Summary Safety Review - Benzodiazepines and barbiturates - Assessing the potential risk of negative effects on the development of children’s brains (neurodevelopmental disorders)

December 22, 2017

Products

Ativan (lorazepam) and midazolam (benzodiazepines); phenobarbital and thiopental (barbiturates)

Potential Safety Issue

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

Key Messages

• Benzodiazepines and barbiturates are sedative and anesthetic drugs often required during surgeries and 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 there is limited evidence suggesting a link between the use of these sedative or anesthetic drugs and potential negative effects 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 this risk and 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 (lorazepam, midazolam, phenobarbital and thiopental) used in early childhood (up to and including 5 years of age) 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, as these concerns were raised by the United States Food and Drug Administration (U.S. FDA), through a communication issued in December 2016.

The Canadian product safety information for lorazepam and midazolam warn that they should not be used during pregnancy. The Canadian product safety information for phenobarbital warns that during pregnancy the drug’s benefit should be weighed against its risk. Also, restrictions for use in children vary from one drug to another.

The risk of neurodevelopmental disorders with the use of sedative and anesthetic drugs other than benzodiazepines and barbiturates (propofol, ketamine, sevoflurane, desflurane and isoflurane) in early childhood or pregnant women is assessed in a separate review.

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.

Use in Canada

• Benzodiazepines and barbiturates are sedative and anesthetic drugs often required during surgeries and procedures in children and adults.
• Phenobarbital, midazolam and lorazepam are available on the Canadian market. Thiopental is authorized for sale, but is not currently sold, in Canada.

Safety Review Findings

• At the time of the review, Health Canada did a search for Canadian^{Footnote a}  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 in young children. There were a total of 137 Canadian reports and 110 international reports. However, due to multiple factors (e.g., symptoms described in the reports did not meet the definition of neurodevelopmental disorders, as described above; use of the drug was different; problem reported was not in pregnant women or children up to and including 5 years of age), Health Canada was unable to use these 247 reports to draw any conclusions.
• Published animal studies in pregnant or young animals and studies in children did not show consistent evidence of negative effects on the development of children’s brains with the use of these sedative and anesthetic drugs.

Conclusions and Actions

• Health Canada’s review of the available information concluded that there is limited evidence suggesting a link between the use of these sedative and anesthetic drugs and neurodevelopmental disorders. The Department will post an Information Update to raise awareness about this issue to parents and healthcare professionals.
• Pregnant women, parents and caregivers should discuss any questions or concerns about the safety of sedatives, general and anesthetic drugs and the necessity of a procedure with their healthcare professional.
• In addition, Health Canada will also look into working with the Drug Safety and Effectiveness Network (DSEN) to look into further studying this issue to better understand the effects that sedative and anesthetic drugs have on the development of children’s brains.
• 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 these sedative and anesthetic drugs both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.