Overview

Propofol is a short-acting intravenous anaesthetic agent suitable for induction and maintenance of general anaesthesia. It may also be used for sedation. Sodium valproate is a broad-spectrum antiepileptic agent which exerts its effect mainly on the central nervous system.

Background of Safety Issue

The European Medicines Agency (EMA) directed the product registration holders of propofol and sodium valproate-containing products to update their package inserts with information on the risk of increased propofol exposure when propofol and sodium valproate are used simultaneously. A dose reduction of propofol may also be considered¹.

The decision was made based on two literature reviews which found that the dose of propofol required for sedation was lower in subjects receiving sodium valproate simultaneously, compared to subjects in the control group^2,3. Both reviews concluded that the interaction between propofol and sodium valproate could be related to the pharmacokinetic and pharmacodynamics properties of the drugs^2,4. The interaction may also lead to complications or delayed recovery from anaesthesia⁴.

In Malaysia, currently, there are 10 products containing propofol that have been registered. As for sodium valproate, there are 11 products registered with the Drug Control Authority (DCA).

Adverse Drug Reaction Reports

The NPRA has received a total of 58 reports with 95 adverse events related to propofol. The most commonly reported adverse event was rash (15, 15.8%), followed by urticaria (9, 9.5%) and hypotension (5, 5.2%). To date, no case of adverse reaction following concomitant use of propofol and sodium valproate has been reported to the NPRA.

Advice for Healthcare Professionals

• Patients taking sodium valproate must be advised to inform their doctor about their medication before undergoing any surgery.
• Consider a dose reduction of propofol if the patient is taking sodium valproate concomitantly.
• Please report all adverse events suspected to be related to the concomitant use of propofol and sodium valproate to NPRA.

A directive [Ruj. Kami: (7) dlm. BPFK/PPP/07/25 Jld. 2] has been issued by NPRA for updates to the local product packaging insert and consumer medication information leaflet (Risalah Maklumat Ubat untuk Pengguna) related to this safety issue. Please refer to the directive for more information. 

References:     

1. EMA (2017). PRAC Recommendations on Signals. EMA/PRAC/5653/2017.
2. Sayar et al. (2014). Influence of Valproate on the Required Dose of Propofol for Anesthesia During Electroconvulsive Therapy of Bipolar Affective Disorder Patients. Neuropsychiatr Dis Treat.10:433-438.
3. Ishii et al. (2012). The Influence of Oral VPA on the Required Dose of Propofol for Sedation during Dental Treatment in Patients with Mental Retardation: A Prospective Observer-blinded Cohort Study. Epilepsia 53(1), e13-e16.
4. American Society of Anesthesiologists (2012). The Anesthesiology Annual Meeting. Abstract: Valproate Increases the Rate of Protein-unbound Free Propofol in Human Serum.

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.