'Diprivan': a change of formulation (2000)

EDITOR: Within 1 year of the launch of 'Diprivan' in the USA, which was introduced in 1989 for the induction and maintenance of anaesthesia, reports of a temporal association with infection were received by the manufacturer, Zeneca Ltd (London, UK; then ICI, now AstraZeneca). While postoperative infection is not uncommon, unusually many of these infections were reported as clusters (several from the same operating room within a similar time period), and affecting patients in whom postoperative infection was unexpected, e.g. after minor orthopaedic procedures. A causative vector was therefore considered. Further investigation revealed that, in contravention of the product labelling, various non-aseptic practices such as storing opened 'Diprivan' for administration to multiple patients were being used. Furthermore, since all tested batches of unopened 'Diprivan' were found to be sterile, it was likely that these infections had resulted from contamination after the 'Diprivan' presentation had been opened. It is well recognised that lipid emulsions can support the growth of micro-organisms and, indeed, in some cases the same micro-organism was identified in the blood of infected patients and in the residue of the administered 'Diprivan', indicating that the extrinsically introduced organism had multiplied during storage. The manufacturer's response was to modify the Prescribing Information to reinforce the need for aseptic handling, immediate use after opening, and single patient use for each vial or ampoule. In addition, it was emphasised that where 'Diprivan' was used for long-term sedation, a single infusion should not exceed 12 h without changing the infusion lines. These changes were accompanied by letters to healthcare professionals in 1990 and 1991, an intense educational campaign and the development of guidelines published by the Anesthesia Patient Safety Foundation [1]. The Centers for Disease Control (CDC), which also monitored reports of infection between 1990 and 1993, made similar conclusions and recommended preventative action [2]. There is some evidence that the communications did reduce misuse and the number of infections; however, the problem was not completely eliminated. Therefore, in agreement with the Food and Drug Administration (FDA), the manufacturer considered other more permanent solutions, such as a change in formulation. Such a development offered the most effective solution but required careful investigation to identify the most appropriate additive. The essential characteristics of such an additive were an ability to suppress the growth of micro-organisms without compromising clinical safety, efficacy, or the stability of 'Diprivan'. The FDA accepted that the chosen additive should be capable of retarding the growth of common micro-organisms to not greater than 1 log increase (i.e. 10 fold) in 24 h following extrinsic contamination equivalent to 'touch contamination', i.e. have a microbial growth potential comparable to a nonlipid infusion. Potential additives were rejected due to a number of factors including toxicity (e.g. benzyl alcohol, phenylmercuric nitrate), adverse effects on emulsion stability or insufficient antimicrobial activity at the required pH (e.g. sodium metabisulphite). Disodium edetate did meet the predefined criteria. However, this agent, which has been used as a chelator in patients with hypercalcaemia, is not normally used as an additive for antimicrobial purposes and is potentially toxic at high concentrations. Indeed, in some patients rapid administration has been associated with hypocalcaemic events including tetany, cardiac arrythmias and epilepsy [3]. However, the required antimicrobial protection of the 'Diprivan' formulation (against > 20 relevant organisms) could be achieved with extremely low levels of disodium edetate (0.005% w/v), which did not incur the risk of affecting calcium homeostasis, either from bolus injection or long-term infusion, nor influence the stability of the formulation. A clinical trial programme confirmed that the addition of disodium edetate (0.005% w/v) did not affect the efficacy or pharmacokinetics of 'Diprivan'. With respect to safety, no clinically significant effects on calcium or magnesium levels were seen and, since its introduction, no disturbance of calcium or magnesium homeostasis from either short- or long-term use of the modified formulation has been reported. Indeed, the adverse event profile of the modified 'Diprivan' did not appear to be clinically different from that of 'Diprivan'. The only notable effect was a higher excretion of zinc in the urine of intensive care unit (ICU) patients receiving the modified formulation for long-term sedation, compared with those receiving a standard sedative agent. The clinical significance of this finding is unclear, but as a precaution the prescribing information was changed to recommend the use of zinc supplementation when administering modified 'Diprivan' as a long-term infusion. Following approval by the FDA in June 1996, Zeneca introduced the modified formulation as a seamless transition. Such a transfer was undertaken to prevent healthcare professionals from assuming that the modified formulation was 'safer' than the original formulation and thereby relaxing their aseptic technique, not using opened presentations immediately, or lengthening line change times during sedation. Shortly after introduction, all available 'Diprivan' was in the form of the modified formulation. Over 3 years' postmarketed experience is now available with the modified 'Diprivan' formulation in the USA, involving exposure in more than 30 million patients (approximately 15% of whom will have received long-term exposure for ICU sedation). Regular review of the safety database indicates that the number of reports of infection remains very low (Figs 1 and 2). One report of a group of infections has been recorded to date in the USA. However, upon investigation, postoperative infection in these four cases was not considered unusual and no causal association with the modified formulation of 'Diprivan' was considered likely.Fig. 1: 'Diprivan': USA and rest of world (ROW) spontaneous reports of infections (Jan 95-Dec 98).Fig. 2: 'Diprivan': USA and rest of world (ROW) spontaneous reports of clusters of infection (Jan 95-Dec 98).The nature and pattern of other adverse events have also been monitored and, although it is not possible to determine precise numbers (due to potential under-reporting of events), the pattern of events reported after introduction of the modified formulation is similar to that prior to its introduction. No new or unexpected adverse reactions have appeared, indicating that the addition of disodium edetate has not affected the safety profile of 'Diprivan'. In particular, there has been no increase in the number of reports that might be associated with the toxicity of disodium edetate, e.g. hypocalcaemic symptoms or renal impairment. Fewer reports of infection, including clusters, have occurred in countries outside the USA following administration of unmodified 'Diprivan'. However, it is difficult to determine if this is reflective of different clinical practices or a feature of various degrees of under-reporting. Nevertheless, clusters continue to be reported (Fig. 2) and, in some cases, there is good evidence that the cause of infection resulted from misuse of 'Diprivan'. The rationale for introducing the modified formulation into other countries therefore exists and AstraZeneca is intending to make the disodium edetate formulation available in all countries, following the required regulatory approval. In conclusion, a modified formulation of 'Diprivan' was developed in response to the observation of a number of cases of infection in patients as a result of inappropriate handling of 'Diprivan' by healthcare professionals. The choice of additive was governed by the need to provide antimicrobial security without altering the efficacy, safety or stability of the formulation, and disodium edetate fulfilled all these criteria. The modified formulation was introduced in the USA in June 1996. Clinical trials predicted that the additive would not adversely affect efficacy or safety and 3 years of postmarketed experience has confirmed this. Furthermore, there have been no outbreaks of infection that could be attributable to mishandling of the modified 'Diprivan' formulation. B. HART Global Clinical Function, AstraZeneca, Alderley Park, Macclesfield, UK