wn specific antidote for azacitidine overdose.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agent, Pyrimidine analogues; ATC code: L01BC07
Mechanism of action
Azacitidine is believed to exert its antineoplastic effects by multiple mechanisms including cytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of DNA. The cytotoxic effects of azacitidine may result from multiple mechanisms, including inhibition of DNA, RNA and protein synthesis, incorporation into RNA and DNA, and activation of DNA damage pathways. Non-proliferating cells are relatively insensitive to azacitidine. Incorporation of azacitidine into DNA results in the inactivation of DNA methyltransferases, leading to hypomethylation of DNA. DNA hypomethylation of aberrantly methylated genes involved in normal cell cycle regulation, differentiation and death pathways may result in gene re-expression and restoration of cancer-suppressing functions to cancer cells. The relative importance of DNA hypomethylation versus cytotoxicity or other activities of azacitidine to clinical outcomes has not been established.
Clinical efficacy and safety
The efficacy and safety of Vidaza were studied in an international, multicenter, controlled, open-label, randomised, parallel-group, Phase 3 comparative study (AZA PH GL 2003 CL 001) in patients with: intermediate-2 and high-risk MDS according to the International Prognostic Scoring System (IPSS), refractory anaemia with excess blasts (RAEB), refractory anaemia with excess blasts in transformation (RAEB-T) and modified chronic myelomonocytic leukaemia (mCMML) according to the French American British (FAB) classification system. RAEB-T patients (21-30 % blasts) are now considered to be AML patients under the current WHO classification system. Azacitidine plus best supportive care (BSC) (n = 179) was compared to conventional care regimens (CCR). CCR consisted of BSC alone (n = 105), low-dose cytarabine plus BSC (n = 49) or standard induction chemotherapy plus BSC (n = 25). Patients were pre-selected by their physician to 1 of the 3 CCR prior to randomisation. Patients received this pre-selected regimen if not randomised to Vidaza. As part of the inclusion criteria, patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients with secondary MDS were excluded from the study. The primary endpoint of the study was overall survival. Vidaza was administered at a subcutaneous dose of 75 mg/m2 daily for 7 days, followed by a rest period of 21 days (28-day treatment cycle) for a median of 9 cycles (range = 1-39) and a mean of 10.2 cycles. Within the Intent to Treat population (ITT), the median age was 69 years (range 38 to 88 years).
In the ITT analysis of 358 patients (179 azacitidine and 179 CCR), Vidaza treatment was associated with a median survival of 24.46 months versus 15.02 months for those receiving CCR treatment, a difference of 9.4 months, with a stratified log-rank p-value of 0.0001. The hazard ratio for the treatment effect was 0.58 (95 % CI: 0.43, 0.77). The two-year survival rates were 50.8 % in patients receiving azacitidine versus 26.2 % in patients receiving CCR (p < 0.0001).
The survival benefits of Vidaza were consistent regardless of the CCR treatment option (BSC alone, low-dose cytarabine plus BSC or standard induction chemotherapy plus BSC) utilised in the control arm.
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