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Published: 2 August 2016
The one hundred and sixty-sixth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 29 June 2016 at Te Papa, 55 Cable Street, Wellington, New Zealand. The meeting commenced at 9.15am and closed at 4pm.
MARC MEMBERS PRESENT
Associate Professor D Reith (Chair)
Dr L Bryant
Professor C Frampton
Dr K Eggleton
Dr S Jayathissa
I Raiman
J Tatler
Dr M Tatley
Dr P Jones
Dr K Wallis attended via video conference
MARC SECRETARIAT PRESENT
J Prankerd (Advisor, Pharmacovigilance)
MEDSAFE STAFF IN ATTENDANCE
R Pollock (Acting Manager, Clinical Risk Management)
S Kenyon (Principal Technical Specialist, Pharmacovigilance)
R Perry (Advisor, Pharmacovigilance)
G Hill (Senior Medical Advisor, Pharmacovigilance)
L Chan (Advisor, Pharmacovigilance)
INVITED GUESTS AND EXPERTS IN ATTENDANCE
Dr R Savage (Senior Medical Assessor, Centre for Adverse Reactions
Monitoring)
The Chair welcomed the attendees to the meeting. Apologies were received from Associate Professor D Menkes, C Ryan and Dr N Cole.
The minutes of the 165th meeting were accepted as a true and accurate record of the meeting.
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.
Professor C Frampton declared that he provides statistical consulting to AFT Pharmaceuticals who are sponsors of some loratadine-containing medicines. The Committee agreed that Professor Frampton should have no participation or voting for agenda item 3.2.1 and should not be present for the discussion.
There were no other potential conflicts of interest which were considered likely to influence the discussions or decisions of the MARC at this meeting.
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:
www.medsafe.govt.nz/profs/MARC/Minutes.asp
At the 165th meeting held on 10 March 2016, the Committee recommended that Medsafe investigates this further and based on the results of the investigation considers an article around the use of quetiapine in New Zealand in a future edition of Prescriber Update.
This issue is ongoing.
The Committee discussed the additional information obtained by Medsafe. The Committee considered further information such as prescribing data should be reported back at a future meeting.
The Committee recommended this issue be reported back to the Committee at a future meeting.
There were no other standing agenda items for which the MARC made further recommendations.
The Committee noted the report detailing Medsafe’s recent pharmacovigilance activities.
[Dr K Eggleton joined the meeting at this time.]
The Committee noted the results of the Prescriber Update survey.
The Committee noted the latest edition of Prescriber Update.
The Committee noted the quarterly summary of Medsafe early warning system communications.
No items
A query was received by Medsafe regarding the age in which sedating antihistamines are contraindicated. There appears to be some misunderstanding around this. The age at which sedating antihistamines are contraindicated is also dependent on other factors such as the indication. A previous review contraindicated the use of sedating antihistamines in children under six years of age when in medicines indicated for the relief of cough and cold symptoms.
The purpose of the report is to provide a summary of the available information on the indications, contraindications and classifications of sedating antihistamines and to determine whether any action regarding the consistency and clarity of current information is required.
The Committee discussed the information presented to them. The Committee noted there is a treatment need for these medicines in children. The Committee also discussed the classification of these medicines.
The Committee discussed the data and noted it is old data and relates to different ages and indications. The Committee considered the data indicates that restricting use by age and/or indication is justified.
The Committee recommended that all sedating antihistamines should be contraindicated in children under 2 years of age.
The Committee recommended that the use of sedating antihistamines for the treatment of cough and colds should remain contraindicated in children under 6 years of age.
The Committee recommended that the use of sedating antihistamines for the treatment of insomnia should be contraindicated in children under 12 years of age.
With regards to the nausea and vomiting and travel sickness indications, the Committee recommended that the Medicines Classification Committee be asked to consider reclassifying sedating antihistamines to prescription medicines when used in children under 6 years of age for these indications.
The Committee recommended that the Label Statements Database be updated to remove ‘anxiety’ as a condition for labelling requirements.
The Committee noted that the Label Statements Database should be updated to reflect all changes.
The Committee additionally recommended that an article should be published in a future edition of Prescriber Update to advise of any changes relating to the use of sedating antihistamines.
The Committee recommended that Medsafe updates the Label Statements Database to contraindicate the use of sedating antihistamines in children under 2 years for all indications and in children under 12 years for the treatment of insomnia. The contraindication in children under 6 years of age for the treatment of cough and colds is to remain.
The Committee recommended the Medicines Classification Committee consider reclassifying sedating antihistamines to prescription medicines when used in children under 6 years of age for the nausea and vomiting and travel sickness indications.
The Committee recommended an article be published in a future edition of Prescriber Update to advise healthcare professionals of any changes relating to the use of sedating antihistamines.
[Professor C Frampton left the meeting at this time. Dr K Wallis joined the meeting at this time by video conference.]
Currently the Label Statements Database (LSD) requires all oral non-sedating antihistamines to display the following warning on the packaging:
Although this medicine is unlikely to affect your ability to drive or operate machinery, a few people may be impaired and care should be taken.
An application was submitted to Medsafe seeking a change to the LSD for loratadine and desloratadine, so that this warning no longer needs to be displayed on the packaging.
The purpose of this report is to evaluate the current data on the sedating effects of loratadine and desloratadine and to seek advice on whether the sedation warning for these medicines remains appropriate.
The Committee discussed the available evidence presented to them and noted the current warning statement in the Label Statements Database.
The Committee also discussed differentiating between patients reporting drowsiness and reporting impaired driving. The Committee noted that the data largely refers to sedation rather than impaired driving. The Committee considered that the risk of sedation, although low, is higher than the risk of a patient experiencing impaired driving.
The Committee considered that a warning should remain for non-sedating antihistamines but amended to reflect the possibility of sedation.
The Committee recommended that the current warning statement should be amended in the Label Statements Database for loratadine and desloratadine.
[Professor C Frampton re-joined the meeting at this time. Dr K Wallis left the meeting by video conference at this time.]
The use of tramadol in children has received some recent attention. The US FDA and Health Canada are currently investigating the “off-label” use of tramadol in children aged 17 years and younger. In August 2015, the Australian TGA issued a reminder that tramadol drops are not approved for use in children under 12 years of age due to lack of established safety or efficacy.
In New Zealand, the oral drops and injection formulations of tramadol are approved for use in adults and children aged 2 years and older.
As with codeine, the metabolism of tramadol to its principal active metabolite is dependent on CYP2D6. Genetic polymorphisms of CYP2D6 result in poor, intermediate, extensive or ultrarapid metabolisers. Therefore, administration of the same dose of tramadol can lead to a lack of effect in some individuals or overdose in others.
The purpose of this paper is to review the information on the use of tramadol in children.
The Committee discussed the evidence available to them and noted the current indication of tramadol. The Committee noted that the available data is in post-operative pain.
The Committee discussed the use of tramadol in children and possible alternatives to tramadol both in hospital and community settings. The Committee considered tramadol is likely to have similar risks to codeine. The Committee also noted that different CYP2D6 genotypes are important in tramadol dosing. In addition, tramadol appears to have at least two complementary mechanisms that appear applicable. These relate to the binding to µ-opioid receptors and the inhibition of reuptake of noradrenaline and serotonin.
The Committee discussed the precautions and warnings of codeine-containing medicines in relation to tramadol. The Committee considered there is a role for tramadol use in children.
The Committee noted the use of tramadol in the United States and Canada is not approved in children aged 17 years and younger and 12 years and younger in Australia.
The Committee considered there is no data to suggest efficacy in under the age of 2 years and tramadol should be contraindicated in children aged under 2 years of age. In addition, the Committee considered the warnings and precautions regarding recent tonsillectomy, adenoidectomy or throat surgery contained in the codeine data sheet are applicable to tramadol and the warnings and precautions in the tramadol data sheet should be updated.
The Committee recommended an article be published in a future edition of Prescriber Update to inform healthcare professionals of any changes to the use of tramadol in children.
The Committee were interested in the outcome of the FDA review investigating the use of tramadol in children aged 17 years and younger and considered that this outcome should be reported back to the Committee at a future meeting.
The Committee recommended that Medsafe request the sponsors of tramadol-containing products to add a contraindication in children under 2 years of age and update the warnings and precautions section of the data sheets.
The Committee recommended the outcome of the FDA review investigating the use of tramadol in children aged 17 years and younger be reported back to the Committee at a future meeting.
The Committee recommended an article be published in a future edition of Prescriber Update to communicate any changes to the product information for tramadol-containing medicines.
[Dr K Wallis re-joined the meeting at this time by video conference.]
A paper looking at the association between proton pump inhibitor (PPI) use and the development of chronic kidney disease (CKD) was published in JAMA Internal Medicine. This paper concluded that there was an association between PPI use and CKD.
Considering the wide use of PPIs in New Zealand, it was considered that this safety concern should be reviewed by the MARC.
The Committee discussed the evidence available to them. The Committee noted that the available studies were observational and it was considered that ascribing a casual effect from observational studies is challenging. This is due to confounding including the concomitant use of non-steroidal anti-inflammatory drugs, and other medications at baseline, as well as comorbidities that may affect kidney function.
The Committee considered that there may be a weak association between PPIs and chronic kidney disease and that there appears to be some biological plausibility. However the effects are likely to be overstated due to difficulties in controlling and adjusting for confounding factors.
The Committee discussed the monitoring of kidney function. The Committee concluded that there was insufficient evidence to provide any specific advice on monitoring for this risk.
After considering the strength and quality of the available evidence, the Committee was not convinced that the evidence suggests the relationship between PPIs and chronic kidney disease is causative. The Committee considered that as no change to the product information for PPIs is recommended, no communication is required at this stage.
Medsafe will continue to monitor the literature and raise the issue again with the Committee if further information becomes available on this topic.
The Committee recommended that no further action or advice is required regarding the risk of chronic kidney disease with the use of proton pump inhibitors.
A paper looking at the association between proton pump inhibitor (PPI) use and the development of dementia was published in JAMA neurology. This paper concluded that there was an association between PPI use and dementia.
Considering the wide use of PPIs in New Zealand, it was considered that this safety concern should be reviewed by the MARC.
The Committee discussed the strength of the available evidence. The Committee noted there are large differences between users and non-users of PPIs and strong confounding factors in the studies. The Committee considered the hazard ratios to likely be overstated.
The Committee considered that these studies showed evidence of a weak association between PPIs and dementia however the current evidence is insufficient to conclude that this is a causal effect. The Committee did not recommend any changes to the product information and as there is no change to the information on this risk, no further action or communication is required at this stage.
The Committee recommended that no further action or advice is required regarding the risk of dementia with the use of proton pump inhibitors.
The Committee discussed a potential safety signal relating to an interaction between roxithromycin and warfarin.
The Committee concluded that this issue should be bought back to a future meeting with additional information relating to the literature and prescribing data of these medicines.
The Committee recommended that this issue be reported back to the Committee at a future meeting.
[Dr K Wallis left the meeting by video conference at this time.]
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.
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.
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.
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.
The Committee did not consider any of the reports required further action.
The Committee discussed proposed updates to the member’s handbook.
The Committee was given an update on the use of document management systems for the electronic dossier.
The Committee was given an update on the therapeutics products regulation project.
3.2.1 Use of dexchlorpheniramine and other sedating antihistamines in children
None
3.2.2 Loratadine and desloratadine: review of sedation warning
3.2.3 Use of tramadol in children
3.2.4 Risk of chronic kidney disease in patients taking proton pump inhibitors
3.2.5 Risk of dementia in patients taking proton pump inhibitors
The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 4pm.
Associate Professor D Reith
Chair, Medicines Adverse Reactions Committee
