Revised: 20 May 2013
Committees
Minutes of the 153rd Medicines Adverse Reactions Committee Meeting - 14 March 2013
INVITED GUESTS AND EXPERTS IN ATTENDANCE
1.2 MINUTES OF THE 152nd MARC MEETING
1.3 DATES OF FUTURE MARC MEETINGS
1.4 POTENTIAL CONFLICTS OF INTEREST
1.5.1 Prescriber Update. Volume 34, Number 1. March 2013
2.1 REPORT ON STANDING AGENDA ITEMS FROM PREVIOUS MEETINGS OF THE MARC
3.1 MATTERS REFERRED TO THE MARC UNDER SECTION 36 OF THE MEDICINES ACT 1981
3.2 MATTERS REFERRED TO THE MARC BY MEDSAFE
3.2.1 Varenicline Tartrate (Champix)
- IMMP study report revised
3.2.2 Miacalcic (calcitonin) and risk of malignancy
3.2.3Serotonergic agents and the risk of reversible cerebral
vasoconstriction syndrome - M² monitoring review
3.2.4 Spiriva (tiotropium) 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
4.1.2 Fatal Cases (Causal Cases Only)
4.1.3 Special Populations: Serious Cases Associated with
Medicines in Children under 18 years (Causal Cases Only)
4.1.4 Special Populations: Serious Cases Reporting Adverse
Events Following Immunisation Terms with Vaccines in Children under 18 years
4.1.5 Special Populations: Serious Non-Fatal Cases Causally
Associated with Critical Terms in Patients Over 80 Years
Preface:
In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.
Names of individuals have also been deleted where that person's contribution is not in the public domain, or will not shortly be so. For example, the names of those to be approached to write an article are deleted, but the names of those who have contributed to a draft article are not usually deleted. In addition, names are not usually deleted when a contribution has been made in an official capacity.
The material listed as being considered on an issue is not intended to be exhaustive.
The recommendations of the Committee are in bold typeface.
MEDICINES ADVERSE REACTIONS COMMITTEE
14 March 2013
MEETING MINUTES
The one hundred and fifty-third meeting of the Medicines Adverse Reactions Committee (MARC) was held on 14 March 2013 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9.00 am and closed at 3.00 pm.
MARC members present
Associate Professor D Reith (Chair)
Dr L Bryant
Dr N Cole
Associate Professor C Frampton
Associate Professor P Jones
Associate Professor D Menkes
C Ryan
Dr S Sime
Dr M Tatley
Dr K Wallis
MARC Secretariat Present
J Carey (MARC Secretary, Medsafe)
MEDSAFE STAFF IN ATTENDANCE
C James (Manager, Clinical Risk Management)
A Taylor (Senior Advisor, Pharmacovigilance) attended part of the meeting.
Invited guests and experts IN ATTENDANCE
Dr R Savage
1. Matters of Administration
1.1 Welcome and Apologies
The Chair welcomed the attendees to the meeting. Apologies were received from Dr Sisira Jayathissa.
1.2 Minutes of the 152nd MARC Meeting
The minutes of the 152nd meeting were accepted as a true and accurate record of the meeting.
1.3 Dates of Future MARC Meetings
The dates for the remaining 2013 MARC meetings were scheduled for 13 June, 12 September, and 5 December.
1.4 Potential Conflicts of Interest
Committee members submitted their Conflicts 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.
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 34, Number 1. March 2013
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 on the Medsafe website: 151st MARC meeting 13 September 2012
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 Varenicline Tartrate (Champix) - IMMP study Report Revised
[…].
Background
Varenicline tartrate (Champix) was approved for use in New Zealand in March 2007 and placed on the Intensive Medicines Monitoring Programme (IMMP) in that same year.
The IMMP study report of the data collected for the first three years since varenicline monitoring was started in 2007 was submitted to Medsafe in June 2012. This report included a final analysis of the data collected since varenicline monitoring was started in 2007. The MARC reviewed this IMMP study report at the 151st meeting in September 2012. The MARC identified a number of issues that needed to be addressed before a robust assessment of the safety profile of varenicline in New Zealand could be made. The MARC recommended that the updated report be provided to Medsafe. The MARC recommended that:
- as they considered that the varenicline IMMP study report has a number of deficiencies and does not represent a 'final' report, they recommended that the IMMP be requested to provide further information
- data from the fourth year of the study and an analysis of these data be provided
- a re-analysis of the IMMP data be undertaken, removing events that occurred between one month and six months after stopping varenicline ('post-medicine' events).
- full case details be provided relating to the section of the report regarding psychiatric events
- the section of the report regarding suicide and suicidal ideation be reanalysed, taking into account the limitations of the data, confounding factors, and the nature of the population included in the study
- the results of the CAT study requested by the FDA be reviewed when they are published
- the lack of discussion in the IMMP report regarding the limitations of the data be addressed
- the lack of discussion in the IMMP report regarding possible confounding factors and comparison with other sources be addressed
- an overall summary of all events reported in the IMMP study, along with line listings of all cases be provided
- the IMMP report on varenicline be brought back to the MARC when sufficient information and clarification had been provided to enable a robust review of the conclusions stated by the IMMP and whether any regulatory action is required.
The purpose of the 2013 Medsafe report is for the MARC to review the revised IMMP study report for varenicline and determine whether any actions are necessary as a result.
Discussion
The Committee noted the 2013 Medsafe report, which reviewed the revised IMMP study report. The IMMP also provided a separate document containing updated safety tables separating adverse events into on-medicine and off-medicine. The Committee noted that Medsafe routinely reviews and assesses the Periodic Safety Update Reports (PSURs) for Champix and any completed safety studies, and the results of this review were incorporated in the March report.
The analysis presented in this final IMMP report included dispensing data from the first three or four years of the study. Patient questionnaire responses and adverse event analysis were presented for the first three years of the study. The report did not include patient questionnaire responses and adverse event information for patients who were dispensed the medicine in the fourth year of the study.
The Committee noted that the analysis of the follow-up data of the fourth year cohort as requested at the September 2012 MARC meeting was still on-going at the present time. The Committee considered that the fourth year data was likely to be informative and more likely to be applicable to the population as a whole, due to the different population receiving varenicline post-PHARMAC funding. The Committee noted that Medsafe had not yet received confirmation from IMMP that the fourth year data would be provided to Medsafe.
The Committee noted that patient age, sex and ethnicity was analysed for all patients dispensed varenicline during the first four year period of the IMMP study. Treatment duration analysis was performed on the first three years dispensing data only. The Committee noted that the dispensing analysis showed that the majority of patients in the first three years (88.2 %) were dispensed less than the recommended 12 week course of varenicline. A Prescriber Update article was published in September 2010 following an interim IMMP analysis, to remind prescribers that the varenicline data sheet advises a 12 week course and that failure to complete the course may have implications for the effectiveness of smoking cessation. No dispensing data was analysed for duration of varenicline treatment for the fourth year of the IMMP study. As the cost of treatment was the second most frequent reason for patients ceasing treatment, the Committee considered that it would have been informative to know if the treatment duration changed following funding of varenicline as more patients would likely to have continued treatment.
The Committee noted that past medical history was determined for the patients receiving varenicline. The IMMP questionnaire specifically enquired whether the patient had a medical history of psychiatric illness, convulsions/seizures, ischaemic heart disease or any other significant history. The Committee noted that over 1000 patients of those patients who responded listed some other unknown significant medical history.
The effectiveness of varenicline was determined for 4521 patients during the first three years of the study who had a valid questionnaire returned. Smoking cessation was successful in 28.7 % of patients, unsuccessful in 37.8 % of patients and unknown in the remaining 33.5 % of patients. However it was unknown at what stage this success rate was measured at. The Committee noted this is roughly in keeping with the continuous quit rate at one year that was demonstrated in clinical trials.
The Committee noted that the most common adverse event reported in the IMMP study was nausea. The Committee noted that of the top ten adverse events, paroniria (nightmare) was the only single event not included in the current New Zealand Champix data sheet. The Committee noted that 'abnormal dreams' is listed. However, the Committee considered that this was a separate event from nightmares, and recommended that nightmares be included in the adverse events sections of the Champix data sheet. .
The Committee noted that the most commonly reported psychiatric events were depression, insomnia, dreams, paroniria, fatigue, sleep disturbance, depression worse, anxiety, irritability, depersonalisation, mood swings, somnolence, malaise, suicidal ideation, concentration impaired, stress reaction and aggression.
The Committee noted that the data sheet includes comprehensive warnings regarding psychiatric events following post-market experience. The Committee recommended that the adverse reactions section of the Champix data sheet regarding psychiatric events be amended to make it more succinct and clearer. The Committee noted that this issue is currently being monitored in a large company trial comparing varenicline, bupropion, and nicotine replacement therapy in patients with and without psychiatric illness. These patients will also be monitored for cardiovascular events. This safety study is due to be completed in 2016/2017.
The Committee noted that there was one report in the IMMP cohort of suicide reported while the patient was taking varenicline. However, this report had limited information. The Committee did not consider that this report provided evidence that varenicline was responsible for this patient's suicide. The Committee noted that the New Zealand Champix data sheet contains a precaution regarding psychiatric symptoms, including information about the need to monitor patients for neuropsychiatric symptoms and that the patient should stop taking varenicline and contact a healthcare professional immediately the patient develops suicidal ideation or suicidal behaviour. The Committee agreed that no further action is required at this time.
The IMMP study suggested that memory impairment is a new signal for varenicline. The Committee noted that memory impairment was difficult to accurately assess and there were other confounding factors, such as the anxiety, associated with smoking cessation. 'Difficulty concentrating' is listed in the New Zealand Champix data sheet as an expected event following smoking cessation. The Committee noted that this potential safety topic has already been identified by the sponsors who currently review this concern in their PSUR. In the most recent PSUR, the sponsor noted no new safety concerns. The Committee agreed that this was a possible signal but that there was not enough evidence to support an association at this time.
The data presented in the final IMMP report includes all adverse events in the circulatory group identified in patients in the first three years of the study. The profile of adverse events in this report is similar to that presented to the Committee in September 2011.
Following a request from the FDA, the company performed a meta-analysis of varenicline randomized, blinded, controlled clinical trials with treatment duration of 12 weeks or longer to evaluate cardiovascular safety of varenicline. The company intends to mention the nature of the findings from this cardiovascular meta-analysis in the varenicline New Zealand data sheet. The Committee noted the sponsor is currently conducting a study designed to have major cardiovascular events as a primary outcome. The Committee requested that Medsafe review the results of this study when they are published.
The IMMP reviewed all reports of new-onset hyperglycaemia, impaired glucose tolerance, diabetes mellitus, non-insulin-dependent diabetes mellitus and worsening diabetes mellitus in the cohort. The cohort reviewed in this instance is the first three years of the IMMP study and some cases from the final year. All events occurring whilst taking varenicline and within one month of the last dose and events occurring between one and six months after the last dose of varenicline were included. The majority of the cases had confounding factors or insufficient information. The New Zealand data sheet currently contains information about the physiological changes resulting from smoking cessation including a precaution that dose adjustments of insulin may be required during smoking cessation. The Committee noted some of the reports of altered glycaemic control were in patients that were not taking insulin. The Committee note that smoking cessation, with or without varenicline treatment, can cause changes in appetite, weight gain which could cause changes in glycaemic control. The Committee recommend that mention of this be included in the data sheet.
The IMMP study undertook a review of all reports coded and entered into the eye group during the first three years of the study. There were six of these were for blurred vision and two for abnormal vision. The Committee noted that many of these five cases were confounded by concurrent illness, medical history or concomitant medications. The Committee noted that a review of vision disorders was included in the company's last PSUR and no new safety concerns were identified.
In the first three years of the IMMP study, there were 10 adverse events in the haematological group that occurred whilst the patient was taking varenicline. The most frequent of these were bleeding (three events) and epistaxis (two events). The NZ Champix data sheet includes a warning that dose adjustments of warfarin may be required during smoking cessation, and mentions that there has been post-marketing reports of haemorrhagic events in patients taking Champix. The Committee agreed that no changes to the New Zealand Champix data sheet are required at this time.
The IMMP reviewed all reports in the first three years of the study that included events coded in the skin group. The most common adverse events whilst the patient was taking varenicline were rash, pruritus and urticaria. There were five severe cutaneous events considered to be at least possibly related to varenicline treatment. The Committee noted that the NZ Champix data sheet has a section regarding hypersensitivity reactions including skin reactions, which may be severe. The Committee agreed that no new information had been identified in the final IMMP report and considered that no regulatory action was required at this time.
The utilisation and safety of varenicline in pregnancy was investigated by the IMMP during the monitoring programme. The varenicline data sheet states that the safety of varenicline in human pregnancy has not been established and that such use is not recommended. The Committee noted that the sponsor is conducting a prospective population-based cohort study to examine whether varenicline use during pregnancy is associated with an increased risk ofmajor congenital malformations in infants above that associated with smoking during pregnancy.
The Committee noted that the sponsor is current conducting four varenicline safety studies. The data from the sponsor's safety studies will be reviewed by Medsafe and taken to the Committee if any new safety issues are identified. The Committee considered that there is insufficient data and evidence provided in the IMMP report to warrant any further regulatory action. The Committee agreed that based on the data provided in the IMMP report, the benefit-risk of varenicline remains positive.
Recommendation 1
The Committee recommended that nightmares be included in the adverse events sections of the Champix data sheet.
Recommendation 2
The Committee recommended that the adverse reactions section of the Champix data sheet regarding psychiatric events be amended to make it more succinct and clearer.
Recommendation 3
The Committee recommended that the data sheet be updated to include a paragraph that smoking cessation, with or without pharmacotherapy, has been associated with change in appetite, weight gain and altered glycaemic control.
3.2.2 Miacalcic (calcitonin) and risk of malignancy
Background
In July 2012 the European Medicines Agency (EMA) completed a review of the benefits and risks of calcitonin containing medicines, concluding that there was evidence of a small increased risk of cancer with long-term use. The Agency's Committee for Medicinal Products for Human Use (CHMP) recommended that they should only be authorised for short-term use in Paget's disease, acute bone loss due to sudden immobilisation and hypercalcaemia caused by cancer. The Committee also concluded that the benefits of calcitonin-containing medicines did not outweigh their risks in the treatment of osteoporosis and that they should no longer be used for this condition. As the nasal spray is only indicated for treatment of osteoporosis, the CHMP recommended that this formulation should no longer be used.
Miacalcic (calcitonin) injection was first approved for use in New Zealand in 1976, and the approved indications are different to those in Europe. The nasal spray is no longer available.
The Committee was asked to advise whether:
- The available evidence supports an association between Miacalcic and cancer risk.
- The potential association between Miacalcic and cancer affect the balance of benefits and risks for the approved indications.
- Any regulatory action is required to improve the benefit risk profile.
- Any communication about this safety concern is warranted.
Discussion
The Committee noted the 2013 Medsafe report.
In New Zealand Miacalcic is currently indicated for bone pain associated with osteolysis and/or osteopenia, Paget's disease of the bone, hypercalcaemia and hypercalcaemic crisis, neurodystrophic disorders (algodystrophy or Sudeck's disease), and adjuvant therapy of acute pancreatitis.
In Europe the licensed indications are prevention of acute bone loss due to sudden immobilisation such as in patients with recent osteoporotic fractures, Paget's Disease, and hypercalcaemia of malignancy.
The Committee noted that an estimated 35 patients in New Zealand are receiving Miacalcic.
The Committee reviewed the study data provided in the report.
The Committee noted that numbers included in the trials are small when considering a rare risk such as cancer. The Committee considered that the relatively short follow-up period of between one and three years was insufficient to determine an effect on malignancy, and the appearance of cancers within six months of starting treatment is unlikely to be due to treatment. The Committee considered that, whilst there is a signal of a safety concern, the effect was likely to be small. They agreed that the information provided is insufficient to be able to confirm or refute an association at this time. They discussed the difficulties in making generalisations about an association between treatments and the development of cancers given the varying biology of the various types of malignancy.
The Committee discussed the benefits compared to the potential risk for each of the current indications included in the New Zealand Miacalcic data sheet.
The Committee noted that the indication for the treatment of bone pain associated with osteolysis and/or osteopenia is approved in over 40 countries. The Committee agreed that the available evidence supports the use of calcitonin for bone pain in patients with recent vertebral fractures and total hip replacement. They noted that calcitonin does not appear to be helpful for bone pain secondary to bone metastases and there is some evidence to support a more restricted indication for the use of calcitonin in bone pain. The expected treatment duration of up to four weeks would be expected to be associated with minimal risk of malignancy, therefore the balance of benefits and risks was considered to be positive. The Committee recommended that the data sheet be updated to better reflect the efficacy evidence.
The Committee agreed that there is adequate evidence of efficacy for the treatment of Paget's disease. They noted that more recent studies indicate that bisphosphonates are more effective and should therefore be first choice. . Given the seriousness of Paget's disease the relegation of Miacalcic to second line therapy for patients intolerant or unable to take bisphosphonates would appear to make the balance of benefits and risks favourable, despite the longer treatment period. The Committee recommended that Miacalcic should be made second line in the treatment of Paget's disease in line with the company's proposal.
The Committee discussed the indication of hypercalcaemia and hypercalcaemic crisis. They noted that the evidence of efficacy in this indication is provided primarily through established use of calcitonin in clinical practice, and that a similar indication has been retained in Europe. The Committee considered that the balance of benefits and risks remains favourable and recommended that Medsafe request that the sponsor make their proposed data sheet changes.
The Committee discussed the use of Miacalcic in the treatment of algodystrophy (Sudeck's disease) and agreed that the efficacy data appears to be weak. They noted that bisphosphonates are considered to be more effective for this indication and recommended that information be included in the data sheet making Miacalcic a second line treatment. Given the short duration of treatment of up to eight weeks, they considered that malignancy would not appear to be a risk. The Committee recommended stating a maximum treatment duration in the data sheet to minimise any risk of malignancy associated with long-term use.
The Committee discussed the use of Miacalcic as an adjuvant treatment for acute pancreatitis. there was some evidence that it can be used as a non-opioid analgesic for the pain relief in patients with mild to moderate acute pancreatitis. Importantly, due to the typically short duration of treatment (5 - 7 days), a potential safety risk with regard to malignancies is not to be expected. The Committee agreed that the balance of benefits and risks remains favourable in this indication.
The Committee noted the summary of the reports made to CARM regarding Miacalcic. They noted agreed that there was no evidence of a safety concern of malignancy in patients exposed to Miacalcic in New Zealand. The MARC agreed that the available evidence is insufficient to confirm a causal association between Miacalcic exposure and malignancy. They agreed that the potential association between Miacalcic and cancer did affect the balance of benefits and risks for some of the approved indications, and agreed that the data sheet changes detailed above outlined any potential malignancy risks as a precaution. The Committee agreed that no specific communication about this safety signal is warranted at this time.
Recommendation 4
The MARC recommended that the indication for the use of Miacalcic in the treatment of bone pain associated with bone pain secondary to bone metastases be restricted, and a maximum treatment of up to four weeks for this condition be included in the data sheet.
Recommendation 5
The MARC recommended that Miacalcic should be made second line in the treatment of Paget's disease and agreed with the company's proposed changes.
Recommendation 5
The MARC recommended that the possibility of long-term treatment of hypercalcaemia and hypercalcaemic crisis be removed from the Maicalcic data sheet.
Recommendation 6
The MARC recommended stating a maximum duration for the treatment of algodystrophy in the Miacalcic data sheet.
3.2.3 Serotonergic agents and the risk of reversible cerebral vasoconstriction syndrome - M² monitoring review
Background
The purpose of the Medsafe report was to review the evidence for an association between serotonin reuptake inhibitors or triptans and the development of recurrent thunderclap headache (TCH) or reversible cerebral vasoconstriction syndrome (RCVS).
The report included an analysis of spontaneous reports received during the monitoring period (1 June 2012 - 1 December 2012), and a review of recently published literature.
The MARC previously reviewed the risk of RCVS associated with the use
of serotonergic agents (SSRIs and/or triptans) in March 2012. The Committee
concluded that the available evidence was insufficient to confirm a causal
association between the use of triptans or SSRI antidepressants and the
development of RCVS. They considered that raising awareness of the condition,
including a possible association with serotonergic agents, amongst New Zealand
health professionals would be beneficial, and recommended that SSRIs/triptans
and RCVS or thunderclap headache (TCH) be placed on the
monitoring scheme, and a Prescriber Update article published.
The
monitoring period was completed on 31 December 2012. A Prescriber Update
article "Reversible Cerebral Vasoconstriction Syndrome - Medicine Induced?"
was published in the June 2012 edition.
The Committee was asked to advise whether:
- There is sufficient evidence to request sponsors list thunderclap
headache and/or reversible cerebral vasoconstriction syndrome in the
adverse effects section of:
- All SSRI data sheets; or only the duloxetine, citalopram, fluoxetine and paroxetine data sheets
- All triptan data sheets or only specific triptan data sheets
- Any further communication with prescribers is necessary.
Discussion
The Committee noted the 2013 Medsafe report. They noted that cerebral vasospasm including RCVS is included in the adverse effects section of the sertraline data sheet, but is not listed in any other SSRI/SNRI or triptan data sheets.
The Committee noted that since the last MARC review, no clinical studies have been published. However, there had been two paediatric case reports published. One report was of a 13-year-old boy who had received sumatriptan, and the other of a 19-month-old girl who had received oxymetazoline in association with phenylephrine-containing mydriatics, diphenhydramine and salbutamol. The MARC noted that there had been further review articles and/or expert opinion articles published but no new data was presented in these articles.
The review identified three reports of severe or thunderclap headache during the six-month monitoring period. Two reports were in patients who had received SSRI treatment and one report was associated with triptan therapy. The MARC considered that the report associated with rizatriptan therapy, and the paediatric literature report that was reviewed, are both consistent with previous reports of RCVS associated with triptan therapy - notably the initial headache occurred prior to triptan therapy but a worsening (or completely different) headache occurred after triptan therapy. The MARC agreed that these cases raise the possibility that triptan therapy is aggravating an underlying vasoconstriction (possibly due to the migraine itself) rather than precipitating the whole process on their own.
The MARC noted that none of the cases reported to CARM fulfilled the criteria for RCVS, particularly because cerebral angiograms were not performed (or reported) in any of the cases.
The MARC noted that the majority of data on this issue has come from uncontrolled observational studies and individual case reports. The Committee agreed that as awareness of the condition increases, the possibility of controlled studies also increases and more information is likely to become available.
The Committee agreed that the available data is insufficient to confirm a causal association at this time but continues to support a signal of thunderclap headache and RCVS in association with serotonergic agents. The MARC discussed the possible biological plausibility of this association , and considered that it is likely to be a class effect.
The MARC agreed that the Prescriber Update article and monitoring had been successful in raising awareness of RCVS and a possible association with serotonergic agents amongst New Zealand health professionals.
The MARC recommended that thunderclap headaches and/or RCVS be added to the adverse effects section of all SSRI and triptan data sheets.
Recommendation 7
The MARC recommended that thunderclap headaches and/or RCVS be added to the adverse effects - post-marketing experience section of all SSRI and triptan data sheets.
3.2.4 Spiriva (tiotropium) update
Background
The purpose of the Medsafe report was to provide the Committee with an update regarding concerns about mortality and cardiovascular adverse events with tiotropium (Spiriva). It was prompted by the publication of a further two editorials in the BMJ and Thorax, calling for the withdrawal of Spiriva Respimat inhaler. The MARC last reviewed Spiriva in 2011 following 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 inhaler. From this review the company was asked to provide Medsafe with data on the pharmacokinetics of tiotropium in patients with renal impairment and on the risk of mortality in patients with renal impairment. This data showed that there was no discernible difference in pharmacokinetic parameters in patients with renal impairment. The mortality data provided did not raise any safety concerns regarding the use of tiotropium in patients with renal impairment.
The Committee was asked:
- Has the benefit/risk profile of Spiriva changed since the last report?
- Is any further action warranted as a result of this update?
Discussion
The Committee noted the 2013 Medsafe report.
The Committee noted the recent literature published since the previous MARC review.
The editorial by Beasley et al was published in the BMJ in November 2012. It provided a brief summary of some of the literature of tiotropium Respimat mist inhaler, the majority of which has been previously reviewed by the MARC, along with some more recent articles. The authors called for the immediate worldwide withdrawal of the tiotropium Respimat mist inhaler based on their belief of strong "evidence of increased mortality from cardiovascular disease and all cause mortality with the tiotropium Respimat mist inhaler".
The editorial written by Jenkins and Beasley, was published in Thorax in January 2013. As with the other editorial, there is a brief summary of the research so far which includes articles already discussed as well as more recent research. Both editorials were based to a large degree on the 2011 meta-analysis by Singh et al.
The Committee noted the 2012 Cochrane review which evaluated data from randomised controlled trials (RCTs) comparing the efficacy of tiotropium and placebo in patients with COPD, upon clinically important endpoints. The review included 19 studies evaluating 18mcg tiotropium once daily via Handihaler, and 3 studies evaluating 5 or 10 μg tiotropium once daily via Respimat. There was no significant difference in overall mortality found between tiotropium and placebo groups. However, there were differences between studies using the dry powder inhaler (i.e. Handihaler) and those using the soft mist inhaler (i.e. Respimat): with the dry powder inhaler there were fewer deaths in the tiotropium group than in the placebo group but with the soft mist inhaler there were significantly more deaths in the tiotropium group than in the placebo group. The Committee noted that in New Zealand only a 5 μg daily dose is approved, and that this review provided no analysis comparing the 5 μg and 10 μg doses of the soft mist inhaler.
The Committee noted the 2012 meta-analysis by Dong et al. This meta-analysis aimed to compare the risk of overall and cardiovascular death for inhaled medications in patients with COPD. The study identified 42 trials using a range of medications (including tiotropium via both Handihaler and Respimat), of which three evaluated Respimat. One of the main findings of the study was tiotropium Soft Mist Inhaler was associated with a universally increased risk of overall death compared with placebo, tiotropium Handihaler, long-acting beta-agonist (LABA), and LABA-inhaled corticosteroid combination. This meta-analysis found very similar results to both the Cochrane review and 2011 Singh et al meta-analyses. It was noted that all the recent meta-analyses included the same trials that were included in the 2011 Singh et al meta-analysis.
The Committee noted the information provided by the sponsor Boehringer Ingelheim. Their analysis of the data from Singh et al, restricted to the approved 5 μg dose, found a non-statistically significant increase in death for tiotropium Respimat compared to placebo. This information is included in the current Spiriva data sheet.
The Committee reviewed data provided by the sponsor on a pharmacokinetic/pharmacodynamic study comparing tiotropium Respimat 5 μg with Handihaler 18 μg. The Committee considered that further review of this study may help to determine the extent of inter-individual variability and recommended that Medsafe request a copy of Boehringer Ingelheim's pharmacokinetic study report.
The Committee noted that the sponsor is undertaking a large trial (TioSpir), designed to address the mortality imbalance between tiotropium Respimat and Handihaler. It began in 2009 and results are expected in 2014.The Committee noted that tiotropium Respimat remains approved but not marketed in New Zealand. The sponsor has advised Medsafe that it is unlikely to be marketed prior to the results of the TioSpir trial, and the Committee supported this decision. The Committee agreed to await the results of the TioSpir trial before considering potential regulatory action.
The Committee agreed that cardiovascular issues with the Respimat mist inhaler may be a signal, however, disagreed that the signal was as convincing as stated in the editorials. They agreed that limited data was available, and there were some unusual inconsistencies.
The Committee agreed that the benefit:risk profile of Spiriva has not changed since the last MARC review, and that no regulatory action is required at this time.
Recommendation 8
The MARC recommended that Medsafe request a copy of Boehringer Ingelheim's pharmacokinetic study report.
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 did not consider any of the reports required further action.
4.1.3 Special Populations: Serious Cases Associated with Medicines in Children under 18 years (Causal Cases Only)
Reports of serious cases associated with medicines in children under 18 years were briefly outlined for the Committee.
The Committee did not consider any of the reports required further action.
4.1.4 Special Populations: Serious Cases Reporting Adverse Events Following Immunisation Terms with Vaccines in Children under 18 years
Reports of events occurring in children under 18 years were briefly outlined for the Committee.
The Committee did not consider any of the reports required further action.
4.1.5 Special Populations: Serious Non-Fatal Cases Causally Associated with Critical Terms in Patients Over 80 Years
Reports of events occurring in patients over 80 years were briefly outlined for the Committee.
The Committee did not consider any of the reports required further action.
4.1.6 Special Reports
The Committee requested further information on report 101850.
5 ANNEXES
3.2.1 Varenicline Tartrate (Champix) - IMMP study Report Revised
- Varenicline tartrate IMMP revised report — January 2013 version
- Varenicline tartrate IMMP new Annex 3: List of events for varenicline patients in the first three years of the IMMP study
- Varenicline tartrate IMMP new Annex 4: List of reports for varenicline patients in the first three years of the IMMP study
- Varenicline tartrate IMMP new Annex 5: List of events for varenicline patients in the first three years of the IMMP study identified from patient NHI records
- Varenicline tartrate IMMP new Annex 6: Expanded tables to separate on-medicine and off-medicine events
- Varenicline tartrate IMMP revised Annex 4: At the time of writing not yet received
- Pfizer New Zealand Ltd. 2012. Champix data sheet. 4 May 2012
- WHO-UMC Causality Categories
- A phase 4 12-week, double-blind, placebo-controlled, multicentre study evaluating the safety and efficacy of varenicline tartrate (CP-526,555) 1 mg BID for smoking cessation in subject with depression
- Tan M, Harrison-Woolrych M. 2012. Memory impairment associated with varenicline: A case series from the New Zealand Intensive Medicines Monitoring Programme. European Journal of Clinical Pharmacology
- Cardiovascular safety of varenicline: meta-analysis of varenicline randomized, blinded, controlled clinical trials with treatment duration of 12 weeks or longer
- Summary of the Risk Management Plan for varenicline
- Summary of varenicline safety studies
3.2.2 Miacalcic (calcitonin) and risk of malignancy
- Reactions reported to CARM- calcitonin report
- Novartis New Zealand Limited. 18 October 2011. Miacalcic (salmon calcitonin) data sheet.
- Knopp-Sihota et al. 2012. Calcitonin for treating acute and chronic pain of recent and remote osteoporotic vertebral compression fractures: a systemic review and meta-analysis. Osteoporosis Int. 23:17-38.
- Reid I. 2012. Pharmacotherapy of Paget's disease of bone. Pharmacother. 13(5)
- Tran et al. 2010. Treatment of complex regional pain syndrome: a review of the evidence. Can J Anesth.57: 149-166
3.2.3. Serotonergic agents and the risk of reversible cerebral vasoconstriction syndrome - M² monitoring review
- Excerpt from the Minutes of the 149th MARC meeting. March 2012
- Prescriber Update article: Reversible Cerebral Vasoconstriction Syndrome - Medicine Induced?
- Medsafe report. Serotonergic agents and the risk of reversible cerebral vasoconstriction syndrome. March 2012
- Ducros A (2012). Reversible cerebral vasoconstriction syndrome. Lancet Neurology (11): 906-917.
- Review and Analysis of
monitoring of SRIs and triptans and TCH or RCVS.
3.2.4 Spiriva (tiotropium) update
- Mortality associated with use of tiotropium (Spiriva) - MARC report, September 2011
- Beasley et al editorial - BMJ, 2012
- Rapid responses to Beasley et al editorial - BMJ, 2012
- Jenkins and Beasley editorial - Thorax, 2013
- Correspondence in response to Jenkins and Beasley editorial - Thorax 2013
- Karner et al - Cochrane Database of Systematic Reviews, 2012
- Dong et al - Thorax, 2012
- Verhamme et al - European Respiratory Society Annual Scientific Meeting, 2012
The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 3.00 pm.
Associate Professor D Reith Chair
Medicines Adverse Reactions Committee
