引 致 更 改 給 病 人 的 產 品 資 訊 的 藥 物 不 良 反 應 警 示
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| Australia: Safety advisory – possible effects on brain development in young children: inhaled or injected general anaesthetic agents and sedative medicines (English Only) |
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The Therapeutic Goods Administration (TGA) announces that it is working with sponsors of certain inhaled or injected general anaesthetic agents and sedative medicines to update information about the potential risk of deficits in learning and behavioural development in children, which may be associated with repeated or prolonged exposure to these products during late pregnancy or early childhood.
This concern applies to all general anaesthetic agents and sedative medicines that block N-methyl-D-aspartate (NMDA) receptors or potentiate gamma-aminobutyric acid (GABA) activity. These medicines include: desflurane, isoflurane, sevoflurane, thiopentone, ketamine, midazolam, propofol, phenobarbitone injection, nitrous oxide and methoxyflurane.
The TGA has assessed the safety of certain general anaesthetic agents and sedative medicines in response to concerns raised from animal studies published in the scientific literature about possible effects on early brain development in babies and young children.
As part of its investigation, the TGA sought advice from the Advisory Committee on Medicines (ACM) at its Dec 2017 meeting. The ACM meeting statementcan be found on the TGA website. The ACM advised that there was good evidence from animal studies that general anaesthetic agents and certain sedative medicines used during anaesthesia had effects on the developing brain, including cell death. Some evidence suggested that these changes were greatest with longer exposure (several hours of exposure to a general anaesthetic).
However, the relevance of these finding to humans is not clear. Studies that are available in humans are not conclusive. Where an association between surgery and developmental outcomes was found, this association may have been confounded by a number of factors such as complications arising from the surgery itself or the underlying illness necessitating surgery. The effect of dose and duration of anaesthesia was not clear.
There is evidence that a single, relatively brief exposure to anaesthesia in otherwise healthy children is unlikely to cause any significant long-lasting effects (clinically detectable deficits) in cognitive function or behaviour.
Consumers are advised that this potential concern only applies to unborn and young children in relation to repeated or prolonged (greater than 3 hours) use of anaesthetic agents or sedative medicines. Surgeries in young children and pregnant women should not be delayed or avoided when there is any possibility that delay may result in an adverse outcome or harm.
Healthcare professionals are advised that before using general anaesthetics and sedatives for a surgical procedure in pregnant women or young children, they should consider discussing the potential effects of these agents on neurodevelopment and learning. They should also be prepared to address questions raised by parents and carers about this issue. These potential risks should obviously be balanced with any adverse outcomes likely to be associated with delaying or avoiding surgery. The timing of any non-urgent procedures should be discussed with patients.
The TGA is working with sponsors to update Product Information to include the following information:
- Some published studies in children have observed cognitive deficits after repeated or prolonged exposures to anaesthetic agents early in life. These studies have substantial limitations, and it is not clear if the observed effects are due to the anaesthetic/analgesic/sedation drug administration or other factors such as the surgery or underlying illness.
- Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy. These studies have demonstrated that anaesthetic/analgesic and sedation drugs that block NMDA receptors and/or potentiate gamma-aminobutyric acid activity during the period of rapid brain growth or synaptogenesis may result in neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis when used for longer than 3 hours. These studies included anaesthetic agents from a variety of drug classes. The clinical significance of these non-clinical findings is yet to be determined.
Please refer to the following website in TGA for details:
http://www.tga.gov.au/alert/inhaled-or-injected-general-anaesthetic-agents-and-sedative-medicines
In Hong Kong, there are 31 registered pharmaceutical products containing general anaesthetics and sedation drugs listed in the above TGA’s announcement, and the previous US Food and Drug Administration’s (FDA) and Health Canada’s announcements on the matter, including desflurane (1 product), etomidate (1 product), isoflurane (5 products), ketamine (5 products), midazolam injection (7 products), pentobarbital (1 product), propofol (6 products), sevoflurane (4 products) and phenobarbitone injection (1 product). Desflurane, isoflurane and sevoflurane are currently over-the-counter medicines but will be up-regulated and controlled as prescription-only medicines with effective from May 2019, while the other products are prescription-only medicines.
So far, the Department of Health (DH) has received 18 cases of adverse drug reaction related to ketamine, 1 case related to lorazepam, 24 cases related to midazolam, 1 case related to propofol, 4 cases related to phenobarbital and 1 case related to thiopentone, but these cases are not related to brain development in children.
Related news was previously issued by the FDA and Health Canada, and was posted on the Drug Office website since 15 Dec 2016, with the latest update posted on 23 Dec 2017. Letters to inform local healthcare professionals were issued on 15 Dec 2016. As previously reported, the matter will be discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/Tuesday, Oct 2, 2018
Issued at HKT 17:30
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