Drug Review

 

Brand name:   VidazaÒ

 

Generic name: azacitidine 

 

Manufacturer: Pharmion Corporation

 

Drug Class:  pyrimidine analog

 

Uses:

VidazaÒ is FDA approved for the treatment of Myelodysplastic Syndrome or MDS. This is a broad term that is intended to include refractory anemia with or without ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia(1). 

 

Mechanism of Action:

VidazaÒ inhibits DNA methyltransferase that impairs DNA methylation. This works to restore normal growth and differentiation of the cells in the bone marrow. Death occurs to the rapidly dividing cells, including the cancer cells responsible for MDS(2).

           

Pharmacokinetics (3,4)

 

Vd

T1/2

Bioavailability

Excretion

 

 

76 ± 26 L

4 hours

89%

85% in urine

 

Urinary excretion is the primary pathway for elimination of VidazaÒ and its metabolites. The cumulative urinary excretion was found to be approximately 85%.  The half life of 4 hours was found to include not only the active drug but its metabolites as well.  The mean half life of VidazaÒ after SC administration was found to be approximately 41 minutes.  It is unknown whether azacitidine inhibits CYP 450. 

 

Efficacy:

Kornblith AB. Et.al. Impact of azacytidine on the quality of life of patients with     Myelodysplastic Syndrome treated in a randomized Phase III trial: a cancer and leukemia group B study. Journal of Clinical Oncology. 2002;20(10):2441-2452.

This study was a randomized controlled clinical trial consisting of 191 patients with myelodysplastic syndrome.  The subjects were randomized to receive either azacitidine or supportive care.  If disease progression occurred, the patients would then cross over to receive azacitidine.  Several limitations of the study included a possibility that the results could be due to placebo effect or Hawthorne effect because the design was nonblinded.  The azacitidine group had more blood transfusions overall possibly contributing to improved quality of life endpoints. The study was limited because it wasn’t double-blinded. There was an improved quality of life when patients were treated with VidazaÒ  for MDS.  Researchers found that the drug delayed the onset of acute myeloid leukemia or death when the medication was compared to supportive care alone. Vidaza showed improvements in fatigue (EORTC, P=0.001), dyspnea (EORTC, P=0.0014), physical functioning (EORTC, P=0.0002), positive affect (MHI, P=0.0077), and psychological distress (MHI, P=0.015) when compared to supportive care alone(5).

 

www.vidaza.com.  clinical studies on VidazaÒ

The study involved a randomized open-label study design. The study compared the quality of life with patients on VidazaÒ with supportive care to supportive care alone. Patients who had AML were not included in the study.  75 mg/m2 of VidazaÒ was administered daily for seven days for a total of four week to the treatment group.  The results of the study indicated that the VidazaÒ treated patients without AML had a statistically significant higher response rate compared to the control group (p<0.0001).  The authors also state that about 24% of the VidazaÒ treated patients were improved and 2/3 of these patients lost the requirement for transfusions.  Only 5 out of 83 patients met the criteria for being improved in the observation group and none lost transfusion dependence. Limitations were not listed in the study, but some of those may include insufficient numbers of patients, the endpoints are difficult to measure, and the treatment group had more blood transfusions.

           

Silverman LR. Et. al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia Group B. Journal of Clinical Oncology. 2002;20(10):2429-2440.

            This study included a randomized controlled design that included 191 patients with MDS.  The comparison that was to be made was between azacitidine and best supportive care.  Both arms of the study received transfusions and other medications as required.  The results were very promising, they indicated that responses occurred in 60% of patients taking azacitidine when compared with only 5% improvement in patients receiving supportive care (P<.001)(6). 

 

Adverse effects: (2,3,4)   

Hypotension (7%), chest pain (16%), pallor (15%), peripheral edema (19%), pitting edema (14%)

 pyrexia (52%), fatigue (13% to 36%), headache (22%), dizziness (19%), anxiety (13%), depression (12%), insomnia (11%), malaise (11%), pain (11%), Alopecia (20%), bruising (30%), petechiae (24%), erythema (17%), skin lesion (14%), rash (14%), nausea (70%; more common/more severe with I.V. administration), vomiting (54%), mucositis (23% to 45%), diarrhea (36%), constipation (34%), anorexia (21%), weight loss (16%), abdominal pain (15%), appetite decreased (13%), abdominal tenderness (12%), anemia (70%), thrombocytopenia (66%), leukopenia (48%), neutropenia (32%), febrile neutropenia (16%)

 

Drug Interactions:

According to the drug monograph, there have not been studies conducted regarding drug-drug interactions(4). 

 

 

Dosing/Administration: (2,4)

VidazaÒ is available as a single-use 1 gram vial of lyophilized powder. 

Usual dose:  The recommended starting dose is 75 mg/m2 subcutaneously once daily for 7 days. These cycles should be repeated every 4 weeks.  If a beneficial effect is not seen after 2 treatment cycles, then the dose may be increased  to 100mg/m2, assuming that toxicity has not been observed.  Recommendations have been reported that patients should be treated for a minimum of 4 cycles.

Geriatric: Care should be taken when giving older patients VidazaÒ and calculating dose due to the possible build-up of metabolites in renal impairment. 

Renal Impairment: If unexplained elevations occur in BUN and serum creatinine after 1 dose of therapy, the next dose should be reduced by 50% and the dose should be held until BUN and Scr return to baseline.

Hepatic Impairment: Caution should be taken when using VidazaÒ in patients with liver disease or with pre-existing hepatic impairment.

Pediatric:  Studies have not been conducted regarding the use of VidazaÒ in pediatric patients.

 

Conclusion:  It appears as if azacitidine is very promising in patients with the different types of MDS.  Prior to the use of Vidaza, the only treatment option that was generally available was supportive care.  It appears to improve quality of life in patients with MDS and proves to be a very useful drug.

 

References:

1.      www.fda.gov. Accessed September 23, 2004.

2.      www.onlinelexi.com. Accessed September 23, 2004.

3.      www.pharmion.com. Accessed September 23, 2004.

4.      www.vidaza.com. Accessed September 23, 2004.

5.      Kornblith et. al. Impact of Azacytidine on the quality of life of patients with Meylodysplastic syndrome treated in a randomized Phase III Trial: A cancer and leukemia group B study. Journal of Clinical Oncology 2002; 20(10):2441-2452.

6.      Silverman LR, et.al. Randomized controlled trial of azacitidine in patients with myelodysplastic syndrome: a study of the cancer and leukemia group B.  Journal of Clinical Oncology. 2002;20(10):2429-2440.