Summary Safety Review - Sedative and anesthetic drugs (DIPRIVAN [propofol], KETALAR [ketamine], SEVORANE [sevoflurane], SUPRANE [desflurane], FORANE/ISOFLURANE USP [isoflurane] - Assessing the potential risk of negative effects on the development of children's brains (neurodevelopmental disorders)

Review decision

A Summary Safety Review complements other safety related information to help Canadians make informed decisions about their use of health products. Each summary outlines what was assessed in Health Canada’s review, what was found and what action was taken by Health Canada, if any.


Issued: 2017-12-22

Product

Diprivan (propofol), Ketalar (ketamine), Sevorane (sevoflurane), Suprane (desflurane), Forane/Isoflurane USP (isoflurane)

Potential Safety Issue

Negative effects on the development of children's brains (neurodevelopmental disorders)

Key Messages

  • Sedative and anesthetic drugs are used by healthcare professionals during surgeries or medical procedures in children and adults.
  • Health Canada reviewed the potential risk of negative effects on the development of children's brains with the use of specific sedative and anesthetic drugs in early childhood or in pregnant women (exposure of the fetus).
  • Health Canada initiated this review to determine if there were concerns in Canada about the negative effects on the development of children's brains with the use of certain benzodiazepines and barbiturates, after concerns were raised by the United States Food and Drug Administration.
  • Health Canada's review concluded that these drugs, when used repeatedly or for a lengthy period of time (more than 3 hours) during the third trimester of pregnancy or in children up to approximately 3 years of age, may potentially lead to neurodevelopmental disorders in children. However, more studies are needed to better understand the effects of these drugs on the development of children's brains.
  • Pregnant women, parents and caregivers should discuss any questions or concerns about the safety of sedative and anesthetic drugs, and the necessity of a procedure requiring these drugs with their healthcare professional.
  • Health Canada will work with the manufacturers to update the Canadian product information of these drugs with warnings about this potential risk. The Department will post an Information Update to raise awareness about this issue to parents and healthcare professionals.

Overview

Health Canada carried out a safety review to assess the potential for negative effects on the development of children's brains (i.e., neurodevelopmental disorders) with specific sedative and anesthetic drugs (propofol, ketamine, sevoflurane, desflurane and isoflurane) used in early childhood or in pregnant women (exposure of the fetus). Health Canada initiated this review to determine if there were concerns in Canada about the negative effects on the development of children's brains with the use of certain benzodiazepines and barbiturates, after concerns wereraised by the United States Food and Drug Administration (U.S. FDA) . In December 2016, the U.S. FDA added warning statements in the product information for several sedative and anesthetic drugs regarding this risk. The risk of neurodevelopmental disorders with the use of other sedative and anesthetic drugs (lorazepam, midazolam, phenobarbital and thiopental) in early childhood or in pregnant women is assessed in a separate review.

The product safety information for propofol and ketamine warn that they should not be used during pregnancy. The product safety information for sevoflurane, desflurane and isoflurane warns that healthcare professionals should use these drugs to treat pregnant patients only if they think that the benefits outweigh the risks. Also, restrictions for use in children vary from one drug to another.

Neurodevelopmental disorders affect the functioning of the brain that may include, for example, intellectual disabilities, learning disabilities or problems with communication and movement. Many factors (e.g., genetic, social, economic and environmental) may play a role in these disorders.

Use in Canada

  • Sedative and anesthetic drugs are used by healthcare professionals during surgeries and medical procedures in children and adults.
  • Propofol, ketamine, sevoflurane, desflurane and isoflurane are currently authorized for use on the Canadian market.

Safety Review Findings

  • At the time of the review, Health Canada did a search for Canadiana and international reports of potential negative effects on the development of children's brains related to the use of sedative and anesthetic drugs in pregnant women or young children. In the reports that were found(39 Canadian and 38 international), 2 reports of international patients were of interest but there was not enough information to further assess these reports.
  • Published studies in animals suggest that repeated or lengthy exposure (more than 3 hours) to sedative and anesthetic drugs during the third trimester of pregnancy or in young animals can cause neurodevelopmental issues, such as problems with learning and memory. In contrast, neurodevelopmental issues were not seen when animals were treated for a shorter period of time (3 hours).
  • Published studies, mostly in children up to 3 years of age, were also found. In these studies, some found no link between the use of these drugs and neurodevelopmental disorders while others found similar results as those seen in the animal studies. However, in studies on children, it was not clear whether the neurodevelopmental disorder was due to the drug or other factors such as illness or the surgery itself.

Conclusions and actions

  • Health Canada's review concluded that repeated or lengthy use (more than 3 hours) of these sedative and anesthetic drugs in the third trimester of pregnancy and in children up to approximately 3 years of age may potentially lead to neurodevelopmental disorders in children.
  • Health Canada will work with the manufacturers to update the Canadian product information of these drugs with warnings about this potential risk. In addition, the Department will issue an Information Update to raise awareness about this issue to parents and healthcare professionals.
  • Health Canada will look into working with the Drug Safety and Effectiveness Network (DSEN) to further study this issue to better understand the effects that sedative and anesthetic drugs have on the development of children's brains.
  • Pregnant women, parents and caregivers should discuss any questions or concerns about the safety of sedative and anesthetic drugs and the necessity of a procedure requiring these drugs with their healthcare professional.
  • Health Canada will continue to monitor safety information involving sedative and anesthetic drugs as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action if and when any new health risks are identified.

Additional information

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international information, and what is known about the use of the sedative and anesthetic drugs both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

Footnotes

  1. Canadian reports can be accessed through the Canada Vigilance Online Database.

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