Bupivacaine (Marcain®) and reports of lack of efficacy

The Vigilance Branch of HSA has from September 2009 to March 2010, received a clustering of reports on the lack of efficacy associated with the use of bupivacaine preparations (Marcain® 0.5% and Marcain® Spinal 0.5% Heavy Injection, AstraZeneca, AZ) when used during spinal anaesthesia. This finding led to a series of follow-up investigations to determine the possible causes of failed spinal anaesthesia (FSA).

Marcain® Spinal 0.5% Heavy Injection and Marcain® 0.5% Injection have been registered in Singapore since April 1991 and July 2006 respectively and are indicated for the production of spinal anaesthesia. Marcain® 0.5% is indicated for lower limb surgery lasting 3 – 4 hours where muscle relaxation is needed; and Marcain® Spinal 0.5% Heavy Injection is indicated for abdominal surgery lasting 45 – 60 minutes and urological and lower limb surgery lasting 2 – 3 hours.

Local reports of lack of efficacy

Three reports of lack of efficacy with Marcain® Spinal 0.5% Heavy Injection were first reported to HSA in September 2009 by different anaesthetists from a tertiary hospital. All three reports were associated with a single batch of Marcain® Spinal 0.5% Heavy Injection.

From December 2009 to February 2010, six additional cases of a similar nature were reported. These involved two different batches of Marcain® Spinal Heavy 0.5% injection.

Laboratory investigations

The HSA's Pharmaceutical Laboratory conducted an analysis of the affected batch involved in the first three cases reported in September 2009. The test result indicated that the bupivacaine content in Marcain® Spinal 0.5% Heavy Injection was within specifications. Nonetheless, the remaining stocks of Marcain® Spinal 0.5% Heavy Injection in the affected batch at the hospital were returned to the company and replaced with another batch.

Following the additional reports in December 2009 and early 2010, HSA contacted hospital pharmacies from both the private and public institutions to ascertain if they had similar experiences. One tertiary hospital provided retrospective reports of 13 cases involving both Marcain® 0.5% and Marcain® Spinal 0.5% Heavy Injection.The hospital also provided ampoules of Marcain® 0.5% Injection from these two affected batches, which were assayed by HSA's Pharmaceutical Laboratory and found to be within specifications.

Additional tests were performed by AZ to confirm that these products complied with the registered specifications. The data submitted by AZ for quality assessment included the certificate of analysis of the finished products, stability data and investigation reports. Based on the available information, it was concluded that the analytical test results were within the registered product specifications and that the products were stable during the specified shelf-life.

Similar experience in other countries and possible causes of FSA

Global estimates on the incidence of FSA range from 0.5 - 17%.^1,2 HSA's further investigations also revealed that some other agencies had also encountered similar patterns of FSA in the past. In all of the reported cases, there was no single identifiable cause and the cases involved more than one batch of the products. The outcome of these investigations showed that the causes of FSA were multifactorial.

Based on available literature, the following factors may contribute towards the occurrence of FSA: abnormalities of the spine such as kyphosis, scoliosis, calcification of ligaments, consequences of osteoporosis; patient's resistance to a specific anaesthetic; lumbar interspace selection; drug dosage; failed lumbar puncture; positioning of the patient and inadequate intrathecal spread.^1,3,4

Conclusion

Spinal anaesthesia is an effective technique commonly used for local anaesthesia. Concerns about the quality of the anaesthetics may arise when a clustering of FSA occur in the hospital within a short period of time for straightforward procedures.

Based on the analyses to date, HSA has assessed that the causes of FSA could be a combination of many factors. As part of its educational efforts, AZ has conducted talks to hospitals to provide more information on the challenges of spinal anaesthesia, increase the awareness of FSA and highlight the importance of reporting such cases if encountered in the future.

Although no new cases of FSA has been reported since March 2010, HSA will continue to monitor this situation and update healthcare professionals when new information arises.

References

1. British Journal of Anaesthesia 2009, 102(6): 739–48

2. European Journal of Anaesth 1992, 9: 7-13

3. Regional Anesthesia 1991, 16: 48-51

4. J Clin Anesth 1990 Sep-Oct, 2(5):336-8