Azacitidine is an antimetabolite pyrimidine nucleoside analogue, indicated in the treatment of haematological pathologies such as myelodysplastic syndrome and acute myeloid leukemia. The recommended dose is 75 mg/m2 of body surface area by subcutaneous injection per day for 7 days, followed by a 21-day rest period. Azacitidine is a lyophilised powder that is reconstituted with water for injections (WFI) to obtain a suspension for injection at 25 mg/mL [1].
This cytotoxic drug is unstable in aqueous solutions. The description of the hydrolysis degradation has been realised by different research teams [2], [3], [4]. Azacitidine is degraded in two steps: the first is a rapid and reversible hydrolysis, to form N-formylribosylguanylurea (RGU-CHO). The second step is an irreversible hydrolysis of RGU-CHO to ribosylguanylurea (RGU).
As recommended by manufacturers, if azacitidine is reconstituted with WFI that has not been refrigerated, the stability has been demonstrated for 45 min at 25 °C and for 8 h between 2 and 8 °C. If the reconstitution is performed with refrigerated WFI, the stability can be extended to 22 h between 2 and 8 °C [5]. The short stability of azacitidine requires to mobilize pharmaceutical personnel for the preparation of syringes on weekends. Duriez et al. have demonstrated a stability of 8 days for frozen suspensions (−20 °C) of azacitidine at 25 mg/mL reconstituted with refrigerated WFI [6]. Under the same conditions, Balouzet et al. have concluded to a stability of 30 days and Walker et al. of 23 days [2, 7]. Regarding storage between 2 and 8 °C, different stability data are demonstrated: 2 days of stability for azacitidine suspensions by Légeron et al. to 5 days by Vieillard et al. [8, 9]. The temperature is a factor which affects the hydrolysis of azacitidine and, consequently, the stability of this molecule [10].
In daily practice of a central cytotoxic preparation unit, an isolator can be used and the preparation requires a sterilization step of the products, bringing heat. Savry et al. compared the temperature of WFI stored between 2 and 8 °C, after the complete decontamination procedure in isolators, in several containers: 50 mL glass vial, 250 mL glass vial, 20 mL plastic ampoule [11]. The mean ± standard deviation (SD) temperatures were 16.6 ± 0.7, 11.9 ± 0.3, and 10.3 ± 0.2 °C for the 20 mL ampoules, 50 mL bottles, and 250 mL bottles, respectively. The temperature is too warm for maximum azacitidine stability. They have concluded that “a better way to reconstitute a 100 mL vial of azacitidine is to freeze a 20 mL plastic ampoule containing sterile WFI, thaw it for 30 min, agitate the ampoule for 30 s, and remove the 4 mL needed for reconstitution. ». However, in this study, the impact of the use of thawed WFI on the stability of azacitidine compared to refrigerated WFI already partially warmed was not studied.
The objective of this work was to study the physicochemical stability of a new generic of azacitidine, from Viatris company (ex Mylan) considering the working conditions in a centralized cytotoxic preparation unit. The impact of the temperature of WFI for the reconstitution and the condition of storage of azacitidine vials were studied.
Azacitidine vials were reconstituted either with refrigerated WFI or WFI initially frozen, placed in the refrigerator the day before, for partial thawing: on the day of the manipulation, the bag is taken out of the refrigerator. The study was carried out under two storage conditions for azacitidine vials: room temperature or 2–8 °C. To simulate the worst condition of storage, a stability study was performed on azacitidine suspensions which were prepared with vials stored at room temperature, reconstituted with refrigerated WFI, stored 24 h between 2 and 8 °C and kept at room temperature up to 2 h. Another study was carried out with storage of the syringes at −20 °C for 28 days then an evaluation of the stability after thawing for 4 days.
The use of a Spike device (ICU Medical) has been studied to replace a needle and to facilitate the preparation of azacitidine suspensions.
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