1.2 MINUTES OF THE 149TH MARC MEETING
1.3 DATES OF FUTURE MARC MEETINGS
1.4 POTENTIAL CONFLICTS OF INTEREST
1.5.1 Prescriber Update. Volume 33, Number 2. June 2012
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 Monoclonal antibodies and
progressive multifocal leukoencephalopathy
3.2.2 Haloperidol – dosing and administration
3.2.3 Review of statins and the risk of new-onset diabetes
mellitus
3.2.4 Is hypnotic use associated with an increased
risk of mortality?
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
3.2.1 Monoclonal antibodies and
progressive multifocal leukoencephalopathy
3.2.2 Haloperidol – dosing and administration
3.2.3 Review of statins and the risk of new onset diabetes
mellitus.
3.2.4 Is hypnotic use associated with an increased risk
of mortality?
Preface:
In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.
Names of individuals have also been deleted where that person's contribution is not in the public domain, or will not shortly be so. For example, the names of those to be approached to write an article are deleted, but the names of those who have contributed to a draft article are not usually deleted. In addition, names are not usually deleted when a contribution has been made in an official capacity.
The material listed as being considered on an issue is not intended to be exhaustive.
The recommendations of the Committee are in bold typeface.
Minutes:
marc members present
Associate Professor D Reith (Chair)
Dr L BryantDr N Cole
Associate Professor C Frampton
Associate Professor P Jones
Dr S Jayathissa
Associate Professor D Menkes
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)
R Jaine (Senior Medical Advisor)
S Kenyon (Senior Advisor, Pharmacovigilance)
R Pollock (Advisor, Pharmacovigilance)
A Taylor (Senior Advisor, Pharmacovigilance)
E Yousuf (Principal Clinical Advisor)
1. Matters of Administration
1.1 Welcome and Apologies
The Chair welcomed the attendees to the meeting. There were no apologies.
1.2 Minutes of the 149th MARC Meeting
The minutes of the 149th 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 13 September and 6 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 33, Number 2. June 2012
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
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 Monoclonal antibodies and progressive multifocal leukoencephalopathy
Background
Immunomodulatory medicines have recently emerged as a new class of drugs associated with the development of progressive multifocal leukoencephalopathy (PML). In particular, several monoclonal antibodies (mAbs) have recently been associated with PML prompting this review.
PML is a rare, but often fatal, demyelinating disease of the central nervous system resulting from infection by the JC virus. Approximately 50 % of the world's population is infected with the JC virus by the time they reach age 20. A major risk factor in the development of PML is a compromised immune system either due to underlying disease or immunosuppressive medications.
The 2012 Medsafe review included all currently PHARMAC funded mAbs, along with examples of different types of mAbs.
The Committee was asked to advise whether:
- there is a causal association between tumour necrosis factor (TNF) inhibitors and PML
- the information currently contained in the data sheets for the mAbs known to be associated with a risk of PML is adequate
- any regulatory action is recommended
- any communication is required.
Discussion
The Committee noted the 2012 Medsafe report.
The Committee considered each of the mAbs separately.
Natalizumab (Tysabri) was approved in New Zealand in 2007 and is indicated for relapsing remitting multiple sclerosis. It was one of the first mAbs to show an association with PML. Natalizumab is not widely used in NZ and is not funded.
The product sponsor has identified three known risk factors for PML in patients being treated with natalizumab. The risk of PML is greatest if the patient has all three known risk factors:
- prior treatment with an immunosuppressant medicine
- longer duration of treatment with Tysabri, especially beyond two years
- the presence of anti-JC virus antibodies.
The sponsor has a comprehensive risk management plan (RMP). As part of the RMP the sponsor is committed to ensure that updated information is regularly provided to prescribers. The New Zealand Tysabri data sheet includes a highlighted warning at the beginning of the information advising that Tysabri is associated with an increased risk of PML, along with extensive information about the risk of PML.
The Committee was reassured by the extent of the company's active monitoring and risk management plan. They considered that no regulatory activity is required with respect to natalizumab at the current time.
Rituximab (Mabthera) was approved for use in NZ in 1999 for cancer treatment and approved for rheumatoid arthritis (RA) in 2007.
The Committee noted that PML has been reported in RA patients who have not been treated with Mabthera, indicating that there is a background rate of PML in RA patients. The Committee noted that PML is included in the sponsor's RMP. The NZ data sheet contains warnings about PML for both cancer and RA approved indications. The Committee noted that the Australian data sheet has an additional general warning regarding PML that advises prescribers to monitor, consult and discontinue use if PML is suspected, which is not included in the NZ data sheet. The Committee recommended that the sponsor strengthened the NZ data sheet with the addition of this warning.
Basiliximab (Simulect) was approved for use in NZ in 1998 for prophylaxis of acute organ rejection in de novo renal transplantation. The Committee noted that there are no confirmed reports from the literature or a sponsor's review of PML in association with basiliximab. The Committee noted that product sponsor considers polyomavirus infection (including JC virus) a safety topic for close monitoring. The Committee agreed that no regulatory activity is required with respect to basiliximab at the current time.
Bevacizumab (Avastin) was approved for use in New Zealand in 2009 for cancer treatment. A review of the three cases of PML identified in association with bevacizumab found that one had underlying chronic myeloid leukaemia (CML) and one did not contain enough information for assessment. The final case appears likely to be PML; however, the case was confounded by the use of chemotherapy medications. The Committee agreed that there is currently insufficient evidence at this time to suggest that bevacizumab is associated with PML and no regulatory action is required at this time.
Trastuzumab (Herceptin) was approved for use in NZ for the treatment of breast cancer in 2009 and for advanced gastric cancer in 2010. The Committee noted that there are no reports from any source at this time of PML in association with trastuzumab and agreed that no regulatory action is required at this time.
A review of three mAb TNF inhibitors (infliximab, adalimumab, etanercept) was presented to the Committee.
Infliximab (Remicade) was approved for use in NZ in 2000 and although is not currently funded by PHARMAC in the Schedule, significant use occurs in District Health Board's hospital settings. Infliximab is currently approved for the treatment of RA, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, psoriasis and ulcerative colitis. A literature search revealed one case of PML in association with infliximab; however, this case was confounded by the concomitant use of immunosuppressants. The NZ data sheet has no mention of PML, in common with the Australia, United States or European product information. The data sheet does however contain a warning about increased infection and demyelinating disease and is included in the RMP.
The sponsor provided a review of PML cases reported with infliximab through to 31 December 2011. There have been five definite and four probable cases of PML with infliximab use identified; however, all cases of PML reported to be associated with infliximab treatment are confounded by either underlying disease or immunosuppressant use. The Committee noted that the reporting rate of PML in association with infliximab was similar to the reported incidence of PML in patients with rheumatic disease.
Adalimumab (Humira) was approved for use in NZ in 2004 and is currently funded for the treatment of RA, Crohn's disease, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis. There is one case report of a patient who was diagnosed with demyelinating leukoencephalopathy following treatment with adalimumab for RA. The patient was also being treated concomitantly with immunosuppressants. The
NZ Humira data sheet does not mention PML, but does mention serious infections and demyelinating disease. PML is not listed in the Australian, US, or European product information.
The sponsor provided a review of PML cases reported with adalimumab through to 31 December 2011. There were seven PML reports in the database, six medically confirmed reports and one consumer report. The Committee noted that the cases appear to be weakly associated with adalimumab therapy; however, there were a number of confounding factors in each case. The sponsor has included PML as an important possible risk in the RMP and is closely monitoring cases.
Etanercept (Enbrel) was approved for use in NZ in 2002 and is currently funded for the treatment of RA, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis. Two published articles of PML and etanercept were identified in a literature search; however, both cases were confounded with systemic lupus erythematosus (SLE), which is a known risk factor for PML.
The NZ Enbrel data sheet does not mention PML but does have a warning about serious infections and CNS disorders including demyelinating disease. There is also no mention of PML in the Australian, US or European product information.
There were five reports of PML following treatment with etanercept identified in the company's safety report and one from the latest periodic safety update review (PSUR). Of these cases, underlying disease confounded three cases (SLE and Wegener's disease). The remaining cases are all confounded by immunosuppressant medication. The Committee noted that as with infliximab, the reporting rate of PML in association with etanercept is similar to the reported incidence of PML in patients with rheumatic disease. PML has been included in the risk management plan and updates are provided in the annual Periodic Safety Update Reviews (PSURs).
The Committee was reassured that sufficient regulatory action has been taken regarding the TNF inhibitors and that they were being adequately monitored internationally. They considered that no regulatory action regarding the TNF inhibitors was required at this time.
The Committee noted that although PML is a very rare result of treatment with some mAbs, it has very serious consequences. They recommended that a Prescriber Update article be published to raise awareness of PML.
Recommendation 1
The MARC recommended that Medsafe requests the sponsor to strengthen the New Zealand Mabthera® data sheet by including the additional general warning regarding progressive multifocal leukoencephalopathy from the Australian data sheet.
Recommendation 2
The Committee recommended that a Prescriber Update article be published to raise awareness of progressive multifocal leukoencephalopathy.
3.2.2 Haloperidol - dosing and administration
Background
In March 2012, Medsafe became aware of some potential issues with the haloperidol data sheet: in particular, the use of intravenous (IV) haloperidol, the safety of IV haloperidol, and the recommended dosing levels.
In September 2007 the FDA issued an alert advising of an update to the labelling (data sheet) warnings for haloperidol. The updated warnings stated:
- Higher doses and intravenous administration of haloperidol appear to be associated with a higher risk of QT prolongation (QTP) and Torsades de Pointes (TdP).
- Although cases of sudden death, TdP and QT prolongation have been reported even in the absence of predisposing factors, particular caution is advised in treating patients using any formulation of haloperidol who:
- have other QT-prolonging conditions, including electrolyte imbalance (particularly hypokalaemia and hypomagnesaemia),
- have underlying cardiac abnormalities, hypothyroidism, or familial long QT syndrome, or
- are taking drugs known to prolong the QT interval.
- Because of this risk of TdP and QT prolongation, electrocardiogram (ECG) monitoring is recommended if haloperidol is given intravenously.
- Haloperidol is not approved for intravenous administration.
Haloperidol is currently available in NZ as Serenace® in tablet, oral liquid, and injection form. Haloperidol decanoate (Haldol®) is available in NZ as a depot intramuscular (IM) injection, and is not to be administered intravenously.
In NZ, Serenace® is currently approved for intravenous administration. The data sheet advises that higher doses and intravenous administration appear to be associated with a higher risk of QT prolongation and TdP, and recommends ECG monitoring when higher doses or parenteral administration are to be used. The recommended doses are 2 - 10 mg IM or IV, with a maximum daily dose of 100mg. The data sheet states that this treatment is not without risk and recommends appropriate precautions in patients with a history of conditions such as cardiovascular disorders. Haloperidol is contraindicated in patients with clinically significant cardiac disorders due to the potential to cause QT prolongation, and the data sheet recommends that it not be used concomitantly with other QT prolonging drugs. It is suggested that all patients have a baseline ECG, especially high risk patients and that ECG monitoring should be assessed on an individual basis. There is no information on use in patients with hypothyroidism in the data sheet, a specific caution in the FDA alert.
The Committee was asked to advise:
- Is the information in the current NZ Serenace® data sheet satisfactory,
in particular in relation to:
- The risk of QTP, TdP, and sudden death;
- Precautions for patients at increased risk of QTP and TdP;
- Intravenous administration; and,
- Dosing recommendations?
- If changes to the data sheet are required?
- Does Medsafe need to raise awareness of this issue or provide advice to prescribers?
Discussion
The Committee noted the 2012 Medsafe report.
The Committee noted that there are four reports in the Centre for Adverse Drug Monitoring (CARM) database in association with haloperidol which include the terms 'death', 'sudden death', 'QT prolonged', 'QT increased' and 'Torsades de Pointes'. IV use was not reported in any of the cases, and the highest dose was 20mg.
The Committee noted the published literature regarding the safety risks of IV use of haloperidol. The Committee noted that the evidence suggested that IV haloperidol is associated with QT prolongation and TdP, particularly with higher dose of haloperidol and in patients with risk factors for these conditions.
The Committee reviewed the evidence for an appropriate dosing regimen. They noted that studies reviewing an appropriate dosage regimen for haloperidol found that there was no effective lowest dose of haloperidol, and that IV doses as low as 0.25mg or 0.5mg could be clinically useful in certain cases. Studies also found no further efficacy but increased risk of adverse events for higher doses.
The Committee reviewed the current NZ data sheet for Serenace®. They noted that the dose for parenteral administration is 2 to 10mg IM or IV initially, with a maximum total daily dose of 100mg. For oral administration, the recommended dose is 1 to 15mg daily, which may be increased to 100mg, or occasionally even higher.
In relation to dosage and administration, the Therapeutics Goods Administration's (TGA) Serenace® Product Information sheet is identical to New Zealand's data sheet.
The US haloperidol prescribing information recommends oral doses between 1.5mg to 15mg daily. It states that doses up to 100mg daily may be necessary in some cases, and infrequently doses above 100mg may be necessary. Haloperidol is not approved for IV administration in the US.
The United Kingdom's Summary of Product Characteristics (SPC) recommends an oral daily dose of 1.5 to 15mg, and up to 30mg. Haloperidol injection is recommended for IM use only, with a dose range of 2 to 10mg initially, and up to a maximum of 18mg daily.
The Committee noted that compared with other international prescribing information, NZ has similar recommended oral dosing for haloperidol, however, IV administration is currently approved in NZ and Australia, but not in the US or the UK. They agreed that the evidence does not suggest that IV administration of haloperidol be contraindicated, but that certain precautions are taken regarding subpopulations, dose level, and monitoring of ECG and electrolytes.
The Committee considered that most of the issues identified in the 2007 FDA alert were adequately covered in the current NZ Serenace® data sheet. They noted that the list of predisposing risk factors for QT prolongation and Torsades de Pointes did not include hypothyroidism and recommended that the data sheet be updated to include this information.
The Committee agreed that evidence from the literature suggests that oral or IV doses greater than 10mg per day are unlikely to provide further efficacy, yet may lead to increased adverse events. They recommended that the NZ Serenace data sheet be harmonised with the UK SPC, and include information that doses above 10mg have not shown increased efficacy, but may be associated with adverse drug reactions. The Committee agreed that a maximum daily dose of 30mg was appropriate and this information be included in the data sheet.
Recommendation 3
The MARC recommended that the Serenace® data sheet be updated to include hypothyroidism as one of a number of predisposing risk factors for QT prolongation and Torsades de Pointes.
Recommendation 4
The MARC recommended that starting and maximum doses for haloperidol be reviewed and clearly outlined in the NZ Serenace® data sheet. They recommended that this information include a lower starting dose for both oral and IV administration, and a statement to indicate that daily doses above 10mg have not shown increased efficacy, but may be associated with adverse drug reactions. The Committee recommended a maximum daily dose of 30mg for both oral and IV administration.
Recommendation 5
The MARC recommended that a Prescriber Update article be published, regarding the appropriate use of haloperidol.
3.2.3 Review of statins and the risk of new-onset diabetes mellitus
Background
The purpose of the 2012 Medsafe report was to review the available data on the risk of new-onset type 2 diabetes mellitus (T2DM) in association with the use of HMG-CoA reductase inhibitors (statins).
In February 2012 the United States Food and Drug Administration (FDA) issued a Drug Safety Communication informing health professionals and patients of important safety label (data sheet) changes for statins to provide more information for safe and effective use. The FDA reported that based on clinical trial meta-analyses and epidemiological data from the published literature, there was sufficient information concerning an effect of statins on the development of incident diabetes and increases to glycated haemoglobin HbA1c and/or fasting plasma glucose, and for these potential risks to be added to statin labels.
The European Medicines Agency (EMA) has since also provided further information to health care professionals and patients about the increased risk of incident diabetes with the use of statins. The Committee for Human Medicinal Products for Human Use (CHMP) Pharmacovigilance Working Party determined statins may increase the risk of new onset T2DM in patients already at risk of developing the disease and that these patients need monitoring. However, they considered that the benefit: risk balance remains positive.
In view of this, Medsafe reviewed the available literature and international regulatory activity on this issue.
Statins are one of the most widely prescribed classes of medicinal products in New Zealand and around the world, with over 400,000 NZ patients receiving prescriptions for statins in 2011. The number of people diagnosed with diabetes in NZ exceeds 200,000, and is predominantly type 2 diabetes mellitus. There is an estimated 100,000 further people with diabetes who have not yet been diagnosed. In view of the potential risk and the number of patients possibly affected, the Committee was asked to advise whether:
- An association between the use of statins and the development of new-onset diabetes mellitus has been established.
- Any 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 2012 Medsafe report.
The Committee discussed the meta-analysis published in the Lancet by Sattar et al which prompted the FDA alert. The study found the patients taking statins were at a slightly increased risk of diabetes compared with those taking placebo. The authors concluded that there is an association of a small higher risk for the development of diabetes; however, the clinical significance of this is questionable. The authors considered that this risk is outweighed by the benefit of statins for the reduction of cardiovascular events in the short and medium term in individuals for whom statin therapy is recommended. The Committee noted that the JUPITER study, which found a positive association with rosuvastatin on the incidence of new-onset T2DM, provided a large percentage of the data in the Sattar study. The Committee agreed that this data may have weighted the results of the meta-analysis.
The Committee was provided with a review of other published meta-analyses on the risk of new-onset T2DM in association with statins. They considered that the meta-analyses have provided a range of results for the risk of new-onset T2DM with statin use, but only suggested a weak association at best. They considered that the meta-analyses had a number of limitations, including:
- lack of adjustment for risk factors or precursors of diabetes mellitus
- none of the trials assessing incidence of T2DM as a primary outcome
- differences in diagnosis of diabetes mellitus between trials
- some variation in baseline characteristics between trials
- adoption of healthier lifestyles
- survival bias
- publication bias
- other confounding factors such as other medications or presence of metabolic syndrome.
The Committee noted that the observational study by Culver et al was included as background for the FDA alert. This study investigated whether the incidence of new-onset T2DM is associated with statin use among postmenopausal women and found a statistically significant risk of new-onset T2DM associated with statins. The Committee queried how this study in a specific population related to the population as a whole.
The Committee noted that the FDA alert did not include further advice to health care professionals if they are concerned about the risk of the development of T2DM, or recommend any further monitoring for those considered at high risk.
The Committee noted the more specific advice provided by the European Medicines Agency (EMA) which specifies those who are more likely to be at risk, (fasting glucose 5.6 to 6.9 mmol/L, body mass index (BMI) greater than 30kg/m², raised triglycerides, hypertension) and recommends monitoring these patients both clinically and biologically according to national guidelines. Raised fasting blood glucose may be a sufficient marker on its own to identify those at risk. This advice is reinforced by the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom.
The Committee noted that the NZ data sheets for statins included varying amounts of information regarding T2DM as an adverse drug reaction. Rosuvastatin includes the most information, including the results from the JUPITER study. The data sheets for simvastatin and pravastatin include no information regarding T2DM as an adverse reaction. Atorvastatin lists both hyperglycaemia and hypoglycaemia as adverse reactions. The Committee agreed that more information would be helpful to aid prescribers and recommended that the advice provided by the EMA and MHRA be included in the NZ datasheets.
The Committee noted that the Centre for Adverse Drug Reactions (CARM) has received five reports of diabetes or hyperglycaemia related reactions associated with statins, two of these reports were associated with atorvastatin and three with simvastatin.
The Committee considered that while the association of statins with the development of T2DM appeared to be a signal, the benefit: risk ratio of the statins to reduce cardiovascular event rates remains positive.
Recommendation 6
The Committee recommended that the NZ data sheets for statins be updated to include the advice similar to that provided by the European Medicines Agency specifying those who are more likely to be at risk of Type 2 Diabetes Mellitus (fasting glucose 5.6 to 6.9 mmol/L, BMI >30kg/m², raised triglycerides, hypertension) and recommending monitoring these patients clinically.
Recommendation 7
The Committee recommended that the outcome of this review of statins in association with the development of Type 2 Diabetes Mellitus be communicated via a Prescriber Update article.
3.2.4 Is hypnotic use associated with an increased risk of mortality?
Background
The purpose of the 2012 Medsafe report was to review the available data on the risk of mortality associated with the use of hypnotic medicines.
On 28 February 2012, a paper by Kripke et al was published in the BMJ Open journal. The authors conducted a retrospective cohort study to investigate whether hypnotic use was associated with an increased risk of mortality. The authors concluded that receiving hypnotic prescriptions was associated with a greater than threefold increased hazard of death even when prescribed less than 18 pills per year. The authors indicated that selective prescription of hypnotics for patients in poor health did not explain the observed excess mortality.
The publication of this study stimulated substantial media interest both in New Zealand and internationally. In response, Medsafe released a preliminary media statement advising the following:
- Medsafe will be reviewing the results of this study and will consider whether the findings have any implications for the prescribing of these medicines in NZ
- Patients should not stop taking their medication, but should discuss any questions or concerns with their doctor or pharmacist.
- Hypnotics should only be used for short periods (i.e. 2 - 4 weeks) for the treatment of severe or disabling insomnia; continuous or long term use is not recommended.
In NZ, approved pharmacological treatments for insomnia include benzodiazepines, zopiclone and antihistamines. NZ guidelines issued by the Best Practice Advocacy Centre (BPAC) in 2008 recommend that non-pharmacological treatments should be used first, with pharmacological treatments only used when other approaches are ineffective. The guidelines recommend that only short-acting benzodiazepines or zopiclone be used. In addition, the following advice should be followed:
- Prescribe the lowest effective dose of a short acting hypnotic.
- Prescribe hypnotics intermittently and for short durations (less than four weeks but preferably no more than five to ten days).
- Avoid hypnotics or use with caution for patients with a history of substance abuse, myasthenia gravis, respiratory impairment or acute cerebrovascular accident.
- Review for side effects - in particular, daytime sleepiness.
- Before prescribing for older patients, give advice about the increased risk of use and enquire about difficulties with balance which may indicate an increased susceptibility to falls.
After reviewing the available data on this issue, the Committee was asked to advise whether:
- A causal association between the use of hypnotics and an increased risk of mortality has been demonstrated.
- Any regulatory action is recommended
- Any communication is necessary.
Discussion
The Committee noted the 2012 Medsafe report.
The Committee discussed the recent study by Kripke et al. They considered that the study design overcame many of the limitations associated with previous studies on this issue; however, significant limitations still remained.
In particular, the Committee considered that the lack of cause of death data prevented an assessment of a causal association between hypnotic use and death. It also prevented any recommendations being possible on how to miminise the potential risks associated with the use of these medicines.
The Committee noted that there was no information on psychiatric comorbidities or social stressors included in the Kripke study. The Committee noted that the CARM database includes 14 spontaneous reports of death associated with hypnotics. In the majority of the reports, the patients were also taking other psychotropic medication, suggesting that insomnia may have occurred as part of a psychiatric illness, secondary to medication used to treat the psychiatric illness or in some cases the benzodiazepine may have been prescribed to treat anxiety symptoms. The Committee agreed that the CARM data indicated that the majority of patients were also taking psychotropic medicines, indicating underlying comorbidities, which were not adjusted for in the Kripke study.
The Committee noted another limitation in that while the Kripke study identified prescriptions for hypnotics, the authors had no information on whether these prescriptions were filled, whether or not the patients actually took the medicine, or the indication for which the medicine being prescribed.
The Committee noted that the two groups were not well matched at baseline for the presence of comorbid conditions and that adjustment for these factors did not include adjustment for the severity of the underlying conditions. Also, smoking and alcohol history were obtained by self-report which introduced significant recall bias. In addition, there was no information on number of pack-years of smoking which would have allowed more accurate adjustment of smoking as a continuous variable. No information was available on how much alcohol was consumed or importantly whether or not the alcohol was consumed at the same time as the hypnotic.
The Committee noted that the hazard ratios reported in this study were much higher than those obtained in previous studies on this issue and this discrepancy was not well explained by the authors. They agreed that due to study limitations it was difficult to estimate the likely hazard associated with the use of these medicines.
The Committee also reviewed a summary of the published literature on the use of hypnotics and a potential mortality hazard since 2005. They agreed that although the majority of these studies found a positive association between hypnotic use and an increased risk of mortality, very few of the results concluded that this association was causal. They noted that the only study to provide cause of death information (Mallon et al, 2009) found a positive association for death due to cancer, coronary artery disease and suicide in men; and suicide only in women. A similar association has been demonstrated in studies of short sleep duration and mortality risk. The Committee considered that this highlighted the fact that the relationship between sleep disturbance and the development of medical and psychiatric conditions including death is highly complex and not well understood. They agreed that more studies were needed in order to determine the risk of mortality in association with both sleep disturbance generally and with the use of hypnotics.
The data sheets for the hypnotic medicines available in NZ confirm that hypnotics are associated with a number of serious adverse reactions (including reduced alertness, depression, suicidality, agitation and confusional states) that if not recognised and/or managed could contribute to an increased risk of mortality. The Committee was reassured that most data sheets clearly indicate that hypnotics should only be used on a short term basis and that periodic re-evaluation is required for any patients needing long-term therapy. They noted that this advice is consistent with that issued by BPAC in 2008. The Committee noted that there were some inconsistencies between the data sheets and recommended that the data sheets be updated to include consistent information regarding the risks associated with the use of hypnotics.
The Committee discussed a paper published in the New Zealand Medical Journal co-authored by one of the members. The paper discussed the decision made by PHARMAC in September 2010 to remove the previous one-month restriction on funded prescription of hypnotics and anxiolytics, and to replace it with a three-month reimbursement limit.
The Committee was concerned that the NZ usage of hypnotics was high and is escalating. They had an intensive discussion regarding the problems around the increasing use of these medicines and strategies to deal with this. They considered there was currently insufficient evidence to recommend regulatory action such as reclassification via the Misuse of Drugs Act 1975. The Committee considered that it would be timely to remind prescribers of the safety issues with the use of hypnotics and the relevant prescribing guidelines, and recommended that a Prescriber Update article be published.
The Committee concluded that there is sufficient evidence to indicate that the use of sleeping tablets is associated with an increased risk of mortality; however, the data are inadequate to determine the size of the risk or whether the association is causal.
Recommendation 8
The MARC recommended that the NZ data sheets for hypnotics be updated to include consistent information regarding the risks associated with the use of these medicines.
Recommendation 9
The MARC recommended that a Prescriber Update article be published regarding the safety issues associated with the use of hypnotics.
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.
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 were given the opportunity to request further information on particular reports which may be discussed at a future meeting.
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 were given the opportunity to request further information on particular reports which may be discussed at a future meeting.
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 had the opportunity to request further information on particular reports which may be discussed at a future meeting.
The Committee did not consider any of the reports required further action.
5. REFERENCES
3.2.1 Monoclonal antibodies and progressive multifocal leukoencephalopathy.
- FDA Information for Healthcare Professionals: Natalizumab Injection for Intravenous Use, August 2008.
- Genentech Dear Healthcare Professional letter: Important safety information regarding Rituxan. September 2008.
- FDA Public Health Advisory Updated Safety Information about Raptiva. February 2009. Wyeth. Personal communication. September 2010.
-
- Biogen Idec NZ Limited. 9 January 2012. Tysabri (natalizumab) data sheet.
- Roche Products (New Zealand) Ltd. 17 October 2011. Mabthera (rituximab) data sheet.
- Novartis New Zealand Limited. 7 July 2011. Simulect (basiliximab) data sheet.
- Roche Products (New Zealand) Limited. 9 November 2011. Avastin (bevacizumab) data sheet.
- Genzyme Australasia Pty Limited. 5 November 2011. Herceptin (trastuzumab) data sheet.
- Genzyme Australasia Pty Limited. 5 November 2007. MabCampath (alemtuzumab) data sheet.
- Janssen-Cilag (New Zealand) Limited. 6 July 2011. Remicade (infliximab) data sheet.
- Abbott Laboratories (New Zealand) Limited. 15 December 2011. Humira (adalimumab) data sheet.
- Pfizer New Zealand Limited. 17 January 2012. Enbrel (etanercept) data sheet.
3.2.2 Haloperidol - dosing and administration
- FDA. September 2007. Information for Healthcare Professionals: Haloperidol.
- Pharmacy Retailing (New Zealand) Limited. 20 May 2009. Serenace data sheet.
- New Zealand Pharmacovigilance Centre. 27 April 2012. Summary of CARM reports at 31 March 2012 - haloperidol.
3.2.3 Review of statins and the risk of new onset diabetes mellitus.
- New Zealand Pharmacovigilance Centre. March 2012.Reports of diabetes or hyperglycaemia in the CARM database searched 15 March 2012 associated with HMGCoA reductase inhibitors or ezetimibe.
- FDA. February 2012. Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs.
- EMA. January 2012. Pharmacovigilance Working Party Monthly report for meeting held 12 - 14 December 2011.
3.2.4 Is hypnotic use associated with an increased risk of mortality?
- Kripke DF, Langer RD and Kline LE. 2012. Hypnotics' association with mortality or cancer: a matched cohort study. BMJ Open;2:e000850 doi:10.1136/bmjopen-2012-000850.
- Supplementary data for the Kripke et al (2012) study.
- BPAC. 2008. Managing Insomnia. BPJ: 14.
The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2.55 pm.
Associate Professor D Reith Chair
Medicines Adverse Reactions Committee
