Original research
Table 3 Percentage of aciclovir remaining in the Accufuser VAWC0100L elastomeric infusion device during storage at room temperature and subsequent exposure to in-use temperature of 32°C
Mean and SD of percent remaining by initial concentration 200 mg/240 mL 2400 mg/240 mL
4500 mg/240 mL
Temperature condition
Time (hours)
Mean
SD
Mean
SD
Mean
SD
Room temperature (<20°C)
0
100.00 100.25
0.00 0.86 1.32 0.93 0.72 0.66 0.90 0.90 0.71 4.19 3.46 1.31
100.00 100.10 100.05 100.77 101.01 100.97 101.29 101.87 101.17 101.07 100.96 101.01
0.00 0.49 0.32 0.33 0.31 0.40 0.51 0.87 0.42 0.60 0.62 0.58
100.00 100.03 100.31 100.20 101.04 101.16 100.78 100.59
0.00 0.51 1.28 1.50 0.75 0.54 1.02 0.84 1.37 4.07 2.96 2.92
12 24 48 96
99.92
100.44 100.55 101.09 100.60
120 168 240 336 344 348 360
99.92
100.49
99.31 69.62 56.17 21.46
In-use temperature (32°C)
97.48 97.57 98.11
fluid balance in outpatient settings may not be practical. Thus, hydration advice and education should be an important part of the OPAT assessment for clinically improving patients to be discharged on aciclovir. Similarly, monitoring of renal function should be undertaken in the OPAT setting as is advised in the inpatient setting in accordance with the product data sheet for IV aciclovir. 23 The pH of the aciclovir solution in the devices was high due to the composition of the clinical formulation used for reconstitu- tion. Each vial of the IV solution for injection contained 92.9 mg NaOH in 20mL designed to keep the pH at approximately 11 for sustained stability of the solution during storage. Further reconsti- tution with saline in the devices did not lower the pH much for the intermediate and high concentrations (tables 1 and 2). The relatively lower pH observed at the low concentration (although >9) is most likely related to the low concentration of NaOH when the clinical formulation was diluted to the low aciclovir concen- tration. Overall, given the high pH of the aciclovir saline solution, infusion via a peripherally inserted central catheter (PICC) line may be necessary to ensure better haemodilution to avoid local irritancy with peripheral infusion. PICC lines are usually recom- mended at the extremes of pH (<5 or >9) to minimise irritation. 24
in-use temperature at very high dosing concentrations (equiv- alent to 45 mg/kg/24 hours for a 100 kg non-obese adult). Such doses are not commonplace in clinical practice but were included in this study in case of emergent evidence for efficacy in severe infection in the future. The observation of precipitation at high concentration is in agreement with others. 11 Precipita- tion of aciclovir is not an in vitro problem only; it can occur in vivo in renal tubules if the maximum solubility of free aciclovir (2500 mg/L at 37°C in water) is exceeded. In one case report, a cloudy white precipitate of needle-shaped crystals was observed at the base of the urinary catheter of a patient following IV aciclovir administration. 19 IV infusion of a high concentration may risk acute kidney injury due to tubular damage and, as such, adequate hydration is an essential co-therapy. 20 21 Indeed, the most common mechanism of aciclovir-induced acute kidney injury is due to crystal obstruction. 22 Any off-label use of higher concentrations (dose) of aciclovir in the OPAT setting requires a careful safety consideration. Although the slow continuous infusion in OPAT is advanta- geous in minimising the risk of precipitation when compared with the traditional 1–2 hours of infusion for inpatient inter- mittent treatment with aciclovir, maintaining and monitoring a
Table 4 Percentage of aciclovir remaining in the Easypump II LT 270–27-S elastomeric infusion device during storage at room temperature and subsequent exposure to in-use temperature of 32°C
Mean and SD of percent remaining by initial concentration 200 mg/240 mL 2400 mg/240 mL
4500 mg/240 mL
Temperature condition
Time (hours)
Mean
SD
Mean
SD
Mean
SD
Room temperature (<20°C)
0
100.00
0.00 1.23 1.03 0.36 0.65 1.02 0.99 0.61 0.66 1.26 1.70 2.79
100.00
0.00 0.11 0.29 0.31 0.35 0.34 0.18 0.46 0.75 1.37 1.14 1.63
100.00 100.38 101.54 100.55 100.18 100.94 100.74 100.51 100.13
0.00 0.61 0.75 1.02 1.46 0.65 0.32 0.31 0.52 9.31
12 24 48 96
99.49 99.73
99.77 99.67
100.13 100.03
100.35 100.46 100.56 100.66 100.66 100.27 100.16
120 168 240 336 344 348 360
99.89
100.01
99.71 99.80
In-use temperature (32°C)
100.11
82.12 69.75 39.86
99.88 98.18
99.99
13.80 20.30
100.26
Sime FB, et al . Eur J Hosp Pharm 2023; 0 :1–6. doi:10.1136/ejhpharm-2023-003784
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