Names of individuals have also been deleted where that person's contribution is not in the public domain, or will not shortly be so. For example, the names of those to be approached to write an article are deleted, but the names of those who have contributed to a draft article are not usually deleted. In addition, names are not usually deleted when a contribution has been made in an official capacity.

The material listed as being considered on an issue is not intended to be exhaustive.

The recommendations of the Committee are in bold typeface.

Minutes:

marc members present

Associate Professor D Reith (Acting Chair)
Dr L Bryant
Associate Professor C Frampton
Associate Professor M Rademaker
Dr R Savage
Dr S Sime
Dr K Wallis

marc secretariat present

J McNee (MARC Secretary, Medsafe)

MEDSAFE STAFF IN ATTENDANCE

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

Invited guests and experts IN ATTENDANCE

Ms A Bailey (Acting Team Leader, Prescription Medicines, Medsafe) attended the meeting as an observer.

1. Matters of Administration

1.1 Welcome and Apologies

The Acting Chair welcomed the attendees to the meeting. Apologies were received from Associate Professor P Ellis, Dr S Jayathissa, and Dr M Tatley.

1.2 Minutes of the 146^th MARC Meeting

The minutes of the 146^th meeting of the Committee were accepted as a true and accurate record of the meeting.

1.3 Dates of Future MARC Meetings

The date for the next MARC meeting was scheduled for 8 December 2011.

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.

One member declared a conflict of interest during the meeting. The Committee agreed that this member could participate in the discussion but would not be able to participate in a vote if the Committee deemed a vote necessary

There were no other 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 3. September 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.asp.

Standing agenda items for which the MARC made further recommendations for action are summarised below.

2.1.1 Hepatic failure with paracetamol (92092)
June 2011 minute item 2.1.1, March 2011 minute item 2.1.2, December 2010 minute item 4.1.1.1

MARC Recommendation

The MARC recommended that Medsafe investigate the new advice released by the MHRA with respect to the adoption of the new dosing advice by NZ.

Outcome

Medsafe advised that at the April meeting of the Medicines Classification Committee, the Committee recommended that the package labelling on paracetamol products be aligned with Australia with respect to warning statements.

Discussion

The MARC noted the above and considered no further action was required.

2.1.3 Additional papers relating to risk of venous thromboembolism associated with combined oral contraceptives containing drospirenone
Update from Pharmacovigilance Activities Paper
June 2011 minute item 2.1.3

MARC Recommendation

The MARC recommended that a letter be written to PHARMAC highlighting the MARC's concern regarding the lack of a fully funded combined oral contraceptive containing 20mcg ethinyloestradiol.

Discussion

Medsafe advised that PHARMAC would be informed of the MARC's concerns.

Secretary's note

Since the meeting, this recommendation has been completed.

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 Mortality associated with use of tiotropium (Spiriva)

Background

This review was prompted by the publication of a meta-analysis by Singh et al showing an increase in mortality in patients with chronic obstructive pulmonary disease taking Spiriva Respimat (tiotropium) inhaler. Previous concerns have been raised in relation to mortality and cardiovascular adverse events with Spiriva. The MARC last reviewed Spiriva in 2007, no regulatory action was taken. Medsafe performed an internal review of the safety of Spiriva in 2010; the results were included in the June 2010 MARC signal detection paper.

This report reviewed information published since the last MARC review, on the efficacy and safety of Spiriva, focussing on mortality and cardiovascular events.

Tiotropium is a long-acting muscarinic receptor antagonist (anticholinergic) indicated for bronchodilator maintenance treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD). Tiotropium was first approved in The Netherlands in 2001 as Spiriva dry powder inhaler (18µg) also known as the HandiHaler formulation. A second formulation developed as a solution for inhalation known as the Respimat inhaler (or mist haler) containing 2.5µg per puff was first approved in Denmark in 2008. Both formulations have been approved for use in New Zealand, however only the HandiHaler is funded and marketed.

Mortality rates in COPD are high, and vary substantially between and within countries. Impaired lung function and exacerbations are linked to mortality. However, all deaths are not linked to COPD. In patients with mild to moderate COPD, who make up the vast majority of all cases, hospitalisations and deaths are more likely to be due to cardiovascular events than respiratory causes. In more severe COPD respiratory and cardiovascular events occur with equal frequency.

With respect to efficacy studies, a Cochrane review concluded that tiotropium reduced the odds of a COPD exacerbation and related hospitalisations compared to placebo.

The data were insufficient to assess tiotropium's effect on mortality, however, the natural history of the disease suggests that treatments reducing exacerbations should also have a beneficial effect on mortality.

There are two Cochrane reviews comparing tiotropium with active treatment, one compared combination inhaled corticosteroid (ICS) and long acting beta-2 agonists (LABA) with tiotropium, and the other assessed the addition of tiotropium to LABA and steroid combination therapy. The comparator data are not as robust as the data comparing tiotropium with placebo. Tiotropium appears to be better than salmeterol but not as effective as ICS plus LABA treatment. There may be an advantage when tiotropium is used with an ICS and LABA. These analyses all used data from studies investigating the HandiHaler formulation.

A number of efficacy analyses have also been performed using the Respimat formulation. The Respimat formulation has been shown to reduce COPD exacerbations and hospitalisations compared to placebo. The Respimat was non-inferior to the HandiHaler. The pharmacokinetic studies suggest a slightly greater systemic exposure to tiotropium delivered via the Respimat compared to the HandiHaler. Treatment with the 5mcg dose of Respimat (two puffs of 2.5 µg) resulted in a slightly higher bioavailability when compared with the HandiHaler. Treatment with the 10mcg dose of Respimat resulted in a substantially higher bioavailability. The 10mcg dose is not approved. This difference may potentially result in a difference in effect between the two formulations.

The report included an overview of the safety of tiotropium, including the PSUR and published studies. The known safety profile is described in the NZ data sheets..

An overview of the Singh et al meta-analysis was provided. The objective of this study was to systematically review the risk of mortality associated with long-term use of tiotropium, delivered using a mist inhaler (Respimat), for symptomatic improvement in chronic obstructive pulmonary disease. The Committee was also provided with an overview of mortality data in association with the HandiHaler formulation and information on cardiovascular adverse events.

The Committee was asked to advise whether an association between tiotropium and increased mortality is supported by the available data, and if any regulatory action should be taken at the present time.

Discussion

The MARC noted the 2011 review of the risk of mortality and cardiovascular adverse reactions associated with two Spiriva formulations provided by Medsafe. They noted that only the HandiHaler formulation was currently marketed and funded in NZ.

They questioned if the risk of adverse reactions could be a dose-related issue and suggested the message not to exceed the recommended once daily dose should be included in the next issue of Prescriber Update.

The Committee discussed the Singh meta-analysis. They agreed that a key issue was survivor bias, with the placebo arm of the trial dropping out earlier than the active arm, with corresponding differing amounts of follow-up. They noted there was a marginally significant increase in mortality, depending on the statistical model followed. They agreed that this may be an early signal, however, not as strong as stated by the authors.

The Committee queried the pharmacokinetic profile of tiotropium, noting there appeared to have been more cardiovascular deaths in renally impaired patients. They questioned if renal impairment could lead to accumulation. They recommended that Medsafe contact the product sponsor and request further information on:

The pharmacokinetics of tiotropium in patients with renal impairment and whether this results in accumulation of tiotropium with the use of both the HandiHaler and Respimat formulations.

Whether the company had performed an analysis of the risk of mortality in patients with renal impairment taking tiotropium, and if so, to provide Medsafe with a copy of this analysis.

The Committee recommended that Medsafe ensure that the data sheets are in line with the product's core data sheet. In addition the Committee recommended that the Respimat data sheet include a precaution regarding its use in patients with cardiac rhythm disorders.

The Committee concluded that an increased mortality risk was not associated with the HandiHaler, but that there was a signal of such a risk with the Respimat formulation.

Recommendation 1

The MARC recommended that Medsafe contact the product sponsor and request further information on:

The pharmacokinetics of tiotropium in patients with renal impairment and whether this results in accumulation of tiotropium with the use of both the HandiHaler and Respimat formulations.
Whether the company had performed an analysis of the risk of mortality in patients with renal impairment taking tiotropium, and if so, to provide Medsafe with a copy of this analysis.

Recommendation 2

The Committee recommended that Medsafe ensure that the data sheets are in line with the product's core data sheet and that the Respimat data sheet include a precaution regarding its use in patients with cardiac rhythm disorders.

3.2.2 Varenicline and cardiovascular events

Background

Varenicline (Champix) was approved in New Zealand in March 2007.

Varenicline was placed on the IMMP in 2007 and since then the cohort has risen to over 15,000 patients.

In March 2008 the MARC was provided with an early IMMP report describing a possible emerging safety issue with varenicline and psychiatric reactions. The New Zealand datasheet had recently been updated to include information about psychiatric adverse events and update warnings and precautions.

In March 2009 the MARC was presented with an overview of the interim IMMP results for the first year of intensive monitoring of varenicline. At that time the most common adverse effects reported in the IMMP cohort were psychiatric events including depression, suicidal ideation, sleep disorders, anxiety disorders and withdrawal symptoms. The Committee recommended that an article be published in Prescriber Update; this article was included in the May 2009 edition.

In December 2009 the MARC was presented with a report following completion of the first year of follow up of the IMMP cohort. Medsafe also provided an update on the varenicline safety profile, including a summary of the latest Periodic Safety Update Report (PSUR) and interim results from a UK based Prescription Event Monitoring (PEM) study.

Psychiatric events accounted for one third of all events identified in the IMMP study at this time. The Committee noted that the majority of these events were now listed in the Champix datasheet. The Committee agreed that no regulatory action was required at the time and that Medsafe would report back to the MARC as necessary.

In December 2010 an article was published in Prescriber Update reminding prescribers about the recommended course of treatment. This followed an IMMP finding that patients were regularly not receiving the full recommended 12 week course.

This MARC review has been prompted by an FDA safety communication in June this year and the publication of results from a meta-analysis by Singh et al in the in Canadian Medical Association Journal (CMAJ).

The FDA communication followed a review of a randomised, double-blinded, placebo controlled clinical trial designed to assess the efficacy and safety of varenicline for smoking cessation in 700 patients aged 35 to 75 years with stable, documented cardiovascular disease.

Singh et al published the results of a meta-analysis conducted to assess the safety of varenicline.

The FDA communication and Singh et al paper both provoked significant media interest in New Zealand.

The Committee was asked to advise whether a causal association between varenicline treatment and cardiovascular events had been demonstrated, and if any regulatory action was recommended or if changes to the medicine datasheet/CMI were warranted.

Discussion

The Committee noted the extent of smoking in NZ, the risks involved, and the strategies designed to aid cessation. To provide background and context for this review, the Committee was advised of the Cochrane review published in 2011. The results of this study demonstrated the efficacy of varenicline in aiding smoking cessation, maintaining abstinence, and also showed improved rates of abstinence when compared with bupropion.

The Committee noted the review by Rigotti et al, which prompted the FDA to communicate in June 2011 to healthcare professionals about a possible increased risk of cardiovascular events associated with the use of varenicline. This study assessed the efficacy of varenicline and the frequency of adverse events in smokers with cardiovascular disease. The study concluded that varenicline was effective in helping patients quit smoking, and remain so for as long as one year. Although the number of adjudicated cardiovascular events reported was low overall, the FDA identified a small absolute increase in event numbers in the varenicline group when compared with the placebo group. This lead the FDA to request that Pfizer conduct a large, combined meta-analysis of randomised controlled trials that investigated cardiovascular events associated with the use of varenicline. The Committee noted that the Rigotti study was not designed or sufficiently powered to be able to detect a small but significant difference in event rates, and noted that the FDA had requested a larger, combined meta-analysis. The Committee was informed that Pfizer had committed to providing Medsafe with a copy of the meta-analysis also.

The Committee noted the Singh et al meta-analysis, which identified double-blind RCTs with at least one week of follow-up comparing varenicline with placebo among tobacco users. This meta-analysis reported a small absolute increased risk in adverse cardiovascular events in those patients taking varenicline compared to placebo (0.24%). However, this result was widely reported as a 72% relative risk increase. The Committee discussed the limitations of the Singh et al meta-analysis. The trials used different populations with different cardiovascular risks, yet combined the data. Although most of the studies were conducted in people who did not have cardiovascular disease, importantly, the majority of events occurred in one trial where participants had stable cardiovascular disease, and so may be considered at higher risk. The meta-analysis also pooled the results from studies using different doses of varenicline, and the studies had different lengths of follow-up. The proportion of participants lost to follow up was also different between those taking varenicline and those taking placebo, resulting in possible bias. In addition, there was no further investigation of whether a dose response relationship was present, or if length of treatment was relevant in terms of cardiovascular events.

The Committee noted the summary of the latest Periodic Safety Update Report (PSUR), in which the sponsor concludes that the risk/benefit profile of varenicline remains positive. The MARC noted that the sponsor has committed to continuing to provide PSURs to Medsafe.

The Committee noted that Champix is currently being monitored on the IMMP, and a research paper was included in the dossier. This paper included data on cardiovascular related events reported in patients either taking varenicline or in the "off-drug" period. As at January 2011, the IMMP data set included 172 adverse events under the cardiovascular event code involving 154 patients.

The Committee noted the IMMP author's discussion and conclusion in addition to Medsafe's review of this study. The Committee noted that Medsafe does not agree with the author's opinion that the cases presented in the IMMP paper appear to support a causal association between the use of varenicline and cardiovascular events. Medsafe does agree with the author's statement that further clinical studies are required to confirm or refute the association. The Committee discussed the limitations of the IMMP study and agreed that the data provided in the IMMP paper is descriptive and does not necessarily support a causal association.

The Committee noted the actions taken by other regulatory agencies. In July this year, the European Medicines Agency stated that the benefit-risk balance for varenicline remains positive, despite the results of the Singh et al meta-analysis. They identified a number of limitations of the meta-analysis, and considered that robust conclusions could not be drawn from the study. In June 2011, the FDA advised that prescribing information for varenicline would include advice regarding a small, increased risk of certain cardiovascular adverse events in patients who have cardiovascular disease.

The Committee noted that the NZ datasheet for Champix contains limited information regarding the reporting of cardiovascular events associated with the use of varenicline. They recommended that the Champix data sheet be updated to include information about cardiovascular related adverse events.

The Committee considers that although cardiovascular related safety concerns have been raised in association with varenicline, a causal relationship has yet to be demonstrated. It agreed that this information does not alter the benefit-risk balance for varenicline, which remains positive. It noted that Medsafe will be reviewing the results of further information requested by the FDA, and will report back to the MARC as necessary.

Recommendation 3

The MARC recommended that the Champix data sheet be updated to include information about reports of cardiovascular related adverse events associated with the use of varenicline.

3.2.3 Pioglitazone and bladder cancer

Background

Pioglitazone was first approved in Europe in October 2000 and in New Zealand in June 2002.

The glitazones were placed on the active monitoring list for annual review in March 2006. A Prescriber Update article on fluid retention, heart failure and macular oedema with glitazones was published in November 2007. In Feb 2011 consent to distribute rosiglitazone in New Zealand was suspended.

In March 2011 the MARC reviewed data published in the previous year on the safety of pioglitazone. This data included an FDA conducted meta-analysis of cardiovascular events seen with pioglitazone, a literature review, PSUR data and a report on the first five years of the Kaiser- Permanente study investigating the risk of bladder cancer with pioglitazone.

At this point the Committee considered that the available evidence did not present any immediate cause for concern.

The current concern regarding the risk of bladder cancer with pioglitazone treatment was raised following the suspension of the marketing authorisation for pioglitazone in France. This action was taken by the French regulator following the final report of an observation study conducted at their request.

The manufacturer of Actos, Takeda, conducted a clinical overview of the efficacy of pioglitazone. The clinical database consisted of 47 studies, including 12 long-term controlled trials of more than one year in duration. The company considered that the efficacy of pioglitazone has been demonstrated, and that it has several key benefits, including a well documented cardiovascular safety profile in type 2 diabetes mellitus (T2DM) patients.

The PROactive study was a randomised controlled trial; bladder tumours were reported in more patients in the pioglitazone group than in the placebo group. However, further investigations revealed that many of the reported tumours occurred within one year, and it was determined that there was no biological plausibility that the tumours could be treatment related. An extension of the PROactive trial (EC445) is ongoing. This assesses total mortality and macrovascular morbidity, as well as the incidence, nature, and pattern of newly diagnosed malignancies in high risk T2DM patients. The total duration of the study is ten years, with the latest analysis being for six years of observation. This analysis showed no increased risk over time.

A meta-analysis of controlled clinical trials was conducted by Takeda. The primary aim was to evaluate the risk of bladder cancer in patients with T2DM treated with pioglitazone against a comparator in the randomised controlled trials in the clinical database. Subjects with bladder cancers with an onset date of less than one year after the first dose of study drug were excluded. The company concluded this meta-analysis does not confirm or refute the association between pioglitazone and bladder cancer.

In June 2011, AFSSAPS, the French Medicines Regulator, announced that they were suspending the marketing authorisation for pioglitazone due to the risk of bladder cancer. The German medicines regulator followed suit shortly after.

The Study conducted for AFSSAPS was an observational study using data from the French National Health System which covers around 86% of the 65 million population. It was noted that one of the major risk factors for bladder cancer, tobacco smoking, could not be accurately accounted for in this study. A number of other limitations were noted. The authors of the study concluded that there was an increased risk of bladder cancer (HR 1.22 (1.05-1.43)) that increased over time and with increased total dose. However this risk was only significant in men. The risk was noted to be similar to that seen in the Kaiser- Permanente study reviewed previously.

In July 2011, the European Medicines Agency (EMA) announced that following a review of the risk of bladder cancer with pioglitazone, it concluded that there was a small increased risk of bladder cancer associated with pioglitazone use. However, the EMA considered that with careful patient selection, the benefits continued to outweigh the risks.

The Committee was asked to advise whether:

A causal association between pioglitazone treatment and bladder cancer has been demonstrated.
Any further regulatory action is recommended.
Any communication is necessary.

Discussion

The Committee noted the 2011 Medsafe report. They noted that risk factors for bladder cancer are varied and include individuals with diabetes, and some occupations, and the condition may take up to 25 years to develop. They noted that the incidence appears to be lower in NZ than in the US or France.

The Committee noted that a meta-analysis of controlled clinical trials was conducted by Takeda on behalf of the company. They noted that the results of this meta-analysis are limited by the small number of subjects exposed to pioglitazone for longer than one year and that most studies were not randomised based on cancer risk. The small number of patients who developed bladder cancer reduces the reliability of the risk estimate. They noted that while the company concluded that given the low overall incidence of bladder cancer and biologic implausibility of developing bladder cancer within 1 year of treatment, it is difficult to draw meaningful conclusions. They agreed that this analysis does not confirm or refute the existence of an association between pioglitazone treatment and bladder cancer.

The MARC noted the study sponsored by the French regulator Afssaps published in June 2011. The MARC noted the confounding factors of the study included tobacco smoking, and considered that the methods used by the authors did not adequately address this. They noted the short follow-up period, and agreed that the hazard ratio of 1.22 was not convincing. They agreed that the studies showed a weak signal of an association between pioglitazone and bladder cancer.

The MARC agreed that no causal association between pioglitazone and bladder cancer has been demonstrated at this time. The Committee recommended that a warning regarding bladder cancer be included in the NZ data sheets. They agreed that healthcare professionals should be made aware of the Committee's conclusions, and recommended that this issue be included in the MARC summary published in Prescriber Update.

Recommendation 4

The MARC recommended that a warning regarding a possible association between pioglitazone and bladder cancer be included in the NZ data sheets, and that this information be included in the MARC summary published in Prescriber Update.

3.2.4 Dabigatran safety profile

Background

In June 2008, dabigatran (Praxada) was approved in New Zealand for prevention of venous thromboembolic events in patients who have undergone major orthopaedic surgery.

In February 2011, New Zealand approved a further indication: prevention of stroke, systemic embolism and reduction of vascular mortality in patients with atrial fibrillation.

On 1 July 2011 PHARMAC funding began in New Zealand.

The purpose of this report was to outline the currently known safety profile of dabigatran (Pradaxa) a relatively new direct thrombin inhibitor. The Committee was presented with a summary of the latest Risk Management Plan (RMP) and Periodic Safety Update Report (PSUR).

An overview of the indications and dosage recommendations for dabigatran was provided. The dosage regimen is different in the two indications. Several factors have been identified which influence the plasma levels of dabigatran. There are recommendations for dosage changes when these factors are present. However, the recommendations are different according to the indication. These recommendations are outlined in the data sheet.

The main reason for these differences in dose adjustment is due to the fact that patients who have had orthopaedic surgery are at high risk of bleeding whereas patients with atrial fibrillation are at lower risk of bleeding.

A synopsis of ongoing and completed clinical trials and postmarketing studies was provided to the Committee.

The exposure of patients in these studies for both indications, by age, gender, renal function and duration was presented. It was noted for the new indication (AF) that over 5,000 patients had been exposed to dabigatran for longer than two years. It was noted that sufficient numbers of patients with moderate renal impairment were included in the studies to determine the efficacy and safety of dosage recommendations.

The main identified risk of dabigatran treatment is bleeding.

In the clinical trials conducted in patients who had undergone orthopaedic surgery, bleeding rates were comparable to enoxaparin. In the RE-LY study (AF patients) bleeding rates on the higher dabigatran dose (150mg twice daily) were not different to warfarin. Bleeding rates were lower in patients taking the lower dose (110mg twice daily) than in those taking warfarin. However, it was noted that patients taking dabigatran were at higher risk of gastrointestinal bleeding than those taking warfarin

Dabigatran is renally excreted; therefore data on the effect of dabigatran plasma levels in patients with renal impairment were presented as this relates to bleeding risk. In the clinical trials investigating dabigatran use after surgery, an increase in risk of bleeding was seen in patients with renal impairment and therefore a dose reduction is recommended. In the RE-LY study, patients with renal impairment had higher rates of major bleeds (compared to those with normal renal function). However, there was no difference in bleeding rates between the group taking the recommended dose of 300mg daily or those taking the reduced dose of 220mg daily. The rates of ischaemic stroke in the 300mg dose group were lower than the 220mg dose group, meaning the benefit risk profile is best for the 300mg daily group. Therefore no dose reduction is necessary for these patients, although it may be considered. It was noted that the FDA have recommended that only the 150mg dose twice daily is used. In New Zealand the data in patients with creatinine clearance < 30ml /min were considered insufficient and therefore use is contraindicated in this population.

In terms of laboratory monitoring, the data sheet recommends that measurement of anticoagulation with dabigatran may be helpful in patients with additional risk factors. The aPTT test is recommended as it is widely available; however, the ecarin clotting time (ECT) test appears to be more useful and should be used where available.

Other known risks associated with dabigatran are: gastrointestinal disorders and hypersensitivity. Potential risks associated with dabigatran treatment include: myocardial infarction, hepatotoxicity and pulmonary embolism. Further information on these issues will be available from ongoing trials and post- market monitoring.

A summary of the company-conducted interaction studies was also provided. No interactions between dabigatran etexilate and cytochrome p450 inhibitors or inducers were found. However there was the potential for an interaction between dabigatran etexilate with P-glycoprotein (P-gp) inhibitors or inducers. Dabigatran is not a substrate for P-glycoprotein therefore relevant interactions only take place in the GI tract. The results of these studies are outlined in the data sheet.

Information on treatment of overdose was reviewed; this information is included in the data sheet. It was noted that PHARMAC has issued additional advice on the management of bleeding with dabigatran.

The Committee was provided with a summary of completed, ongoing and proposed clinical studies considered to address the need for more information on the safety of dabigatran (pharmacovigilance plan) and the company's risk mitigation proposals.

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 Medsafe report.

The Committee discussed the excretion of dabigatran and questioned if there was evidence of active filtration or whether the process was entirely passive. The Committee recommended that Medsafe contact the product sponsor and request further information on this topic.

The Committee noted that there was a high level of discontinuation of dabigatran compared with warfarin in RE-LY. This was largely due to gastrointestinal side effects. The Committee noted that the data sheet should be updated to reflect that patients taking dabigatran have a higher risk of gastrointestinal bleeds than those on warfarin.

The Committee discussed the mechanisms whereby patients could be switched between different anti-coagulants. The Committee considered that switching between dabigatran and other anticoagulants should be considered by the company to be an additional potential safety issue for the Risk Management Plan.

The Committee discussed the relative efficacy of dabigatran in the RE-LY study and noted that the study was a non-inferiority study with wide margins.

It was noted that the bioavailability of the product is low and is affected by opening of the capsule.

The Committee noted that while there were no specific laboratory monitoring requirements for dabigatran, monitoring may an important aspect of the management of some dabigatran patients, particularly those at high risk of bleeding. Both aPTT and ecarin clotting time (ECT) were significant predictors of life-threatening bleeds, with ECT performing better overall. INR measurement was not useful and it is noted that data from the RE-LY study showed that the INR was not raised above 2 in patients taking dabigatran.

CARM provided an overview of the adverse reactions reports received to date. CARM advised that there were 117 reports for dabigatran in the database. CARM considered these fall into four groups: gastrointestinal symptoms (non-haemorrhagic), bleeding events, cardiovascular/respiratory terms, and inappropriate prescribing/ medication errors. The prescribing/ medication error reports largely involved patients incorrectly changed from warfarin to dabigatran or elderly patients not being given the recommended lower dose.

The Committee noted there was uncertainty about how patients who presented with major bleeds were to be treated. They recommended that Medsafe contact the sponsor and request information regarding how patients with major bleeds taking dabigatran were treated in clinical trials.

The Committee considered that the Risk Management Plan was generally satisfactory. Data from the latest Periodic Safety Update Report did not raise any new safety concerns. The Committee did not consider that there was a need for additional studies at present, but that Medsafe should review the results of ongoing studies when they became available.

The Committee considered that the data sheets should be updated to include information on the potential risk of myocardial infarction, increased risk of gastrointestinal bleeding compared to warfarin and use of the Ecarin Chromogenic test. In addition the Committee recommended that the data sheet be reviewed to determine whether the readability could be improved.

The MARC noted that Medsafe will continue to closely monitor dabigatran through spontaneous reports, the RMP, and PSURs. In the event that new safety issues are identified Medsafe will seek MARC advice as appropriate.

Recommendation 5

The Committee recommended that Medsafe contact the sponsor and request the following information:

Whether the renal clearance of dabigatran was purely due to filtration, or if there is evidence of an active transport mechanism.
The treatment of major bleeds in patients taking dabigatran in clinical trials.

Recommendation 6

The Committee recommended that the sponsor be requested to add an additional potential safety issue to the RMP - switching between dabigatran and other anticoagulants.

Recommendation 7

The Committee recommended that the data sheets be updated to include information on the potential risk of myocardial infarction, increased risk of gastrointestinal bleeding compared to warfarin and use of the Ecarin Chromogenic test. In addition the Committee recommended that the data sheet be reviewed to determine whether the readability could be improved.

3.2.5 Oral ketoconazole and hepatotoxicity

Background

In June 2011, the French medicines regulatory agency suspended the marketing of oral ketoconazole for the treatment of fungal infections. The suspension was stated to be due to the potential for hepatotoxicity with a higher frequency and severity compared with other antifungal agents. Following the actions taken in France, the MARC was asked to advise whether the known risk of hepatotoxicity associated with oral ketoconazole required any further regulatory action in New Zealand.

Nizoral is the only oral ketoconazole product approved in New Zealand and is funded by PHARMAC. Nizoral is indicated for systemic and deep mycoses, recalcitrant cases of superficial mycosis, and chronic recurrent vaginal candidosis.

The risk of hepatotoxicity with oral ketoconazole was first noted in the early 1980s and the risk was communicated to healthcare professionals in New Zealand in 2006.

In 2008, the UK medicines regulatory agency (MHRA) restricted the indications for oral ketoconazole to second-line treatment of superficial infections due to the risk of serious hepatotoxicity (including cases resulting in transplant or fatality), and the availability of other effective antifungal treatments. The MHRA also advised against using oral ketoconazole for longer than 10 days as the risk of hepatotoxicity increases with duration of use. The MHRA also recommended close monitoring of liver function with tests conducted before treatment, weeks two and four of treatment, and monthly thereafter if longer courses are necessary.

PHARMAC data suggest that approximately 700 patients receive oral ketoconazole each year in New Zealand. Local NZ data provided by the Centre for Adverse Reactions Monitoring (CARM) identified three reports of hepatic events associated with oral ketoconazole had been received in the past ten years.

The risk of hepatotoxicity is outlined in the NZ data sheet for Nizoral. However, Medsafe advised that many sections of the data sheet could be updated. Medsafe proposed changes to the data sheet to ensure it is up-to-date and consistent with international prescribing documents.

Discussion

The Committee noted the 2011 Medsafe report.

The Committee noted that the available literature supports previous conclusions that all anti-fungal agents are associated with a risk of hepatic injury, that this risk is very rare, and that the incidence associated with ketoconazole is higher than that associated with other anti-fungals

The MARC agreed that there does not appear to be any new or recent safety data or concerns which triggered the French regulatory action. The Committee considered that there is insufficient data to warrant any significant regulatory action at this time.

The Committee noted that the PHARMAC data suggests oral ketoconazole is not being used as a first-line anti-fungal agent, and agreed that it remains useful as a second-line anti-fungal agent, particularly in the treatment of pityriasis versicolor.

The Committee agreed that the NZ data sheet should be updated as suggested by Medsafe.

Recommendation 8

The MARC recommended that the NZ data sheet for Nizoral be updated.

3.2.6 Quetiapine and cardiomyopathy

Background

In November 2010, Medsafe reviewed a report of dilated cardiomyopathy in a young woman who had been taking paroxetine 60mg daily and quetiapine 100mg daily for an unknown duration of time. The patient developed SOB and was diagnosed with cardiomyopathy with an EF of 15% (which improved to 30% after treatment). According to the reporter, there was no evidence of an underlying cause for the cardiomyopathy including alcohol, viral infection, other drugs or diabetes. The reporter attributed the cardiomyopathy as being due to quetiapine use.

A review of the available literature at that time identified a previous New Zealand case report from 2008 of fatal cardiomyopathy attributed to quetiapine use. In addition, three cases of cardiomyopathy in patients receiving quetiapine were identified in the IMMP atypical antipsychotic cohort. It was noted that the current New Zealand data sheets did not include any information on cardiomyopathy.

To highlight the potential for quetiapine to cause cardiomyopathy, this combination was added to the M²(M-squared, Medicine's Monitoring) list. CARM received one further report of cardiomyopathy associated with quetiapine during the M² monitoring period. This case was subsequently published in the NZMJ.

Discussion

The Committee noted the 2011 Medsafe report.

The NZPhvC has received a total of seven reports of cardiomyopathy in patients taking quetiapine and two reports of myocarditis. Five of the seven reports of cardiomyopathy were assessed as at least possibly related to quetiapine use. However, the two reports of myocarditis with quetiapine were confounded by the concomitant use of clozapine.

The MARC noted that international medicines regulators have also received post-marketing reports of cardiomyopathy and myocarditis associated with quetiapine use.

An analysis of the WHO pharmacovigilance database shows that reporting of the combination of quetiapine and cardiomyopathy has become statistically prominent over time. There is also evidence for a signal for olanzapine and cardiomyopathy which raises the possibility of a class effect for the benzazepine derivative atypical antipsychotic medicines. The MARC also noted that both quetiapine and olanzapine are structurally related to clozapine which is known to cause cardiomyopathy and myocarditis.

The MARC considered that data from spontaneous reports and published case reports supports an association between quetiapine use and the development of cardiomyopathy. However, there is currently insufficient evidence to determine whether or not this association is causal. They recommended that cardiomyopathy and/or myocarditis be added to the adverse effects section of the quetiapine data sheet. They considered that it was important that this signal be communicated widely and recommended that the outcome of the M-squared review be communicated in Prescriber Update.

Recommendation 9

The MARC recommended that cardiomyopathy and/or myocarditis be added to the adverse effects section of the quetiapine data sheet.

Recommendation 10

The MARC recommended that the outcome of the M-squared review be communicated in Prescriber Update.

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.

Discussion

The MARC noted the Report of Fatal Cases assessed as causal.

They noted a case of tachycardia in association with cyclizine (95976). They noted that this is included as a warning in the cyclizine data sheet, however, a reminder would be timely. The Committee recommended that a reminder regarding the risk of tachycardia in association with cyclizine be included in the MARC round-up section of Prescriber Update.

Recommendation 11

The Committee recommended that a reminder regarding the risk of tachycardia in association with cyclizine be included in the MARC round-up section of Prescriber Update.

The Committee noted a case of intracranial haemorrhage in association with anticoagulants (95040). They agreed that there was a lack of integrated guidelines for the use of anticoagulants. The MARC recommended that a letter from the Committee be written to the Quality and Safety Commission, expressing their concern about the lack of integrated guidelines for the use of anticoagulants.

Recommendation 12

The MARC recommended that a letter from the Committee be written to the Quality and Safety Commission, expressing their concern about the lack of integrated guidelines for the use of anticoagulants.

The Committee noted the report of death associated with yellow fever vaccine. (95582). The patient had experienced a very rare, but known side effect.

The Committee noted a report of convulsions in association with norfloxacin (95036). The event was considered to have occurred because of a sudden arrhythmia due to an increase in QT prolongation leading to hypoxia and seizure. The Committee recommended that more information be obtained on this case.

Recommendation 13

The MARC recommended that more information be obtained on the case of convulsions in association with norfloxacin (95036).

4.1.3 Special Populations: Serious Cases Associated with Medicines in Children under 18 years (Causal Cases Only)

Reports of serous cases associated with medicines in children under 18 years were briefly outlined for the Committee. The Committee were given the opportunity to request further information on particular reports which may be discussed at a future meeting.