of quinine in Nicobrevin is similar to that of tonic water. The Australian Food Standards code permits up to 100mg/kg for tonic drinks. The maximum exposure to quinine through Nicobrevin is 45mg i.e. around 500ml of tonic water.

The available information was consistent with the doses of the substances contained in Nicobrevin not being likely to result in clinically significant medicine interactions.

Medsafe undertook a search of the scientific literature and Martindale to obtain information regarding the risks associated with each ingredient.

There appears to be evidence that low dose quinine can, rarely, cause adverse effects including hypersensitivity reactions and thrombocytopenia.

The European monograph for valerian notes that adverse reactions include gastrointestinal symptoms such as nausea and abdominal cramps. It is also noted in the monograph that valerian may impair driving ability. There is one contraindication for those with known hypersensitivity to the active substance. Martindale notes that chronic ingestion of valerian has been associated with headache, insomnia, agitation and hepatotoxicity. Cardiac complications and delirium have been reported following abrupt withdrawal.

Martindale notes that seizures in association with camphor have been reported in children.

Martindale does not provide any adverse effects for therapeutic use of eucalyptus oil.

In total CARM have received a total of nine reports where Nicobrevin was considered to be the suspect medicine. These reports include reports of reactions such as:

Ageusia, anosmia and malaise in a patient taking Nicobrevin and cimetidine. There is a potential interaction between quinine and cimetidine.
Abdominal pain, epistaxis, vomiting, headache and dyspnoea in a patient only taking Nicobrevin. There is the potential for quinine to cause thrombocytopenia.
Maculo-papular rash in a patient taking only Nicobrevin.
Thrombocytopenia and petechial rash. A positive rechallenge was reported.
Hepatic function abnormal, fever and malaise patient who was hospitalised. CARM considered the relationship to Nicobrevin to be probable. There is the potential for all of the components of Nicobrevin to cause hypersensitivity reactions.

It is unclear if the low number of reports indicates the rarity of these reactions or is representative of the low rate of reporting for over-the-counter medicines in general.

Medsafe considers that based on the available data the balance of benefits and risks cannot be determined. Therefore the risks of using this medicine to give up smoking rather than a different medicine should be considered. Given that the majority of smokers will need to try to quit smoking more than once, Nicobrevin may offer smokers an additional alternative. Even if the efficacy is no better than placebo it is noted that some smokers successfully manage to quit using placebo treatment. There are some potential harms associated with Nicobrevin, but the available data suggested that these are very rare.

Medsafe concludes that the risks associated with taking this medicine are low, but that consumers should be fully informed of these risks.

The Committee was asked to advise whether:

The balance of benefits and risks for Nicobrevin can be determined.
Nicobrevin represents a potential hazard to the population of New Zealand.
Regulatory action needs to be taken (and if so what this action should be).
The results of this review should be communicated (and if so how).

Discussion

The Committee noted the 2011 Medsafe report.

The Committee agreed that the Dankwa study was outdated and would not meet study criteria at the present time. The requirements for demonstrating efficacy of these types of products have changed significantly since this trial was conducted; more recent studies measure efficacy at 12 months after finishing treatment. The Committee considered that there were some imbalances in patient characteristics between the treated and placebo groups in the Dankwa study that may have favoured the treatment group. Since, the efficacy end point is different the data from this trial cannot be compared to data from trials for other medicines intended to help smokers quit.

The Committee considered that there was little evidence of benefit from using Nicobrevin. The Committee concluded that there was insufficient evidence demonstrating serious harm to the New Zealand population to require revocation of consent for this medicine.

The Committee noted that Nicobrevin is not included in the national anti-smoking subsidy program, and is not funded by PHARMAC.

Whilst the risk associated with the use of Nicobrevin was considered to be low, the Committee did consider that there was sufficient evidence of a risk of hypersensitivity reactions, gastrointestinal reactions, and impairment of driving ability that patients should be informed of these risks. It was noted that there are similar risks associated with use of tonic water, but that Medsafe does not regulate foods. The Committee recommended that the package labelling and package insert for Nicobrevin be updated to fully inform patients.

Recommendation 4

The MARC recommended that the package labelling and package insert for Nicobrevin be updated to reflect the risk of hypersensitivity reactions, gastrointestinal reactions, and impairment of driving ability.

3.2.3 Tramadol - a year on from funding

Background

The purpose of the 2011 Medsafe report was to provide the MARC with a comparison of usage data and spontaneous reports involving tramadol before and one year following funding of Arrow-Tramadol 50mg capsules by PHARMAC. The report focused on oral tramadol 50mg capsules, as this is the only presentation currently funded by PHARMAC.

PHARMAC data suggests that the number of patients receiving tramadol capsules has been steadily increasing since the commencement of funding in June 2010. With regard to spontaneous data, 16% of all reports in the CARM database were received since funding. However, it is important to note that the spontaneous report data is not limited to the 50mg capsules. An analysis of the reports received pre and post funding did not identify additional adverse events not already outlined in data sheets.

The most commonly reported suspected reactions associated with tramadol treatment both before and since funding include: nausea, dizziness, increased sweating and pruritis. These reactions are well known, common and are described in the tramadol data sheets.

The spontaneous data suggests proportionally more reports involve patients 80 years and over; however the data does not identify any particular trends in adverse reactions in this patient group.

Medsafe identified that reactions of possible concern were serotonin syndrome, convulsions, suicidality, and drug interactions. These reactions were further reviewed.

Cases in the CARM database detailing serotonin syndrome or its symptoms generally involved patients who were taking other serotinergic agents. The potential for serotonin syndrome and the interaction with serotoniergic medicines is described in data sheets for tramadol-containing medicines, and has also been the subject of a number of Prescriber Update articles.

Almost 25% of adverse reaction reports involving tramadol received by CARM since commencement of funding for Arrow-Tramadol 50mg capsules detail convulsions.

Most involved patients receiving either high doses of tramadol, patients with a history of epilepsy, or patients receiving other medicines that are known to lower the seizure threshold. The potential for convulsions and interactions with other medicines which lower the seizure threshold is described in data sheets, and also has been the subject of Prescriber Update articles.

There is one report in the CARM database detailing suicidal tendency. This report may be confounded by pre-existing depression, as well as the indication for which tramadol was used. Suicidality is not currently listed in the data sheets for tramadol, which is consistent with the Australian Product Information, and the European Summary of Product Characteristics. There does not appear to be enough evidence of a causal association at this time to warrant revisions to the data sheets for tramadol-containing medicines to include a warning regarding worsening of depression or suicidality.

Cases noting potential drug interactions detailed adverse events such as serotonin syndrome (or its symptoms), convulsions or bleeding events. These cases involved patients who were receiving concomitant medicines associated with the above events. The reported interactions are already outlined in the data sheets for tramadol.

Discussion

The Committee noted the 2011 Medsafe report.

The Committee acknowledged that the adverse event reports received since the commencement of funding have been similar in nature and proportion to those received prior to funding.

It was agreed that the current data sheets for tramadol are adequate with regard to the safety profile, and potential interactions.

NZPhvC advised that in a previous review of convulsions in the CARM database, tramadol was associated with the highest proportion of reports involving convulsions. They advised that they would continue to monitor these reports.

A member noted that tramadol may inhibit noradrenaline and serotonin re-uptake in a similar way to SSRI and related antidepressants such as venlafaxine. It was noted that the SSRIs and venlafaxine have been associated with an increased risk of suicidality and it was queried if the same potential mechanism could exist for tramadol. The Committee recommended that Medsafe investigate whether this is a safety signal in other data sources.

The Committee agreed that no regulatory action is necessary at the present time with the exception of close monitoring of reports involving the elderly and those detailing worsening of depression or suicidality.

Recommendation 2

The Committee recommended that Medsafe investigate whether the risk of suicidality with tramadol is a safety signal in other data sources.

Recommendation 3

The Committee also recommended that Medsafe and NZPhvC continue to closely monitor reports involving tramadol in the elderly and those detailing worsening of depression or suicidality.

4. Matters arising from the New Zealand Pharmacovigilance Centre

4.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

4.1.1 Potential Safety Signals from Single Case Reports

No potential safety signals were identified by CARM this quarter.

4.1.2 Fatal Cases (Causal Cases Only)

Members were given a brief description of the fatal reports for which CARM had assessed the causality to be at least possible. The Committee were given the option of requesting that any particular reports be discussed at the current or a subsequent meeting if they considered that there may be a safety issue that prescribers should be informed about or for which regulatory action was required.